The Journal of the Semiology Club | Medical Semiology

Volu me 4 | 2 018 . Ju ne

Editor
Assistant Professor dr. Olga Hilda Orășan

Associate Editors The journal of the

SEMIOLOGY
Assistant Professor dr. Ovidiu Fabian
2018
Editorial secretary Vol. 4
Instructor dr. Bogdan Man

Editing Board
Associate Professor Vasile Negrean
Club
Associate Professor Dorel Sâmpelean
Dr. Nicolae Rednic
Assistant Professor Angela Cozma
Assistant Professor Simina Țărmure Sarlea Rare diseases
Associate Professor Alina Ioana Tanțău
Assistant Professor Teodora Alexescu
Instructor dr. Flaviu Mureșan
Dr. Corina Lucaci
Dr. Sorina Cezara Secară
Student George Ciulei
Student Renate Schvarczkopf
Student Tudor-Costinel Șerban

Desktop publishing
Krisztina Hajdú

w w w.j s e m i o l o g y. r o

ISSN 2537-2963
ISSN-L 2537-2963

medical semiology
 Foreword Contents

The Journal of Semiology Club comprises a series of materials reflecting the activity of Neurofibromatosis 7
3rd year students, members of the student “Semiology Club” of the Faculty of Medicine George Ciulei
of the “Iuliu Haţieganu” University of Medicine and Pharmacy Cluj-Napoca.
The activity of the Semiology Club is intended to assist students in deepening their IgA vasculitis (Henoch-Schönlein purpura): A literature review 13
recently acquired knowledge of clinical and imaging semiology notions, under the Tamás Rácz
guidance of a professor, in the spirit of teamwork.
The aim of the creation of The Journal of Semiology Club is to bring semiology into Valentino’s syndrome 23
current focus through a detailed and nuanced analysis of diseases and syndromes. The Mădălina Ștețca
presented semiology articles are didactic updates meant to develop reasoning and to
harmonize classic and traditional semiology with what the contribution of modern Clinical aspects of scleroderma 29
technology can offer to semiological interpretation. The presented materials facilitate Ioana Roșca
the students’ understanding of difficult medical or surgical cases as early as their third
year of study. Not least, this publication offers students and residents the opportunity Reactive arthritis 40
to practice journalism. Noémi Mosonyi
The Journal of Semiology Club will be generously open to all those who wish to share,
with competence and dedication, their ideas and analyses in the field of semiology and Prader-Willi syndrome 45
will encourage young doctors at the beginning of their careers to assert themselves as Patriciu Protopopu
scientists.
I wish to thank all the teaching staff and students who brought their contribution to Ichthyosis vulgaris 51
this publication. Tudor-Costinel Şerban

Assist. Prof. Dr. Olga Hilda Orăşan Addison’s disease and autoimmune thyroiditis with hypothyroidism
– A case report 56
Breabăn Iulia, Stefan Andreea Maria
Neurofibromatosis
George Ciulei
Student, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca

Abstract. The neurofibromatosis disease group includes type 1 and type 2 neurofibromatosis and
schwannomatosis. All three are genetic diseases with autosomal dominant inheritance and a high rate of
spontaneous mutations. Type 1 neurofibromatosis presents with: café-au-lait macules, axillary and inguinal
freckling, Lisch nodules, neurofibromas. There are also skeletal anomalies, cardiovascular defects and a
degree of cognitive impairment. Optic gliomas and malignant peripheral nerve sheath tumors are specific
for this disease. Neurofibromatosis type 1 increases a patient’s risk for different types of malignancy. The
hallmark for neurofibromatosis type 2 is the bilateral presence of schwannomas on the vestibular nerves.
Schwannomas can be located in other parts of the central nervous system (cranial nerves, spinal cord). Me-
ningiomas are the specific optic nerve tumor. Cutaneous signs are less present than in neurofibromatosis
type 1: café-au-lait macules, plaques, nodular schwannomas and neurofibromas. There are ophthalmologi-
cal abnormalities such as cataract and retinal changes. Neurofibromatosis type 2 with onset in childhood
has a worse presentation. Schwannomatosis is the rarest type of neurofibromatosis and has no cutaneous
signs. Intense, chronic pain is its main symptom.
Keywords: neurofibromatosis type 1, neurofibromatosis type 2, schwannomatosis, neurofibromas, symp-
tomatology

Introduction
The neurofibromatosis disease group includes
three different genetic disorders: neurofibroma­
to­sis type 1 (NF1), neurofibromatosis type 2
(NF2), and schwannomatosis. All three pres-
ent with nerve sheath tumors, but each of them
has a distinct clinical presentation and a geneti-
cally different cause. NF1 is the most prevalent
of the three, affecting 1 in 3000 people glob-
ally. The mark of NF2 is the presence of bilat-
eral vestibular schwannomas, alongside other
tumors of the central nervous system. Patients
with schwannomatosis do not present with oth-
er non-tumor related changes [1]. All three dis-
eases have an autosomal dominant transmission,
but patients are often affected by spontaneous
mutations (more prevalent in schwannomatosis)
[2,3,4].
NF1
Formerly known as von Recklinghausen’s
disease, NF1 presents with numerous cutane-
ous, ske­le­tal and neurological changes, while
also in­crea­sing the risk for benign and malig-
nant tumors.
Most patients with NF1 will have café-au-
lait macules. They are light to brown in color,
with an ovoid shape and uniform borders, and
a diameter between 5-30 mm. They darken af-
ter exposure to sun and fade with advanced age.
They appear at birth and in early childhood.
They can be found anywhere on the body ex-
cept the scalp, palms and soles [2,5,6]. Axillary
and inguinal freckling (Crowe’s sign) develops
between the age of 3 and 5. Freckling can also
be found around the lips, under the neck and
breasts [7]. Lisch nodules are melanocytic ham-

