- Aarskog-Scott Syndrome is a genetic disorder caused by mutations in the FGD1 gene, affecting development and causing distinctive facial features and limb abnormalities. - It mainly affects males and causes short stature, hand abnormalities like short fingers and single palm creases, and genital abnormalities like shawl scrotum. - There is no cure, but treatment focuses on improving quality of life through procedures to correct physical abnormalities, growth hormone therapy, education support, and genetic counseling.

1. By,
Aleena Georgekutty
Pharm D Intern

2. AARSKOG-SCOTT SYNDROME
• Aarskog-Scott Syndrome is a genetic disorder that affects the
development of many parts of the body. This condition mainly affects
males, although females may have mild features of the syndrome.
• People with Aarskog-Scott Syndrome often have distinctive facial
features, such as widely spaced eyes (hypertelorism) , a small nose, a
long area between the nose and the mouth(philtrum), and a widow’s
peak hairline.
• Frequently have mild to moderate short stature during childhood, but
their growth usually catches up with that of their peers during puberty.
• Hand abnormalities are common in this syndrome and include short
fingers(brachydactyly), curved pinky fingers(fifth finger
clinodactyly), webbing of the skin between some fingers(cutaneous
syndactyly) and a single crease across the palm.

3. • Other abnormalities in people with Aarskog-Scott Syndrome
include heart defects and a split in the upper lip(cleft lip) with
or without an opening in the roof of the mouth(cleft palate)
• Most males with syndrome have a shawl scrotum, in which the
scrotum surrounds the penis instead of hanging below. Less
often they have undescended testes(cryptorchidism) or a soft
out-pouching around the belly-button(umbilical hernia) or in
the lower abdomen(inguinal hernia).

4. Hypertelurism
Philtrum

5. BrachydactylyWidows peak hairline

6. clinodactyly Cutaneous syndactyly umbilical hernia

7. Cleft palate cleft lipSingle crease
across the palm

8. History:
• The syndrome is named for Dagfinn Aarskog, a Norwegian
pediatrician and human geneticist who firstly described it I
1970, and for Charles.I.Scott, Jr.,an American medical
geneticist who independently described the syndrome in
1971.

9. Affected Populations
• Approximately 50 reports of Aarskog syndrome confirmed by
identification of a FGD1gene 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.

10. Other names:
• Aarskog Scott Syndrome
• Faciodigitogenital syndrome
• Faciogenital dysplasia
• Aarskog disease
• FGDY
• Scott Aarskog Syndrome
CAUSES:
Aarskog syndrome is a genetic disorder that is linked to the X
chromosome. It affects mainly males, but females may have a milder
form. The condition is caused by changes (mutations) in a gene called
“faciogenital dysplasia”(FGD1).

11. SYMPTOMS:
• Belly button that sticks out
• Bulge in the groin or scrotum
• Delayed sexual maturity
• Delayed teeth
• Downward palpebral slant to eyes (slant from outer to inner corner of eye)
• Hairline with a widows peak
• Mildly sunken chest
• Mild to moderate chest problems
• Mild to moderate short height which may not be obvious until the child is
1-3 years old
• Poorly developed middle section of the face
• Rounded face
• Scrotum surrounds the penis(shawl scrotum)
• Short fingers and toes with mild webbing
• Single crease in the palm of the hand
• Small broad hands and feet with short fingers and curved in fifth finger
• Small nose with nostrils tipped forward

12. Genetics

13. Genetics
• Mutations in the FGD1 gene are the only known genetic cause of
aarskog-scott syndrome. The FGD1 gene provides instructions for
making a protein that turns on (activates) another protein called
Cdc42, which transmits signals that are important for various aspects
of development before and after birth.
• Mutations in the FGD1 gene lead to the production of an abnormally
functioning protein. These mutations disrupt Cdc42 signalling, leading
to the wide variety of abnormalities that occur in people with
Aarskog-Scott Syndrome.
• Only about 20 percent of people with this disorder have identifiable
mutations in the FGD1 gene. The cause of Aarskog-Scott Syndrome in
other affected individuals is unknown.

14. Pathophysiology:
• The Aarskog-Scott Syndrome is due to mutation in the FGD1 gene. FGD1 encodes a
guanine nucleotide exchange factor(GEF) that specifically activates Cdc42, a
member of the Rho(Ras homology) family of the p21 GTPases. By activating
Cdc42,FGD1 protein stimulates fibroblasts to form filopodia, cytoskeletals involved
in cellular signalling,adhesion and migration. Through Cdc42, FGD1 protein also
activates the c-jun N-terminal kinase(JNK) signalling cascade, a pathway that
regulates cell growth,apoptosis,and cellular differentiation.
• Within the developing mouse skeleton,FGD1 protein is expressed in
precartilagenous mesenchymal condensations,the perichondrium and
periosteum,proliferating chondrocytes, and osteoblasts. The characterization of the
spatiotemporal pattern of FGD1 expression in mouse embryos has provided
important clues to the understanding of the pathogenesis of Aarskog-Scott
Syndrome.
• Primary defect in syndrome is an abnormality of FGD1/Cdc42 signalling resulting
in anomalous embryonic development and abnormal endochondral and
intramembranous bone formation.

15. Mode of Genetic Exhibition
• Normally, of the 23 pairs of chromosomes that a human possesses, the
last pair is anasomal, meaning that this chromosome determines the
sex of a child. Male offspring have one X and one Y chromosome,
while for a female there are two X chromosomes.
• This particular disorder is X-linked recessive. Hence, in a male who
has only one X-chromosome, if a mutation happens, this will likely
result in the development of the disease.
• In females who have two X chromosomes, if one allele is mutated , it
does not show any major effects as the allele on the other X-
chromosome compensates and they become carriers of the syndrome.
Such people never exhibit any signs of the disease.

