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A rare disorder characterized by multiple congenital anomalies. The name is a mneumonic for the common features observed in SHORT syndrome that include; short stature, hyperextensibility of joints, ocular depression, Rieger anomaly and teething delay. Other common manifestations of SHORT syndrome are mild intrauterine growth restriction, partial lipodystrophy, delayed bone age, hernias and a recognizable facial gestalt.
ORPHA:3163Classification level: Disorder
The prevalence of SHORT syndrome is unknown. Less than 50 cases have been reported in the literature to date.
Individuals with SHORT syndrome often display mild intrauterine growth restriction. Feeding difficulties and/or failure to thrive present in early childhood and final adult height is shorter than average (155-163 cm in males and 143-160 cm in females). Most patients have a characteristic facial gestalt, often described as progeroid, with triangular face shape, prominent forehead, ocular depression, hypoplastic alae nasi, low-hanging columella, downturned corners of the mouth, micrognathia and prominent (but not typically low-set or posteriorly located) ears. Partial lipodystrophy may be evident in the face at birth and later in the chest and upper extremities (including the hands), but it is usually not reported in the buttocks and legs. Delayed dentition, hypodontia, enamel hypoplasia, malocclusion and multiple dental caries are frequently reported. Ophthalmic anomalies (e.g. Rieger anomaly, Axenfeld anomaly (see these terms), glaucoma) are also characteristic of the disease. Diabetes is seen in approximately 2/3 of individuals with SHORT syndrome after the age of 15 years. Other less common manifestations include hyperextensibility of joints and/or hernias, sensorineural hearing loss and ovarian cysts in females. Intellectual development and cognition are usually unaffected although mild impairment with speech delay has been reported.
SHORT syndrome is due to mutations in the PIK3R1 gene (5q13.1), encoding phosphatidylinositol 3-kinase regulatory subunit alpha. Mutations are thought to impair the PI3K/AKT/mTOR pathway, which plays an important role in cellular proliferation and growth.
Diagnosis is based on the presence of the characteristic features and confirmed by molecular genetic testing identifying a PIK3R1 mutation. The presence of all 5 features of the acronym is not necessary for a positive diagnosis.
Differential diagnoses include Silver-Russell syndrome, Alagille syndrome, Floating-Harbor syndrome, growth delay due to insulin-like growth factor I resistance, Berardinelli-Seip congenital lipodystrophy and Hutchinson-Gilford progeria syndrome.
Prenatal diagnosis is possible in families with a known disease-causing mutation.
SHORT syndrome is inherited in an autosomal dominant manner. Genetic counseling is recommended for at-risk families. De novo cases have also been described. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
Treatment is symptomatic and requires a multidisciplinary team. Screening for insulin resistance is recommended starting in mid-late childhood. Glucose intolerance and diabetes mellitus can be treated with diet, lifestyle, oral medication and insulin, while growth hormone therapy is contraindicated. Ophthalmological management and follow-up (i.e. regular eye examinations) are necessary to reduce and stabilize ocular pressures and to preserve vision. Dental anomalies can be treated using standard methods (e.g. crowns and dental prostheses).
Individuals with SHORT syndrome are considered to have a normal life-expectancy.