CLINICAL MANIFESTATIONS

IN A HIGHLY SUSPECTED PATIENT WITH

SENSENBRENNER SYNDROME

Case Report

Presented by :
Nurani Widianti, dr.

Consultants :
Prof. Mohammad Sjaifullah Noer, dr., Sp.A(K)

Dr. Ninik Asmaningsih Soemiarso, dr., MM.Paed., Sp.A(K)

Dr. Risky Vitria Prasetyo, dr., Sp.A(K)

Muhammad Riza Kurniawan, dr., Sp.A

Department of Child Health

Faculty of Medicine Universitas Airlangga
Dr. Soetomo Academic General Hospital
Surabaya
2019
 2

INTRODUCTION

Renal ciliopathies are a group of disorders characterised by

nephronophthisis, cystic kidneys or renal cystic dysplasia whose underlying
disease pathogenesis is related to abnormal structure or function of the primary
cilia complex. 1 Ciliopathies are inherited in an autosomal recessive manner that
affect genes encoding proteins that localize to primary cilia or centrosomes. 2
They are caused by mutation at the level of genes that cause changes in multiple
structure in the human body. Some of the syndromes are Jeune syndrome, short
rib polydactily, and cranioectodermal dysplasia also known as Sensenbrenner
syndrome. 3
Cranioectodermal dysplasia (CED) or Sensenbrenner syndrome is a
3 4
rare autosomal disorder. First described in 1975 by Judith Sensenbrenner,
the syndrome is defined by the patient who suffered with multiple anomalies in
skeletal, dental, and hair.1 This syndrome is caused by mutations in the gene
that encode proteins of the intraflagellar transport (IFT122) gene.4 This
mutation causes ciliopathic condition that will present the patient not only with
the skeletal, dental abnormalities, but also the cystic kidney or nephronophthisis
leads to renal failure, retinal degeneration, and ectodermal anomalies (sparse
hair, small, missing teeth, short nails). The characteristics of craniofacial
condition such as forehead bossing, dolichocephaly, and craniosynostosis can
be found.3 Clinical manifestations of Sensenbrenner syndrome are highly
variable and may differ between and within families. 5
Cranioectodermal dysplasia is rare, its exact frequency is unknown.
Fewer than 60 affected individuals have been reported. In the Dutch population
of 17 million people only five families (6 affected individuals) with CED are
known. The diagnosis of CED is established in those with typical clinical
findings and can be confirmed in 40% of affected individuals by identification
of biallelic pathogenic variants in one of the four genes known to be associated
with CED: IFT122 (previously WDR10), WDR35 (previously IFT121),
WDR19 (previously IFT144), or IFT43 (previously C14orf179). 3
 3

Correct diagnosis can lead to good management and make a good

prognosis for the patient.3 The management of the syndrome depends on the
clinical manifestations. Surgery is required to correct the craniosynostosis,
polydactyly and hip dysplasia. Monitoring should be considered for respiratory
4
function to prevent pneumonia caused by narrow thorax cavity. The
nephronophthisis condition in Sensenbrenner syndrome cannot be prevented,
only supportive and dialysis or renal transplant can be considered in terminal
renal failure condition. 5

The objective of this paper is to report a rare case of highly suspected

Sensenbrenner syndrome focused on clinical manifestations.
 4

CASE REPORT

A, three year old boy was referred to Pediatric Nephrology

Outpatient Clinic of Dr. Soetomo Hospital on July 2019, with chief complaint
of impaired renal function. He was referred from Sidoarjo General Hospital on
March 2019 to Orthopaedic and Traumatology Outpatient Clinic Department of
Dr. Soetomo Hospital with the diagnosis of dysplasia of the hip. He came on
July 2019 and he was planned for surgery of the hip. The only complaint was
inability to walk. There were no pallor, no fever, no seizure, no weakness, no
dyspnea, no cough, no abdominal pain, and no vomit found in this patient. He
had good appetite and the urine production was sufficient with clear colour and
no micturition pain.
The patient never had an illness like this before and never got
trauma. His family living in the same house never experienced an illness like
him before. This was the first child born of non-consanguineous marriage from
a 28-year-old father and the 26-year-old mother with uneventful pregnancy. The
baby was delivered at 40 weeks of gestational age by caesarean section due to
prolonged second stage of labor. He cried vigorously soon after birth with a
birth weight of 2500 gram, length 49 cm, and there was no history of jaundice
or cyanosis. The patient is the only child in his family and he lives with his
parents.
He already completed all basic immunizations (BCG, hepatitis B,
DPT, polio, and measles) in primary health care and there was no allergy
history. He was never breastfed but got formula feeding since birth and
complementary feeding since six months old. It was milk porridge at 6 months,
steamed rice at 9 months then ate family food at 13 months. He could lift his
head at 4 months and sat on his own at 7 months. He stood up at 13 months but
unable to walk. He just could say one word unclearly.
Physical examination showed an alert boy with vital signs of blood
pressure 90/60 mmHg, heart rate 120 beats per minutes with regular rhythm,
respiratory rate 24 times per minutes, axillary temperature 36.8°C, and oxygen
saturation 99%. Head and neck examination showed there were no pale
 5

conjunctiva, icterus, cyanosis, and dyspnea. He showed unusual appearance

with dolichocephaly, forehead bossing with high anterior hairline, telecanthus,
short nose, depressed nasal bridge, broad philtrum, full cheeks, low set ears, and
sparse hair and lashes. His teeth were small and widely spaced. There was no
hearing loss and no nystagmus. There were no cervical lymph nodes
enlargement in neck and axilla.

Figure 1. The facial dysmorphic features of 3 year old boy

Chest examination showed no narrow thorax with pectus excavatum

and no chest retraction. There was no murmur, gallop sound, extra systole,
stridor, rhonchi or wheezing. Abnormality was not found in abdomen or
gastrointestinal system examination.
Urogenital examination showed there were bilateral hernia
inguinals, no pain, no hyperemi, and reponnible. Through extremities
examination, there was no oedema with capillary refill time less than 2 seconds
and normal physiological reflex without pathological reflex. There were long
bones shortening. There were no short fingers, no polysyndactyly,
 6

no single bridged palmar creases with generally hypoplastic creases, no

overlapping toes, and no puffiness of hands and feet. He had no hypotonia, and
no joint laxity.
The body weight was 7.3 kg, classified as severely underweight
(below percentile -3 based on WHO Child Growth Standards). The body length
was 78 cm, classified as severely stunted (below percentile -3 based on WHO
Child Growth Standards). The weight for length revealed severely wasted. The
head circumference was 44 cm revealed microcephaly. The arm circumference
was 12 cm and the body mass index was 12 kg/m2.

