NORD gratefully acknowledges Dr. Alfredo Orrico, Molecular Medicine and Genetics, Azienda Ospedaliera Universitaria Senese, Viale Bracci. Siena, and Clinical Genetics. USL SudEst. Misericordia Hospital. Grosseto, Italy, for assistance in the preparation of this report.
Aarskog syndrome is a rare genetic condition characterized by short stature and multiple facial, limb and genital abnormalities. Additionally, some types of cognitive disorders may occasionally be present. Up to now, the FGD1 gene on the X chromosome is the only gene known to be associated with Aarskog syndrome.
Aarskog syndrome primarily affects males. Affected boys exhibit a characteristic set of facial, skeletal, and genital abnormalities. Clinical signs may vary from person to person (clinical heterogeneity), even within families. 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.
These children 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).
Aarskog syndrome is basically a skeletal dysplasia and affected males 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). Individuals with Aarskog syndrome may 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).
Signs that help to make a diagnosis in males with Aarskog syndrome are the genital abnormalities, including a characteristic 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).
Intellectual disability has been described in some affected boys but it is not a consistent feature of the disorder. Affected individuals may present with a range of mild learning difficulty and/or behavioral disorders: affected children may exhibit developmental delay during infancy, hyperactivity, attention deficit, impulsivity and opposition. Due to this possible spectrum of characteristics, the condition is also referred to as an ADHD syndromic disorder (MRXS16). Failure to gain weight and grow at the expected rate (failure to thrive) and development of chronic respiratory infections have also been described.
An additional spectrum of signs and/or 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). Some patients have been reported to have a tendency to be overweight.
Although Aarskog syndrome is a clinically and genetically heterogeneous condition, the best characterized form of the disorder is inherited as an X-linked trait and caused by changes (mutations) in the FGD1 gene. Aarskog syndrome primarily affects males. However, females who carry a single copy of a FGD1 gene mutation (heterozygotes) may exhibit some of the symptoms associated with the disorder. FGD1 gene mutations have been identified in approximately 22% of affected males; therefore, it is likely that other genes not yet identified may also be associated with this condition.
X-linked recessive genetic disorders are conditions caused by mutations in a gene located on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” to correct a dosage imbalance and almost all of the genes on that chromosome are silenced (inactivated) through a process defined as X-chromosome inactivation. Females who have a disease causing mutation 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 “silenced”. Males have one only X chromosome and, if they inherit the X chromosome that contains a disease gene, they will develop the disease. In turn, males with a X-linked disorder will pass the disease gene to all of their daughters, who will be carriers of the trait (obligate carriers). Males cannot pass X-linked traits to their sons because they 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.
Approximately 60 reports of Aarskog syndrome confirmed by identification of a FGD1 gene 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.
A diagnosis of Aarskog syndrome may be considered based upon a thorough clinical evaluation, a detailed patient and family history, and the identification of characteristic findings. Molecular genetic testing for FGD1 gene mutations is available to confirm the diagnosis. If a FGD1 gene mutation is not identified, molecular genetic testing for genes associated with similar conditions may be suggested, such as the ROR2 and WNT5A genes associated with Robinow syndrome.
The transition from the classic sequencing of single genes to protocols of next generation sequencing (NGS), recommends at least the use of panels that include, in addition to FGD1, the genes that cause overlapping conditions such as ROR2, WNT5A, PIK3R1, SRCAP, KMT2D, KDM6A, SHOX, CUL7.
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 (hypospadias, inguinal or umbilical hernias, cryptorchidism, unusually severe craniofacial features). Individuals with Aarskog syndrome should receive complete eye and dental evaluations. Growth hormone treatment has been reported to improve height in some children, but confirmation is needed to determine appropriate management and expectations for response. For the possibly neurodevelopmental symptoms, a neuropsychiatric evaluation and input may be indicated. Other treatment is symptomatic and supportive.
Genetic counseling is recommended for affected individuals and their families to clarify the genetic and clinical characteristics, the inheritance, and the recurrence risks of the condition in their families.
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