Clinical characteristics: INSR-related severe syndromic insulin resistance comprises a phenotypic spectrum that is a continuum from the severe phenotype Donohue syndrome (DS) (also known as leprechaunism) to the milder phenotype Rabson-Mendenhall syndrome (RMS).
DS at the severe end of the spectrum is characterized by severe insulin resistance (hyperinsulinemia with associated fasting hypoglycemia and postprandial hyperglycemia), severe prenatal growth restriction and postnatal growth failure, hypotonia and developmental delay, characteristic facies, and organomegaly involving 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 DS, 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 DS. 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-related severe syndromic insulin resistance is established in a proband with characteristic clinical findings and biallelic INSR pathogenic variants identified by molecular genetic testing.
Management: Treatment of manifestations:
DS. No effective treatments for insulin resistance or other manifestations of DS 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.
Anti-androgen therapies can be used to treat hyperandrogenism. Oophorectomy may be needed.
Surveillance: Routine monitoring of psychomotor development; glucose levels, HbA1c levels, thyroid function for evidence of hypothyroidism; cardiac status; ovarian size by ultrasound examination; urine for hypercalciuria and kidneys for nephrocalcinosis by ultrasound examination.
Agents/circumstances to avoid in DS: Agents that cause hypoglycemia; prolonged fasting; contact with persons with contagious disease.
Pregnancy management: Heterozygotes for an INSR pathogenic variant are at increased risk for gestational diabetes and require monitoring for glucose intolerance before and during pregnancy. Of note, gestational diabetes, which can be hard to control, requires high doses of insulin. A high-resolution fetal ultrasound examination with fetal echocardiogram to screen for malformations is recommended; referral to a maternal-fetal medicine specialist for diabetic management during pregnancy may be considered.
Therapies under investigation: Recombinant human IGF-1(rhIGF-1) shows promise in the treatment of severe insulin resistance; however, its benefit is not well established and it is more likely to be effective in individuals with less severe insulin resistance as the few individuals with prolonged survival with rhIGF-1 treatment had milder phenotypes. Although treatment of RMS with meterleptin (leptin replacement therapy) was beneficial to metabolic control, data to date are insufficient to support its use in patient care.
Genetic counseling: INSR-related severe syndromic insulin resistance is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the INSR pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.
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