Figure 2. Weight for age birth to 5 years old WHO growth chart for boys
revealed severely underweight
 7

Figure 3. Length for age birth to 5 years old WHO growth chart for boys
revealed severely stunted

Figure 4. Weight for length birth to 5 years old WHO growth chart for boys
revealed severely wasted
 8

Figure 5. Head circumference for age birth to 5 years old WHO growth chart
revealed microcephaly

Figure 5. Family pedigree of the patient

 9

He was unable to eat by himself, unable to wear and put off his
clothes, and unable to build up blocks. He was able to sit independently, stand
up with hold on, but unable to walk. He just could say a word unclearly and was
classified as global developmental delay.

F F
F
F F
F

F
F
F. F
F F

Figure 6. Global developmental delay based on Denver II

 10

The laboratory tests on July 2019 showed white blood count

9210/ml, haemoglobin 14.7 g/dl, haematocrit 41.8%, platelets 362000/ml, C-
Reactive Protein 0.1 mg/L, albumin 3.4 g/dl, blood urea nitrogen 67 mg/dl,
creatinine serum 2.8 mg/dl, glomerular filtration rate 14.14 ml/min/1.73m2,
sodium 142 mmol/L, potassium 4 mmol/L, chloride 99 mmol/L, calcium 9.5
mmol/L. The urinalysis showed yellow clear, pH 6.5, specific gravity 1.002,
cast 1.5/HPF, bacteria 0.6/HPF, no leucocyte, no erythrocyte, no nitrite, no
protein, no glucose, no ketone, and no bilirubin.
The laboratory tests on March 2019 from Sidoarjo General Hospital
showed white blood count 8410/ml, haemoglobin 12.3 g/dl, haematocrit 37.8%,
platelets 324000/ml, blood urea nitrogen 57 mg/dl, creatinine serum 2.73 mg/dl,
glomerular filtration rate 15.7 ml/min/1.73m2, sodium 140 mmol/L, potassium
4.1 mmol/L, chloride 101 mmol/L, calcium 9.3 mmol/L.
Renal ultrasonography showed multicystic renal bilateral, mild
bilateral hydronephrosis, and nephronophthisis (figure 7).

Figure 7. Multicystic renal bilateral, mild bilateral hydronephrosis, and

nephronophthisis were seen on renal ultrasonography
 11

Ophthalmological examination showed normal fundus, there were

no myopia, no amblyopia, no nistagmus, and no pigmentosa retinitis.
Radiographs showed dolichocephaly. There was no shortness of the
limbs and shortness of the long bones of hands and feet and the bone age rontgen
revealed 3 year old boy (figure 8).

Figure 8. Skull X-ray AP lateral revealed dolichocephaly

Figure 9. Thorax X-ray of the patient

 12

Figure 10. Bone survey X-ray revealed no shortness of long bone

Figure 12. Bone survey X-ray showed developmental dysplasia of hip

 13

Figure 11. Bone age X-ray revealed 3 year old boy

Figure 13. Head CT scan without contrast showed within normal limit
 14

Cranial CT scan showed no bleeding, no infarct, no mass, and no

space occupying lesion. Liver ultrasonography and echocardiogram findings
were normal.
He was diagnosed by suspect Sensenbrenner syndrome with chronic
kidney diseases stage V, multicystic renal bilateral and mild hydronephrosis
bilateral, nephronophthisis, developmental dysplasia of hip, bilateral hernia
inguinalis, and global developmental delay. The differential diagnosis of this
patient are Jeune syndrome, short rib polydactyly, and Meinzer-Saldino
syndrome. He was planned for genetic PCR to establish the diagnosis,
continuous ambulatory peritoneal dialysis, hip surgery, consulted to pediatric
surgeon, and consulted to growth and developmental division. He got treatment
sodium bicarbonate for three times a day, vitamin B12 for three times a day,
folic acid for three times a day, and fluid restriction maximal 800 ml per day.
 15

DISCUSSION
In this case, patient came to Orthopaedic Outpatient Clinic with
chief complaint inability to walk and the pelvis x-ray showed the dysplasia of
the hip. Developmental dysplasia of the hip (DDH) is οne of the most common
skeletal deformities. DDH is a complex syndrome that encompasses a broad
spectrum of anatomical malformations of the growing hip, sharing in common
the abnormal relationship between the femoral head and acetabulum.
Deformities in the shape, size and orientation of the femoral head, acetabulum
or both are variably expressed. The hips that are grossly deformed, either
subluxated or dislocated, are easily recognized at birth and are managed
accordingly. However, some subtle characteristics of dysplastic hips, such as
shallowness and underdevelopment of the acetabulum, may escape diagnosis. 6
In this case, the patient planned for hip surgery but the impaired
renal function was found with multicystic renal bilateral, mild bilateral
hydronephrosis, and chronic kidney disease stage V that revealed
nephronophthisis. Nephronophthisis (NPHP) is a clinical condition caused by a
group of autosomal recessive cystic kidney disorders that typically progresses
to end-stage renal disease (ESRD). It is caused by mutations in a large number
of genes that encode proteins involved in the function of primary cilia, basal
bodies, and centrosomes, resulting in renal disease and extrarenal
manifestations. 7
According to mutations in a large number of genes that encode
proteins involved in the function of primary cilia, cilia are hair-like organelles
projecting from the surface of cells and can be divided into two main subgroups:
motile cilia, occurring in bundles of hundreds and single non-motile (primary)
cilia. While the presence of motile cilia is restricted to highly specialized tissues
such as the respiratory tract, brain ventricles, reproductive tract and embryonic
node in mammals, primary cilia can be found on nearly every cell throughout
the organism. 8
 16

Figure 14. Schematic of the cilia ultrastructure

Each cilium contains nine pairs of microtubules (9 + 0 structure) and

a 10th pair, the so-called central pair, is additionally present in motile cilia (9+2
structure). These motile cilia also contain other proteins necessary for the motile
apparatus such as dynein arms and radial spokes not observed in primary cilia.
The main function of motile cilia is fluid movement and mucociliary clearance.
Defects in genes encoding for proteins of the motile apparatus lead to a cystic
fibrosis like disease named primary ciliary dyskinesia. Roughly, half of
individuals affected by PCD present with laterality defects, which are due to
impaired motile ciliary function in the embryonic node. Laterality defects can
also occur in non-motile ciliopathies, usually in combination with many other
features. Over the past two decades, an increasing number of human genetic
conditions have been linked to malfunction of primary cilia, such as polycystic
kidney disease, nephronophthisis, Joubert syndrome, Bardet-Biedl syndrome,
and the ciliary chondrodysplasias. 9
 17