7
artomas of the iris that appear after the age of
2. Their numbers and dimensions increase with
age. They are white, yellow or brown nodules
with 2 mm in diameter. They do not impair the
vision and are located bilaterally in more than
90% of the cases [8,9].
Neurofibromas are benign tumors that pres-
ent as multiple types: cutaneous, subcutaneous,
plexiform (nodular or diffuse), and spinal neuro­
fib­roma. Cutaneous neurofibromas develop in
pu­berty/early adolescence, and subsequently their
number may increase. Cutaneous neurofibro­mas
are fleshy, small, dome-shaped tumors with a pal-
pable depression (“button-hole” sign), while sub-
cutaneous neurofibromas are firm and nodular,
with variable pigmentation. They can associate
with increased local pruritus. Hundreds or thou-
sands of neurofibromas can be present anywhere
on the skin surface. There are variants of cutane-
ous neuro­fib­romas: blue-red and pseudoatrophic
macules. Blue-red macules are soft, slightly el-
evated or dome-shaped, and are located on the
torso. Pse­udoatrophic macules are depressed, oval
regions of the skin with a size between 5-10 cm,
with no change in skin color or texture.
Plexiform neurofibromas can evolve towards
malignant peripheral nerve sheet tumors. These
are diffuse tumors that grow along the length of a
nerve and can include structures in the skin, face,
muscles and internal organs, causing pain and
disfigurement. Superficial plexiform neurofibro-
mas cause hyperpigmentation and hypertrichosis.
They are also usually present at birth, when they
can be mistaken for a congenital melanocytic ne-
vus. They enlarge the most in the first decade of
life. Spinal neurofibromas can affect only one or
multiple nerve roots; they can be asymptomatic or
associated with motor or sensitive deficits [2,6,7].
Juvenile xanthogranuloma (JXG) is a type of
non-Langerhans cell histiocytosis present in a
third of children with NF1. Only less than 1%
of adult patients have it. It lasts for years, af-
ter which it disappears spontaneously [10]. JXG
can occur as single or multiple yellow-brown
nodules localized mainly on the face, head and
neck, or on the upper torso and limb extremi-
ties [11]. Nevus anemicus appears as pale mac-
8 9
ules, single or multiple, which develop mainly
in the presternal region. Their shape is irregular,
with sizes of a few millimeters or centimeters.
They are better seen by rubbing the affected skin
mildly. Glomus tumors are small blue-red pap-
ules or nodules that are located subungually in
fingers or toes. They cause pain when mechani-
cal or cold stimuli are applied [7].
Skeletal anomalies are present in NF1: osteope-
nia, scoliosis, pseudarthrosis, tibial and sphenoid
wing dysplasia. Patients may not achieve their ex-
pected height. Absence or thinning of the sphe-
noid wing can occur as a stand-alone abnormality
or may be caused by the presence of a plexiform
neurofibroma. Because of it, one of the patient’s
eyes is sunken in the orbital cavity or is proptotic
[2]. Long bone dysplasia occurs in more than 10%
of the cases and is often obvious in the first year of
life. Tibial dysplasia is the most common, causing
an anterolateral bowing of the affected bone. In
29-45% of the patients, macrocephaly can be ob-
served [7]. Children and adolescents can develop
the dystrophic or non-dystrophic form of scoliosis.
In dystrophic scoliosis, which can start before the
age of 10, the curvature is sharply angulated with
wedging, rotation and scalloping of the apical
vertebral bodies. Patients may complain of neck
and upper back pain, paresis of a limb, and the
physical examination may show hyperreflexia or
ankle clonus. The most severe cases advance to
paraparesis and paraplegia [12].
Unilateral gingival enlargement can be pres-
ent. Parts of the gingivae may have symmetric
and persistent melanin pigmentation. Displaced,
impacted, or supernumerary teeth are common.
Neurofibromas can appear in any part of the oral
cavity or within the tongue. There are bone defor-
mities of the maxilla, mandible, or temporoman-
dibular joint [13].
Heart and vascular defects are found in NF1,
ranging from congenital heart disease (CHD)
and vasculopathy to hypertension [7]. CHD pres-
ents with heart defects such as valve stenosis (es-
pecially pulmonary), mitral or aortic insufficiency,
ventricular septal defect, hypertrophic cardiomy-
opathy, intracardiac tumors [14]. Vasculopathy
affects any part of the vascular system, but more
often the renal arteries (leading to arterial hyper-
tension in children). Myocardial infarction has
been reported in adolescents. Cerebral vasculopa-
thy causes focal neurological deficits or seizures
[15,16,17]. Pulmonary hypertension with exer-
tional dyspnea has been described decades after
NF1 was first diagnosed in subjects [18].
A degree of cognitive impairment is common.
Subjects have reduced language skills and dys-
lexia, and a greater prevalence of attention defi-
cit hyperactivity disorder. Anxiety or depression
is more frequent. A third of the children display
autism spectrum disorder symptoms. Intelligence
quotient test results tend to be at the lower end of
the normal value range [19].
Optic gliomas are low-grade tumors that ap-
pear mainly in the first decade of life. 80% are on
the optic pathway, but there are other locations:
the brainstem, cortex, or cerebellum [2]. Fundos-
copy may show optic atrophy. Gliomas located on
the anterior optic pathway cause unilateral vision
loss, proptosis or strabismus. A tumor at the optic
chiasm level leads to nystagmus, vision field and
visual acuity loss. Gliomas near the hypothalamic
region cause precocious puberty and other endo-
crinological changes, hydrocephalus, or dience-
phalic syndrome (growth acceleration, hyperki-
nesia and euphoria, emaciation) [20].
NF1 leads to a fivefold increased risk of devel-
oping glioblastomas, usually in early adulthood.
Malignant peripheral nerve sheath tumors are
more frequent, with an increased 20-fold risk if
an internal plexiform neurofibroma is present.
Signs and symptoms that require further investi-
gation are: an increase in the existing volume of a
plexiform neurofibroma, a change in tumor con-
sistency (from soft to hard), increased and diffi-
cult to treat pain, appearance of a new neurologi-
cal deficit. Other non-nervous system tumors also
have a higher prevalence: breast cancer, leukemia
or lymphoma, pheochromocytomas, rhabdomyo-
sarcomas, neoplasms of the periampullary region,
gastrointestinal stromal tumors [2,21].
NF1 is diagnosed in the presence of at least
two of the following: 6 or more café-au-lait mac-
ules, axillary or inguinal freckling, two or more
Lisch nodules, at least two neurofibromas of any
type, or at least one plexiform neurofibroma, an
osseous lesion (such as long-bone dysplasia, sphe-
noid wing dysplasia), optic pathway glioma, a
first-degree relative with NF1 [2].
There are multiple mosaic forms of NF1: seg-
mental, generalized and gonadal. In generalized
mosaicism, clinical examination evidences signs
of the disease on the body surface. When leu-
kocytes in the blood sample are screened for the
gene mutation, this is not present [7].
NF2
NF2 mainly presents with neurological, cuta-
neous, and optical signs and symptoms.
Neurological lesions are the result of the pres-
ence of bilateral vestibular schwannomas (also
called acoustic neuromas), which are the most
common finding in NF2 (90-95% of the patients).
Neurinomas affect the hearing (deafness, tin-
nitus) and the vestibular function (poor balance,
dizziness). Hearing loss usually occurs in a pro-
gressive manner, but sudden onsets are described.
While they are benign in nature, the extension of
tumors can lead to facial nerve paralysis or brain-
stem compression. Bilateral schwannomas do not
necessarily develop si­mul­tane­ously. Schwanno-
mas can be present bilaterally in other cranial
nerves (especially the oculomotor nerve or the
trigeminal nerve) in about 24 to 51% of the cases.
Some tumors may regress in size. Schwannomas
of cranial nerves IX, X and XII, located in the
jugular foramen, may lead to difficulty in speech
and swallowing. Vagus nerve affliction may be
indicated by a hoarse voice. Children have more
cranial nerve deficits such as facial palsy, third
nerve palsy, and swallowing impairment.
Meningiomas that lead to increased intra-
cranial pressure, seizures and hydrocephalus can
be present in 45 to 77% of the cases. They are
typically located in the optic nerve sheath, caus-
ing complete vision loss. Spinal tumors (present
in 63 to 93% of the times) can be located ex-
tramedullary (schwannomas or meningiomas)
or intramedullary (ependymomas, as­tro­cytomas,
schwannomas). Compression of the spine leads
to paresis, gait abnormality, paralysis, tingling
or numbness in the limbs, bowel and bladder
dysfunctions. NF2 patients have a higher risk
of malignant nervous system tumors [3,22,23].
Peripheral neuropathy can be found in up to
67% of cases with NF2 after electrophysiologi-
cal examination. Neuropathy affects the sen­
sory function, with hypoesthesia (occurring in a
stocking-glove pattern), hypesthesia, or pall­
hypes­thesia (loss of vibration sense). Motor func-
tion is affected by the appearance of a distal re-
flex loss that leads to progressive muscle atrophy
and paresis in the later stages. Clinical signs of
neuropathy are not always correlated with the ac-
tual presence of peripheral nerve schwannomas.
There are localized forms of neuropathy such
as mononeuropathy simplex or multiplex, and a
symmetrical form of polyneuropathy [24]. Chil-
dren diagnosed with NF2 are more likely to have
mononeuropathy of a limb in the absence of a
nervous system tumor [22].
NF2 patients do not present with learning dis-
abilities as is the case of NF1 [25].
Patients with NF2 have café-au-lait macules,
but these are fewer and smaller than in NF1.
The macules have irregular borders and are paler.
Plaques are slightly raised cutaneous schwanno-
mas with well-defined borders, hyperpigmenta-
tion, hypertrichosis, and a diameter under 2 cm,
with a prevalence of 41-48%. They develop in
childhood on the torso and limbs. There are also
nodular schwannomas that are organized sub-
cutaneously around peripheral nerves and do not
change the skin pigmentation. Profound lesions
are elastic and painful when palpated, while su-
perficial lesions are softer. Most children have
nodular schwannomas, usually no more than 10
tumors. Neurofibromas are similar to those seen
in NF1 [6,22,23,25].
Ophthalmological signs include: cataract (60
to 81%, often bilateral), epiretinal membranes
(12-40%), retinal hamartomas (6 to 22%), and
optic atrophy. Ocular changes are more preva-
lent in NF2 starting in childhood [22,23].
Subjects with NF2 have higher arterial blood
pressure when compared to normal controls [26].
The Gardner type of NF2 is milder, with on-
set between 22 and 27 years. Bilateral vestibular
10 11
schwannomas are the main feature, or the only
one. The Wishart type includes children that
have a disease onset before puberty. It is more
severe, with multiple tumors in the central ner-
vous system (before the formation of vestibular
schwannomas) and more ophthalmological and
cutaneous signs. A third group of subjects have
congenital NF2. Bilateral vestibular schwanno-
mas are present in the first days or months fol-
lowing birth. Individuals remain asymptomatic
for decades before the disease has a sudden onset.
Lens opacities and retinal changes are present
in the first months of life. In the mosaic form of
NF2, the vestibular schwannoma is seen in only
one vestibular nerve along with ipsilateral me-
ningiomas, or there are multiple schwannomas
grouped in only one part of the peripheral ner-
vous system [25]. Diagnosing NF2 is possible if
any one of the following criteria is met:
▶▶ bilateral vestibular schwannomas before
the age of 70;
▶▶ unilateral vestibular schwannoma before
the age of 70 and a first-degree relative
with NF2;
▶▶ any two of the following: meningioma,
non-vestibular schwannoma, neurofibro-
ma, glioma, cerebral calcification, cata-
ract, and:
▷▷ a first-degree relative with NF2 OR
unilateral vestibular schwannoma and
negative genetic testing for LZTR1;
▶▶ multiple meningiomas and:
▷▷ unilateral vestibular schwannoma OR
any two of the following: non-ves-
tibular schwannoma, neurofibroma,
glio­ma, cerebral calcification, cataract;
▶▶ constitutional or mosaic pathogenic gene
mutation in NF2 from the blood or by
identification of an identical mutation
from two separate tumors in the same
individual [23].
Screening for NF2 should be done in first-de-
gree relatives of patients with NF2, patients with
an isolated unilateral vestibular schwannoma un-
der the age of 30, non-vestibular schwannoma
(including spinal or intracutaneous schwannoma)
or meningioma in patients under 25, children
with retinal hamartoma [27,28].
The differential diagnosis of NF2 includes NF1,
sporadic vestibular schwannomas, schwannoma-
tosis, and familial syndrome of multiple meningi-
omas. Sporadic vestibular schwannomas occuring
after the age of 30 are most likely not due to NF2.
Schwannomatosis with LZTR1 gene mutation
can have unilateral vestibular schwannomas. In
familial meningioma there is no mutation in the
NF2 gene [23].
Schwannomatosis
Schwannomatosis is the third genetic form of
neurofibromatosis. It is defined by the presence
of multiple schwannomas in a patient, but with
no bilateral schwannomas, and no cutaneous
signs like in NF1 and NF2. The most prevalent
mutations involve the SMARCB1 and LZTR1
genes. Besides schwannomas, SMARCB1 mu-
tations are associated with malignant peripher-
al nerve sheath tumors, rhabdoid-type tumors
of the kidney, atypical teratoid rhabdoid tumors
of the central nervous system, and extra-renal
childhood rhabdoid tumors [29].
Cranial schwannomas can be non-vestibular,
or unilateral vestibular in LZTR1 mutations
[23,30]. Spinal schwannomas are found in al-
most 75% of the times, mostly in the lumbar
region, followed by the thoracic and cervical
region. Incidence of meningiomas is 5% in pa-
tients with schwannomatosis (higher than 50%
in NF2), and there are no ependymomas [31].
Spinal tumors are mainly localized to a single
region, or they are found in two or more areas.
Peripheral schwannomas are present in 89% of
the times, mainly on the arms and legs, followed
by the head and neck, chest, abdomen and pel-
vis. Subcutaneous masses are present in 23% of
the cases. A third of the patients have segmental
schwannomatosis: schwannomas located in only
one limb or in only two spinal segments [30].
The main symptom in schwannomatosis is
local, multifocal or diffuse pain which in some
cases may reach a high, debilitating intensity.
Pain severity does not correlate with the tumor
number, size or location, and may not respond
to medication or surgery. Patients also complain
of migraines and have a higher prevalence of de-
pression [29,30].
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IgA vasculitis (Henoch-Schönlein purpura):
A literature review
Tamás Rácz
Student, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca
Abstract. Immunoglobulin A vasculitis (IgAV, formerly called Henoch-Schönlein purpura) is one
of the most common vasculitides of pediatric patients. The disease is characterized by leukocytoclastic
vasculitis with deposition of IgA immune complexes in the vessel walls of the affected organs. IgAV is
considered a self-limited disease with an excellent outcome and spontaneous resolution of the symptoms.
However, a small percentage of patients, who are most frequently adults, can develop end-stage renal
disease. The main causes of morbidity and mortality are the renal and gastrointestinal complications of
IgAV. Adult patients with IgAV need to be carefully monitored because there is no correlation between
the initial presentation of adult patients and long-term renal outcome. There is a possibility that initial
mild symptomatology develops into a serious renal disease. The management of patients with gastroin-
testinal and renal complications is controversial. Currently, there are many treatment possibilities, but no
evidence-based algorithm has been developed.
This review article gives a general overview of IgA vasculitis, focusing on the pathogenesis, symptom-
atology, diagnosis, treatment and prognosis of the disease.
Keywords: immunoglobulin A vasculitis, Henoch-Schönlein purpura, symptomatology, immuno-
globulin A nephritis, prognosis
Introduction ence for Nomenclature of Vasculitides, experts
Immunoglobulin A vasculitis (IgAV, Henoch-­ decided to replace the eponym with IgA vascu-
Schönlein purpura) was first described in 1802 litis, which indicates the pathogenetic feature
by William Heberden, who presented in his of the disease, the deposition of IgA immune
work the case of two boys who had the typical complexes into the walls of small vessels [3].
symptomatology of IgAV [1]. The disease was
named after two German physicians, Johann Epidemiology
Lukas Schönlein (1793-1864) and Eduard The annual incidence of IgAV is 20 per
Henoch (1820-1910). In 1837, Schönlein de- 100,000 children younger than 17 years [4].
scribed the association between purpura and The annual incidence of the disease in the adult
arthralgia. A few years later, Henoch added population is much lower, 0.1 to 1.8 cases per
gastrointestinal and renal involvement [2,3]. 100,000 adults [3]. The peak incidence of the
Up until 2012, the disease was called Henoch- disease is between 4 and 7 years [4].
Schönlein purpura. In 2012, at the revised IgAV predominantly occurs in the cold
Chapel Hill International Consensus Confer- months of the year (autumn, winter, spring) and
is associated with upper respiratory tract infec-
tions, especially those caused by Streptococcus
[2,5]. The disease rather affects boys than girls;
male-to-female ratios of 1.2-1.8:1 have been de-
scribed. IgAV is less frequent in African Ameri-
can compared to Caucasian or Asian children [5].
Etiology and pathogenesis
The majority of IgAV cases are associated
with previous upper respiratory tract or gastro-
intestinal tract infections. The most commonly
found pathogens of these infections are Strep-
tococcus, Staphylococcus and human parainfluenza
virus. Other infectious agents, drugs, insect
bites and vaccination can also be a possible trig-
ger of IgAV. In the literature there are a few re-
ported cases of IgAV triggered by influenza vac-
cination, during the pandemic influenza A virus
(H1N1) outbreak in 2009 [6]. Even though
there were a number of post-vaccination vascu-
litis cases described in the literature, systematic
reviews do not allow to establish a significant
connection between vasculitides such as IgAV
and patient vaccination history [7].
Infection with Helicobacter pylori (H. pylori)
has been shown to play a potential pathoge-
netic role in the case of IgAV [8]. There are
many mechanisms that could explain the role
of H. pylori in the pathogenesis of IgAV. Firstly,
mucosal infection causes upregulation of inter-
leukin 6 (IL-6) production which could alter
the normal glycosylation process of IgA1 and
lead to IgAV [9]. Secondly, a major virulence
factor of H. pylori, the cytotoxin associated gene
A protein (CagA), promotes the underglyco-
sylation of IgA1 by downregulating galactos-
yltransferase and its chaperone involved in the
glycosylation process [10]. A meta-analysis from
China showed that H. pylori-positive children
are 3.8 times more predisposed to develop
IgAV compared to uninfected children and
eradication therapy is capable of reducing the
recurrence rate of IgAV in infected children
[8,11,12]. Although the meta-analysis showed
some positive associations, it cannot be consid-
ered as a high level of evidence. The reason for
this is that the meta-analysis comprised stud-
14 15
ies in which different diagnostic tests for the
detection of H. pylori infections were used and
the clinical studies included only the Chinese
population, where high-toxicity CagA positive
strains are dominant compared to other parts
of the world [11,12].
There are numerous pieces of evidence which
support the claim that genetics plays a crucial
role in the pathogenesis of IgAV. One of these
is the fact that the incidence of the disease dif-
fers between ethnic groups [5,13]. A few cases
of familial aggregation of IgAV have also been
reported. Although no mutations have been de-
scribed which could directly cause IgAV, sever-
al polymorphisms of different genes have been
associated with the disease. When the genetic
code of healthy individuals was compared with
the genetic code of IgAV patients, the most im-
portant difference was found in human leuko-
cyte antigen (HLA) genes. The disease has been
associated with HLA class I and class II region,
the strongest connection being described with
HLA-DRB1*01 [13,14]. HLA-DRB1*07 was
negatively associated with IgAV [13]. A poten-
tial association between IgAV and the poly-
morphisms of the genes regulating immune
and inflammatory pathways such as cytokines,
chemokines, adhesion molecules has been sug-
gested by several studies. These polymorphisms
play a less important role in the pathogenesis of
the disease than the HLA region [13,14]. Some
studies concluded that the Mediterranean fever
(MEFV) gene, which encodes pyrin, a protein
absent or abnormally functioning in patients
with familial Mediterranean fever, can play a
role in the pathogenesis of IgAV [14,15].
The most important pathogenetic feature of
IgAV is the formation of IgA1-containing im-
mune complexes and their deposition in the
small vessels of the human body. IgA is an an-
tibody subclass which plays a crucial role in the
immune function of mucosal defense. IgA can
be found in mucosal secretions where it binds,
agglutinates pathogens (SIgA), and in serum
where it is present as a monomeric molecule
(mIgA). In diseases such as immunoglobulin A
nephropathy (IgAN) and IgAV, the hinge region
of IgA, which in normal individuals is heavily alternative complement pathway, which leads
glycosylated, presents structural abnormalities to tissue destruction, inflammation and organ-
[2,13]. In both diseases, patients have galactose specific manifestations of the disease [2,13,16].
(Gal) deficient glycosylation of the hinge region, Like in systemic lupus erythematosus and
which exposes N-acetylgalactosamine (GalNAc) other immune-mediated diseases, IgAV has
as terminal glycan. The newly produced galactose been associated with the presence of anti-endo-
deficient IgA1 antibodies (Gd-IgA1) can func- thelial cell antibodies (AECAs) [8]. It is believed
tion as a neoepitope and induce the formation that infection with microorganisms leads to pro-
of anti-Gd-IgA1 autoantibodies [13]. Another duction of IgA1 autoantibodies which cross-
theory has also been described which explains react with endothelial cells (ECs) and become
the production of autoantibodies by the pres- AECAs. A possible antigen for AECAs in IgAV
ence of previous microbial or viral infection. patients is β2-glycoprotein I (β2GPI) [5,8,17,18].
Because many microorganisms express GalNAc Anti-β2GPI antibodies are at the same time anti-
on their surface, it is possible that IgG antibod- cardiolipin (aCL) antibodies [19]. β2GPI adheres
ies against GalNAc on the microorganisms to EC membranes and reveals epitopes which
cross-react with the terminal glycans of Gd- are normally hidden and which bind AECAs.
IgA1. This leads to the formation of Gd-IgA1- After AECAs, β2GPIs and ECs interact, they
IgG immune complexes. produce endothelial cell activation and comple-
ment-dependent cytotoxicity [8,17]. It has been
described that IgA AECAs in IgAV patients in-
duce interleukin 8 (IL-8) production by the ECs
which promote neutrophil chemotaxis [8,20]. It
has been shown that increased systemic levels of
tumor necrosis factor alpha (TNF-α) might en-
hance the production of AECAs, which increas-
es inflammation by activating ECs and forms a
positive feedback loop [8,18].
IgG – immunoglobulin G; Clinical manifestations in children
anti-Gd-IgA1 – anti-galactose deficient IgAV is characterized by a tetrad of symptoms:
immunoglobulin A1. ▶▶ Palpable purpura without thrombocyto-
penia and coagulopathy
Figure 1. The formation of IgG anti-Gd- ▶▶ Arthritis, arthralgia
IgA1 immune complexes [8] ▶▶ Abdominal pain
▶▶ Renal disease [5].
The clinical manifestations of IgAV may de-
In healthy individuals, IgA1 is metabolized velop in days or weeks and their order of pre-
in the liver, after interaction with asialoglyco- sentation may vary. Palpable purpura and joint
protein receptors (ASGP-R) expressed on the pain are in general the first symptoms of the
surface of hepatocytes, which is followed by the disease. In case of absence of the classic purpu-
internalization and degradation of IgA1. After ric rash, the diagnosis of IgAV may not be that
the formation of Gd-IgA1-IgG immune com- obvious [5].
plexes, these cannot reach the space of Disse and ▷▷ Skin manifestations
be metabolized, but they cross the endothelial In three quarters of the cases, rash is the first
fenestrae and deposit in the glomerulus or in the sign of the disease. At the beginning, the rash
small vessels of other organs. This is followed by is characterized by erythematous, macular or
the activation of the mannan-binding lectin and urticarial wheals. Lesions tend to merge and
evolve into ecchymoses, petechiae and palpable
purpura, which can be itchy, but almost never
painful [5]. The rash appears in crops and is
localized in gravity-dependent areas and pres-
sure points. In toddlers, the most frequently
involved area is the buttocks, but in older chil-
dren, facial, trunk and upper extremity involve-
ment can also be observed [5]. In <2% of the
patients, blisters, either vesicles (≤0.5 in diam-
eter) or bullae (≥0.5 in diameter) can be seen.
They are distributed in the same regions of the
body and develop concomitantly with palpable
purpura [21]. After skin lesions disappear, the
previously affected skin will be discolored by
the remaining hemosiderin [22].
Figure 2. Classical skin lesions of immuno-
globulin A vasculitis (Henoch-Schönlein
purpura), with palpable purpura on the
extremities
16 17
▷▷ Joint manifestations
Up to 84% of the patients present arthritis
or arthralgia [5]. The majority of the pediatric
patients present these symptoms simultaneously
with the rashes, but joint symptomatology can
occur even 11 days after the appearance of pal-
pable purpura [24]. Joint involvement can be
the first manifestation of IgAV in about 15%
of the cases. Arthritis is typically oligoarticular,
transient or migratory, affecting the large joints
of the lower limbs, such as hips, knees, ankles
and feet. The involvement of elbows, wrists and
hands is less frequent [25]. Arthritis is charac-
terized by periarticular swelling and tenderness,
but it lacks joint effusion, erythema or warmth.
Arthritis is non-deforming, disappearing in a few
weeks time without any sequelae. Some studies
show that about one third of patients experience
the recurrence of joint symptomatology within 6
months of the appearance of the first symptoms
[5,24].
▷▷ Gastrointestinal involvement
Gastrointestinal (GI) symptomatology is a
relatively frequent manifestation of IgAV, oc-
curring in approximately two thirds of the af-
fected children. Symptoms are caused by the
deposition of immune complexes in the small
vessels of the gastrointestinal tract, which leads
to vasculitis of the splanchnic circulation (mes-
enteric vasculitis) [26]. Typically, GI symptoms
develop 8 days after the appearance of purpura,
but in about 25% of patients they occur before
the first signs of skin involvement. In a minor-
ity of patients, GI symptomatology is the first
clinical manifestation of the disease [27]. In such
patients, the diagnosis of IgAV can be difficult
for clinicians. Differential diagnosis with acute
abdomen, especially in children, has to be con-
sidered [5,22].
The most important GI symptom is diffuse,
colicky abdominal pain, which worsens after
meals. Other symptoms include nausea, vomit-
ing, hematemesis, melena, hematochezia, tran-
sient paralytic ileus, acute acalculous cholecys-
titis, intestinal perforation, hemorrhagic ascites
with serositis, acute pancreatitis, biliary cirrho-
sis [26]. More severe symptoms include gastro-
intestinal hemorrhage, bowel ischemia, bowel
necrosis, intussusception, bowel perforation [5].
Submucosal hemorrhage and edema can lead to
a positive guaiac fecal occult blood test in one
half of the patients. Massive gastrointestinal
hemorrhages are rare [2,5]. Hypoalbuminemia
without proteinuria can indicate mucosal injury
and protein loss [22].
The most common endoscopic findings are
erythema, edema, petechiae, ulcers, hematoma-
like protrusions, ecchymotic lesions, superficial
ulcers and strictures. Typically, the stomach and
the descending duodenum are involved. On co­
lo­noscopy, ileal and rectal ulcers can be observed.
The terminal region of the ileum is most fre-
quently involved, where the lesions are more se-
vere compared to other areas [5,26].
Intussusception is present in 3-4% of the cases
and is typically ileoileal, in contrast with idio-
pathic intussusception, which is usually ileocolic
[2,5,26].
Recent studies show that increased fecal cal-
protectin is associated with GI involvement [28].
▷▷ Renal involvement
Renal manifestations of IgAV are reported in
20-55% of children and consist of an inflamma-
tory reaction, called IgA nephritis (HSP nephri-
tis, HSPN), which is the most important factor
determining the morbidity and mortality of the
disease [2,26,29]. The first renal symptoms de-
velop within the first month after the appear-
ance of initial symptomatology. The most com-
mon finding on the urinalysis of IgAV patients
is isolated microscopic hematuria, but in some
patients macroscopic hematuria with or without
red cell casts can be observed. In the majority
of the patients, proteinuria occurs along with
hematuria, but less frequently it can also be iso-
lated. Exceptionally, in 2% of the cases, patients
can present with nephrotic syndrome [30,31].
Arterial hypertension may develop either at the
onset or during the recovery phase of IgA ne-
phritis [22]. Most IgA nephritis cases are mild;
only a small percentage of children develop end-
stage renal disease (ESRD). Although the time
course of the renal disease is unpredictable, pa-
tients with persistent hematuria, proteinuria and
patients older than 8 years are at a higher risk of
developing ESRD. Because renal involvement
occurs in 97% of the cases in the first 6 months,
patients should be followed up for one year after
the beginning of the first symptoms in order to
diagnose and treat efficiently the renal manifes-
tations of the disease [26,32].
▷▷ Other organ involvement
Scrotal and testicular involvement can be ob-
served in 2-38% of boys with IgAV. Common
symptoms are scrotal pain, tenderness, swelling
of the scrotum or of the involved testicle. Be-
cause in some patients unilateral presentation of
scrotal symptoms can occur, it is important to
make the differential diagnosis with testicular
torsion. In rare cases, epididymitis and orchitis
as a consequence of IgAV have also been de-
scribed [5,33].
Rarely, IgAV patients can present with signs
of either central or peripheral nervous system
involvement. The deposition of IgA can extend
to cerebral vessels and cause edema, ischemia,
infarction and hemorrhage. In the peripheral
nervous system, nerve damage can occur as a
result of ischemia produced by inflammation in
the walls of the vasa nervorum. The most sig-
nificant neurological symptoms that may oc-
cur in the case of IgAV are headaches, seizures,
ataxia, intracerebral hemorrhage, hypertensive
and posterior reversible encephalopathy syn-
drome (PRES), peripheral neuropathy [5,34,35].
Another rare, but extremely dangerous compli-
cation of IgAV is pulmonary hemorrhage [5].
Ophthalmologic manifestations include keratitis,
uveitis, scleritis, but anterior ischemic optic neu-
ropathy and central retinal artery occlusion have
also been described [5,34].
Clinical manifestations in adults
Adult IgAV symptomatology is very similar
to manifestations seen in children. The most
important difference between these two groups
is that adults develop ESRD more often and
intussusception rarely [5,36].
 Table I. Diagnostic criteria for immunoglobulin A vasculitis (IgAV, HSP), developed by complications such as ESRD, a tendency has
EULAR/PRINTO/PRES [37] been observed to study non-invasive biomark-
ers of HSPN in order to avoid kidney biopsies.
Sensitivity Specificity A recent study concluded that serum Gd-IgA1
Criterion Description (%) (%)
and urinary IgA, IgM, IgG, IL-6, IL-8, IL-10,
IgA-sCD89 (immunoglobulin A-soluble cluster
Palpable purpura or petechiae (without
Mandatory criterion: of differentiation 89), IgG-IgA could differen-
thrombocytopenia), with lower limb predo- 89 86
purpura tiate IgAV patients with nephritis from IgAV
minance
patients without nephritis at the time of diag-
nosis (38). Further clinical research is required
Diffuse colicky abdominal pain with acute
1. Abdominal pain 61 64 in order to introduce in clinical practice such
onset
non-invasive biomarkers for diagnosing HSPN.
Leukocytoclastic vasculitis with predominant
2. Histopathology deposition of IgA or proliferative glomerulo- 93 89 Treatment
nephritis with predominant deposition of IgA The management strategies of IgAV are con-
troversial. There is a general agreement that treat-
Arthritis is defined as acute onset joint swel- ment is mainly decided depending on the pres-
ling or joint pain with limitation of motion ence or absence of renal involvement [22]. Because
3. Arthritis or arthralgia 78 42 the majority of the patients recover spontaneously,
Arthralgia is defined as acute onset joint pain the management of patients without renal in-
without joint swelling or limitation of motion volvement is primarily supportive. In these cases,
treatment includes adequate hydration, rest, pain
Proteinuria >0.3 g/24 h or urine albumin/cre- relief and patient monitoring for the development
atinine ratio >30 mmol/mg in a spot morning of severe complications, such as intussusception
sample
or intracranial hemorrhage [2,22,39].
4. Renal involvement 33 70 For children with HSPN, both nonsteroidal
Hematuria or red blood cell casts: >5 red
blood cells/high power field or red blood anti-inflammatory drug (NSAID) treatment
cell casts in the urinary sediment or ≥2+ on and glucocorticoid treatment are weak, grade
dipstick 2C recommendations, coming from small stud-
ies or case reports. Randomized controlled trials
Purpura or petechiae (mandatory criterion) for pain management in IgAV are needed [2,39].
EULAR/PRINTO/PRES
and at least one of the other four criteria for Glucocorticoid treatment should not be
HSP criteria for the
diagnosing IgAV (abdominal pain, histopa- 100 87
diagnosis of IgAV used for the prevention of renal complications
thology, arthritis or arthralgia, renal involve-
(HSP) (grade 1B recommendation). An updated Co-
ment)
chrane review from 2015 concluded that glu-
EULAR - European League Against Rheumatism; cocorticoid treatment does not reduce the risk
PRES - Paediatric Rheumatology European Society; of developing renal complications [40]. The
IgAV - immunoglobulin A vasculitis; HSP - Henoch-Schönlein purpura. Kidney Disease: Improving Global Outcomes
(KDIGO) guideline concluded that HSPN
patients with persistent proteinuria should be
Diagnosis treated with angiotensin-converting enzyme
The diagnosis of IgAV is based on clinical cri- ing IgAV. When applied to children, the criteria inhibitors (ACEIs) or angiotensin II receptor
teria. In 2010, the revised EULAR/PRINTO/ have a sensitivity of 100% and a specificity of blockers (ARBs) [41].
PRES criteria for the diagnosis of Henoch- 87%, but in the case of adult patients, both per- In case of ESRD, renal transplantation can
Schönlein purpura (IgAV) replaced the older centages are lower [22,37]. (Table I.) be performed. Even though graft loss due to
American College of Rheumatology (ACR) cri- Because HSPN occurs in 20 to 54% of chil- recurrent disease is more frequent in IgAV
teria and became the gold standard in diagnos- dren with IgAV and it can lead to serious renal than in non-IgAV patients, it has been shown
18 19
that the diagnosis of IgAV has little effect on
overall renal allograft survival [31,42].
Prognosis
Patients with IgAV have an excellent prog-
nosis. It has been generally observed that chil-
dren have a much better prognosis than adults
due to the less frequent development of ESRD.
Patients without significant renal manifesta-
tions have spontaneous resolution of symptoms
within one month [39]. Two-thirds of children
do not have recurrent disease, but in one-third
of the cases recurrence occurs within four
months after the development of initial symp-
toms [2]. Children with nephritic, nephrotic
syndrome or renal failure on diagnosis have a
higher risk of developing long-term renal im-
pairment [43]. The best predictors for relapses
are joint, gastrointestinal manifestations at di-
agnosis and a longer duration of the first epi-
sode of palpable purpura. During the relapse
episode, patients most frequently present cu-
taneous, gastrointestinal and renal symptoms
[44]. In general, relapse episodes have the same
clinical manifestation, but a milder symptom-
atology and a shorter duration [39]. In patients
with relapses, an infectious trigger of IgAV has
been less frequently described [44].
Several studies report that nephrotic syn-
drome, renal insufficiency, hypertension, cres-
centic glomerulonephritis with crescents in-
volving more than 50% of the glomeruli are
associated with poor renal outcome [31,45].
Morbidity in the initial phase of the disease is
due to GI complications such as intussuscep-
tion, bowel ischemia, bowel perforation and
acute pancreatitis. The main causes of later
morbidity are renal complications [39].
Conclusions
IgA vasculitis (Henoch-Schönlein purpura)
is the most common small vessel vasculitis of
childhood, with very good outcome for the
majority of pediatric patients. The disease is
characterized by a tetrad of symptoms: pur-
pura, arthralgia/arthritis, GI and renal mani-
festations. In the last years, there has been
progress in understanding the pathogenesis of
the disease, but the underlying cause is still un-
known. The pathogenesis of IgAV is similar to
that of IgA nephropathy; in both cases the de-
position of IgA-containing immune complexes
in small vessels has been observed. IgAV is less
frequent in adults, but adult symptomatology is
more severe than the symptomatology of chil-
dren with IgAV, older patients having a higher
risk of developing ESRD. The management of
IgAV is controversial, and an evidence-based
algorithm is needed.
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Henoch-Schonlein Purpura: A Review, Curr Urol,
2015, 8(2):66–73
30. Chang WL, Yang YH, Wang LC, Lin YT,
Chiang BL - Renal manifestations in Henoch-
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31. Dedeoglu F, Kim S, Sundel R TE - Renal ma-
nifestations of Henoch¬Schönlein purpura (IgA
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in-purpura-iga-vasculitis, updated on Sep 23, 2017,
accesed on Oct 2017
32. Pohl M - Henoch–Schönlein purpura nephritis,
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33. Ha TS, Lee JS - Scrotal involvement in childho-
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34. Bérubé MD, Blais N, Lanthier S - Neurolo-
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35. Garzoni L, Vanoni F, Rizzi M, Simonetti GD,
Simonetti BG, Ramelli GP, et al. - Nervous system
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matic review of the literature, Rheumatology, 2009,
48(12):1524–1529
36. Kang Y, Park J, Ha Y, Kang M, Park H-J, Lee
S-W, et al. - Differences in clinical manifestations
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37. Ozen S, Pistorio A, Iusan SM, Bakkaloglu
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dhood polyarteritis nodosa, childhood Wegener
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Conti G, Peruzzi L, et al. - Predictors of Outcome
in Henoch-Schönlein Nephritis in Children and
Adults, Am J Kidney Dis, 2006, 47(6):993–1003
Valentino’s syndrome
Mădălina Șteţca
Student, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca
Abstract. Valentino’s syndrome represents a clinical manifestation of duodenal perforation. Often,
the first symptom experienced by the patient is a sudden, sharp pain in the upper abdominal region. The
clinical presentation of the syndrome, however, bears a great degree of resemblance to that of appendici-
tis, a surgical emergency often regarded as the least life-threatening. To prevent any significant repercus-
sions that diagnostic errors can lead to, an early and precise differential diagnosis should be made. While
clinical evaluation represents the first step in reaching correct diagnosis, the more detailed examination
of the lesion is to be provided by the use of imaging exams. The most commonly preferred methods
are abdominal ultrasound, radiography and computed tomography (CT). These allow the examiner to
acknowledge the severity of the case and select the most appropriate treatment for the patient. Unless
Valentino’s syndrome is diagnosed early, diagnosis will be upgraded to severe sepsis, which eventually
might lead to death. Early diagnosis may spare the patient of this tragic consequence.
Keywords: perforation of duodenal ulcer, Valentino’s syndrome, acute appendicitis, peritoneal irrita-
tion, pneumoperitoneum, perforated ulcer.

