Insulin resistant diabetes mellitus in SHORT syndrome: case report and literature review

• Published in: Endocrine Journal Vol. 68; no. 1; pp. 111 - 117
• Main Authors: Masunaga, Yohei, Fujisawa, Yasuko, Muramatsu, Mayumi, Ono, Hiroyuki, Inoue, Takanobu, Fukami, Maki, Kagami, Masayo, Saitsu, Hirotomo, Ogata, Tsutomu
• Format: Journal Article
• Language: English
• Published: Japan The Japan Endocrine Society 01.01.2021; Japan Science and Technology Agency
• Subjects: Age; Case reports; Children; Developmental disabilities; Diabetes; Diabetes mellitus; Diurnal; GH therapy; Glucose transporter; Hyperglycemia; Hypoglycemia; Insulin; Insulin resistant diabetes mellitus; Literature reviews; Metformin; Nocturnal; Physical growth; Pubertal development; Puberty; SHORT syndrome; Sodium glucose co-transporter 2 inhibitor; GH therapy; SHORT syndrome; Insulin resistant diabetes mellitus; Sodium glucose co-transporter 2 inhibitor; Pubertal development
• DOI: 10.1507/endocrj.EJ20-0291
• ISSN: 0918-8959; 1348-4540

SHORT syndrome is a rare developmental disorder frequently associated with growth failure and insulin resistant diabetes mellitus (IRDM). Since GH has a diabetogenic effect, GH therapy has been regarded as a contraindication. We observed a Brazilian girl with SHORT syndrome who received GH therapy from 4 6/12 years of age for SGA short stature. GH dosage was increased from 0.23 to 0.36 mg/kg/week, but statural response to GH therapy remained poor. Her blood HbA1c level, though it remained 5.5–6.0% in childhood, began to elevate with puberty and increased to 9.2% at 10 6/12 years of age, despite the discontinuation of GH therapy at 9 11/12 years of age. Laboratory studies indicated antibody-negative IRDM. She was treated with metformin and canagliflozin (a sodium glucose co-transporter 2 (SGLT2) inhibitor), which ameliorated overt diurnal hyperglycemia and mild nocturnal hypoglycemia and reduced her blood HbA1c around 7%. Whole exome sequencing revealed a de novo heterozygous pathogenic variant (c.1945C>T:p.(Arg649Trp)) in PIK3R1 known as the sole causative gene for SHORT syndrome. Subsequent literature review for patients with molecularly confirmed SHORT syndrome revealed the development of IRDM in 10 of 15 GH-untreated patients aged ≥12 years but in none of three GH-treated and six GH-untreated patients aged ≤10 years. These findings imply a critical role of pubertal development and/or advanced age rather than GH therapy in the development of IRDM, and a usefulness of SGLT2 inhibitor in the treatment of IRDM.