Figure 15. Schematic architecture of a cilium and ciliary transport

The cilium is a tail-like protrusion from the apical plasma membrane

of the cell. It is composed of two compartments: the basal body from which the
cilium is initially assembled, and the ciliary axoneme that protrudes from the
plasma membrane. Cilia assembly and signaling depend on ciliary transport
known as intraflagellar transport (IFT). This transport process occurs
bidirectionally along the axonemal microtubules from the ciliary base to its tip
(anterograde transport) and back (retrograde transport). While anterograde
transport is driven by the kinesin-2 motor and the IFT-B complex, the dynein-
2 motor and the IFT-A complex regulate transport in the opposite direction. The
IFT-A complex consists of six different proteins; biallelic pathogenic variants
have been identified in four of the six genes that encode these IFT-A complex
proteins in individuals with cranioectodermal dysplasia. The IFT-B complex
consists of at least 12 proteins. 3
The mutation causing ciliopathic condition that will present the
patient not only with the skeletal (narrow ribs, short arms and generalized
osteoporosis), dental abnormalities, but also the cystic kidney or
nephronophthisis leads to renal failure, retinal degeneration, liver cysts and
ectodermal anomalies (sparse hair, small, missing teeth, short nails). The
craniosynostosis condition is unique and found in patient with Sensenbrenner
 18

syndrome. 4 Due to the mutation of IFT genes, the differential diagnosis of the
nephronopthisis condition are Joubert syndrome and related disorder (JSRD),
polycystic kidney disease (PKD) and Bardet-Biedl syndrome (BBS). 5 In PKD,
characterized by formation of fluid-filled cysts caused by mutation in PKD 1
and PKD2 that leads to cystogenesis.6 In JSRD it differs by the molar tooth sign
or neural tube defects (posterior omphalocele) condition in cerebellum. 4
All known genes associated with cranioectodermal dysplasia encode
proteins of the intraflagellar transport (IFT). IFT is a highly evolutionary
conserved process which plays an essential role in the assembly, maintenance
and function of cilia). Cilia are microtubule-based structures extending from the
surface of almost all cell types of the human body. Those structures function
either as a motor providing motility or as a sensor that detects environmental
and physiological signals. Cilia play a crucial role during embryogenesis, as
well as during the postnatal life, where they are transducing signals and
maintaining several signaling pathways, such as the Hedgehog (Hh), Wnt,
platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor
(FGF) pathways. Defects in ciliary proteins, cilia structure and function lead to
a broad range of phenotypes collectively known as ciliopathies. 4
Ciliary chondrodysplasias represent a group of phenotypically and
genetically related disorders inherited in an autosomal recessive fashion
including short-rib polydactyly syndromes, which are also referred to as short-
rib thoracic dystrophy, Jeune asphyxiating thoracic dystrophy or Jeune
syndrome, Mainzer-Saldino syndrome, Sensenbrenner syndrome or cranio-
ectodermal dysplasia, and Ellis-van Creveld syndrome. 10
Cranioectodermal dysplasia (CED) is part of a spectrum of disorders
caused by disruption of the cilium, an organelle of the cell that appears and
functions as an antenna. These disorders, collectively referred to as ciliopathies,
display marked phenotypic overlap. Typical clinical features of ciliopathies are
renal cystic disease, retinal dystrophy, shortening of ribs, phalanges and long
bones, polydactyly, hepatic fibrosis, and developmental delay. 2
 19

Cranioectodermal dysplasia (CED) belongs to a spectrum of

disorders known as "ciliopathies". Ciliopathies are thought to result from
defects in cilia, projections from the cell that occur almost ubiquitously
throughout the human body. These microtubule-based organelles are thought to
function as signaling hubs regulating pathways that are essential for normal
human development and tissue homeostasis. 11
A process that is required for ciliogenesis and regulation of signaling
pathways is ciliary transport (also known as intraflagellar transport [IFT]).
Upward (anterograde) movement of cargo or signaling molecules occurs
through the multi-subunit IFT-B complex in association with the heterotrimeric
kinesin-2 motor, while downward (i.e., tip-to-base [retrograde]) ciliary
transport is regulated by the dynein-2 motor in association with the IFT-A
complex. 12

Table 1. Differential Diagnosis of Cranioectodermal Dysplasia

Develop
Skeletal Renal Liver Obe Situs
Condition Inheritance Retinopathy mental Gene Other
phenotype phenotype phenotype sity inversus
delay
Most often
polydactyly,
Always lethal
short ribs,
perinatal due to
shortened
cardio-respiratory
long bones,
Often, insufficiency
Short rib- brachy- Cysts and Not DYNC2H1, NEK1,
NPHP- resulting from
polydactyly Autosomal dactyly, fibrosis applicabl WDR60, IFT80,
like or Not evident - Rarely severe thoracic
syndromes recessive abnormal may occur e (early WDR35, WDR34
polycystic constriction. Heart
(SRPS) pelvis con- lethal)
defects and gastro-
figuration,
intestinal anomalies
sometimes
occur
orofacial
clefts

Short ribs, Frequently

shortened elevated
30%, DYNC2H1, WDR34,
Jeune long bones, liver
mainly Sinl Often severe WDR60, IFT80,
asphyxiatin polydactyly, enzymes
Autosomal NPHP- e Not cardiorespiratory IFT172, IFT140,
g thoracic abnormal Rarely but rarely -
recessive like, case described distress with ∼40% WDR19, TTC21B,
dystrophy pelvis con- progression
rarely s lethality CSPP1
(JATD) figuration, into liver
cystic
scoliosis failure

Always,
Mildly
Mainzer- mainly Mild thorax
shortened Cholestasis
Saldino Autosomal NPHP- Always Single Not phenotype, usually no IFT140, IFT172
ribs, cone and hepatic -
syndrome recessive like, cases described cardiorespiratory
shaped fibrosis
(MZSDS) rarely lethality
epiphyses
cystic
 20

Facial dysmorphism
with
telecanthus/epicanthus
Mildly , high forehead, broad
Inconsistent
shortened nasal bridge, low-set
hepatic
ribs, brachy- Very prominent ears, thin
CED cysts and
Autosomal dactyly, often, and sparse growing
(Sensenbre fibrosis, Sometim Usually IFT122, WDR19,
recessive craniosynos- mainly Sometimes - hair, nail dysplasia,
ner ductal plate es not IFT43, WDR35
tosis leading NPHP teeth abnormalities,
syndrome) malforma-
to dolicho- like heart defects; usually
tion
cephalus mild thorax phenotype
and no
cardiorespiratory
lethality

Short ribs and

long bones,
Ellis-van abnormal Hypoplastic nails,
Autosomal
Creveld pelvis con- teeth abnormalities, EVC, EVC2
recessive - - - - - -
(EVC) figuration, heart defects
syndrome polydactyly
of the hands

Polycystic
liver
disease,
multiple
Caroli Autosomal
- - - simple - - - - PKHD1
disease recessive
biliary
hepatic
cyst, biliary
hamartomas

