Rare Disease Database

Aarskog Syndrome
NORD gratefully acknowledges Dr. Alfredo Orrico, Molecular Medicine and Genetics, Azienda
Ospedaliera Universitaria Senese, Viale Bracci. Siena, and Clinical Genetics. USL SudEst.
Misericordia Hospital. Grosseto, Italy, for assistance in the preparation of this report.

Synonyms of Aarskog Syndrome

 Aarskog disease
 Aarskog-Scott syndrome
 AAS
 faciodigitogenital syndrome
 faciogenital dysplasia
 FGDY
 Scott Aarskog syndrome

General Discussion
Aarskog syndrome is a rare genetic condition characterized by short stature
and multiple facial, limb and genital abnormalities. Additionally, some types
of cognitive disorders may occasionally be present. Up to now, the FGD1
gene on the X chromosome is the only gene known to be associated with
Aarskog syndrome.

Signs & Symptoms

Aarskog syndrome primarily affects males. Affected boys exhibit a
characteristic set of facial, skeletal, and genital abnormalities. Clinical signs
may vary from person to person (clinical heterogeneity), even within
families. Males with Aarskog syndrome often have a rounded face with a
broad forehead. Additional characteristic facial features include widely
spaced eyes (ocular hypertelorism), drooping (ptosis) of the eyelids,
downwardly slanting eyelid folds (palpebral fissures), a small nose with
nostrils that are flared forward (anteverted nares), an underdeveloped upper
jawbone (maxilliary hypoplasia), and a widow’s peak. Affected individuals
may also have an abnormally long groove in the upper lip (philtrum) and a
broad nasal bridge.
These children may also have a variety of abnormalities affecting the ears
and teeth. Ear abnormalities include low-set ears and thickened, “fleshy”
earlobes. Dental abnormalities include missing teeth at birth, delayed
eruption of teeth, and underdevelopment of the hard outer covering of teeth
(enamel hypoplasia).
Aarskog syndrome is basically a skeletal dysplasia and affected males
develop characteristic malformations of the skeletal system including
disproportionate short stature; broad, short hands and feet; short, stubby
fingers (brachydactyly) with permanent fixation of the fifth fingers in a bent
position (clinodactyly); abnormally extendible finger joints; and wide flat feet
with bulbous toes. In addition, affected individuals may have a sunken chest
(pectus excavatum), protrusion of portions of the large intestine through an
abnormal opening in the muscular lining of the abdominal cavity (inguinal
hernia), and a prominent navel (umbilicus). Individuals with Aarskog
syndrome may have spinal abnormalities such as incomplete closure of the
bones of the spinal column (spina bifida occulta), fusion of the upper bones
of the spinal column (cervical vertebrae), and underdevelopment of the
“peg-like” projection of the second cervical vertebra (odontoid hypoplasia).
Signs that help to make a diagnosis in males with Aarskog syndrome are the
genital abnormalities, including a characteristic abnormal fold of skin
extending around the base of the penis (“shawl” scrotum) and/or failure of
one or both of the testes to descend into the scrotum (cryptorchidism). In
addition, the urinary opening (meatus) may be located on the underside of
the penis (hypospadias) and the scrotum may appear clefted or divided (bifid
scrotum).
Intellectual disability has been described in some affected boys but it is not a
consistent feature of the disorder. Affected individuals may present with a
range of mild learning difficulty and/or behavioral disorders: affected children
may exhibit developmental delay during infancy, hyperactivity, attention
deficit, impulsivity and opposition. Due to this possible spectrum of
characteristics, the condition is also referred to as an ADHD syndromic
disorder (MRXS16). Failure to gain weight and grow at the expected rate
(failure to thrive) and development of chronic respiratory infections have
also been described.
An additional spectrum of signs and/or symptoms may occur less frequently,
including congenital heart defects; abnormal side-to-side curvature of the
spine (scoliosis); additional pairs of ribs; incomplete closure of the roof of the
mouth (cleft palate) and/or a vertical groove in the upper lip (cleft lip); mild
webbing of the fingers; and a short neck with or without webbing. Additional
eye abnormalities may be present including crossed eyes (strabismus),
farsightedness (hyperopia), and paralysis of certain eye muscles
(ophthalmoplegia). Some patients have been reported to have a tendency to
be overweight.

