ESPE Abstracts

Background: “SHORT syndrome” is a rare condition and mnemonic for Short stature, Hyperextensibility, Ocular depression, Rieger anomaly and Teething delay. The features most consistently observed in SHORT syndrome are mild intrauterine growth restriction; mild to moderate short stature; partial lipodystrophy; and a characteristic facial gestalt (small chin, triangular shaped face, prominent forehand, abnormal positioning large ears and thin wrinkled skin). Insulin resistance may be evident in mild-childhood or adolescence although diabetes mellitus typically does not develop until early adulthood. The diagnosis is established with compatible clinical features and a heterozygous pathogenic variant in PIK3R1gene (5q13.1), encoding phosphatidylinositol 3-kinase regulatory subunit alpha.

Case Presentation: A 12-years-old male presented at the endocrinology clinic at the age of 3 years because of failure to thrive and short stature (3rd percentile). The proband was born full term with IUGR features (Birth Weight: 2200gr, Length: 48 cm, Head Circumference: 32 cm) and dysmorphic facial characteristics, suggestive of Russel Silver syndrome. However normal genetic testing ruled it out. He had normal male karyotype (46,XY), and the molecular karyotyping did not reveal any chromosomal aberrations. During follow up, his height and weight were always below the 3rd percentile. At the age of 5, failing to demonstrate catch-up growth, treatment with growth hormone was initiated, showing moderate response. At the age of 10, due to the combination of lipodystrophy, short stature and dysmorphic features, whole-exome sequencing (WES) study was performed, reporting no genetic alterations. At the age of 11, while he was still under treatment with GH, he developed acanthosis nigricans. Oral glucose tolerance test was performed, revealing normal glucose response but severe insulin resistance. This new finding in combination with child’s phenotype, were highly suggestive of SHORT syndrome. Hence, a reevaluation of WES was requested, detecting a de novo mutation c.1945C>T (P.ARG649Trp, R649W) at the exon 15 of the gene PIK3R1, confirming the hypothesis. This mutation is thought to impair the PI3K/AKT/mTOR pathway which plays an important role in cellular proliferation and growth and appears to disrupt the insulin signaling pathway and thereby predispose the patient to insulin resistance and diabetes mellitus.

Discussion: This case also underlines the importance of re-analysis of WES when new clinical data emerge. Diagnosis of SHORT syndrome is important for the appropriate personalized treatment, considering that GH administration can induce hyperinsulinemia which might aggravate insulin resistance and accelerate the onset of diabetes. Subsequently despite short stature, GH is not recommended.