Within the ciliopathies, Jeune asphyxiating thoracic dystrophy,

Mainzer-Saldino syndrome, Ellis-van Creveld syndrome, and the short rib-
polydactyly syndromes resemble cranioectodermal dysplasia the most. Each is
described in more detail below. Other ciliopathies that clinically overlap with
cranioectodermal dysplasia include isolated nephronophthisis, isolated retinal
dystrophy, Caroli disease, Senior-Løken syndrome, Joubert syndrome, Meckel-
Gruber syndrome, and Bardet-Biedl syndrome. 13
Jeune asphyxiating thoracic dystrophy (JATD) has a strong
phenotypic overlap with CED. Skeletal abnormalities that occur in both
disorders are polydactyly, brachydactyly, and rhizomelic limb shortening.
Extraskeletal features that may be present in both include renal cystic disease,
3
liver anomalies, and/or retinal dystrophy. Jeune syndrome is caused by
mutations in the ciliogenesis genes IFT80 (MIM 611177) or DYNC2H1 (MIM
603297), but the underlying genetic defect in CED is unknown. 10
Both CED and JATD are characterized by a narrow rib cage
phenotype; however, the phenotype is usually mild in CED and more
 21

pronounced in JATD, often leading to severe respiratory distress; in a review of

ten newborns or infants with JATD, six died of respiratory insufficiency. The
main difference between CED and JATD is that JATD lacks the ectodermal
changes and craniosynostosis characteristic of CED. JATD is inherited in an
autosomal recessive manner. It can be caused by biallelic pathogenic variants
in IFT80, DYNC2H1, TTC21B, IFT140, or WDR19. Of note, pathogenic
variants in WDR19 have been reported in both JATD and CED. 14
Mainzer-Saldino syndrome (MZSDS) is mainly characterized by
phalangeal cone-shaped epiphyses, retinal dystrophy, and nephronophthisis.
Cerebellar ataxia, a narrow thorax, scaphocephaly, and hepatic fibrosis are
variably present. MZSDS usually lacks the typical ectodermal features of CED.
MZSDS is inherited in an autosomal recessive manner. Biallelic pathogenic
variants in IFT140 have been identified in both MZSDS and JATD. 15
Ellis-van Creveld (EVC) syndrome first described by Ellis & van
Creveld 1940, is a skeletal dysplasia characterized by postaxial polydactyly,
shortening of the limbs and ribs, and ectodermal dysplasia affecting hair, nails,
and teeth. EVC syndrome was considered in the differential diagnosis of CED
several decades ago. Congenital heart disease is also a major finding in EVC
syndrome; septal defects (mainly atrial) occur in 60% of affected individuals.
The frequency of heart defects in EVC syndrome is greater than in CED. EVC
syndrome is inherited in an autosomal recessive manner. Biallelic pathogenic
variants in one of two genes positioned head-to-head on chromosome 4, EVC
and EVC2, have been identified in affected individuals. 16
Short rib-polydactyly syndromes (SRPS), five disorders that are
lethal in the perinatal period due to a severe narrow rib cage phenotype, are
generally characterized by extremely short ribs and limbs, polydactyly, and
malformations in a variety of organs. The five short rib- polydactyly syndromes
are not always clinically distinguishable: phenotypic and genetic overlap has
been reported.
The five short rib-polydactyly syndromes are:
SRPS I: Saldino-Noonan syndrome
 22

SRPS II: Majewski syndrome

SRPS III: Verma-Naumoff syndrome
SRPS IV: Beemer Langer syndrome
SRPS V: SRPS V is caused by pathogenic variants in WDR35, which
is also mutated in individuals with CED
Senior-Løken syndrome is a heterogeneous autosomal recessive
disorder that is characterized by nephronophthisis and retinal dystrophy.
Pathogenic variants in various genes have been detected in persons with Senior-
Løken syndrome, including WDR19, which is also mutated in CED. 17
Caroli disease is characterized by polycystic liver disease and
cholangitis. It is part of the autosomal recessive polycystic kidney disease
(ARPKD) spectrum of disorders and can occur as an isolated finding as well as
in combination with other features including renal cystic disease. 18
Autosomal recessive retinal dystrophy (also known as retinitis
pigmentosa) can be an isolated finding or occur in syndromic disorders such as
CED. Retinitis pigmentosa usually starts with night blindness and can progress
to complete blindness later in life due to loss of the photoreceptors (rods and
cones). The fundus often displays attenuation of retinal vessels and may reveal
abnormal peripheral pigmentation (referred to as bone-spicule deposits). Over
50% of families with isolated retinitis pigmentosa have an autosomal recessive
form. Pathogenic variants in more than 30 genes can cause RP, and almost two
thirds of these genes encode ciliary proteins. 19
EEM syndrome (ectodermal dysplasia, ectrodactyly [split hand-split
foot malformation], and progressive macular dystrophy) is a rare disorder that
is clinically related to CED. EEM syndrome can be distinguished from CED as
split hand-split foot malformation does not occur in CED. Biallelic pathogenic
variants in CDH3 are causative. Inheritance is autosomal recessive. 3
Sensenbrenner patients with mutations were more likely to have
sagittal craniosynostosis, joint laxity, dental anomalies, retinal abnormalities,
and congenital heart defects. As expected, considerable overlap with ATD-JS
was noted, but the distinctive Sensenbrenner facial appearance (dolichocephaly,
 23

high hairline, forehead bossing), sagittal craniosynostosis, ectodermal

anomalies (teeth, hair, nails), and syndactyly appear to differentiate the two
syndromes. Severe forms of Sensenbrenner syndrome and ATD-JS have been
diagnosed as short rib-polydactyly syndromes (SRPs). While the SRP
syndromes (I–IV) have similar radiological abnormalities to Sensenbrenner and
ATD-JS syndromes with changes of the rib cage (shortened ribs), pelvis
(shortened ilia with a downward hook at the greater sciatic notches trident
pelvis), and limbs, each have distinguishing findings. SRP type III is thought to
be most similar to ATD-JS. There is some overlap with Saldino-Mainzer
syndrome since both have short (cone-shaped) phalanges, retinopathy, and renal
disease. 5
In this case, the patient showed unusual appearance with
dolichocephaly, forehead bossing with high anterior hairline, telecanthus, short
nose, depressed nasal bridge, broad philtrum, full cheeks, low set ears, and
sparse hair and lashes. Sensenbrenner syndrome is a rare multiple anomaly
syndrome with distinctive craniofacial findings (forehead bossing,
dolichocephaly), metaphyseal dysplasia (short limbs, small thorax), ectodermal
anomalies (sparse hair, small and missing teeth, short nails), connective tissue
abnormalities (loose skin, joint laxity), retinal dystrophy, and chronic renal and
liver disease. 5
CED is inherited in an autosomal recessive manner. Of the 41
affected individuals reported to date, 23 are simplex cases (i.e., a single
occurrence in a family) and 18 are familial from a total of eight families. Each
sib of an affected individual has a 25% chance of being affected, a 50% chance
of being an asymptomatic carrier, and a 25% chance of being unaffected and
not a carrier.3 The most common mutated gene was WDR35 (6 patients, 42%).
5
All known CED genes encode proteins that are part of the intraflagellar
transport complex, which plays an important role in the assembly and
maintenance of cilia. 4
Cranioectodermal dysplasia (CED), a ciliopathy also known as
Sensenbrenner syndrome, is a multisystem disorder with skeletal involvement
 24

