Aarskog syndrome

Definition

Aarskog syndrome is an inherited disorder that causes a distinctive appearance of the face, skeleton, hands and feet, and genitals. First described in a Norwegian family in 1970 by the pediatrician Dagfinn Aarskog, the disorder has been recognized worldwide in most ethnic and racial groups. Because the responsible gene is located on the X chromosome , Aarskog syndrome is manifest almost exclusively in males. The prevalence is not known.

Description

Aarskog syndrome is among the genetic disorders with distinctive patterns of physical findings and is confused with few others. Manifestations are present at birth allowing for early identification. The facial appearance and findings in the skeletal system and genitals combine to make a recognizable pattern. The diagnosis is almost exclusively based on recognition of these findings. Although the responsible gene has been identified, testing for gene mutations is available only in research laboratories. Aarskog syndrome is also called Faciogenital dysplasia , Faciogenitodigital syndrome, and Aarskog-Scott syndrome.

Genetic profile

Aarskog syndrome is caused by mutations in the FGD1 gene, located on the short arm of the X chromosome (Xp11.2). In most cases the altered gene in affected males is inherited from a carrier mother. Since males have a single X chromosome, mutations in the FGD1 gene produces full expression in males. Females who carry a mutation of the FGD1 gene on one of their two X chromosomes are usually unaffected, but may have subtle facial differences and less height than other females in the family.

Female carriers have a 50/50 chance of transmitting the altered gene to daughters and each son. Affected males are fully capable of reproduction. They transmit their single X chromosome to all daughters who, therefore, are carriers. Since males do not transmit their single X chromosome to sons, all sons are unaffected.

The gene affected in Aarskog FGD1 codes for a Rho/Rac guanine exchange factor. While the gene product is complex and the details of its function are incompletely understood, it appears responsible for conveying messages within cells that influence their internal architecture and the activity of specific signal pathways. However, the precise way in which mutations in FGD1 produce changes in facial appearance and in the skeletal and genital systems is not yet known.

Demographics

Only males are affected with Aarskog syndrome, although carrier females may have subtle changes of the facial structures and be shorter than noncarrier sisters. There are no high risk racial or ethnic groups.

Signs and symptoms

Manifestations of Aarskog syndrome are present from birth. The facial appearance is distinctive and in most cases is diagnostic. Changes are present in the upper, middle, and lower portion of the face. Increased width of the forehead, growth of scalp hair into the middle of the forehead (widow's peak), increased space between the eyes (ocular hypertelorism), a downward slant to the eye openings, and drooping of the upper eyelids

(ptosis) are the major features in the upper part of the face. A short nose with forward-directed nostrils and simply formed small ears that may protrude are the major findings in the mid-part of the face. The mouth is wide and the chin small. As the face elongates in adult life, the prominence of the forehead and the increased space between the eyes becomes less apparent. Dental abnormalities include slow eruption, missing teeth and broad upper incisors.

The fingers are often held in a distinctive position with flexion at the joint between the hand and the fingers, over extension at the first joint of the finger and flexion at the second joint. This hand posturing becomes more obvious when there is an attempt to spread the fingers. There may also be some mild webbing between the fingers. The fingers are short and there is often only a single crease across the middle of the palm. The toes are also short and the foot is often bent inward at its middle portion. All of the joints may be unusually loose. Excessive movement of the cervical spine may lead to impingement on the spinal cord. In some cases, the sternum (breastbone) may appear depressed (pectus excavatum).

Changes in the appearance of the genitals may also be helpful in diagnosis. One or both testes may remain in the abdomen, rather than descending into the scrotal sac. The scrotum tends to surround the penis giving a so-called "shawl scrotum" appearance. Hernias may appear in the genital and umbilical regions. Linear growth in childhood and adult height are generally less than in unaffected brothers. The head size is usually normal.

Although most affected males have normal intellectual function, some individuals will have mild impairments. There does not appear to be any particular association with behavioral disturbances. However, attention deficit occurs among some boys with learning difficulties.

Diagnosis

Diagnosis of Aarskog syndrome is made on the basis of clinical findings, primarily analysis of the family history and characteristic facial, skeletal, and genital findings. There are no laboratory or radiographic changes that are specific. Although the diagnosis can be confirmed by finding a mutation in the FGD1 gene, this type of testing is available only in research laboratories.

In families with a prior occurrence of Aarskog syndrome, prenatal diagnosis might be possible through ultrasound examination of the face, hands and feet, or by testing the FGD1 gene. However, this is not generally sought since the condition is not considered medically severe.

Few other conditions are confused with Aarskog syndrome. Noonan syndrome , another single gene disorder that has short stature, ocular hypertelorism, down-slanting eye openings, and depression of the lower chest, poses the greatest diagnostic confusion. Patients with Noonan syndrome often have wide necks and heart defects, which is helpful in distinguishing them from patients with Aarskog syndrome.

The older patient may pose greater difficulty due to loss of facial findings and obscuring of shawl scrotum by pubic hair.

As in many disorders, there is a range of severity of the clinical appearance even within the same family. In these cases, examination of several affected family members and attention to family history may be helpful.

Treatment and management

Since there are no major malformations or major mental disabilities in Aarskog syndrome, the diagnosis may be reassuring. Developmental milestones and school progress should be monitored, as there may be impairment of intellectual function in some individuals.

The X-linked inheritance pattern should be described to the family.

Prognosis

Short-term and long-term prognosis is favorable. Life threatening malformations or other health concerns rarely occur. Special educational attention may be necessary for those with learning difficulties. A minority of affected persons will have spinal cord compression, usually in the neck, causing pain or injury to peripheral nerves. Neurosurgical intervention is necessary in some cases. Hernias in the umbilical and groin areas may be surgically repaired.

Resources

PERIODICALS

Aarskog, D. "A familial syndrome of short stature associated with facial dysplasia and genital anomalies." Journal of Pediatric Medicine 77 (1971): 856.

Pasteris, N. G., et al. "Isolated and characterization of the faciogenital dysplasia (Aarskog-Scott syndrome) gene: A putative Rho/Rac guanine nucleotide exchange factor." Cell 79 (1994): 669.

ORGANIZATIONS

Alliance of Genetic Support Groups. 4301 Connecticut Ave. NW, Suite 404, Washington, DC 20008. (202) 966-5557. Fax: (202) 966-8553. <http://www.geneticalliance.org>.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.

Roger E. Stevenson, MD