Introduction quadrant, with appendicitis being the principal

Acute abdominal pain is a medical emergency
requiring prompt assessment with which clinical
doctors are constantly confronted. Its cause can
be attributed to a spectrum of conditions, rang-
ing from less severe to lethal. Various factors, such
as unreported drug intake or performed surger-
ies can obscure the clinical presentation of acute
abdominal pain and prevent the clinician from
reaching a diagnosis. Meticulous care is required
when considering all the possible diagnoses of
abdominal pain. Therefore, complete history tak-
ing and physical evaluation are considered to be
the cornerstone of medical practice [1].
The cause of an acute abdomen may be very of-
ten missed, as it presents with certain symptoms
that are never related to a specific pathology.
Pain is most often described in the right lower
surgical emergency. Until recently, clinical as-
sessment with minimal investigational support
was sufficient to perform an appendicectomy [2],
but for some time now, it has been proved that
a number of pathologies share a similar clini-
cal presentation, thereby leading to misdiagno-
sis from the beginning. One such case is a rare
clinical presentation of a perforated duodenal
ulcer, medically known as Valentino’s syndrome.
Pathophysiology
Although the exact etiology and nature of
the disease process behind perforation remains
largely undetermined, the effect that the imbal-
ance between aggressive and defensive factors
has on the gastroduodenal mucosa is indisputable.
In this respect, the contribution of Helicobacter