(narrow thorax, shortened proximal limbs, and brachydactyly), ectodermal

features (widely-spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity,
abnormal nails), joint laxity, growth retardation, and characteristic facial
features (frontal bossing, low-set simple ears, high forehead,
telecanthus/epicanthus, full cheeks, everted lower lip). 20
Most affected children develop nephronophthisis that often leads to
end-stage renal disease (ESRD) in infancy or childhood, a major cause of
morbidity and mortality. Hepatic fibrosis and retinal dystrophy, other
manifestations of ciliopathies, are also observed. Dolichocephaly, often
secondary to sagittal craniosynostosis, is a primary manifestation that
distinguishes CED from most other ciliopathies. Brain malformations and
3
developmental delay may also occur. Although it is difficult to define
Sensenbrenner syndrome despite the exhaustive analysis, the most frequent
manifestation were a characteristic facial appearance, sagittal craniosynostosis,
brachydactyly, narrow thorax, short long bones, joint laxity, abnormalities of
hair and teeth, and renal disease. 5
The diagnosis of CED requires at least two frequent features and two
other abnormalities, including at least one ectodermal defect (i.e., involvement
of the teeth, hair, or nails). Of note, dolichocephaly is a characteristic that
distinguishes CED from most other ciliopathies. Of note, the diagnosis of CED
is not always easy to make, especially in a neonate in whom characteristics such
as tooth defects and abnormalities of the retina, kidney, and liver are not
necessarily evident. Also, craniosynostosis is not seen in every child. 3
The “cardinal findings” for diagnosis must include brachydactyly
and ectodermal anomalies (small, wide-spaced teeth, hypo/oligodontia, sparse
hair, short nails), and frequently, a distinctive facial appearance, sagittal
craniosynostosis, narrow thorax, joint laxity, and limb shortness. 5
Dolichocephaly (apparently increased antero-posterior length of the
head compared to width) and frontal bossing are usually secondary to sagittal
craniosynostosis, which is usually present at birth. Sib pairs may show
3
discordance for sagittal craniosynostosis. Sagittal craniosynostosis occurred
 25

in 80.0% (4/5), 25.0% (1/4), 50% (1/2), and 50% (1/2) of patients with WDR35,
5
IFT122, C14ORF179/IFT43, and WDR19 mutations, respectively.
Characteristic facial features often seen: Frontal bossing, bitemporal narrowing,
and a tall forehead, low-set, simple and/or posteriorly rotated ears, telecanthus,
epicanthal folds, and/or down/upslanting palpebral fissures, full cheeks,
micrognathia, everted lower lip, anteverted nares. 3

Table 2. Clinical Features of Cranioectodermal Dysplasia

Individuals w/a
Affected
Molecularly
Individuals
Frequency Features Confirmed
Reported in
Diagnosis
Detail (N=33)
(N=15)
Characteristic facial
31 15
features
Brachydactyly 31 15
Narrow thorax (with
Frequent dysplastic ribs and 30 15
(>75%) pectus excavatum)
Dolichocephaly 28 12
Shortening (and
bowing) of proximal 27 12
bones (mostly humeri)
Dental abnormalities
(malformed, widely
23 12
Common spaced, and/or
(50%- hypodontia)
75%) Sparse and/or thin hair 23 7
Short stature 20 11
Nephronophthisis 21 13
 26

Individuals w/a
Affected
Molecularly
Individuals
Frequency Features Confirmed
Reported in
Diagnosis
Detail (N=33)
(N=15)
Joint laxity 15 12
Liver disease
(hepatic fibrosis,
14 9
cirrhosis, and/or
hepatomegaly)
Syndactyly 13 5
Abnormal nails 12 4
Less
Developmental
common 11 5
delay
(25%-50%)
Heart defect 9 4
Skin laxity 11 9
Recurrent lung
8 4
infections
Polydactyly 6 5
Bilateral inguinal
6 6
hernias

Occasional Retinal dystrophy 7 2

to infrequent Hip dysplasia 4 2
(<25%) Cystic hygroma 1 1

Prenatal echography may detect polydactyly during mid-gestation;

however, brachydactyly is not discernible earlier in development. Neonates
often have: brachydactyly (middle and distal phalanges often short and/or
abnormally shaped) and cutaneous syndactyly of fingers and toes (most
 27

frequently mild cutaneous syndactyly of toes 2 and 3). Epiphyses of phalanges

can have a normal appearance on x-ray or can be flattened or cone shaped. 18
Other findings of the hands and feet variably seen: Fifth finger
clinodactyly, abnormal palmar creases, restricted finger flexion, osteoporosis,
sandal gap, triphalangeal hallux. A narrow thorax with short dysplastic ribs may
be noted as early as mid-gestation; however, this finding was most commonly
first noted at birth. Pectus excavatum is often observed. Rib deformities (e.g.,
short ribs or coat-hanger-shaped ribs) may normalize during childhood.
Shortening (and bowing) of proximal long bones has been noted as early as 23
weeks' gestation. Upper limbs are often shorter compared to lower limbs;
humeri are particularly affected. Long bones may display bowing, and
epiphyses may be flattened and/or display metaphyseal flaring. 8
Growth retardation is commonly reported in CED. At birth the
length as related to gestational age may be within the normal range, but can also
be below the third centile. Infants may have a retarded growth with length below
the third centile, but growth retardation may also be milder (length between the
5th and 10th centile). In 11 of 31 children with CED ranging in age from three
to 11 years, height was specifically reported to be below the third centile. 3
Kidney involvement is nephronophthisis (tubulointerstitial
nephritis). At least 60% (21/33) of persons with CED were reported to have
renal insufficiency. Although end-stage renal disease (ESRD) can be evident
prenatally as poly/oligohydramnios and small cystic kidneys in the second
trimester of pregnancy, the first signs of renal disease are often evident in early
childhood (age ~2 years) Initially reduced urinary concentrating ability leads to
polyuria and polydipsia. Nocturnal enuresis may be evident. Hypertension,
proteinuria, hematuria, and electrolyte imbalances usually develop later in the
disease course as a result of renal insufficiency and filtration defects. In ten of
21 children renal disease progressed to ESRD. Of note, this number may have
increased over time as follow-up studies are limited. Most children developed
ESRD between ages two and six years. Renal ultrasound examination in infancy
and early childhood usually shows normal-sized or small kidneys with
 28

