Aarskog syndrome.

NORD gratefully acknowledges Marc B. Taub, OD, Associate Professor, Chief of Vision Therapy and Rehabilitation Services, The Eye Center, Southern College of Optometry, Memphis, Tennessee, 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 an extremely rare genetic disorder marked by stunted growth that may not become obvious until the child is about three years of age, broad facial abnormalities, musculoskeletal and genital anomalies, and mild intellectual disability.

Signs & Symptoms

Aarskog syndrome primarily affects males who exhibit a characteristic set of facial, skeletal, and genital abnormalities. In some cases, female carriers may develop a mild form of the disorder. Symptoms may vary from case to case. 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.

Affected individuals 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).

Males with Aarskog syndrome also 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). Approximately 50 percent of individuals with Aarskog syndrome 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).

Males with Aarskog syndrome develop genital abnormalities including an 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).

Mild intellectual disability has occurred in some cases, but is not a consistent feature of the disorder. In some cases, affected children may exhibit hyperactivity, fail to gain weight and grow at the expected rate (failure to thrive), and develop chronic respiratory infections.

Additional 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).

Causes

Clinical genetic investigations have demonstrated conclusively that Aarskog syndrome is transmitted as an X-linked recessive trait. Further studies indicate that the defective gene is located at Gene Map Locus Xp11.21. There is also some evidence that a second form of the disorder is distinguishable, and that this form is transmitted as a “sex-influenced autosomal dominant” trait. The occurrence of male dizygotic twins with an identical de novo mutation in FGD1 that resulted from germline mosaicism has recently been reported.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xp11.21” refers to band 11.21 on the short arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present 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 turned off. Males have one X chromosome and if they inherit an X chromosome that contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. Males cannot pass an X-linked gene to their sons because males 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

Aarskog syndrome is a rare disorder that primarily affects males. However, females who carry a single copy of the disease gene (heterozygotes) may exhibit some of the symptoms associated with the disorder. The disorder is estimated to occur in 1 in 1 million individuals in the general population. However, some mild cases often go unrecognized, making it difficult to determine the true frequency of Aarskog syndrome in the general population.

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 common genetic disorder that is typically evident at birth (congenital). 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. (For more information on this disorder, choose “Noonan” as your search term in the Rare Disease Database.)

Robinow syndrome is an extremely rare inherited disorder 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 case to case. (For more information on this disorder, choose “Robinow” as your search term in the Rare Disease Database.)

“LEOPARD,” an acronym for the characteristic abnormalities associated with the disorder, stands for (L)entigines, multiple black or dark brown “freckle-like” 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 lower right chamber (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 individuals with LEOPARD Syndrome may also exhibit mild mental retardation, speech difficulties, and/or, in some cases, additional physical abnormalities. In most cases, LEOPARD Syndrome appears to occur randomly for unknown reasons (sporadically). However, in other cases, the disorder is thought to be inherited as an autosomal dominant trait. (For more information on this disorder, choose “LEOPARD” as your search term in the Rare Disease Database.)

Diagnosis

A diagnosis of Aarskog syndrome is made based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic findings. X-ray studies can identify distinctive characteristics of Aarskog syndrome and help to differentiate it from similar disorders.

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. Individuals with Aarskog syndrome should receive complete eye and dental evaluations. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

NOTE: The above information is for processing purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.

Original Site: https://rarediseases.org/rare-diseases/aarskog-syndrome/