PIK3R1-Related SHORT Syndrome

Excerpt

Clinical characteristics: PIK3R1-related SHORT syndrome is a mnemonic for short stature, hyperextensibility, ocular depression (deep-set eyes), Rieger anomaly, and teething delay. It is now recognized that the features most consistently observed in PIK3R1-related SHORT syndrome are a characteristic facial gestalt (triangular face, broad forehead, deep-set eyes, narrow nasal tip, thin nasal alae, low-hanging columella, downturned corners of the mouth, chin dimple, and prominent ears), delayed dentition, mild intrauterine growth restriction, mild-to-moderate short stature, and partial lipodystrophy (evident in the face and later in the chest and upper extremities, often sparing the buttocks and legs). 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, vision issues, other dental issues, and sensorineural hearing loss. Cardiac anomalies, connective tissue findings (joint laxity, inguinal hernia), and frequent infections have also been reported.

Diagnosis/testing: The diagnosis of PIK3R1-related SHORT syndrome is established in a proband with characteristic clinical features and a heterozygous pathogenic variant in PIK3R1 identified by molecular genetic testing.

Management: Treatment of manifestations: Treatment for glucose intolerance and diabetes mellitus per endocrinologist; glaucoma treatment by ophthalmologist to reduce and stabilize intraocular pressure and preserve vision; standard management for other ocular findings; treatment for dental anomalies may include crowns and dental prostheses; standard hearing aids for sensorineural hearing loss; speech therapy as needed; treatment of cardiac anomalies per cardiologist; standard treatments for joint laxity, inguinal hernia, and frequent infections.

Surveillance: Assess growth including height, weight, and body mass index every six to 12 months; screening for insulin resistance by oral glucose tolerance test every five years in the absence of diabetes; fasting glucose, insulin, and hemoglobin A1c annually beginning at age ten years; eye examinations to include measurement of intraocular pressure annually; dental examination every six months; hearing assessment every two to three years; assess for joint laxity, hernias, and frequent infections annually.

Agents/circumstances to avoid: Administration of human growth hormone as it may exacerbate insulin resistance. Three individuals with PIK3R1-related SHORT syndrome had worsening insulin resistance when treated with metformin.

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

Genetic counseling: PIK3R1-related SHORT syndrome is inherited in an autosomal dominant manner. Some individuals diagnosed with PIK3R1-related SHORT syndrome have an affected parent; 70% of affected individuals have the disorder as the result of a de novo pathogenic variant. Each child of an individual with PIK3R1-related SHORT syndrome has a 50% chance of inheriting the pathogenic variant. Once the PIK3R1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.