increased echogenicity and poor corticomedullary differentiation. Renal biopsy

shows interstitial fibrosis with focal inflammatory cell infiltrates, tubular
atrophy, glomerulosclerosis, and occasional cysts. 3
Although the majority of children develop normally, milestones may
be (mildly) delayed in a subset. Sitting unsupported may be delayed to nine to
15 months, and walking to three years. Delays in speech may vary from a few
words at age 19 months to no words at age five years. No information is
available on how affected individuals respond to speech and physical therapy.
Cognitive and social abilities are usually normal. Brain imaging has revealed
the following abnormalities: cortical atrophy, ventriculomegaly, large cisterna
magna, hypoplasia of the corpus callosum, focal microdysgenesis, enlarged
3
extracerebral fluid spaces, a large posterior fossa cyst. Bilateral inguinal
hernias and/or umbilical hernia can present in neonates or during the first year
of life. 3
Certain disorders have organ-specific overlap such as
nephronophthisis (NPHP) in Joubert syndrome and related disorders (JSRD);
and renal disease in all syndromes. Whereas polydactyly is common in the
SRPS, it is less frequent in Sensenbrenner syndrome and JSRD. The main
characteristic of Joubert syndrome is the “molar tooth sign” of the cerebellum.
Eye abnormalities in Sensenbrenner syndrome include problems
with acuity and the posterior segment, some of which are more easily observed
and reported, whereas the retinal anomalies may require specialized testing
outside the newborn period. Any type of eye problem more commonly in the
patients with a mutation (21% vs. 12%), which compares to ATD-JS, and
Joubert syndrome. 5
In addition to the syndromes listed on, with comparison of
Sensenbrenner syndrome to ATD-JS, SRPS, MKS, and JSRD, there are
additional ciliopathies that have clinical overlap with Sensenbrenner syndrome,
albeit to a lesser extent. Examples include Bardet-Biedl syndrome, Caroli
syndrome and autosomal recessive polycystic kidney disease (ARPKD). 5
 29

The diagnosis of CED is confirmed in a proband with biallelic

pathogenic variants in one of the four genes – IFT122 (previously WDR10),
WDR35 (IFT121), WDR19 (IFT144), or IFT43 (previously C14orf179).
However, it is unclear from reports in the literature whether all four known
genes were tested in all reported individuals. If the cause of CED is indeed more
heterogeneous than presently known, it is reasonable to expect that variants in
genes that (directly or indirectly) regulate intraflagellar transport and/or are
mutated in other ciliopathies similar to CED are causative.

Table 3. Molecular Genetic Testing Used in Cranioectodermal Dysplasia

Proportion of
Gene / CED Attributed
Variants
Locus to Pathogenic Test Method
Detected
Name Variants in This
Gene
IFT122 / Sequence
4/41 Sequence analysis
CED 1 variants
Sequence
Sequence analysis
variants
WDR35 / Unknown; no
9/41
CED 2 Deletion/duplication deletions/
analysis duplications
reported
IFT43 / Sequence
2/41 Sequence analysis
CED 3 variants
WDR19 / Sequence
2/41 Sequence analysis
CED 4 variants
Unknown 23/41 NA NA

In the WDR35 gene missense variants in combination with nonsense

mutations have been reported. The WDR35 gene contains 28 exons and encodes
the IFT121 protein, comprising 1181 amino acids and five WD40 functional
domains. To date 10 families with Sensenbrenner syndrome and WDR35
mutations have been described in the literature. 4 Recent studies found that the
 30

mutation occurs in two genes, IFT122 and WRD35 gene. Both genes encode
proteins that are part of the IFT A (IFT-A) complex which is required for ciliary
assembly, disassembly, and homeostasis. 4 A study performed in a Morrocan
descent family showed homozygous mutation in the initiation codon in
C14ORF179 which encodes a member of IFT-A particle (IFT43). The identified
genetic defect results shortened protein and consisted with disruption of IFT-A
protein complex. These mutations characterized as Sensenbrenner syndrome.
WDR35 is the only gene causing developmental delay, although not
in all cases. Renal insufficiency often develops in infancy or early childhood in
children with biallelic mutations in IFT122, WDR35, IFT43, or WDR19. 5 An
in-frame WDR35 homozygous 2,847-bp deletion spanning exon 5 was
identified in a family with short rib-polydactyly syndrome type V. Compound
heterozygous changes (p.Arg545Ter and p.Trp261Arg) were identified in
another family with short rib-polydactyly syndrome type V. WDR35 comprises
28 exons. This gene is expressed in at least two WDR35 splice variants. The
largest transcript encodes an 1,181-amino-acid protein. 21
The majority of variants associated with CED have been identified
in WDR35; i.e., six of the 11 families with CED with a molecular diagnosis had
pathogenic variants in this gene. The WDR35 pathogenic variants include seven
missense variants, one splice site variant, one stop variant, and a single-bp
deletion, scattered throughout the gene. 22
WDR35 encodes one of the six members of IFT-A protein complex
that regulates retrograde trafficking in the cilium. Defects in WDR35 affect the
process of intraflagellar transport. Immunocytochemistry revealed
accumulations of IFT-B proteins (IFT57 and IFT88) in ciliary tips of cells
derived from an individual with CED with biallelic WDR35 pathogenic
variants. Such accumulations represent a typical "IFT-A" defect, and have
previously been observed in ciliated cells of many different species, including
C. elegans, C. reinhardtii, D. melanogaster, T. brucei, and M. musculus,
wherein IFT-A orthologues were knocked out. A Wdr35 knockout mouse (yeti)
was recently published. Homozygotes for a splice acceptor pathogenic variant
 31