Causes
Although Aarskog syndrome is a clinically and genetically heterogeneous
condition, the best characterized form of the disorder is inherited as an X-
linked trait and caused by changes (mutations) in the FGD1 gene. Aarskog
syndrome primarily affects males. However, females who carry a single copy
of a FGD1 gene mutation (heterozygotes) may exhibit some of the symptoms
associated with the disorder. FGD1 gene mutations have been identified in
approximately 22% of affected males; therefore, it is likely that other genes
not yet identified may also be associated with this condition.
X-linked recessive genetic disorders are conditions caused by mutations in a
gene located on the X chromosome. Females have two X chromosomes but
one of the X chromosomes is “turned off” to correct a dosage imbalance and
almost all of the genes on that chromosome are silenced (inactivated)
through a process defined as X-chromosome inactivation. Females who have
a disease causing mutation on one of their X chromosomes are carriers for
that disorder. Carrier females usually do not display symptoms of the
disorder because it is usually the X chromosome with the abnormal gene
that is “silenced”. Males have one only X chromosome and, if they inherit the
X chromosome that contains a disease gene, they will develop the disease.
In turn, males with a X-linked disorder will pass the disease gene to all of
their daughters, who will be carriers of the trait (obligate carriers). Males
cannot pass X-linked traits to their sons because they always pass their Y
chromosome instead of their X chromosome to male offspring. Female
carriers of an X-linked disorder have a 25% chance with each pregnancy to
have a carrier daughter (like themselves), a 25% chance to have a non-
carrier daughter, a 25% chance to have a son affected with the disease, and
a 25% chance to have an unaffected son.

Affected Populations
Approximately 60 reports of Aarskog syndrome confirmed by identification of
a FGD1 gene mutation have been published worldwide. However, it is
possible that some mildly affected children may be unrecognized, making it
difficult to determine the true frequency of this condition in the general
population. An estimated population prevalence of Aarskog syndrome is
equal to or slightly lower than to 1/25,000.

Related Disorders
Symptoms of the following disorders can be similar to those of Aarskog
syndrome. Comparisons may be useful for a differential diagnosis:
Noonan syndrome is a relatively common genetic disorder characterized by
short stature, dysmorphic facial features and congenital heart disease. The
disorder is characterized by a wide spectrum of symptoms and physical
features that vary greatly in range and severity. In many affected
individuals, associated abnormalities include a distinctive facial appearance;
a broad or webbed neck; a low posterior hairline; a typical chest deformity
and short stature. Characteristic abnormalities of the head and facial
(craniofacial) area may include widely set eyes (ocular hypertelorism); skin
folds that may cover the eyes’ inner corners (epicanthal folds); drooping of
the upper eyelids (ptosis); a small jaw (micrognathia); a depressed nasal
root; a short nose with broad base; and low-set, posteriorly rotated ears
(pinnae). Distinctive skeletal malformations are also typically present, such
as abnormalities of the breastbone (sternum), curvature of the spine
(kyphosis and/or scoliosis), and outward deviation of the elbows (cubitus
valgus). Many infants with Noonan syndrome also have heart (cardiac)
defects, such as obstruction of proper blood flow from the lower right
chamber of the heart to the lungs (pulmonary valvular stenosis). Additional
abnormalities may include malformations of certain blood and lymph vessels,
blood clotting and platelet deficiencies, learning difficulties or mild
intellectual disability, failure of the testes to descend into the scrotum
(cryptorchidism) by the first year of life in affected males, and/or other
symptoms and findings. Noonan syndrome is may be caused by mutations in
a number of genes, including PTPN11, KRAS, SOS1, RAF1, NRAS, RIT1 and
SOS2 (For more information on this disorder, choose “Noonan” as your
search term in the Rare Disease Database.)
Robinow syndrome is a rare genetic disorder that can be inherited in either a
dominant or recessive pattern and is characterized by mild to moderate
short stature due to growth delays after birth (postnatal growth retardation);
distinctive abnormalities of the head and facial (craniofacial) area; additional
skeletal malformations; and/or genital abnormalities. The facial features of
infants with Robinow syndrome resemble those of an eight-week-old fetus;
within the medical literature, this condition is often referred to as “fetal
face.” Characteristic craniofacial features may include an abnormally large
head (macrocephaly) with a bulging forehead (frontal bossing); widely
spaced eyes (ocular hypertelorism) that are abnormally prominent; a small,
upturned nose with nostrils that are flared forward (anteverted); and/or a
sunken (depressed) nasal bridge. Skeletal malformations may include
forearm bones (radius and ulna) that are unusually short (forearm
brachymelia), abnormally short fingers and toes, permanent fixation of the
fifth fingers in a bent position (clinodactyly), unusually small hands with
broad thumbs, malformation of the ribs, abnormal side-to-side curvature of
the spine (scoliosis), and/or underdevelopment of one side of the bones in
the middle (thoracic) portion of the spinal column (hemivertebrae). Genital
abnormalities associated with Robinow syndrome may include an abnormally
small penis (micropenis) and failure of the testes to descend into the
scrotum (cryptorchidism) in affected males and underdevelopment
(hypoplasia) of the clitoris and the outer, elongated folds of skin on either
side of the vaginal opening (labia majora) in affected females. The range and
severity of symptoms vary from person to person. The Robinow syndrome
may be caused by mutations in different genes, such as WNT5A, ROR2, DVL3
and DVL1 (For more information on this disorder, choose “Robinow” as your
search term in the Rare Disease Database.)
Noonan syndrome with multiple lentigines (NSML) is a rare genetic disorder
characterized by abnormalities of the skin, the structure and function of the
heart, the inner ear, the head and facial (craniofacial) area, and/or the
genitals. In individuals with the disorder, the range and severity of symptoms
and physical characteristics may vary from person to person. LEOPARD is an
acronym for the characteristic abnormalities associated with the disorder: L
stands for (L)entigines (multiple black or dark brown spots on the skin);
(E)lectrocardiographic conduction defects (abnormalities of the electrical
activity and the coordination of proper contractions of the heart); (0)cular
hypertelorism (widely-spaced eyes); (P)ulmonary stenosis (obstruction of the
normal outflow of blood from the right ventricle of the heart); (A)bnormalities
of the genitals; (R)etarded growth resulting in short stature; and (D)eafness
or hearing loss due to malfunction of the inner ear (sensorineural deafness).
Some affected individuals may also exhibit mild intellectual disability, speech
difficulties, and/or, in some cases, additional physical abnormalities. NSML is
an autosomal dominant genetic disorder. NSML and Noonan syndrome are
both caused by mutations in the PTPN11 and RAF1 genes. (For more
information on this disorder, choose “LEOPARD” as your search term in the
Rare Disease Database.)

