INSR-Related Severe Insulin Resistance Syndrome

Clinical characteristics: INSR-related severe insulin resistance syndrome (INSR-SIRS) comprises a phenotypic spectrum that is a continuum from the severe phenotype of Donohue syndrome to the milder phenotype of Rabson-Mendenhall syndrome (RMS).

Donohue syndrome is characterized by severe insulin resistance (hyperinsulinemia with associated fasting hypoglycemia and postprandial hyperglycemia), severe prenatal growth restriction, postnatal growth failure, hypotonia, developmental delay, characteristic facies (proptosis, infraorbital folds, large, low-set, posteriorly rotated ears, thick vermilion of the upper and lower lips, and gingival hypertrophy), and organomegaly involving the heart, kidneys, liver, spleen, and ovaries. Death usually occurs before age one year.

RMS, at the milder end of the spectrum, is characterized by severe insulin resistance that, although not as severe as that of Donohue syndrome, is nonetheless accompanied by fluctuations in blood glucose levels, diabetic ketoacidosis, and – in the second decade – microvascular complications. Findings can range from severe growth delay and intellectual disability to normal growth and development. Facial features can be milder than those of Donohue syndrome. Complications of longstanding hyperglycemia are the most common cause of death. While death usually occurs in the second decade, some affected individuals live longer.

Diagnosis/testing: The diagnosis of INSR-SIRS is established in a proband with characteristic clinical, laboratory, radiographic, and prenatal ultrasound findings and biallelic INSR pathogenic variants identified by molecular genetic testing.

Management: Treatment of manifestations: Donohue syndrome: no effective treatments for insulin resistance or other manifestations of Donohue syndrome are currently available. Frequent feedings as well as increased protein content of evening feedings can help prevent fasting hypoglycemia.

RMS: Insulin sensitizers are used first to decrease levels of glucose and glycosylated hemoglobin (HbA1c); however, their effect diminishes with time, often requiring dose adjustments and multidrug therapy. When hyperglycemia persists, insulin is started – usually in high doses, especially during the treatment of diabetic ketoacidosis. Standard treatment for hypothyroidism; oral contraceptives, antiandrogen therapies, and gonadotropin-releasing hormone agonists can be used to treat hyperandrogenism; oophorectomy may be needed for enlarged ovaries; nutritional, developmental, and educational support; rigorous workup and treatment of intercurrent infections; beta-blockers for cardiomyopathy; treatment of nephrocalcinosis per nephrologist; treatment of cholestasis per gastroenterologist; treatment of rectal prolapse per surgeon; standard treatments for malignancies; social work and family support.

Surveillance: Capillary glucose levels during fasting and after feeding, when clinically indicated, or continuous monitoring; HbA1c, insulin, and C-peptide levels every three months; thyroid function and hyperandrogenism lab assessment every six months or as clinically indicated; ovarian ultrasound every three months until age two years, then every six months or as indicated; nutrition and growth assessment at each visit; assess psychomotor development every three months; assess for recurrent infections at each visit; echocardiogram and cardiac MRI every six months (each test alternating every three months) until age two years, then annually (each test alternating every six months) or as indicated; urine calcium and kidney ultrasound every six months; gynecologic evaluation for endometrial cancer in those with abnormal vaginal bleeding.

Agents/circumstances to avoid: In Donohue syndrome, avoid agents that cause hypoglycemia, prolonged fasting, and contact with persons with contagious disease. In RMS avoid agents that cause hypoglycemia, high-carbohydrate diet, and contact with persons with contagious disease.

Genetic counseling: INSR-SIRS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an INSR pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected with INSR-SIRS, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial INSR pathogenic variants. Heterozygotes are usually asymptomatic but may have features of the allelic disorder type A insulin resistance. Once the INSR pathogenic variants have been identified in an affected family member, heterozygote testing for at-risk relatives and prenatal and preimplantation genetic testing are possible. (Of note: Heterozygotes for an INSR pathogenic variant are at increased risk for gestational diabetes and require monitoring for glucose intolerance before and during pregnancy.)