Aarskog syndrome is a genetic condition affecting an individual's height, facial features, hands, feet, genitals, urinary tract, and overall appearance. It is inherited through the X chromosome and is caused by mutations (changes in the DNA sequence) in a specific gene called "faciogenital dysplasia" (FGD1).

Overview

Aarskog syndrome, sometimes called faciogenital dysplasia, is a rare, X-linked recessive genetic condition characterised by short stature and multiple facial, genitourinary tract (genital and urinary system), and limb abnormalities. It was first described by Aarskog in 1970 and further refined by Scott in 1971. The syndrome predominantly impacts males. Carrier females may exhibit subtle characteristics, such as a widow's peak or shorter stature. Aarskog syndrome affects 1 in 25.000. Mutations in the FGD1 gene are the only known cause of this syndrome. While most people affected do not have delayed intellectual development, some may show neurobehavioural characteristics which can range from attention deficit and hyperactivity disorder (ADHD) to severe intellectual disability.^1,2

Symptoms

Symptoms of the disease may include:

A soft protrusion around the belly button (umbilical hernia) or the lower abdomen (inguinal hernia).

Bulge in the groin or scrotum

Scrotum that surrounds the penis (shawl scrotum)

Testis that have not come down (cryptorchidism)

Delayed sexual maturity

Delayed teeth

Hairline with a "widow's peak"

Widely spaced eyes (hypertelorism) with droopy eyelids

Chest wall deformity (pectus excavatum)

Mild to moderately short stature, which may not become apparent until the child is 1 to 3 years old

Poorly developed middle section of the face

Rounded face

Small nose with nostrils tipped forward

Slight fold in the upper part of the ear

Small, broad hands

Short fingers (brachydactyly)

Curved pinky fingers (fifth finger clinodactyly)

Webbing of the skin between some fingers

Single palmar crease 

Feet are typically flat and wide, with broad, rounded toes and mild webbing

Most people with Aarskog-Scott syndrome have average intelligence; however, some may have mild challenges with learning and behaviour, including those with ADHD,³ and in rare cases, severe intellectual disability. 

Causes

Mutations in the FGD1 gene are the primary known cause of Aarskog syndrome, but only about 20% of those affected have confirmed variants in the FGD1 gene. A recently published study explained that this could be due to additional undetected FGD1 variants or the involvement of epigenetic or other external factors.

The FGD1 gene provides instructions for making a protein that regulates many physiological functions, such as cell structure, bone cell formation, tissue remodelling, and cell trafficking. Research has shown that the essential role of the FGD1 protein is in bone development.

The FGD1 protein activates another protein called Cdc42, which transmits signals important for various aspects of development before and after birth. It is thought that dysregulated FGD1/Cdc42 signalling could play a significant role in early bone formation and contribute to Aarskog syndrome.^4,5 

X-linked recessive genetic disorders are characterised by mutations in genes located on the X chromosome. Females have two of the same sex chromosomes in their cells (XX), whereas males possess one X and one Y sex chromosome (XY) in their cells. As males only have one copy of each X chromosome gene, if they carry the pathogenic variant, they will be affected by the condition themselves. Males with an X-linked disorder will pass the disease gene to all their daughters, making them carriers of the condition. However, males cannot pass X-linked conditions to their sons because sons inherit their X chromosome from their mothers, not their fathers.

A female with a mutation on one X chromosome and a normal gene on the other is usually unaffected or affected only mildly. Females carrying a disease-causing mutation on one X chromosome are considered carriers. Typically, these carriers do not display symptoms because the X chromosome with the abnormal gene is often “inactivated”. In each pregnancy, a female carrier of an X-linked disorder has a 25% chance of having a daughter who is also a carrier of the condition, a 25% chance of having a non-carrier daughter, a 25% chance of having a son with the disease, and a 25% chance of having an unaffected son.

Tests and diagnoses

A diagnosis of Aarskog syndrome can be made through a careful medical exam, a detailed family history, and the identification of typical features of the condition.

 The following tests may be done:

• Molecular genetic tests to find mutations in the FGD1 gene
• Next-generation sequencing (NGS) using targeted gene panels that include not only FGD1 but also genes associated with related conditions, such as ROR2, WNT5A, PIK3R1, SRCAP, KMT2D, KDM6A, SHOX, and CUL7
• X-rays

Treatment

Treating Aarskog syndrome often involves a multidisciplinary approach, requiring collaboration among specialists such as paediatricians, cardiologists, dentists, speech therapists, audiologists, surgeons, ophthalmologists, and other healthcare providers.

Sometimes surgery is required to treat specific congenital or structural abnormalities associated with the syndrome, such as hypospadias, inguinal or umbilical hernias, cryptorchidism (undescended testicles), and severe craniofacial features. People with Aarskog syndrome should get detailed eye and dental check-ups.

Growth hormone treatment has been shown to increase height in some children. For potential neurodevelopmental symptoms, a neuropsychiatric evaluation may be recommended. Affected individuals and their families are advised to seek genetic counselling to understand the genetic and clinical aspects of the condition, including inheritance patterns and the risk of recurrence within their families.

Prognosis

Some individuals may have slowed thinking. Generally, children affected by the syndrome have good social interactions. Some males may experience fertility issues.

Potential complications

The following complications may arise:

Brain changes

Difficulty in growth during the first twelve months of life

Teeth that are not properly aligned

Undescended testicles

Seizures

Alternative names of the disease

Aarskog disease

Aarskog-Scott syndrome

Scott Aarskog syndrome

AAS

Faciodigitogenital syndrome

Faciogenital dysplasia

FGDY

Summary

Aarskog syndrome is a rare genetic disorder characterised by short stature and various facial, genitourinary tract, and limb abnormalities. Although mutations in the FGD1 gene are considered a primary cause, confirmed variants in this gene are found in only about 20% of affected individuals. Genetic testing for Aarskog syndrome involves either specifically testing the FGD1 gene to identify variants or using next-generation sequencing (NGS) to check a group of genes that includes FGD1 and related genes like ROR2, WNT5A, PIK3R1, SRCAP, KMT2D, KDM6A, SHOX, and CUL7. Treating Aarskog syndrome usually requires a team of specialists such as paediatricians, dentists, audiologists, ophthalmologists, and other healthcare providers. In some cases, surgery is necessary to correct specific birth defects or structural abnormalities associated with Aarskog syndrome, such as hypospadias, inguinal or umbilical hernias, cryptorchidism, and significant craniofacial features. People affected by Aarskog syndrome and their families are advised to seek genetic counselling to learn about the genetic and clinical aspects of the condition, including its inheritance.