22 23

Figure 1. Circulation of gastric fluids in the
peritoneal cavity directed by the attachments
of peritoneal ligaments
pylori (HP) and the chronic usage of nonsteroidal
anti-inflammatory drugs (NSAIDs) have been de-
bated [3].
A lack of self-care in terms of personal hy-
giene is correlated with a higher chance of con-
tracting HP, especially during childhood [4].
The improvement of current diagnostic tests al-
lows a more accurate diagnosis of HP infection,
treatment being now accessible to any physician.
As regards NSAIDs, these are a class of drugs
widely used for their anti-inflammatory and an-
algesic effects, which are indispensable in pain
management due to the combined role of the
cyclooxygenase (COX) pathway in the process
of inflammation and in the cellular recognition
of pain. It is widely accepted that withholding
medication in acute situations does not benefit
the diagnostic process and would only make the
patient uncooperative for distinct reasons [5].
The typical patient suffering from Valentino’s
syndrome is a male adult with a history of chron-
ic illness for which medication is administered
constantly. It bears noting that the most aggra-
vating symptom is pain in the upper abdominal
region, in relation to meals [3]. Nonetheless, cas-
es of Valentino’s syndrome have been observed
in children, but these are exceptionally rare [6,7].
24 25
Figure 2. The path taken by gastric fluids
in Valentino’s syndromes
Following ulcer perforation, digestive fluids
invade the peritoneal cavity, forming a passage to
compartments in different parts of the abdomen
(Figure 1). Digestive fluids are prone to ac­cu­mu­
late in the lower spaces due to the right paracolic
gutter (Figure 2). Clinically, this translates into
considerable pain perceived around the area [8].
Clinical features
Typical features of a duodenal ulcer include
abdominal pain, distention and dyspepsia. Once
the ulcer perforates, the gastroduodenal contents
invade the peritoneal cavity, generating a sharp
pain which does not subside regardless of the
administered medication [9].
The manifestation of duodenal ulcer perfora-
tion can be captured in three clinical phases:
▷▷ In the initial phase (up to 2 hours), the
pain is located in the epigastrium. In ad-
dition, a slight increase in body tempera-
ture and tachycardia can also be observed.
▷▷ An intermediate phase (between 2 to 12
hours) follows, in which the patient expe-
riences pain amelioration due to the dilu-
tion of duodenal contents by the exudate
from the peritoneum. Subsequently, the
accumulation of gastroduodenal contents
in the right lower quadrant (RLQ ) leads
to abdominal tenderness, guarding and
rigidity, which are signs of peritoneal ir-
ritation that can be clearly highlighted by
physical examination.
▷▷ In the third phase, (more than 12 hours)
severe signs of circulatory collapse, in-
cluding hypotension, hyperpyrexia and
abdominal distention can influence the
patient’s condition [3].
Other symptoms such as nausea or vomiting
have been described, but they are inconsistent.
Pain usually starts in the epigastrium, being
followed by an amelioration, and then it shifts
to the right iliac fossa and increases in intensity.
The association of the three clinical elements
consisting of sudden onset abdominal pain,
tachycardia and abdominal rigidity character-
izes duodenal ulcer perforation. In such cases, it
is very important to distinguish acute appendi-
citis from Valentino’s syndrome [9]. The clinical
picture is questionable, especially in elderly or
children, or in the obese [10]. Therefore, clinical
evaluation along with identification of the af-
fected organ and slowing of disease progression
are critical to treatment efficacy.
Laboratory and imaging investigations
in Valentino’s syndrome
Currently, there are no valid diagnostic labo-
ratory tests for the perforation of duodenal ul-
cer. Their usefulness lies solely in the evaluation
of the patient’s condition and exclusion of other
pathologies. Accordingly, it seems reasonable to
perform a complete blood count and a C-reac-
tive protein (CRP) measurement [10]. Markers
of inflammation are ought to be elevated, im-
plying that the process of inflammation unfolds.
Manifestations of a systemic inflammatory re-
sponse syndrome (SIRS), including leukocytocis,
increased body temperature and tachycardia,
can be reported. Also, an arterial blood gas test
is compulsory, as it excludes disorders of acid
base balance with metabolic acidosis found to be
the most frequently related [11].
Since hyperamylasemia is often associated
with acute pancreatitis, the serum amylase level
should be measured. This is routinely ordered in
cases of upper abdominal pain, especially in re-
lation to meals [12]. In this context, it has been
shown that elevated levels may also be associated
with perforated ulcer, especially if the perfora-
tion is produced shortly after meal, when the
pancreas releases large amounts of enzymes into
the circulation. It is considered to be a conse-
quence of massive absorption through the peri-
toneal surfaces, as a result of interruption of the
gastrointestinal barrier [13].
In addition to laboratory findings, another ac-
cessible examination is chest radiography that
reveals the pneumoperitoneum under the dia-
phragm.
Free air within the peritoneal cavity can also
be detected on an abdominal radiograph in dif-
ferent compartments, as follows:
▷▷ Around the bowel, marking the pres-
ence of air on both sides of the intestine
- Rigler sign (or double wall sign) [14];
▷▷ Involving the peritoneum, forming round
black areas - football sign [6];
▷▷ Outlining the falciform ligament - Silver
sign [15];
▷▷ Retroperitoneal, masking the right kidney
- veiled right kidney sign [16,17].
A major part in the process of diagnosing a
patient with right lower quadrant pain and sus-
pected acute appendicitis plays helical CT, which
is thoroughly recommended not only for its ac-
curacy in indicating the pneumoperitoneum, but
also for discarding other diagnoses. Some of its
benefits include offering an imaging technique
that is non-invasive, along with a better shape
and contour of the lesion. Its availability in all
medical facilities remains to be discussed [18].
 Table I. Differential diagnosis between acute appendicitis and duodenal perforation [3,6,9,10,14-22] from the beginning, therefore being better local- 5. Ong CKS, Lirk P, Tan CH, Seymour RA - An
ized. Correct history taking and clinical evalua- Evidence-Based Update on Nonsteroidal Anti-In-
Valentino’s syndrome
tion are all the more important since symptoms flammatory Drugs, Clin Med Res, 2007, 5(1):19-34
Acute appendicitis due to
duodenal perforation related to certain pathologies hide a condition 6. Blundell S, Campbell A, Patel R, Besarovic S -
situated in a different place than it may seem [2]. Valentino’s Syndrome in An Adolescent Boy with
The recommended medical approach when Peptic Ulcer Perforation Simulating Acute Appen-
Progressive (mild in the initial phase, reaching a diagnosis seems impossible is explor- dicitis, Journal of Pediatric Surgical Specialties,
Epigastric pain subsequently increasing in intensity, Sudden, sharp
accompanied by nausea and anorexia) atory laparoscopy. An appendix without signs of 2015, 9(4):40-42.
inflammation or perforation but surrounded by 7. Hussain K, Munir A, Wahla MS, Masood J -
turbid content implies an upper gastrointestinal Valentino's Syndrome: Perforated Peptic Ulcer
Right lower quadrant pain source [3]. Mimicking Acute Appendicitis Managed Through
Present Present
and Bloomberg’s sign
Rutherford Morrison Incision, J Coll Physicians
Conclusion Surg Pak, 2016, 26(8):727-728
Abdominal guarding Localized General Valentino’s syndrome embodies a rare form 8. Amann CJ, Austin A, Rudinsky SL - Valentino’s
of duodenal ulcer perforation. Despite being an syndrome: A Life- Threatening Mimic of Acute
± If present, it suggests more exceptionally rare case, the clinical presentation Appendicitis, 2016, Clinical Practice and Cases in
Abdominal distention Absent
than uncomplicated appendicitis
of Valentino’s syndrome may require stre­nuo­us Emergency Medicine, 2017, 1(1)
effort in reaching diagnosis. Clinical expres- 9. Chung KT, Shelat VG - Perforated peptic ul-
Usually present (duodenal ul-
History of chronic illness Absent sions that can be of help to diagnosis would be: cer - an update, World J Gastrointest Surg, 2017,
cer and the usage of NSAIDs)
sudden onset abdominal pain, tachycardia, abdom- 9(1):1-121
Collection of fluids in the
inal rigidity. 10. Søreide K, Thorsen K, Harrison EM, Bingener
Thickness of appendix, cecal and right lower quadrant. It may Also, these strengthen the necessity of recog- J, Møller MH, Ohene-Yeboah M, et al. - Perforated
Abdominal ultrasound nizing signs of peritoneal irritation and symp- peptic ulcer, Lancet, 2015, 386(10000):1288-1298
ileal wall come from the perforation of
an appendix or an ulcer toms of systemic inflammatory response syn- 11. Di Saverio S, Bassi M, Smerieri N, Masetti M,
drome from the onset. Ferrara F, Fabbri C, et al. - Diagnosis and treatment
Thoracic and abdominal Given that neglecting the perforation of an of perforated or bleeding peptic ulcers: 2013 WSES
- Pneumoperitoneum ulcer can lead to ruthless consequences for a pa- position paper, World J Emerg Surg, 2014, 9:45
radiography
tient’s health evolution, Valentino’s syndrome 12. Rogers FA - Elevated serum amylase: a review
Collection in RLQ ± in the should always be born in mind when approach- and an analysis of findings in 1,000 cases of perfo-
CT Thickness of appendix rest of the abdomen, pneumo- ing a case of atypical appendicitis. In all cases of rated peptic ulcer, Ann Surg, 1961, 153(2):228-240
peritoneum doubt, exploratory laparoscopy is considered the 13. Rogers FA - Serum amylase in peptic gastro-
gold standard. duodenal perforation. A study to determine the
Localized peritonitis in the significance of abnormally high levels, Calif Med,
supramesocolic compartment, 1960, 93(1):6-10
Laparoscopy Inflammation of the appendix
perforation and free fluid References 14. Ahmad R, Mohamad N, Latiff AKA, Ahmad
around the area
1. Durai R, Hoque H, Ng P - The Acute Abdomen Z, Idrus II - Pneumoperitoneum following blunt
- Commonly Missed And Mis-diagnosed Condi- abdominal injury: Does it warrant laparotomy? Int
tions: Review, Webmed Central Surgery, 2010, J Case Rep Imag, 2011, 2(12):23-27
Discussion to pain that is felt in the RLQ. In the onset, vis- 1(10):WMC001036 15. Chou PC, Su YJ - Falciform Ligament Sign,
First brought to the public’s attention after the ceral pain plays a great part in delaying diagnosis 2. Sultan R, Pal KM - Valentino appendix: A report N Engl J Med, 2017, 377:e28
famous actor Rudolph Valentino died from com- as it refers only to poorly localized pain perceived of 3 cases, J Pak Med Assoc, 2015, 65(2):223-224 16. Lakshmi AY, Lakshmi BV, Sarala S, Muttes-
plications that his initial health condition led to around the umbilicus. When it spreads to the 3. Bertleff MJ, Lange JF - Perforated peptic ul- waraiah B - The veiled right kidney sign, Indian J
in 1926, Valentino’s syndrome remains one of peritoneum, pain becomes intense and easy to lo- cer disease: a review of history and treatment, Dig Nephrol, 2008, 18(3):134
the medical concerns questioned when assessing calize. It is important to note that the migration Surg, 2010, 27(3):161-169 17. Wang HP, Su WC - Veiled Right Kidney Sign
a case of pain in the right iliac fossa [8]. of pain is a specific feature of appendicitis [2]. 4. Rajindrajith S, Devanarayana NM, de Silva HJ in a Patient with Valentino's Syndrome, N Engl J
As noted above, the evolution of a peptic ulcer Contrary to the pain felt in appendicitis, the - Helicobacter Pylori Infection in Children, Saudi J Med, 2006, 354:e9
may sometimes be mistaken for appendicitis, due pain caused by perforation of an ulcer is somatic Gastroenterol, 2009, 15(2):86–94

26 27
18. Yu J, Fulcher AS, Turner MA, Halvorsen RA -
Helical CT Evaluation of Acute Right Lower Qua-
drant Pain: Part I, Common Mimics of Appendici-
tis, Am J Roentgenol, 2005, 184(4):1136-1142
19. Abbas AMK - Surgical and Clinical Review
of Acute Appendicitis, Int J Multidiscip Curr Res,
2016, 4:280-287
20. Mostbeck G, Adam EJ, Nielsen MB, Claudon
M, Clevert D, Nicolau C, et al. - How to diagnose
acute appendicitis: ultrasound first, Insights Ima-
ging, 2016, 7(2):255-263
21. Wijegoonewardene SI, Stein J, Cooke D, Tien
A - Valentino's syndrome a perforated peptic ul-
cer mimicking acute appendicitis, BMJ Case Rep,
2012, 2012: bcr0320126015
22. González Chávez AM, García Vázquez AA,
Gómez López JM, Pavón NL, Lemus Gómez JL,
Álvarez Hernández DA, et al. - Valentino’s syn-
drome: the simulation of an appendicitis, Int Surg
Journal, 2017, 4(5):1813-1817
Clinical aspects of scleroderma
Ioana Roșca
Student, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca
Abstract. Scleroderma is a rare autoimmune connective tissue disorder, characterized by skin indu-
ration and heterogeneous clinical manifestations, with a chronic and progressive course. There are two
major groups of scleroderma: localized scleroderma and systemic sclerosis (SSc). Localized scleroderma
is limited to the skin, while systemic sclerosis affects both the skin and internal organs, with significant
disability. SSc can affect any organ; however, the digestive system, the lungs, and the blood vessels are
the most commonly involved. Skin changes are different in these two types of disease. In localized
scleroderma, skin involvement is represented by unique or multiple plaques or nodules with different
sizes and shapes, while in SSc, skin changes are present starting distally from the fingers and advancing
proximally to the limbs, trunk, and face. This paper aims to review the semiology of a rare connective
tissue disorder, underlining the fact that clinical aspects of the disease can lead to a positive diagnosis.
Keywords: scleroderma, systemic sclerosis, morphea, skin induration, Raynaud’s phenomenon,
scleroderma renal crisis.

Introduction ment is late and tends to show an insidious pro-

Scleroderma can be defined as “hard skin”
and it is an autoimmune connective tissue dis-
ease. It is characterized by excessive collagen
production and deposition in the skin and inter-
nal organs, associated with antibody production
and vasculopathy [1]. Scleroderma is more likely
to affect women than men, and it has a higher
occurrence in black rather than white patients
[2, 3]. It is classified into two major groups: lo-
calized scleroderma (morphea) and systemic scle-
rosis (SSc). The systemic form can be divided
into limited cutaneous systemic sclerosis (lcSSc)
and diffuse cutaneous systemic sclerosis (dc-
SSc), defined by the pattern of skin involvement
[4]. Limited cutaneous SSc is characterized by
Raynaud’s phenomenon, which precedes the
other manifestations of SSc by years, and skin
thickening is limited to the fingers, limbs, and
face. In these patients, visceral organ involve-
gression. The limited form was often termed
CREST syndrome (calcinosis, Raynaud’s phe-
nomenon, esophageal dysmotility, sclerodactyly,
telangiectasia) [5,6], but these manifestations
can also be present in the diffuse form, so the
term CREST syndrome is no longer used when
just referring to lcSSc. Diffuse cutaneous SSc is
associated with rapid extensive skin induration,
starting distally, from the fingers, extremities,
and ascending proximally to the limbs, trunk,
and face. Sometimes, Raynaud’s phenomenon
and other internal organ involvement can occur
in the absence of skin induration, and this syn-
drome is called SSc sine scleroderma. Also, there
are some conditions that can mimic systemic
sclerosis, which are termed scleroderma-like syn-
dromes [1]. The localized form of scleroderma
is characterized by induration of the skin, but
it clinically differs from SSc because internal