resulting in a frameshift failed to form cilia, died during mid-gestation, and

displayed a short rib-polydactyly phenotype. 8
WDR19 compound heterozygous pathogenic variants (p.Val345Gly
and p.Tyr1023Ter) were reported in a family with isolated nephronophthisis,
and a homozygous pathogenic missense variant (p.Leu7Pro) was found in a
family with Jeune asphyxiating thoracic dystrophy. 3
Although shortening of cilia in fibroblasts from persons with CED
has also been reported, this is not always observed. It is thought that defective
IFT and resulting structural defects in the ciliary architecture disturb important
developmental signaling cascades (e.g., hedgehog signaling), resulting in CED.
IFT122 comprises 31 exons and is alternatively spliced in at least four variants.
The largest transcript is encoding a 1,292-amino-acid product. To date six
IFT122 pathogenic variants (4 missense variants, a splice site variant, and a
truncating variant) have been associated with CED. The pathogenic variants are
located in or close to WD40 domains. It has been suggested that pathogenic
variants that give rise to CED do not completely abolish the function of IFT122
and, thus, the CED phenotype is relatively mild. IFT122 encodes intraflagellar
transport 122 homolog, one of the six proteins of the intraflagellar transport A
(IFT-A) protein complex. This complex regulates retrograde transport in the
cilium. Pathogenic variants in IFT122 are thought to impair retrograde (tip-to-
base) transport in the cilium. A study of cilia of fibroblasts from an individual
with CED with biallelic IFT122 pathogenic variants revealed shortened cilia as
compared to control cells. 1
The longest IFT43 transcript comprises eight exons. To date, three
protein-encoding isoforms of IFT43 are known. The largest transcript encodes
a protein of 213 amino acids. To date, IFT43 pathogenic variants have only been
reported in one family with CED, a consanguineous family of Moroccan
descent. The identified homozygous variant (c.1A>G) is located in the
translation initiation codon of IFT43, and is predicted to result in an in-frame
deletion of the first 21 amino acids of IFT43. It has been suggested that the
resulting IFT43 protein is still partly functional, and that the CED phenotype is
 32

most likely relatively mild. IFT43 encodes the intraflagellar transport 43

homolog, a member of the IFT-A complex comprising six proteins. Recent
insights into the composition of the IFT-A protein complex in the unicellular
alga Chlamydomonas reinhardtii revealed that the IFT-A proteins IFT43 and
IFT121 (the ortholog of WDR35) directly interact. A study of ciliated
fibroblasts of a person with CED with a homozygous translation initiation
codon variant (c.1A>G) in IFT43 revealed accumulations of IFT-B proteins
(IFT88 and IFT57) in ciliary tips. This defect is consistent with a dysfunctional
IFT-A protein complex. 15
WDR19 comprises 37 exons, of which 36 are protein coding. A
single WDR19 transcript encodes a 1,342-amino-acid protein. To date, one
family with CED and pathogenic variants in WDR19 has been described. The
two affected sibs of this Norwegian family had compound heterozygous
variants, including a missense variant and a stop variant. WDR19 encoding
intraflagellar transport protein 144 is one of the six subunits of the IFT-A
protein complex that regulates retrograde ciliary transport. The discovery that
WDR19 (IFT144) is associated with the IFT machinery was initially made in
Chlamydomonas reinhardtii and later in Caenorhabditis elegans. Fibroblasts
from one of the Norwegian sibs with CED were studied; no WDR19/ IFT144
protein was detectable in cilia from the affected individual. In addition, cilia
were less abundant and shorter in the patient's cells compared to cilia from
control cells. These findings indicate that IFT-A mediated transport is
interrupted and can result in abnormal architecture of cilia. 14
The main transcript of IFT122 encodes a 1292 amino acid
cytoplasmic protein that has a molecular weight of approximately 140 kDa and
contains seven WD40 domains, which are involved in the formation of b-
propeller structures acting as platform for the association of binding partners.
As a component of the intraflagellar transport complex A, the IFT122 protein
is involved in retrograde ciliary transport, which returns proteins from the tip of
the cilia to the cell body and plays an important role in the assembly and
10
maintenance of eukaryotic cilia and flagella.
 33

None of the mutations in IFT122, WDR35, IFT43, and WDR19 are

biallelic nonsense, deletion, or other null mutations; such mutations would most
likely result in early embryonic lethality. Similarly, biallelic null mutations are
not observed in the clinically and genetically overlapping SRPs presumably due
to early embry- onic lethality. WRD19 appears to have the most phenotypic
hetero- geneity thus far ranging from Sensenbrenner syndrome to isolated
retinal or renal disease. 5
Defects in the WDR35 and IFT122 genes are commonly identified
in patients with Sensenbrenner syndrome. Also, the WDR35 gene has been
associated with an unclassified form of short-rib polydactyly syndrome (SRP)
and Ellis-van Creveld syndrome (EVC). These clinically overlapping syn-
dromes can result from a similar molecular defect. Sensenbrenner syndrome is
considered to be a mild form of the embryonically lethal SRP. Less than 60
patients with Sensenbrenner syndrome have been described to date. The
phenotypic spectrum among the patients with Sensenbrenner syndrome is
variable, with some intrafamilial and interfamilial differences. The biallelic
variants identified in six known genes associated with Sensenbrenner syndrome
(IFT122, WDR35, IFT43, WDR19, IFT52, and IFT140) are not phenotypically
distinct. 10
In BBS the obesity, polydactily, retinal degeneration, mental
retardation and renal malformations are the characteristics and it caused by BBS
1-12 genes mutation. 6 The hepatic cysts and ductal malformation are common
7
in Sensenbrenner syndrome but retinal dystrophy is less common. The
complexity and diversity of ciliopathies often make it difficult to give a clear
clinical diagnosis.8 Non invasive diagnostics method should be applied first to
establish the diagnosis. Familial pedigree and clinical condition (brachydactily
3
and ectodermal anomalies) are important to enrolled the diagnosis of the
Sensenbrenner syndrome, despite its more specific with genetic examination.
Radiologic examination such as skull and extremities examination also needed
to determine the pathology of the bone. The biopsy of the solid organs (liver
 34

and renal) also important to rule out the cystic condition, it is important because
cyst can leads to hepatic and renal failure. 19
As needed, surgery to correct sagittal craniosynostosis (usually age
<1 year) and/or polydactyly of the hands and feet. Routine treatment of inguinal
and umbilical hernias, nephronophthisis, liver disease, and/or cardiac
anomalies. For those with developmental delay: speech and physical therapy,
and appropriate educational programs. For those with progressive visual
impairment: low vision aids and appropriate educational programs. Human
growth hormone therapy should be considered in those who meet standard
treatment criteria. 3
Treatment includes the following: Surgery for correcting
craniosynostosis (usually in first year of life), correction of polydactyly
(optional), orthopaedic care as required (e.g., for hip dysplasia), growth
hormone treatment to stimulate growth when standard criteria for this treatment
are met. Growth hormone should only be prescribed to children with severe
growth retardation in whom the therapy is expected to be successful. Dental
care is important due to detection and intervention of structural tooth
abnormalities and/or oligodontia may limit aesthetic, functional, and
psychological issues. Standard treatment for renal and liver abnormalities.
While liver transplantation is a treatment option in advanced stages, it has only
been proposed once for an individual with CED. For those with progressive
visual impairment, low vision aids and appropriate educational programs.
Mechanical ventilation as required in newborn to treat respiratory insufficiency
due to pulmonary hypoplasia. 12
For those with developmental delay, speech therapy and physical
therapy to improve motor skills and appropriate educational programs. Surgical
intervention as required for inguinal/umbilical hernias 3
 35