16. Mode of gGenetic Transformation
Case 1: Inheritance from a carrier mother and a normal father
• Let us consider the genetic pattern of the affected mother as X1 X, where “X1” is the mutated
allele. In this case, the father would be normal with the XY pattern.
• While transferring traits to the next generation, a child can have any one of the following
patterns: X1X, X1Y, XX, or XY. Here, there is a 50% chance of inheritance of the affected
gene. The girl child with this trait will act as a carrier due to the presence of only one affected
X-allele, while a boy child who has acquired the trait will surely be affected by the syndrome.
Thus, the male child of an affected mother is more prone to the syndrome than a female child.
Case 2: Inheritance from an affected father and a normal mother
• Let us now consider the genetic pattern of the affected father as X1Y, where X1 is the
mutated gene. Here, the mother would be normal with the XX pattern.
• In the genetic transfer that happens in this case, the possible inheritances are X1X and XY.
This shows that the boy child of an affected father and a normal mother will not get the
syndrome, while the girl child of this pair remains a carrier.

17. Case 3: When mother is carrier and father is affected
• In this case, the genetic pattern of the mother may be X1X and for the father it
would be X1Y. The possible inheritance here would be X1X1, X1Y, X1X, and XY.
Of the two chances of a female child, one can be highly infected while the other
remains a carrier. Similarly, there is a 50% chance for the boy child to be affected
while the remaining 50% will be normal.
• The above cases can differ accordingly when the mother has the disease , which is a
very rare case.
Diagnosis of Aarskog Syndrome
• Most signs of Aarskog syndrome are visible from the time of birth. Persons with this
syndrome have typical facial abnormalities, which is diagnostic in most cases.
Changes are commonly seen in the lower, middle, and upper portions of the face.
For example:
• widow’s peak hair (scalp hair growth in the center of the forehead)
• excessive distance between the eyes, known as ocular hypertelorism
• expanded width of the forehead
• descending slant of the opening of the eye
• drooping of the eyelids

18. • Aarskog syndrome diagnosis for children is done by examining of
these facial changes as well as other genital and skeletal features. The
physician might execute a full-body examination for the child. The
family medical history also plays a vital role in diagnosis of this
disease. If a child is suspected to have Aarskog, the doctor may advise
for a genetic test to identify the mutation in the child’s FGD1 gene.
• This test is only available in research laboratories. X-rays also help in
determining the severity of the disease.
• In rare cases, families tend to notice the hereditary occurrences of
Aarskog syndrome. In such cases ultrasound examination of feet, face,
and hands is done to identify the disease. Clinically, this is not widely
used because the syndrome does not have any medical severities.

19. Possible Treatment Plans
• Treatment is provided to improve the quality of life, as there is no
permanent cure yet for this syndrome. Usually, symptoms are visible
by the time the child is three years old, so treatment is started at this
early stage so that patients can achieve a reasonable degree of
normality as they grow older. Every patient with Aarskog syndrome
needs an individual comprehensive therapy plan for treatment.
• The peculiar abnormalities in the patient with their characteristic
symptoms require the services of a specialist team of healthcare
providers to provide a harmonized treatment.
• Facial and dental irregularities are corrected by orthodontic treatment.
• Surgical procedures are carried out to treat anomalies like cleft lip or
palate and genital defects.
• Growth hormone (GH) treatment is given to correct growth
retardation in stunted people.
• Auxiliary treatments are given to persons with intellectual
deficiencies, including educational assistance
• Genetic counseling may be required for the parents.

20. Surgeries
• Genital disorders like inguinal hernia and undescended testicles are treated
with the help of surgery.
• Inguinal hernia repair surgery: This surgery is performed when the child
is 12 months old. An internal opening in the inguinal canal located near the
abdominal or belly wall is called the hernia orifice. Various abdominal
structures may descend through this opening to form an inguinal hernia. A
small incision is made on the abdomen through which the hernial sac is
removed and the opening in the inguinal canal is closed by applying
sutures.
• Cryptorchidism surgery: The condition in which either one or both the
testicles have not dropped to their correct position in the scrotum is termed
as cryptorchidism (undescended testicles). Surgery in this condition is
usually performed in infants at 5-15 months of age. A small incision near
the groin locates the testicles and a second incision in the scrotum is made
to replace them in the proper location. Both the incisions are closed with
biodegradable sutures.
• Cleft lip or palate surgery: This surgery is done within 12 months of the
birth of the child. Here, the lip abnormality is repaired and the cleft closed
through a surgical procedure. Presurgical procedures of lip repairing
include:
– Improving the position of the maxillary alveolar arches by orthopedic
treatment
– Performing nasoplasty if nasal deformity is present as well

21. • Cleft palate surgery: Submucous cleft palate is corrected onlly if the child
has problems during feeding and speech activity. This surgery can be
performed on a secondary level to correct the nasal tip deformity after the
completion of nasal growth.
Growth Hormone Treatment
• GH is generally used to enhance the height of a person. Studies reveal that
individuals who had ASS, when treated with GH, showed an increase in
their height without any side effects. Here, selected doses of GH are
administered for a period of six months to two years at specific intervals.
However, some patients did not show any improvement in height even after
receiving higher doses of GH.
Treatment of Eye Defects
• Some persons with ASS have defects in the eyes, which commonly result in
strabismus and nystagmus.
• Strabismus treatment: This condition refers to the irregular positioning of
the eyes, which leads to improper vision. The treatment involves either:
• patching of the normal eye to attain normal vision in the lazy eye
• performing surgery to modify the eye muscles, so that they can move in a
coordinated manner.
• Nystagmus treatment: An involuntary back-and-forth movement of the
eyes is referred to as nystagmus. Glasses and contact lenses are used to
treat this condition.