Aarskog-Scott syndrome is a genetic disorder that affects the development of many parts of the body, most commonly the head and face, the hands and feet, and the genitals and urinary system (genitourinary tract). 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 mouth (philtrum), and a widow's peak hairline. They 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. Affected individuals can also have wide, flat feet with broad, rounded toes. 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 Aarskog-Scott 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).

The intellectual development of people with Aarskog-Scott syndrome varies widely. Most individuals with Aarskog-Scott syndrome have normal intelligence; however, some may have mild learning and behavior problems, and in rare cases, severe intellectual disability has been reported.

Variants (also known as 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.

Variants in the FGD1 gene lead to the production of an abnormally functioning protein. These variants disrupt Cdc42 signaling, 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 variants in the FGD1 gene. The cause of Aarskog-Scott syndrome in other affected individuals is unknown.

Normal Function

The FGD1 gene provides instructions for making a protein that functions as a guanine nucleotide exchange factor (GEF). GEFs turn on (activate) proteins called GTPases, which play an important role in chemical signaling within cells. GTPases are turned off (inactivated) when they are attached (bound) to a molecule called GDP and are turned on (activated) when they are bound to another molecule called GTP.

The FGD1 protein activates the GTPase known as Cdc42 by stimulating the exchange of GDP for GTP. Once Cdc42 is active, it transmits signals that are critical for various aspects of development before and after birth, particularly the development of bones. The FGD1 protein may also be involved in maintenance (remodeling) of the extracellular matrix, which is the intricate lattice of proteins and other molecules that forms in the spaces between cells. Through this process, the protein appears to play a role in cell movement (migration) and the remodeling of blood vessels.

Health Conditions Related to Genetic Changes

Aarskog-Scott syndrome

More than 40 variants (also known as mutations) in the FGD1 gene have been found to cause Aarskog-Scott syndrome, a rare condition that occurs primarily in males. Affected boys typically have distinctive facial features, genital abnormalities, childhood short stature, and other skeletal abnormalities. The FGD1 gene variants lead to the production of an abnormally functioning FGD1 protein, which disrupts Cdc42 signaling. Altering the transmission of Cdc42 signals likely impairs normal development of bones and other tissues, resulting in the wide variety of abnormalities that occur in people with Aarskog-Scott syndrome.

Other Names for This Gene

• AAS
• faciogenital dysplasia protein
• FGD1_HUMAN
• FGDY
• ZFYVE3

Genomic Location

When caused by FGD1 gene variants, Aarskog-Scott syndrome is inherited in an X-linked recessive pattern. The FGD1 gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a variant would have to occur in both copies of the gene to cause Aarskog-Scott syndrome. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. Females who carry one altered copy of the FGD1 gene may show mild signs of the condition, such as hypertelorism, short stature, or a widow's peak hairline. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Evidence suggests that Aarskog-Scott syndrome is inherited in an autosomal dominant or autosomal recessive pattern in some families, although the genetic cause of these cases is unknown. In autosomal dominant inheritance, one copy of the altered gene in each cell is sufficient to cause the disorder. In autosomal recessive inheritance, both copies of the gene in each cell have variants. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

Aarskog-Scott syndrome is believed to be a rare disorder; however, its prevalence is unknown because mildly affected people may not be diagnosed.

When do symptoms of this disease begin? 2-11 years

When meeting with your Medical Team:

Describe details about the symptoms. Because there may be many different causes for a single symptom, it is best not to make a conclusion about the diagnosis. The detailed descriptions help the medical provider determine the correct diagnosis.

To help describe a symptom:

• Use a smartphone or a notebook to record each symptom before the appointment
• Describe each symptom by answering the following questions:
  • When did the symptom start?
  • How often does it happen?
  • Does anything make it better or worse?
• Tell the medical team whether any symptoms affect daily activities

Preparing for the First Visit

Working with a medical team to find a diagnosis can be a long process that will require more than one appointment. Make better health decisions by being prepared for the first visit with each member of the medical team.

Make informed decisions about health care:

• Prepare a list of questions and concerns before the appointment
• List the most important questions first, not all questions may be answered in the first visit
• Ask questions about symptoms, possible diagnoses, tests, and treatment options

For future appointments:

• Discuss what was not addressed at the last visit
• Discuss changes in the quality of life for the patient, family, and caregivers
• Discuss health goals and other issues in the patient’s and family’s life that may affect the health care decisions

Take notes during the appointments to help remember what was discussed.