28 29
organ involvement is unusual, and skin involve-
ment is represented by firm cutaneous plaques
or nodules, which are often hypo- or hyperpig-
mented and may have an erythematous border,
depending on their stage of evolution [7, 8].
Clinical Assessment
Patients with scleroderma develop important
skin changes, but they can also have some other
manifestations that can be grouped by systems:
▷▷ General manifestations
There are no specific general manifestations for
scleroderma, but the most common symptoms
are represented by fatigue, stiff joints, pain (ar-
thralgia and myalgia), weight loss, loss of ap-
petite, loss of strength, and sleep difficulties [9].
Depressive symptoms and body dissatisfaction
are very important in these patients [10]. Sclero-
derma often involves important pain symptoms,
due to Raynaud’s manifestation, skin break-
down, and gastroesophageal reflux. Many pa-
tients with rheumatic disorders usually com-
plain about sleeping difficulties. In SSc, sleep
disturbances are common and frequently associ-
ated with worsening dyspnea, depressive mood,
and severe gastric reflux symptoms [11]. Some
patients may develop dry eyes or dry mouth (sic-
ca symptoms) if SSc evolves with a secondary
Sjogren’s syndrome. In some cases, SSc can be
associated with thyroid fibrosis, leading to hy-
pothyroidism. Other thyroid disorders that may
be associated with SSc are autoimmune thyroid-
itis, which leads to hypothyroidism, and Graves’
disease, leading to hyperthyroidism [12].
▷▷ Skin involvement
In systemic sclerosis, skin changes can evolve
in 3 stages: edematous, indurative, and atro-
phic [13]. The initial stage is an inflammatory,
edematous one. Edema can cause local tissue
compression. The hands look puffy, sometimes
patients may present carpal tunnel syndrome,
and the fingers may have a sausage-like appear-
ance (sclerodactyly), due to edema. The disease
leads to loss of skin appendages, evolving with
decreased hair growth and loss of sweat and
exocrine glands. The skin is dry with cracking,
30 31
because of a decreased sweat and oil produc-
tion, often associated with alopecia and hypo-
hydrosis. This phase is also accompanied by er-
ythema of the skin, pruritus, paronychia, and
sores over the metacarpophalangeal and inter-
phalangeal joints, which may have slow or poor
healing. Pain is neuropathic, with a “pins and
needles” sensation [14]. In this inflammatory
phase, induration and thickening of the skin
begin to develop [1]. The second stage starts
once the inflammatory phase quiets down, and
it is called the progressive fibrosis stage. Skin
thickening usually begins distally and may or
may not progress proximally, depending on the
form the patient develops. In patients who de-
velop lcSSc, skin involvement is limited to the
face, neck, and distal extremities. In patients
with dcSSc, induration advances proximally
to the chest and abdomen. Some patients with
the dcSSc form may have truncal skin involve-
ment, but no changes in the extremities. Facial
involvement may occur in both dcSSc and lc-
SSc, and the characteristic changes are termed
Mauskopf facies, pathognomonic of scleroderma
[15]. The Mauskopf facies is characterized by
an expressionless face, reduced mobility of eye-
lid, cheek and mouth, with shiny, taut skin and
loss of wrinkles. The lips are thinning, the oral
aperture is reduced (microstomia), and the nose
takes a pinched, beak-like appearance. The
front teeth may appear prominent due to the
retraction of the gums and lips. Neck skin in-
volvement can also occur in both types of SSc,
and it is characterized by vertical striations
of the neck’s skin with neck extension, also
known as Barnett’s sign [16]. The chest or ab-
domen skin can also be affected along pressure
areas, such as the bra line or the belt region,
which is characteristic of dcSSc. Regarding
extremities, skin changes are limited distally
to elbows and knees in lcSSc, while in dcSSc
they may progress proximally. Digital ulcers
are characteristic of systemic sclerosis and they
have an ischemic nature and a painful evolu-
tion [7, 17]. They occur early during the course
of SSc and can be a clinical predictor of dis-
ease evolution because they can be associated
Table I. Skin changes in the limited and diffuse form of systemic scleroderma [1, 5, 15-16, 19]
Skin Limited cutaneous Diffuse cutaneous
involvement systemic sclerosis systemic sclerosis
Distal extremities, face,
Skin induration pattern
Limited to distal extremities,
neck,and proximal progression
face, and neck
to chest and abdomen
Skin induration
Insidious Rapidly
development
Face involvement Mauskopf facies Mauskopf facies
Neck skin involvement Barnett’s sign Barnett’s sign
Induration along pressure
Chest skin involvement None
areas (bra line)
Induration along pressure
Abdomen skin involvement None
areas (belt region)
Hand mobility Limited Limited
with cardiovascular worsening and decreased lcSSc and dcSSc, in patients with lighter skin.
survival [18]. Hand mobility is limited due to The number of these lesions increases with the
skin induration, joint limitations, digital ulcers disease duration, and they usually appear on the
and pain, so the performance of everyday tasks fingers, palms, face, and mucosal membranes [1].
is reduced [19]. Pigmentation changes occur dur- Later, as the disease progresses, they can appear
ing both the edematous and indurative stage and on the arms, chest, and back.
they cause the skin to present a “salt and pepper” Table I. compares the most important skin
appearance. The last stage occurs in the diffuse changes which occur in lcSSc and dcSSc, under-
form of SSc, which is characterized by skin soft- lining the similarities and differences between
ening that can allow the skin to recover its nor- these two forms of systemic sclerosis.
mal clinical appearance, and it usually develops In localized scleroderma (morphea), skin chang-
on the trunk and upper arms. Patients can have es occur as focal cutaneous fibrosis, without sys-
improved joint mobility, and regrowth of hair temic involvement. Morphea can be classified
on the forearms can be observed. In the late into circumscribed, generalized, linear, and
stage of scleroderma, the skin becomes atrophic mixed forms [7]. The clinical features of mor-
and feels thinner, usually on the fingers, hands phea are single or multiple indurated, often
and lower legs. The degree of skin thickness dyspigmented cutaneous plaques that may have
is quantified using the modified Rodnan skin an erythematous border, which represents ac-
score, a validated method used in clinical trials tive inflammation. The inflamed areas tend to
[20]. Other cutaneous changes are represented resolve in time, leaving a sclerotic plaque, as-
by telangiectasias and they can be seen in both sociated with post-inflammatory pigmentary
changes. Circumscribed morphea is also known as
plaque morphea and is the most frequent form of
morphea (65%) [21]. It is characterized by well-
defined indurated plaques that do not meet the
criteria for generalized morphea. Generalized
morphea is characterized by the presence of four
or more plaques, involving at least two different
anatomic sites, lesions that usually begin on the
trunk and spread distally, in contrast with SSc.
Linear morphea (known as linear scleroderma)
is defined by indurated plaques arranged in a
linear distribution, usually on the extremities or
on the face. This type of morphea also involves
deep tissues, subcutaneous tissue, muscle, even
bones, and can lead to significant deformities.
A particular form of linear morphea is the mor-
phea “en coup de sabre” that affects only the head
and neck, and lesions are represented by atro-
phic, hyperpigmented plaques, resembling the
cut of a sword [7]. Some patients can develop a
rare form of morphea, termed pansclerotic mor-
phea, mimicking cutaneous fibrosis of SSc. They
have a skin induration pattern that involves the
upper “V” of the chest and the trunk, sparing
the axillary area, a unique sign of this condition,
called “the tank top sign” [22].
Calcinosis cutis is caused by calcific depos-
its in the skin and soft tissues [23] and it is often
associated with pain, local inflammation, and
functional impairment. This condition is un-
common for localized scleroderma, while in SSc
it often occurs in patients with the lcSSc sub-
type, who are ACA (anticentromere antibody)
positive. The deposits present as subcutaneous
nodules, with different sizes or shapes, usually
at sites of recurrent microtrauma. The most fre-
quent body involvements in patients with SSc
are the hands, especially the fingers, and feet;
however, the elbows, knees, legs, trunk, and
face can also be affected [24]. Complications of
calcinosis are usually the ulcerations at the le-
sion site, pain, infection and nerve compression.
Ulcerations may occasionally occur through
the overlying skin, by drainage of chalky white
fluid, producing local inflammation and pain.
Pain occurs due to calcific deposits over pressure
areas and associated inflammation or infection.
32 33
Paraspinal soft tissue deposits can produce neu-
rological complications [5].
▷▷ Raynaud’s phenomenon
Raynaud’s phenomenon is characterized by a
triphasic color change (pallor, cyanosis, and hy-
peremia), due to an exaggerated vasospastic re-
sponse to cold temperature or emotions. In the
first phase, the digits turn white, due to ischemia
(arterial vasospasm), then blue, from deoxygen-
ation, and then they turn red, due to reperfusion,
after the regular blood flow is restored [25]. Ray­
naud’s phenomenon is uncommon in patients
with localized scleroderma, but it can be very
severe in patients with SSc. In the lcSSc form,
Raynaud’s phenomenon can precede other mani-
festations of the disease by years, while in the dc-
SSc form, it may appear at the same time with
skin lesions and it may progress with irreversible
tissue injuries, due to ischemia. The most impor-
tant ischemic complications are critical ischemia
and digital ulcers. They both may be very pain-
ful and can result in digit loss, with a negative
impact on quality of life [26]. Digital ulcers are
common in patients with SSc, especially in those
with the lcSSc form, and they can often be seen
in the early phase of the disease course [27]. They
tend to occur in fingerprints in patients with lc-
SSc, and over the extensor surfaces in patients
with dcSSc [8], and they can be very difficult to
heal, due to the poor blood supply.
▷▷ Gastrointestinal involvement
Gastrointestinal manifestations are the most
common internal organ involvement in pa-
tients with SSc, especially those with the dc-
SSc form, and they can be a major cause of
morbidity [28]. At the time of SSc diagnosis,
many patients describe symptoms of dysphagia.
Regarding the oropharyngeal segment, SSc
patients present microstomia, oral ulcers, gin-
gival retraction, and a fibrous tongue [29]. Sic-
ca symptoms may occur in case of overlap syn-
drome, when SSc is associated with Sjogren’s
syndrome. These patients develop defective
salivation [30], which can lead to dysphagia.
The esophagus may be affected by dysmotility (ILD) and pulmonary arterial hypertension
and gastric reflux, therefore many patients re- (PAH), with a poor survival if these two con-
port heartburns. Later, Barret’s metaplasia may ditions manifest simultaneously [36, 37]. Other
occur, due to chronic reflux [31], which may lung manifestations, but less common in SSc,
lead to esophageal adenocarcinoma. Regard- include aspiration pneumonia, pleural disease,
ing the stomach, the most common manifesta- endobronchial telangiectasia, malignancy, and
tions are delayed emptying and post-prandial obstructive airways disease [1].
bloating, but the most important complication ILD begins at the base of the lungs, can be pres-
is represented by gastric antral vascular ectasia ent in both dcSSc and lcSSc, but tends to be
(GAVE), usually termed “watermelon stomach” more common and severe in patients who devel-
[32]. The endoscopic appearance of this condi- op dcSSc. Firstly, ILD is usually asymptomatic
tion is characterized by multiple longitudinal and, as the disease progresses, fatigue, dyspnea,
stripes of blood vessels, which radiate from the and dry cough may appear. Chest pain and he-
pylorus to the antrum, having the aspect of a moptysis are rare [38]. On physical exam, the
watermelon. These blood vessels can bleed out, most characteristic finding of ILD is bilateral
which may lead to important anemia. fine inspiratory crackles, at the base of the lungs,
The small bowel may also be affected by hypo- termed “Velcro rales” [39]. These rales occur
motility, which can result in episodes of ady- when pulmonary fibrosis has developed.
namic ileus (pseudo-obstruction). The classical SSc-associated PAH is defined as a mean pul-
symptoms of these bowel changes are abdominal monary artery pressure equal to 25 mmHg or
distension and frequent, floating, foul-smelling more, with a pulmonary capillary wedge pres-
stools [33]. The slow intestinal transit may lead to sure equal or lower than 15 mmHg, in a SSc
intestinal bacterial overgrowth [34], and patients patient without coexisting ILD [40]. The prev-
may develop diarrhea, bloating and malabsorp- alence of PAH is similar in both dcSSc and
tion. Malnutrition is another common condi- lcSSc forms [41]. PAH may be either primary
tion in patients with SSc, due to malabsorption or secondary to cardiac disease or ILD [1]. Pri-
or poor nutritional intake, but also to pancre- mary PAH often occurs in patients with lcSSc,
atic enzymes, which can damage the intestinal usually years after the onset of Raynaud's phe-
mucosa, because of mucosal enzyme deficiency. nomenon. The most common symptoms are fa-
Lower gastrointestinal complications of SSc are tigue and dyspnea, while chest pain, lighthead-
frequent, can occur early, and they are represent- edness, syncope, and signs of right-sided heart
ed by atonia or hypotonia of the sigmoid colon failure may occur later in the course of PAH.
or rectum, which can lead to severe constipation. Physical examination may include tachypnea,
Anorectal incontinence is a very common prob- accentuated second heart sound, due to the P2
lem for SSc patients and it is frequently associ- component, elevated jugular venous pressure,
ated with rectal prolapse [8]. and edema [5].
The liver is rarely affected; however, primary
biliary cirrhosis may be associated with SSc, ▷▷ Cardiac involvement
especially the lcSSc form [35]. These patientsCardiac involvement is usually clinically silent;
show intense pruritus and excoriations on the however, if clinical cardiac manifestations are
skin may be observed, due to scratching. present, it can indicate a poor prognosis [48].
Cardiopathy can be primary or secondary to
▷▷ Pulmonary involvement ILD, PAH or severe renal disease. All cardiac
Pulmonary involvement is a very important structures can be affected, causing myocardial
cause of death in patients with SSc. The two abnormalities, pericardial disease, coronary
main pulmonary disorders that occur in pa- ischemia, and conduction abnormalities; how-
tients with SSc are interstitial lung disease ever, valvular involvement is less common [49].
Myocardial involvement in patients with SSc
usually combines myocardial ischemia and fibro-
sis. Myocardial ischemia is caused by a coronary
microcirculation abnormality, characterized by
vasospasm that leads to recurrent ischemia and
reperfusion injury [50]. Microvascular myocar-
dial abnormality can also lead to angina pectoris
or even acute myocardial infarction [51]. Repeat-
ed ischemia-reperfusion conditions may lead to
irreversible myocardial fibrosis. Fibrotic lesions
are distributed in both ventricles; however, the
left ventricle appears to be more affected in SSc,
and diastolic dysfunction is more frequent than
systolic dysfunction [52, 53]. Furthermore, the
degree of myocardial fibrosis is increased in
patients with a long history of Raynaud’s phe-
nomenon [54]. The symptoms and signs in SSc
patients that may suggest possible myocardial
involvement are shortness of breath, chest pain,
frequent arrhythmias or palpitations, and heart
failure symptoms [8]. Heart failure may be sys-
tolic, with reduced ejection fraction, or diastolic,
with preserved ejection fraction. The symptoms
of systolic heart failure and diastolic heart fail-
ure are similar [55]. They include dyspnea, fa-
tigue, pulmonary rales, jugular venous pressure,
and lower extremity edema [56].
Pericardial disease may include pericardial inflam-
mation, fibrous pericarditis, fibrinous pericarditis,
pericardial effusion, pericardial adhe­si­ons, con-
strictive pericarditis, and cardiac tam­po­nade [49].
Pericardial disease is rarely symptomatic; however,
if the disease is significant, it can cause important
morbidity in patients with SSc. The symptoms of
pericardial effusion include dyspnea on exertion,
which may progress to orthopnea, chest pain, and
fullness. Sometimes, due to local compression,
nausea (compression on the diaphragm), dyspha-
gia (esophageal compression), hiccups (phrenic
nerve), and hoarseness (recurrent laryngeal nerve)
may appear [57]. Physical examination may be
normal; however, if tamponade develops, clinical
signs are very important. Cardiac tamponade is
a condition that may endanger the patient’s life.
Clinical signs include arterial hypotension, tachy-
cardia, pulsus paradoxus, raised jugular venous
34 35
pressure, diminished heart sounds, and pericar-
dial friction rubs [57, 58].
Conduction disease is rare in patients with SSc
[59]. The conduction system may be affected
by fibrosis and the most common involvement
is sinoatrial node fibrosis [60]. Conduction
abnormalities are frequently asymptomatic.
Symptoms and signs may include fatigue, pal-
pitations, dizziness, syncope, or even sudden
death. In contrast with conduction disease,
ventricular and supraventricular arrhythmias
are common in patients with SSc [60].
▷▷ Musculoskeletal involvement
Musculoskeletal symptoms are common in
patients with SSc, frequently associated with the
dcSSc form [61]. Usually, the first symptoms ex-
perienced by SSc patients are arthralgia and my-
algia. The most affected joints are the metacar-
pophalangeal, proximal interphalangeal, wrist
and ankle joints [1]. Patients who present the
overlap syndrome, when SSc is associated with
rheumatoid arthritis, who also have Raynaud’s
phenomenon or the anti-cyclic citrullinated pep-
tide antibody, may develop erosive, destructive
joint disease. The prevalence of this condition is
estimated between 5-10% in the first 5 years of
SSc [62]. Many SSc patients develop proximal
limb muscle weakness, while distal weakness can
be difficult to distinguish from the limitation of
movement, due to indurated skin [8]. Patients
with limited scleroderma also develop myopathy,
typically in the same region as the skin involve-
ment [63]. Tendonitis may also occur in SSc
patients, and this is described by the term “ten-
don friction rubs” [64]. These patients frequently
complain about pain in the area concerned, or
even “rubbing” when the joint moves. This con-
dition appears due to inflammatory fibrinous
deposits on the tendon’s surface or around the
tendon. The tendons that are typically involved
are the triceps, extensors and flexors of the wrist,
extensors and flexors of the ankle, and patellar
tendons. Bone can be affected in SSc, and this
condition is characterized by resorption of the
terminal phalangeal tuft (acro-osteolysis) [65].
Thus, it is frequently associated with acral softfacial, glossopharyngeal, and auditory nerves
tissue thinning or pulp atrophy. can also be affected [68]. Vasomotor integrity is
controlled by the sympathetic and parasympa-
▷▷ Renal involvement thetic nervous system, therefore ANS dysfunc-
Renal involvement is common in SSc patients tion involves microcirculation and may lead to
and the most important manifestation is the endothelial damage. Furthermore, other sev-
scleroderma renal crisis (SRC). It occurs in eral clinical features of SSc may be seen in pa-
12% of patients with dcSSc and up to 2% of tients with ANS dysfunction. They include di-
lcSSc patients [42]. SRC is a microangiopathy minished peristalsis of the esophagus, reduced
[43] that may associate anemia, thrombocy- lower esophageal sphincter pressure, delayed
topenia, and acute kidney injury (AKI), with gastric emptying, abnormal colonic peristalsis,
proteinuria. Patients present new-onset hy- anal rectal sphincter incontinence, and impo-
pertension, which can lead to severe headache, tence [8, 69].
blurred vision, and encephalopathy [44]. Fever,
seizures, and general malaise may also be asso- Clinical practice
ciated. Congestive heart failure is common in 2013, a joint EULAR (European League
patients with SRC and is described by dyspnea, Against Rheumatism) and ACR (American Col-
paroxysmal nocturnal dyspnea, or even pulmo- lege of Rheumatology) committee published the
nary edema. Ventricular arrhythmias and im- revised classification criteria for systemic sclerosis
portant pericardial effusions may be observed [70]. Patients with a total score of 9 can be classi-
[45]. About 10% of the patients may present fied as having definite systemic scleroderma. Skin
with normal blood pressure. This phenomenon fibrosis, internal organ involvement, evidence of
is called normotensive renal crisis [46] and is vasculopathy, and production of autoantibodies
associated with a particularly poor outcome represent the hallmark features of systemic scle-
[47]. Other renal processes in patients with SSc rosis, and all of them are included in score cal-
include interstitial nephritis, glomerulonephri- culation. Skin thickening of the fingers of both
tis, and renal vasculitis, conditions that may hands extending to the metacarpophalangeal
lead to renal failure [8]. joints is a sufficient criterion (9 points) to clas-
sify a patient as having SSc. Other skin involve-
▷▷ Neurologic involvement ments included in score calculation are puffy fin-
Neurologic involvement can be associated with gers (2 points), sclerodactyly of the fingers distal
both systemic sclerosis and localized scleroder- to the metacarpophalangeal joints (4 points),
ma, mainly localized scleroderma “en coup de digital tip ulcers (2 points), and fingertip pitting
sabre” (LScs) [66]. In LScs, the most frequent scars (3 points). The vascular disorders included
neurological manifestation is epilepsy [67]. in score calculation are telangiectasia (2 points),
Neurological symptoms and signs that may be abnormal nailfold capillaries (2 points), PAH (2
observed in LScs include diplopia, hemianop- points), ILD (2 points), Raynaud’s phenomenon
sia, headache, aphasia, hemiparesis, or pyrami- (3 points). SSc-related autoantibodies are scored
dal signs, cognitive impairment, and dizziness 3 points. Thus, the patient’s history and physi-
[66]. SSc may affect the central nervous system cal exam may be sufficient for the physician to
(CNS), the peripheral nervous system (PNS), diagnose a patient with SSc.
and the autonomic nervous system (ANS). The
most common manifestations are depression, Conclusions
anxiety, headaches, stroke, cognitive impair- Scleroderma is a rare autoimmune connective
ments, and seizures [66]. The most commonly tissue disease with a chronic, progressive course.
involved cranial nerve is the trigeminal nerve, It is characterized by collagen deposition in the
but the optic, oculomotor, trochlear, abducens, skin and internal organs and antibody produc-
tion. Like any other autoimmune disease, sclero-
derma is more encountered in women than men.
Localized scleroderma usually involves the skin
only. Systemic sclerosis affects the skin and it
can involve the internal organs and blood vessels.
Every organ can be affected by the disease. The
gastrointestinal and pulmonary systems are the
most affected by SSc; moreover, renal and car-
diovascular involvement can be life-threatening.
The clinical aspects of scleroderma are the most
significant for diagnosing the disease, according
to EULAR/ACR revised classification criteria.
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 Table I. Bacteria triggering ReA and the clinical findings they cause at the entry site Modified after [12, 13]

