SHORT Syndrome

Excerpt

Clinical characteristics: SHORT syndrome is a mnemonic for short stature, hyperextensibility, ocular depression (deeply set eyes), Rieger anomaly, and teething delay. It is now recognized that the features most consistently observed in SHORT syndrome are mild intrauterine growth restriction (IUGR); mild to moderate short stature; partial lipodystrophy (evident in the face, and later in the chest and upper extremities, often sparing the buttocks and legs); and a characteristic facial gestalt. Insulin resistance may be evident in mid-childhood or adolescence, although diabetes mellitus typically does not develop until early adulthood. Other frequent features include Axenfeld-Rieger anomaly or related ocular anterior chamber dysgenesis, delayed dentition and other dental issues, and sensorineural hearing loss.

Diagnosis/testing: The diagnosis of SHORT syndrome is established in a proband with compatible clinical features (with emphasis on the facial gestalt) and a heterozygous pathogenic variant in PIK3R1 identified by molecular genetic testing.

Management: Treatment of manifestations: Glaucoma: reduce and stabilize intraocular pressure and to preserve vision. Sensorineural hearing loss: use of hearing aids. Dental anomalies: standard treatment; may include crowns and dental prostheses. Glucose intolerance and diabetes mellitus: to be followed by an endocrine specialist.

Surveillance: Regular monitoring of growth including height, weight, and body mass index. For all individuals with and without apparent anterior chamber anomaly: routine eye examinations to include measurement of intraocular pressure. Hearing assessment every two to three years. Screening for insulin resistance by oral glucose tolerance test every five years in the absence of diabetes. Annual screening lab tests for diabetes mellitus beginning after age ten years.

Agents/circumstances to avoid: Administration of human growth hormone as it may exacerbate insulin resistance. One individual with SHORT syndrome had worsening insulin resistance when treated with metformin; additional study is needed to determine the effects of this drug.

Pregnancy management: If present, diabetes mellitus is managed as appropriate.

Genetic counseling: SHORT syndrome is inherited in an autosomal dominant manner. The proportion of individuals with SHORT syndrome caused by a de novo pathogenic variant is unknown but appears to be significant. Each child of an individual with SHORT syndrome has a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk and preimplantation genetic testing are possible if the pathogenic variant has been identified in an affected family member.