Table 3. Management Guidelines for Sensenbrenner Syndrome

Tests to be performed when Comments
diagnosis is suspected
Detailed physical examination, Inquire about consanguinity
detailed family history MRI brain with individuals with
Skull radiograph, CT with three- development delay
dimensional reconstruction Neonatal babygram is insufficient
Complete skeletal survey Include electroretinogram (ERG), but
Eye examination with funduscopy this test may be difficult to perform
appropriately in young individuals
Dental examination Treat small and missing teeth
Renal imaging begins with Obtain appropriate chemistries
ultrasound
Echocardiogram
Abdominal ultrasound with attention Obtain appropriate chemistries
to liver
Molecular genetic confirmation Ciliome or whole-exome sequencing
Evaluate hypotonia, developmental Have a low threshold for providing
delays with neurology consultation therapies
Pulmonology consultation Frequent infections

In infancy and childhood monitoring growth and development, and

tooth development; periodic assessment of renal and liver function; annual
ophthalmologic examinations starting at age four years to detect early signs of
retinal degeneration. 3 Monitoring growth and development during infancy and
childhood starting at the time of diagnosis. Beginning at age one year,
examination of teeth with regular follow-up to detect tooth damage and
oligodontia. Periodic monitoring starting at the time of diagnosis for signs of
nephronophthisis (renal insufficiency, renal cyst formation), including
 36

osmolarity testing in morning urine, urine collection assays to test for polyuria,
measurement of blood pressure, determination of serum creatinine and blood
urea concentrations to establish renal function, and periodic renal ultrasound
examination to establish kidney size and presence of cysts. Periodic
measurement of liver enzymes starting at the time of diagnosis.
Annual ophthalmologic examinations starting at age four years.
Electroretinography (ERG) and fundoscopy can be performed at an earlier age
if it is evident that vision is reduced. Evaluation for respiratory infection (with
x-rays and sputum analysis) when clinical findings suggest pneumonia. In those
with structural heart defects, periodic monitoring of cardiac function including
auscultation, ECG, and echocardiography. 3
Carrier testing for at-risk relatives and prenatal testing for
pregnancies at increased risk are possible if the pathogenic variants in the family
have been identified. Second- trimester ultrasound examination may detect
3
renal cysts, shortening of the limbs, and/or polydactyly. If the pathogenic
variants are known in a family, it is appropriate to clarify the genetic status of
at-risk infants to allow early diagnosis and appropriate management and
surveillance, particularly for respiratory complications, renal and liver disease,
and visual impairment. If the pathogenic variants are not known in a family, the
following is recommended for at-risk children: In the newborn period: physical
examination by a pediatrician, and consultation with a clinical geneticist as
determined by the clinical findings. Age 0-3 months: kidney and liver
evaluation, including ultrasound examination and measurement of blood
pressure, serum creatinine concentration, and liver enzymes. At six-month
intervals: repeat the kidney and liver evaluations. 15
Parents should be alerted to the signs of CED and advised to contact
their child's health care provider if suspicious symptoms, such as polydipsia
and/or jaundice, appear. 3 Parents of a proband: The parents of an affected child
are obligate heterozygotes (i.e., carriers of one mutated allele), heterozygotes
(carriers) are asymptomatic. In such cases, one parent may not be a carrier.
Thus, documentation of carrier status in both parents is appropriate. 10
 37

At conception, each sib of an affected individual has a 25% chance

of being affected, a 50% chance of being an asymptomatic carrier, and a 25%
chance of being unaffected and not a carrier. Once an at-risk sib is known to be
unaffected, the risk of his/her being a carrier is 2/3. Heterozygotes (carriers) are
asymptomatic. Rarely, as a result of a de novo pathogenic variant, the risk to the
sibs of a proband of being affected is likely no more than 1%-2%. However, it
is difficult to assign a specific risk as it is unclear in whom the pathogenic
variant arose (i.e., de novo mutation in the proband or germline mosaicism in a
parent). The offspring of an individual with CED in whom biallelic pathogenic
variants have been identified in IFT122, WDR35, IFT43, or WDR19 are
obligate heterozygotes (carriers) for a pathogenic variant. It is currently unclear
whether individuals with CED are fertile as no individuals with CED have been
reported to reproduce. This may be due to the severity of the disorder and to
limited life span expectancy. Yet, CED may also be characterized by infertility
as the genes that are mutated in this disorder encode proteins that are functional
in cilia. These organelles are essential for sperm cell motility, and cilia in the
Fallopian tube in turn sweep egg cells from the ovaries toward the uterus. Each
sib of the proband's parents is at a 50% risk of being a carrier. If one of the
parents has germline mosaicism, the risk to the sibs of that individual is lower.
3

Renal and liver disease are the main contributors of morbidity and
mortality in patient with Sensenbrenner syndrome. 5 Morbidity is high in CED
and hospitalization may be frequent and/or long-term. Mortality rates are
unclear, although 7/33 of children with CED died before age seven years of
respiratory failure, heart failure, hypovolemic shock (as a result of
coagulopathy), or unknown causes. 3
 38

SUMMARY
A case of clinical manifestations in a highly suspected patient with
Sensenbrenner syndrome has been reported. A, three year old boy was referred
to Pediatric Nephrology Outpatient Clinic of Dr. Soetomo Hospital with chief
complaint of impaired renal function. He was referred from Orthopaedic and
Traumatology Outpatient Clinic Department of Dr. Soetomo Hospital with the
diagnosis of dysplasia of the hip and he was planned for hip surgery. The only
complaint was inability to walk.
Physical examination presents facial dysmorphic features, bilateral
hernia inguinalis, malnutrition, and global developmental delay. Laboratory
examination resulted of glomerular filtration rate reduction that indicated
chronic kidney disease stage V. Renal ultrasonography showed multicystic
renal bilateral, mild bilateral hydronephrosis, and nephronophthisis. X-ray
examination showed dolichocephaly and dysplasia of the hip.
He was diagnosed by suspect Sensenbrenner syndrome with
chronic kidney diseases stage V, multicystic renal bilateral and mild
hydronephrosis bilateral, nephronophthisis, developmental dysplasia of hip,
bilateral hernia inguinalis, and global developmental delay. He was planned for
genetic PCR to establish the diagnosis, continuous ambulatory peritoneal
dialysis, hip surgery, consulted to pediatric surgeon, and consulted to growth
and developmental division. He got treatment sodium bicarbonate for three
times a day, vitamin B12 for three times a day, folic acid for three times a day,
and fluid restriction maximal 800 ml per day.
For all Sensenbrenner patients, renal and liver disease are the main
contributors of morbidity and mortality. Morbidity is high in cranioectodermal
dysplasia and hospitalization may be frequent and long-term.
 39

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