Reactive arthritis Entry site Infection Pathogen

Chlamydia trachomatis
Urethritis, cystitis, cervicitis,
Noémi Mosonyi Urogenital tract prostatitis, epidymitis, salpingitis,
Ureaplasma urealyticum
Mycoplasma hominis
Student, University of Medicine and Pharmacy "Iuliu Hațieganu", Cluj-Napoca endometritis

Yersinia enterocolitica
Diarrhea, gastroenteritis, Salmonella spp
Gastrointestinal tract
enterocolitis Shigella flexneri
Campylobacter jejuni
Abstract. Reactive arthritis occurs following a gastrointestinal or genitourinary infection. Incidence
varies between 0.6-30/100,000, frequently involving men aged between 20-40 years old with a history Sinusitis, bronchitis, pneumonia, Chlamydia pneumoniae
of genitourinary Chlamydia trachomatis infection. The most important symptom is arthritis of the lower Airways
tonsillitis Group A Streptococcus
limbs affecting the large joints, such as the knee or ankle. Viable microbes in the joint cavity have not yet
been found; only bacterial genetic material suggests their presence and metabolic activity. Other mani- Lyme disease Borrelia burgdorferi
festations include conjunctivitis, urethritis and mucocutaneous lesions similar to psoriasis. The triad of Other Skin, connective tissue infections Staphylococcus spp
arthritis, urethritis and conjunctivitis is known as Reiter’s syndrome. Most of the cases are self-limited,
but the chronic form also exists. Currently there are no validated diagnostic criteria, diagnosis relying
mainly on clinical findings and evidence of the initiating infection, along with exclusion of other diag-
noses through the workup. Differential diagnosis includes septic arthritis, rheumatoid arthritis, psoriatic Epidemiology of the lower limbs. The most frequently encoun-
arthritis, Crohn’s disease and disseminated gonococcal infection. First-line treatment is represented by Two main types of infections can trigger ReA: tered is the knee, followed by the ankle and the
non-steroidal anti-inflammatory drugs. Intra-articular glucocorticoids can reduce inflammation if one or gastrointestinal and genitourinary. Table I. de- metatarsophalangeal joint. Patients complain
few joints are affected. scribes the most common causative pathogens. about localized pain, swelling, tenderness, heat,
Keywords: reactive arthritis, Reiter’s syndrome, conjunctivitis, urethritis, Chlamydia trachomatis, From all these, Chlamydia trachomatis is the most with or without redness, and walking difficulties
mucocutaneous lesion frequent pathogen observed to trigger ReA [9-11]. [17, 18, 21]. In 30% of cases, after a prolonged
Population-based studies assess the annual course of the disease, patients develop inflamma-
incidence of ReA between 0.6-27/100,000 [13], tory low back pain, a symptom of possible sacroi-
so it can be considered a rare disease. Milder liitis that can further progress to ankylosing spon-
Introduction ing keratoderma blennorrhagica and circinate cases frequently go unreported, leading to un- dylitis (AS) [17, 22]. Enthesis is mainly present in
Reactive arthritis (ReA) is defined as a spon- balanitis are frequent [5, 6]. derdiagnosis of ReA [14, 15]. the plantar aponeurosis and Achilles tendon and
dyloarthropathy that consists of aseptic inflam- The clinical triad of arthritis, conjunctivitis A typical ReA patient is a 20-40 years old may cause limping [23]. The so-called “sausage
matory arthritis usually following an enteric or and non-gonococcal urethritis is known as Re- male, with a history of recent genitourinary in- digit” or dactylitis is swelling of the whole toe or
genitourinary microbial infection [1,2]. Spon- iter’s syndrome, but since the triad is not found fection. Regarding gastrointestinal infections, finger, with moderate pain and tenderness [23].
dyloarthropathies involve inflammatory arthri- in every patient and because of Reiter’s part in the male:female ratio is equal [11, 16, 17]. Conjunctivitis is found in 50% of patients
tis, enthesis (inflammation at the site where Nazi medical experimentation, the term Re- The correlation with HLA-B27 is still in de- with genitourinary infection and 75% of pa-
ligaments, tendons and joint capsules insert iter’s syndrome should be avoided and reactive bate. Supposedly, reported high HLA-B27 fre- tients with gastrointestinal infection, being the
into the bone), absence of the rheumatoid factor arthritis should be used instead [7, 8]. quencies are a result of including complex hos- most frequent extra-articular manifestation
referred to as seronegativity, and a strong cor- Due to the lack of validated diagnostic crite- pital based cases [2, 18, 19]. In contrast, around and also part of the classic triad [10, 21, 22].
relation with HLA-B27 [3]. ria for ReA [2], the definition is still evolving; 75% of HLA-B27 positive and human immu- Preceding arthritis, it is mild and appears in-
Initially, only antigens of the infectious agent thus, history taking and clinical exam play an nodeficiency virus-infected patients will develop termittently on both sides, patients experienc-
could be identified in the joint cavity; later on, ge- important role in the diagnostic process. Being ReA [20]. ing pain, irritation, redness, blurry vision, ster-
netic material of Chlamydia species was isolated, subjected to the physician’s personal opinion, ile ocular discharge for up to 4 weeks [17, 22].
suggesting its viability and metabolic activity [4]. the cases include a wide spectrum of symptoms Clinical presentation Mucocutaneous lesions appear either before
A series of extra-articular manifestations such and clinical signs. The main symptom is oligoarthritis with acute or after arthritis and are similar to psoriasis
as conjunctivitis, urethritis, skin changes includ- and asymmetrical onset, affecting the large joints macroscopically and microscopically [5, 17].