Diagnosis
A diagnosis of Aarskog syndrome may be considered based upon a thorough
clinical evaluation, a detailed patient and family history, and the
identification of characteristic findings. Molecular genetic testing for FGD1
gene mutations is available to confirm the diagnosis. If a FGD1 gene
mutation is not identified, molecular genetic testing for genes associated
with similar conditions may be suggested, such as the ROR2 and WNT5A
genes associated with Robinow syndrome.
The transition from the classic sequencing of single genes to protocols of
next generation sequencing (NGS), recommends at least the use of panels
that include, in addition to FGD1, the genes that cause overlapping
conditions such as ROR2, WNT5A, PIK3R1, SRCAP, KMT2D, KDM6A, SHOX,
CUL7.

Standard Therapies
Treatment
The treatment of Aarskog syndrome is directed toward the specific
symptoms that are apparent in each individual. Treatment may require the
coordinated efforts of a team of specialists. Pediatricians, surgeons,
cardiologists, dental specialists, speech pathologists, specialists who asses
and treat hearing problems (audiologists), eye specialists, and other health
care professionals may need to systematically and comprehensively plan an
affected child’s treatment.
Surgery may be necessary to treat specific congenital or structural
malformations sometimes associated with Aarskog syndrome (hypospadias,
inguinal or umbilical hernias, cryptorchidism, unusually severe craniofacial
features). Individuals with Aarskog syndrome should receive complete eye
and dental evaluations. Growth hormone treatment has been reported to
improve height in some children, but confirmation is needed to determine
appropriate management and expectations for response. For the possibly
neurodevelopmental symptoms, a neuropsychiatric evaluation and input
may be indicated. Other treatment is symptomatic and supportive.
Genetic counseling is recommended for affected individuals and their
families to clarify the genetic and clinical characteristics, the inheritance,
and the recurrence risks of the condition in their families.

Investigational Therapies
Information on current clinical trials is posted on the Internet at
www.clinicaltrials.gov All studies receiving U.S. government funding, and
some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical
Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the
NORD website:
https://rarediseases.org/for-patients-and-families/information-
resources/news-patient-recruitment/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

Resources
Please note that some of these organizations may provide information
concerning certain conditions potentially associated with this disorder (e.g.,
visual handicaps, heart disease, etc.)

NORD Member Organizations

  Children’s Craniofacial Association
o 13140 Coit Road
o Suite 517
o Dallas, TX 75240 USA
o Phone: (214) 570-9099
o Toll-free: (800) 535-3643
o Email: contactCCA@ccakids.com
o Website: http://www.ccakids.com

Other Organizations
 Aarskog Syndrome Parents Support Group
o 62 Robin Hill Lane
o Levittown, PA 19055-1411
o Phone: (215) 943-7131
o Email: shannonfaith49@msn.com
 Genetic and Rare Diseases (GARD) Information Center
o PO Box 8126
o Gaithersburg, MD 20898-8126
o Phone: (301) 251-4925
o Toll-free: (888) 205-2311
o Website: http://rarediseases.info.nih.gov/GARD/
 MAGIC Foundation
o 4200 Cantera Dr. #106
o Warrenville, IL 60555
o Phone: (630) 836-8200
o Toll-free: (800) 362-4423
o Email: contactus@magicfoundation.org
o Website: http://www.magicfoundation.org
 NIH/National Institute of Arthritis and Musculoskeletal and Skin
Diseases
o Information Clearinghouse
o One AMS Circle
o Bethesda, MD 20892-3675 USA
o Phone: (301) 495-4484
o Toll-free: (877) 226-4267
o Email: NIAMSinfo@mail.nih.gov
o Website: http://www.niams.nih.gov/
 The Aarskog Foundation
o UK
o Phone: 01108000016623
o Email: support@aarskogsyndromefoundation.co.uk
o Website: http://www.aarskogsyndromefoundation.co.uk/

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