40 41
 Keratoderma blennorrhagica consists of hy-
perkeratotic lesions similar to pustular psoria-
sis. Initially clear plantar and palmar vesicles,
they gradually develop to macules and papules
that intertwine into hyperkeratotic plaques.
Nails are also affected, from red swelling to
thickening of the nail plate, similar to psoriatic
onychodystrophy or mycotic infection [5].
Circinate balanitis appears on the glans of
the penis or urethral meatus and is character-
ized by well-defined, painless erythematous
lesions accompanied by small ulcers that grow
centrifugally. It is present in a similar way on
the vaginal mucosa or vulva [5].
Urethritis is linked to sexually acquired in-
fections, but it can also occur after enteric in-
fection. It usually precedes conjunctivitis and
is marked by dysuria, urethral or vaginal dis-
charge and pollakiuria especially in men, but it
is not unusual to go unnoticed [17, 22, 24].
Subclinical acute gastrointestinal inflamma-
tion can also be found. The lesions are asymp-
tomatic, located in the terminal ileum or colon,
and are similar to Crohn’s disease when viewed
by colonoscopy [2, 23].
Diagnosis
Given the lack of validated diagnostic cri-
teria, the clinical exam plays a crucial role.
While the triggering infection is frequently
asymptomatic and the classical triad seldom
appears, it can be challenging to make an ac-
curate diagnosis.
Three objectives should be achieved during
workup [2, 12]: finding a typical or at least fit-
ting clinical picture, evidence of initiating in-
fection, and excluding other diagnoses.
Preliminary diagnostic criteria for ReA
were proposed during the Fourth International
Workshop on ReA, differentiating between a
definite and probable diagnosis, but since their
announcement no consensus has been reached
by the scientific community [2].
After the clinical exam and a presumptive
diagnosis, laboratory studies can be performed:
blood tests reveal inflammation, with elevat-
ed acute-phase reactants, such as erythrocyte
42 43
sedimentation rate (ESR), C-reactive protein
(CRP) and mild leukocytosis. The rheumatoid
factor (RF) and antinuclear antibodies (ANA)
are negative. Urinalysis shows pyuria and the
presence of red blood cells (RBC), white blood
cells (WBC), and proteins in small amounts.
In order to identify the involved pathogen, after
detailed history taking, cultures from urethral
exudate or stool samples should be performed
and the most frequent bacteria, mentioned in
Table 1, searched for [20].
Radiography can assess arthritis, revealing
periarticular osteoporosis, erosions, joint space
loss and soft tissue swelling [25].
Arthrocentesis and fluid sample analysis
should always be performed when dealing with
an inflamed joint, excluding most importantly
septic arthritis, an orthopedic emergency.
Differential diagnosis
ReA should always be considered for lower
extremity arthritis but only diagnosed for sure
if all other possible causes are ruled out.
The most important differential diagnosis is
septic arthritis. Elevated WBC count (10,000-
40,000/µL) and positive fluid culture sustain
the diagnosis [17, 20, 23].
Rheumatoid arthritis (RA) can resemble
dactylitis, but instead of joint swelling, the
whole fingers are swollen. Serologic testing
(positive RF and ANA) supports rheumatoid
arthritis [17].
Psoriatic arthritis presents in a similar way
to ReA due to the skin and mucosal lesions al-
ready discussed. Small joint involvement in a
symmetric manner and a younger age of onset
is more characteristic of psoriatic arthritis [5].
Conjunctivitis and arthritis occur together in
a number of inflammatory diseases such as RA,
psoriasis, Sjögren sindrome or Still’s disease.
Inflammatory bowel diseases such as Crohn’s
disease are accompanied, along with diarrhea,
by asymmetric arthritis of the lower limbs.
Medical history and gastrointestinal symptoms
should guide the diagnosis. In viral gastritis,
arthritis is non-specific and self-limited, its
etiology being suggested by fever and myalgias.
Disseminated gonococcal infection is trig-
gered by a sexually transmitted infection and
systemic spreading of Neisseria gonorrhoea. It
causes asymmetric polyarthralgia of small or
large joints in young patients after a symptom-
atic sexually transmitted infection. Urethral
exudate cultures rule out this diagnosis [20].
Course of ReA
Hypercalcemia has multiple causes and it is
often suspected when alterations in renal func-
tion, cardiac function and metabolic disorders
occur. However, hypercalcemia deserves to be
taken into consideration in patients with less
specific clinical manifestations linked to the
gastrointestinal function and nervous system.
Treatment
Although the course of ReA is usually self-
limited, management is aimed at reducing pain
and inflammation and at preventing relapses or
progression to chronicity. The indication of drugs
depends on the duration and extent of symptoms.
Alongside medication, physiotherapy seems to be
beneficial for a faster recovery [27].
First-line therapy for arthritis and enthesis
consists of non-steroidal anti-inflammatory
drugs (NSAIDs), in association with pure
analgesics if needed. The lowest dose for the
shortest time period should be administered.
Further, intra-articular administration of cor-
ticosteroids is suggested if one or few joints are
affected. In case of multi-articular involvement
or resistance to NSAIDs, systemic corticoste-
roids should be chosen [6, 12, 27]. These seem
to also improve the extra-articular features.
Conclusions
ReA is a post-infectious disease that is not a
serious life-threatening condition, patients re-
covering on their own fully or with some mo-
tor deficiencies in two thirds of cases. There is
a need to establish exact diagnostic criteria in
order to assess the true incidence and to bet-
ter identify the eligible cases for early treat-
ment initiation. Today, despite a challenging
diagnostic process, managing the symptoms
is more important than a precise diagnosis;
prompt initiation of treatment can prevent the
chronic form and further development to an-
kylosing spondylitis, thus improving the pa-
tients’ daily living and quality of life.
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Prader-Willi syndrome
Protopopu Patriciu
Student, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca
Abstract. Prader-Willi syndrome is a rare genetic disease affecting 1 in 25,000 people worldwide.
These patients suffer from hypotonia and feeding difficulties during early childhood, motor and language
developmental delays, low IQ with a degree of mental disability, metabolic issues such as obesity and type
2 diabetes caused by excessive food consumption, short stature due to low growth hormone levels, hy-
pogonadism and personality/behavioral problems such as temper tantrums, stubbornness and obsessive-
compulsive behavior. In this article we look at the main features of the disease, diagnostic criteria and at
how different management and treatment options can be used to improve the outcome and the quality of
life for PWS patients.
Keywords: Prader-Willi syndrome, hyperphagia, hypotonia, growth hormone deficiency, hypogonadism,
obesity, developmental delay, DNA methylation analysis.
Introduction Clincal manifestations
Prader-Willi Syndrome (PWS), also known ▷▷ Prenatal
as Prader-Willi-Labhart syndrome, is a genetic Prenatal hypotonia, manifesting as decreased
disorder characterized by the lack of expression fetal movement, is a constant feature and can
of the paternally inherited imprinted genes on lead to an abnormal fetal position at delivery,
chromosome 15q11-q13. This can be caused which increases the incidence of assisted delivery
by a paternal deletion, a uniparental maternal and might require cesarean section. While fetal
disomy or by a faulty imprinting mechanism. size is within the normal range, birth weight and
The main characteristics of the syndrome are the body mass index are on average 15% lower
the presence of neonatal hypotonia, early onset than in healthy newborns [2].
of hyperphagia which leads to the development ▷▷ Newborn and infant
of morbid obesity and type II diabetes, cogni- This phase is characterized by severe hypo-
tive and developmental delays, behavioral and tonia, so profound that it can lead to asphyxia,
psychiatric problems, and multiple endocrine at which point PWS needs to be differentiated
manifestations such as growth hormone defi- from severe neonatal hypotonia [3]. Affected
ciency, hypogonadism, hypothyroidism. The infants often have feeding difficulties, includ-
global prevalence of PWS is approximately 1 ing poor suck, weak cry and genital hypoplasia
in 15,000 to 25,000 live births [1], and both (e.g., cryptorchidism, scrotal hypoplasia, or cli-
sexes are affected equally. The majority of cases toral hypoplasia). Depigmentation of the skin or
are sporadic. The recurrence risk for siblings is eyes may also be present. Another differential
up to 25 percent. diagnosis that should be considered is Temple
syndrome (TS), also characterized by hypotonia,
developmental delay and excessive weight gain
later in life. One study, consisting of 143 patients
suspected of PWS who were also tested for
Temple syndrome, found 3 patients with PWS
and 3 with TS [4]. While poor feeding and thus
poor weight gain is one of the features of this
stage, studies have documented the presence of
excessive body fat by skin fold measurements [5].
▷▷ Early childhood
Hypotonia persists into early childhood and
the patient has a positive history of poor suck.
Global development is delayed.
▷▷ Late childhood and adolescence
Patients have a positive history of hypotonia
and of poor suck. Hypotonia may persist. Physi-
cal and cognitive delays are more evident. With-
out proper dietary control, hyperphagia may
cause central obesity.
▷▷ Adulthood
Excessive eating with central obesity can be
seen in this phase, but the appetite may subside
in adulthood. Sexual maturity is not achieved
because of hypothalamic hypogonadism. Pa-
tients show cognitive impairment with mild in-
tellectual disability.
Evaluation of comorbidities
▷▷ Dysmorphism
The facial features of PWS are a narrow bi-
frontal diameter, fair hair, almond shaped pal-
pebral fissures, hypopigmentation of the eyes,
a narrow nasal bridge, thin upper lip and down
turned mouth. Individuals with this syndrome
have small hands, with narrow palms and hy-
poplasia of the hypothenar bulges, and small
feet. Hypopigmentation of the hair and eyes
is more frequent among individuals with dele-
tion-type PWS.
▷▷ Nutrition, hyperphagia and obesity
While in the first stage there is poor feeding
and a delay in development, later in childhood,
around 5-8 years of age, is the onset of hyper-
phagia. This transition is complex and follows
multiple stages (Table I.) [6]
Food seeking behaviors may include eating ▷▷ Growth hormone deficiency
garbage, eating frozen food and stealing resourc-
es to obtain food. Studies show decreased satiety nor­ma­lity of PWS, rather than a consequence
46 47
and increased reward feedback in response to
food [7]. High levels of ghrelin, the “hunger hor-
mone” that regulates satiety and the metabolic
rate, can be observed even before the onset of
hyperphagia. Hyperghrelinemia was more strik-
ing in PWS females than males, which may con-
tribute to hyperphagia and excessive weight gain,
but adiponectin levels were higher in females,
maintaining insulin sensitivity [8]. Decreasing
ghrelin levels with somatostatin analogs does
improve eating habits. The intense food seek-
ing behavior and the decreased lean body mass
index and thus decreased metabolic rate, with-
out external control of dietary input, will lead to
the onset of obesity. This can result in multiple
health problems such as cardiorespiratory failure,
cor pulmonale, sleep apnea and severe infections
[9]. Respiratory failure is the most common
cause of death reported for PWS patients [10].
Patients may develop abnormal glucose metabo-
lism with increased insulin resistance; therefore
early and strict dietary intervention with proper
monitoring of nutrition has shown good results.
▷▷ Type 2 diabetes
In a study aimed at determining the health prob-
lems affecting patients with PWS, type 2 diabe-
tes was present in 25% of the cases and the mean
age of onset was 20 years of age. The mean body
mass index of these patients was 37 kg/m2 [11].
Among children suffering from PWS, type 2
diabetes is not common, but impaired glucose
tolerance can be present [12]. Another study
conducted on an Italian Cohort shows a high
prevalence of abnormal glucose metabolism in
adults and in obese patients (regardless of age),
further emphasizing the importance of early nu-
tritional intervention [13]. The introduction of
hGH replacement therapy can also increase the
risk of developing type 2 diabetes, since it in-
creases glucose levels and negatively impacts in-
sulin sensitivity, and screening is recommended
before and during treatment.
Endocrinopathies
Low growth hormone levels are a primary ab­
Table I. Nutritional phases in PWS [6]
phase Median age Clinical characteristics
Decreased fetal movements and
0 Prenatal - birth
lower birth weight than sibs
Hypotonia with difficulty feeding and
1a 0-9 months
decreased appetite
Improved feeding and appetite;
1b 9-25 months
growing appropriately
Weight increasing without appetite increase or
2a 2.1-4.5 years
excess calories
2b 4.5-8 years Increased appetite and calories, but can feel full
3 8 years - adulthood Hyperphagic, rarely feels full
4 Adulthood Appetite no longer insatiable for some
of obesity. Small stature is first noticed at the be found in the literature, but pregnancies have
age of 2, being further exacerbated by the lack been reported [17]. Hypogonadism is both pe-
of growth spurts during puberty. Low levels of ripheral and hypothalamic in origin, therefore
IGF-1 and low basal and stimulated hGH lev- low testosterone and estrogen levels are associ-
els are present, especially in obese patients [14]. ated with low FSH and LH values.
The average height is 1.62 m for male patients ▷▷ Osteoporosis
and 1.49 for females [15]. Treatment should be- The late onset or the lack of pubertal devel-
gin before the onset of obesity, which is usually opment associated with hypogonadism and low
around the age of 2. Early introduction of hGH levels of growth hormone are a major risk factor
replacement therapy shows positive effects on for the development of osteopenia or osteoporo-
physical and cognitive development. sis. This can lead to multiple bone fractures and
▷▷ Hypogonadism spine deformities. With proper GH replacement
It is a constant feature in PWS patients and therapy, bone development and density remain
manifests as hypogonadism throughout life, ab- stable until the age of puberty, when they start
sent or incomplete pubertal development and to decline in the absence of proper sex hormone
infertility. The scrotum is poorly rugated and secretion [18]. Therefore proper initialization of
hypopigmented, unilateral or bilateral cryptor- sex hormone replacement therapy in hypogo-
chidism can be present. In females, the labia ma- nadal patients, together with GH replacement
jor is hypoplastic, a sign that is often overlooked, therapy is critical in preventing the decline of
and while the onset of puberty is the same as bone density in PWS patients [19].
in the general population, progression is delayed
and menstrual cycles tend to be irregular [16].
Among PWS patients, no case of paternity can
Developmental and cognitive delays in these patients is both central and obstruc-
▷▷ Growth hormone deficiency
Motor developmental delay is present in 90-
100% of children with Prader-Willi syndrome,
with early milestones achieved at double the
normal age (e.g., sitting at 12 months, walking
at 24 months). Language development is also
delayed. By the time the child reaches preschool
age, intellectual disabilities become evident. The
mean IQ of patients with PWS is in the 60s to
70s, with 40% having borderline disability and
around 20% having moderate disability [2]. In
the absence of proper behavioral guidance, aca-
demic achievements can be lesser than predicted
by the IQ score [20].
▷▷ Behavioral and psychiatric disturbances
Behavioral problems are a frequent manifesta-
tion of the disease, with the first symptoms ap-
pearing in early childhood in 70-90% of the cases.
It is characterized by temper tantrums, stub-
bornness, obsessive-compulsive behavior, skin
picking which causes skin lesions, and other self-
mutilating acts. Patients with attention problems
responded well to stimulants, which might be
caused by the presence of ADHD, even if hyper-
activity was not observed in these patients [21].
When studying autism spectrum disorder symp-
toms, there was a marked discrepancy between
direct observational assessment and parental as-
sessment [22], and the variable results were possi-
bly related to sex differences and genetic subtype
composition [23]. Compulsivity and insistence
on sameness in routine or events were seen in
76-100% of children and were highly correlated
with lower adaptive functioning [22]. One study
observed the role of rigid routines in the behav-
ior of PWS patients, showing that during early
primary school years there is a higher response to
lower rigidity in routines, results that could also
be observed later in life. However, the presence
of a balance between low rigidity and high ri-
gidity routines is also recognized, the latter being
beneficial for the patients’ current behavior [24].
▷▷ Sleep abnormalities
Throughout childhood, PWS patients mostly
experience typical sleep patterns and only later
in life does sleep apnea occur [25]. Sleep apnea
48 49
tive, and obesity can worsen the symptoms. One
study reports that the prevalence of OSA among
PWS patients is around 79.91% and that among
children, mild OSA was more frequent [26].
Abnormal circadian rhythms, abnormal arousal
response and excessive daytime sleepiness are
characteristic. The literature suggests that ad-
enotonsillectomy is an effective treatment in 60-
85% of the cases; therefore, alternative strategies
should be considered [27].
Diagnosis
In individuals with typical clinical findings
or with cytogenetic findings, Prader-Willi syn-
drome should be suspected, but diagnosis must
be confirmed by genetic testing [28]. The pres-
ence of all age-specific clinical manifestations is
sufficient to justify DNA methylation analysis.
Approximately 70% of patients with PWS have a
15q11.2-q13 deletion on one of the chromosomes.
DNA methylation analysis is very important in
confirming diagnosis for all suspected individu-
als, and even more so in patients with atypical
clinical manifestations. This method detects ab-
normal imprinting in the Prader-Willi critical
region on chromosome 15 (e.g., if the paternally
inherited gene is absent) and can differentiate
between PWS and Angelman syndrome (when
deletion on chromosome 15 is present). It detects
more than 99% of the affected individuals [2].
Complications and prognosis
PWS is a disease with many complications and
comorbidities, among which respiratory failure
is the most prevalent and the most dangerous.
Hyperphagia presents a high risk for developing
metabolic abnormalities such as obesity, high
cholesterol, type 2 diabetes, leading to obstruc-
tive sleep apnea, cardiorespiratory failure, cor
pulmonale. Fast paced eating and lack of sati-
ety in response to food frequently lead to chok-
ing episodes, food poisoning and sometimes to
acute gastric dilation and gastric necrosis. Due
to the lack of proper bone ossification caused by
the early onset of hypogonadism, patients often
develop scoliosis, osteoporosis and pathological
fractures. A study from 2015 reveals that a total
of 486 deaths were reported between 1973 and
2015 (263 males, 217 females, 6 unknown), with
a mean age of 29.5 ± 16 years (2mo–67yrs), 70%
occurring in adulthood. Respiratory failure was
the most common cause, accounting for 31% of
all deaths [10]. Recently, the number of acciden-
tal deaths in males has increased, possibly due
to enhanced weight management and mobility,
while the overall risk of death from respiratory
failure has remained unchanged [30].
Table II. Diagnostic criteria for Prader-Willi
syndrome [29]
Birth to age two years
Hypotonia with poor suck (neonatal period)
Age two to six years
Hypotonia with history of poor suck,
global developmental delay
Age six to 12 years:
History of hypotonia with poor suck
(hypotonia often persists), global
developmental delay, excessive eating
with central obesity if uncontrolled
Age 13 years to adulthood
Cognitive impairment, usually mild
intellectual disability, excessive eating with
central obesity if uncontrolled,
hypothalamic hypogonadism and/or
typical behavior problems
Conclusions
In conclusion, Prader-Willi syndrome is a
complex disease with multiple comorbidities that
require thorough examination and early inter-
vention, such as metabolic problems, endocrine
abnormalities, mental disability and behavioral
problems. PWS should be suspected in any pa-
tient with typical clinical findings, and diagnosis
should be confirmed by DNA methylation anal-
ysis. Hormone replacement therapy and proper
nutritional and behavioral guidance are necessary
to improve the quality of life of PWS patients.
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Ichthyosis vulgaris
Tudor-Costinel Şerban
Resident in cardiology
Abstract. Ichthyoses represent a heterogeneous group of rare diseases that affect the skin. These are
characterized by hyperkeratotic accumulations on the skin surface [1]. The word ichthyosis is derived from
the Greek “ichthys” which means fish; the disease is also called fish scale disease due to the resemblance of
hyperkeratotic deposits to fish scales [2]. Ichthyoses are classified, depending on their development pattern,
into congenital and acquired (Figure 1). Acquired ichthyoses appear at adult age and have a systemic cause.
Congenital ichthyoses occur during childhood and are caused by genetic mutations in the proteins respon-
sible for skin keratinization. The most frequent form of ichthyosis is represented by ichthyosis vulgaris, with
an incidence of 95%, being included in the list of rare diseases [3]. The disease affects about 1 in 250 new-
borns, it is equally distributed between the sexes and there is no predisposition depending on the race [3-5].
Keywords: ichthyosis vulgaris, squamae, hyperkeratosis, dry skin, pilar keratosis
Etiopathogenesis toms are improved compared to the cold season,
PIchthyosis vulgaris is caused by a mutation in which exacerbates clinical manifestations [10].
the gene of profillagrin – the filaggrin (FLG) Ichthyosis vulgaris is characterized by dry skin
precursor. The FLG gene encodes the synthesis and the presence of squamae over the entire skin
of a protein called profilaggrin, produced in the surface. Squamae may have variable sizes from 1
skin granular layer, which is subsequently cleaved mm up to 1 cm in diameter, they frequently have
to filaggrin. Filaggrin is a filament protein that a polygonal shape, are distributed similarly to a
binds to keratin in the horny layer and plays an mosaic and may vary in color depending on the
important role in the skin barrier function [5-7]. patient’s complexion. The edges of squamae can
The loss or reduction of filaggrin leads to an al- be curved, which gives the sensation of rough
teration of the keratinization process [8]. skin on touch. Squamae are more obvious in the
extensor areas such as the elbows and knees, the
Clinical picture rest of the skin having a normal or quasi-normal
Ichthyosis vulgaris has an autosomal dominant appearance. They are not present in the folds
inheritance pattern and equally affects both sex- (neck, axilla, popliteal fossa), and there is a clear
es. Onset is most frequently around the age of delineation between the healthy and pathologi-
5 years and manifests throughout life. Patients cal skin. The lower limbs are more affected than
have a positive family history of ichthyosis. A the upper limbs, squamae predominantly occur-
particularity is that clinical manifestations vary ring on the anterior side of the calf, giving a scaly
depending on the season and humidity. During appearance to the skin in this area. The scalp is
summer, because of increased humidity, symp- also frequently affected. When squamae develop

Figure 1. Classification of ichthyoses [6, 9]
on the trunk, they are more obvious in the dor-
sal part. On the palms and soles, hyperkeratosis
leads to deepening of the sulci. In these areas, the
skin may crack, inducing painful lesions with a
risk of superinfection [6].
On the cheeks, neck, thighs and buttocks, pilar
keratosis may occur, which manifests as kera-
totic papules of small sizes, with a hair in the
center and surrounded by erythema. These may
sometimes develop in the absence of squamae,
being the only clinical manifestation of ichthy-
osis vulgaris [11].
Because of dry skin, the sensation of pruritus
occurs, which leads to scratch lesions.
52 53
In some cases, ichthyosis vulgaris is accompa-
nied by allergic diseases, the FLG gene mu-
tation being also involved in the pathogenesis
of atopic dermatitis. Patients having this mu-
tation are predisposed to develop eczemas or
other allergic diseases: seasonal allergic rhinitis
or bronchial asthma.
Diagnosis
Ichthyosis vulgaris is suspected based on char-
acteristic clinical changes. The certainty diag-
nosis is established based on paraclinical ex-
aminations and genetic analysis.
▷▷ Paraclinical examinations
Skin biopsy. It is indicated that biopsy speci-
mens should be taken from the most severely
affected areas, i.e., from the anterior side of
the calf; otherwise, the results can be nega-
tive or inconclusive. Optical microscopy evi-
dences hyperkeratotic areas and the absence
or thinning of the skin granular layer, but in
some cases this can have a normal appearance.
Perivascular lymphocytic infiltrate can ap-
pear in the dermis. The sebaceous glands and
pilous follicles are not affected. Electron mi-
croscopy does not show specific changes, only
a spongy, crumbling appearance of keratohya-
lin granules. These ultrastructural changes are
correlated with the severity of the FLG gene
mutation. The immunohistochemical analysis
of biopsy specimens shows a weak signal of fil-
aggrin, which indicates a low amount of this
protein [2, 6, 10, 11].
Genetic analysis. Ideally, the diagnosis of ich-
thyosis vulgaris should be confirmed by detec-
tion of the FLG gene mutation, which allows
genetic family counseling, given that the dis-
ease is genetically transmitted. DNA analysis
is performed in specialized centers and often
only for scientific purposes, because the disease
is not yet fully understood [11].
Differential diagnosis
▶▶ With other forms of ichthyosis: lamellar ich-
thyosis, X-linked ichthyosis, harlequin ich-
thyosis
▶▶ Dermatitis: allergic dermatitis, irritative
dermatitis
▶▶ Asteatotic eczema
▶▶ Impetigo
▶▶ Drug-induced rashes
Treatment
Ichthyosis vulgaris is a chronic disease that
requires treatment throughout life despite im-
provement of symptomatology. Treatment is
aimed at hydrating the skin and preventing de-
hydration [12, 13].
▶▶ Skin hydration. Clinical improvement follow-
ing hydration explains why symptoms are
ameliorated during seasons with increased
humidity. Moreover, this explains why symp-
toms initially develop several months after
birth, since newborns are bathed very fre-
quently. Moisturizing creams act on the horny
layer, promoting desquamation by increasing
hydrolytic enzyme activity, and enhance sus-
ceptibility to desquamating mechanical forces.
These are based on alpha hydroxy acids such
as lactic, pyruvic or glycolic acid [13].
▶▶ To prevent dehydration, emollient creams
are used, which provide a film on the skin
surface and prevent water evaporation, thus
maintaining skin hydration [12].
▶▶ Keratolytic agents. Salicylic acid, a frequently
used keratolytic agent, in a 5% concentra-
tion, induces desquamation by breaking the
bonds between corneocytes [6, 14]. Urea-
based creams have both keratolytic and hy-
drating properties.
▶▶ Retinoids. Applied topically, they reduce
the connection between corneocytes, in-
hibit keratin synthesis and stimulate mito-
sis and cell turnover [3].
Other forms of ichthyosis
▷▷ X-linked ichthyosis
Is the second most frequent form of ichthyosis.
This form of ichthyosis only affects the male
sex, with an incidence of 1 in 6000 men, and
is caused by a mutation in the steroid sulfatase
gene: STS. STS is involved in the develop-
ment of the horny layer of the skin. The disease
manifests at birth by the development of fine
skin squamae or desquamations. Symptoms
remit, but reoccur after 2-6 months through
brown squamae that cover the trunk, limbs
and neck and give a dirty skin appearance. The
folds, palms and soles are not affected. Patients
frequently have corneal opacities. X-linked ich-
thyosis can be associated with ADHD, autism
or cryptorchidism [15, 16].
▷▷ Autosomal recessive ichthyoses.
They include several forms of non-syndrome
ichthyosis caused by various mutations in the
genes encoding proteins involved in lipid or
fatty acid metabolism or in the assembling of
skin structures.
▶▶ Harlequin ichthyosis is the most severe form
of autosomal recessive ichthyosis, having a
mortality of about 44%. It manifests since
birth, through thickened skin with large
squamae and cracks similarly to an armour.
Children have severe bilateral ectropion
with both everted eyelids, which predis-
poses to corneal and conjunctival lesions,
eclabium, and a fixed, immobile oral ori-
fice that prevents feeding. These children
are predisposed to skin infections, as well
as respiratory infections, which are the
main cause of death [15, 17].
▶▶ Lamellar ichthyosis manifests since birth,
the newborn being covered with a mem-
branous layer – collodion, which after 2
weeks peels off. The skin is covered with
squamae that can vary in size and are ar-
ranged similarly to fish scales. Nail chang-
es occur: onychodystrophy, nail striations,
accelerated growth; alopecia, ectropion,
eclabium and finger motility disorders due
to thickened skin [15, 18].
▶▶ Collodion baby represents a transient con-
dition present at birth in which the new-
born is covered by a membrane similar to
a parchment that peels off within several
weeks. In about 80% of the cases, this con-
dition evolves into an autosomal recessive
form of ichthyosis [15].
Conclusion
Ichthyoses are a heterogeneous group of chronic
diseases that affect the skin and are found on the
list of rare diseases. The diagnosis of ichthyoses is
based on the presence of squamae. These are pre-
dominantly present in certain skin areas and give
the skin a scaly appearance. Most of them are
caused by genetic mutations, but there are also
ichthyoses that develop in the context of systemic
diseases. Since ichthyoses are caused by genetic
mutations and their pathophysiological mecha-
nism is not completely understood, treatment is
aimed at improving symptoms by hydrating the
skin and preventing dehydration [1, 15].
54 55
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2. Hunter JC, Savin J, Dahl M, Weller R - Clini- Cox N, Griffiths C - Rook's Textbook of Derma-
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view, J Am Acad Dermatol, 1983, 8(3):285-305
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ics and emollients and their role in the therapy of
 algia, loss of appetite and nausea. No past history mEq/L), azotemia (urea = 97 mg/dl, creatinine
of tuberculosis, diabetes mellitus, thyroid disor- 1.7), hypertriglyceridemia (triglycerides 400 mg/
Addison’s disease and autoimmune ders, alcoholic liver disease, drug consumption or dl) and elevated serum transaminases (glutamic

thyroiditis with hypothyroidism any other comorbid illness was identified. There
was no relevant family history.
oxaloacetic transaminase (GOT) 40 UI/L, glu-
tamic-pyruvic transaminase (GPT) 46 UI/L).
On clinical examination, the patient was apy-
– A case report retic, with blood pressure of 90/50 mmHg, pulse
of 90 bpm and generalized skin hyperpigmenta-
tion (Figure 1.), more accentuated on the elbows
Breabăn Iulia (Figure 2.) and palmar creases (Figure 3.).
Resident in gastroenterology

Stefan Andreea Maria

Resident in gastroenterology

Abstract. Addison’s disease is a relatively rare endocrine condition with an annual incidence of 4.7-
6.2 per million people in Western populations [1], most frequently (about 80% of cases) of autoimmune
etiology [2]. As part of a polyglandular autoimmune syndrome, it can also associate with autoimmune
thyroiditis, diabetes mellitus and mucocutaneous candidiasis.
We herein report the case of a 30-year-old man with Addison’s disease and autoimmune thyroiditis
with hypothyroidism, with a history of approximately one year of asthenia, unintentional weight loss, my- Figure 1. Hyperpigmentation of the skin Figure 3. Hyperpigmentation of
algia and nausea, general melanoderma, chronic hepatocytolysis syndrome and mild elevated creatinine. the palmar creases
Keywords: Addison’s disease, autoimmune thyroiditis with hypothyroidism, polyglandular autoim-
mune syndrome
Based on clinical and laboratory findings, Ad­­
di­son’s disease was suspected as the main diag-
nosis, therefore cortisol and adrenocorticotropic
Introduction into the polyglandular autoimmune syndrome hormone (ACTH) were dosed. Up to the mo-
Addison’s disease is a rare endocrine disorder [2]. Apart from the autoimmune etiology, other ment of confirmed diagnosis (ACTH 1738 pg/
defined by the inability of the adrenal cortex to causes of adrenal insufficiency are: infectious ml [upper normal value 63.3 pg/ml], 8 AM se-
produce sufficient amounts of glucocorticoids adrenalitis (tuberculosis, disseminated fungal rum cortisol 24.01 nmol/L [normal values 275-
and mineralocorticoids [3], [4]. It is a life threat-infections, HIV infection, syphilis), metastatic 555 nmol/L; morning serum cortisol concentra-
ening disorder with variable clinical presenta- cancer (primarily lung, breast, stomach and co- tion less than 80 nmol/L is strongly suggestive
tion, the hormone deficit altering the energy, lon cancer or lymphoma), adrenal hemorrhage of adrenal insufficiency]), the patient received a
salt and fluid homeostasis [2]. or infarction, drugs (ketoconazole, fluconazole, symptomatic treatment with the intent of low-
The delay in making diagnosis or in institut- rifampin, phenytoin, barbiturates, etomidate, ering serum K+ and its effect on cardiac muscle
ing the right treatment explains the life threat- mitotane, etc.) and other rare conditions such as Figure 2. Hyperpigmentation of and to increase serum Na+ and volemia. He re-
ening nature of the disease [5]. adrenoleukodystrophy. the elbows ceived glucose 5% associated with insulin, NaCl
The disease was first described by Thomas 0.9%, gluconic calcium and salbutamol, with no
Addison in 1855. During time, the main etiol- Case report improvements in laboratory findings.
ogy has changed from infectious causes, such A 30-year-old male presented with the follow- Laboratory investigations revealed thrombo- Abdominal ultrasound detected no abnor-
as tuberculosis, to autoimmune causes, asso- ing complaints: asthenia, unintentional weight cytosis (375,000/ul), moderate hyponatremia malities of the adrenal glands that could cause
ciating itself with other autoimmune diseases loss (approximately 9 kilos in the last year), my- (Na 127 mEq/L), severe hyperkalemia (K 7.1

56 57
primary adrenocortical insufficiency (adrenal The best characterized one is polyglandular
hemorrhage/ infarction/ infiltrative process).syn­drome type I, which has its usual onset in
Furthermore, considering the primary adre- childhood and consists of hypothyroidism, ad-
nocortical insufficiency and the hepatocytolysis
renal failure and mucocutaneous candidiasis.
syndrome of unknown etiology, we suspected However, the more common presentation of
an autoimmune mechanism, therefore we dosed: autoimmune adrenocortical insufficiency is as-
antinuclear antibodies (ANA), antimito­chon­ sociated with human leukocyte antigen (HLA)
drial antibodies (AMA), anti-smooth muscle related disorders including type I diabetes mel-
antibodies (SMA), liver-kidney microsome an- litus and autoimmune thyroid disease [2].
tibodies (LKM), all negative; and also thyroid-­ When part of a polyglandular syndrome, the
stimulating hormone (TSH), free thyroxine disease is two times more common in female Figure 4. Addison’s disease emergency bracelets
(FT4), anti-thyroid peroxidase antibodies patients, aged 30 to 50 years old [2].
(ATPO), anti-thyroglobulin antibodies (ATG). The disease becomes symptomatic in a gradu-
Viral markers, anti-HCV antibodies and HBs al manner, beginning with a non-specific clini- the usual gastrointestinal symptoms consist of dehydrogenase type 1 activity before exerting
antigen were negative. Also, HIV infection wascal panel consisting of chronic fatigue, loss of nausea and vomiting, in the acute adrenal cri- biological activity [6].
excluded. The high levels of TSH (10.5 uIU/ appetite, unintentional weight loss, generalized sis, diagnosis can be misled by the suggestion of Patients with associated mineralocorticoid
mL) and ATPO (68.3 U/mL) [normal values weakness, arterial hypotension, musculoskeletal an acute abdomen. Weakness, apathy, confusion deficiency should receive fludrocortisone and
<34 UI/ml], with a normal level of FT4 (0.88 pain, abdominal pain and depression [3]. Apart and fever are also common in the Addisonian should not restrict their salt intake [6].
ng/dl) confirmed the diagnosis of autoimmune from weight loss and orthostatic hypotension due crisis and they can evolve towards shock, coma As described in other studies, the association
thyroiditis with subclinical hypothyroidism. to dehydration, the deficit of gluco- and miner- and finally death in untreated patients [2]. between Addison’s disease and elevated trans-
The patient was referred to the endocrinology
alocorticoids results in hyponatremia, hyperka- The gradual adrenal destruction is suggested aminases is not uncommon [10], [11]. In our
department, with the following diagnosis: Ad- lemia, changes in blood count (normochromic by hyponatremia and hyperkalemia as classi- clinical case, in contrast to the findings of these
dison’s disease, autoimmune thyroiditis, hepa-nor­mo­cytic anemia, eosinophylia, lymphocyto- cal manifestations. Other hematological mani- studies [10], [11], after initiation of steroid re-
tocytolysis syndrome, hypertriglyceridemia andsis) and hypoglycemia [6]. festations include normocytic normochromic placement, transaminase values did not decrease.
acute renal injury. During hospitalization in theHyperpigmentation of the skin and mucous anemia, neutropenia, eosinophilia and relative On the other hand, the associated subclini-
endocrinology department, he received predni- membranes is a classic physical sign and its lymphocytosis. Azotemia with increased con- cal hypothyroidism of this patient can explain
sone, hydrocortisone, bromazepam, omeprazole, presence in association with the above men- centrations of blood urea nitrogen and serum the elevated GPT and triglyceride levels, as
vitamin B1 and B6, NaCl 0.9% and glucose 5%. tioned symptoms should suggest primary adre- creatinine is due to volume depletion and de- thyroid hormones have an important impact
His laboratory findings improved after hy- nocortical insufficiency. This is due to enhanced hydration [2]. on lipid metabolism. They tend to enhance
povolemia correction and the beginning of hor-secretion of ACTH and its stimulant effect on From the moment of diagnosis, primary ad- the utilization of the lipid substrate, increase
monal correction, urea and creatinine normal- melanocytes to produce melanin. Hyperpig- renocortical insufficiency is a lifelong disease, the synthesis and mobilization of triglycer-
ized, and normochromic normocytic anemia mentation is usually generalized, but most fre- which is associated with complications due to ides stored in adipose tissue and increase the
became apparent. The patient’s blood cell count
quently affects the sun exposed areas and pres- its course or to its treatment. concentration of non-esterified fatty acids and
also revealed leukocytosis with neutrophilia sure areas such as knuckles, toes, elbows and Glucocorticoid therapy should be adminis- lipoprotein-lipase activity [12], [13].
secondary to corticoid therapy. knees. It is accompanied by black, dark brown tered to all patients with Addison’s disease. During treatment, patients need to be moni-
The patient was discharged with normal elec-
freckles and hyperpigmentation of the palmar The first choice of treatment should be hy- tored by their primary physician or endocrinolo-
trolyte levels, hypertriglyceridemia, elevated GPT
creases [7]. Vitiligo may also be seen in asso- drocortisone or cortisone acetate divided into gist for any sign of inadequate glucocorticoid re-
(108 UI/L) and normalized renal parameters. ciation with hyperpigmentation due to autoim- two or three oral doses with the highest dose placement (overdosing: weight gain, insomnia
He received as home treatment: fludrocor- mune destruction of melanocytes [8]. in the morning, imitating the circadian pattern and peripheral edema; insufficient dosing: nau-
tisone, prednisone, omeprazole, silymarin and The symptoms of adrenal insufficiency prog- of glucocorticoid secretion. As an alternative to sea, poor appetite, weight loss, lethargy, hyper-
Centrum multivitamins. He was also advised to ress slowly and are usually ignored until some hydrocortisone, especially in patients with re- pigmentation) or inadequate mineralocorticoid
increase his prednisone doses during intercur-stress factors such as infection, trauma, dehydra- duced compliance, prednisolone should be giv- replacement (salt craving, postural hypotension,
rent infections, trauma or surgery. tion can worsen this condition and lead to the en orally, once or twice daily. Hydrocortisone edema) [6], [7].
Addisonian crisis. This consists of penetrating and prednisolone are active glucocorticoids, Glucocorticoids tend to accelerate reduction
Discussion pain in the lower back region, abdomen and whereas cortisone acetate and prednisone re- in bone mass; therefore, in order to detect early
There are two main syndromes in which au- legs, associated with severe vomiting, low blood quire activation via hepatic 11β-hydroxysteroid osteoporosis in patients with overdosed main-
toimmune Addison’s disease frequently occurs. pressure and loss of consciousness [9]. Although

58 59
tenance treatment, a periodic bone dual-energy
X-ray absorptiometry scan can be useful [7], [14].
In the case of polyglandular autoimmune
syndromes that associate hypothyroidism, like
in our patient’s situation, thyroxine replace-
ment can be postponed as thyroid disease may
be steroid responsive [15].
Regarding the education of patients, they
should wear medical alert bracelets (Figure 4.)
so that in case of an emergency situation they
can receive appropriate treatment consisting of
life saving steroids.
They should be given a prescription for par-
enteral hydrocortisone to be used in those situ-
ations when oral intake may not be possible or
in case of marked vomiting or diarrhea [7]. As
a safety measure, patients should always carry
a vial of dexamethasone (or another glucocor-
ticoid) in their handbag. In certain situations,
patients should have a dexamethasone injec-
tion administered intramuscularly, usually in
the thigh, by themselves, a family member or
a friend: after a major injury with substantial
blood loss, or shock; during an episode of nau-
sea and vomiting if oral medications are thrown
up; if there are any signs or symptoms of ad-
renal crisis; if the person wearing the medical
alert bracelet is found unconscious [16].
Patients should be instructed to double or
triple their steroid replacement doses in stress-
ful situations such as infections or surgeries.
Mineralocorticoids need no adjustment in
stressful situations [7].
They should be given a prescription for par-
enteral hydrocortisone to be used in those situ-
ations when oral intake may not be possible or
in case of marked vomiting or diarrhea [7]. As
a safety measure, patients should always carry
a vial of dexamethasone (or another glucocor-
ticoid) in their handbag. In certain situations,
patients should have a dexamethasone injec-
tion administered intramuscularly, usually in
the thigh, by themselves, a family member or
a friend: after a major injury with substantial
blood loss, or shock; during an episode of nau-
sea and vomiting if oral medications are thrown
up; if there are any signs or symptoms of ad-
60 61
renal crisis; if the person wearing the medical ursache für chronisch erhöhte transaminasen, Z
alert bracelet is found unconscious [16]. Gastroenterol, 2006, 44(2):179–183
Patients should be instructed to double or tri- 12. Pucci E, Chiovato L, Pinchera A - Thyroid and
ple their steroid replacement doses in stressful lipid metabolism, Int J Obes, 2000, 24:S109–S112
situations such as infections or surgeries. Mi­ 13. Eshraghian A, Jahromi AH - Non-alcoho-
ne­ra­lo­cor­ti­coids need no adjustment in stressful lic fatty liver disease and thyroid dysfunction: A
situations [7]. systematic review, World J Gastroenterol, 2014,
In conclusion, Addison’s disease remains a 20(25):8102–8109
challenge in regard to its diagnosis, being a 14. Løvås K, Gjesdal CG, Christensen M, Wolff
rare disease with non-specific symptoms, but AB, Almås B, Svartberg J, et al. - Glucocortico-
also in regard to its treatment and life-long id replacement therapy and pharmacogenetics in
surveillance. Addison’s disease: effects on bone, Eur J Endocri-
nol, 2009, 160:993–1002
15. Gharib H, Hodgson SF, Gastineau CF, Scholz
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