INSR – Rabson-Mendenhall Syndrome

Rabson-Mendenhall syndrome (RMS; MONDO:0009874) is a rare autosomal recessive disorder caused by biallelic loss-of-function variants in the insulin receptor gene (INSR, HGNC:6091). Affected individuals present in infancy with severe insulin resistance, hyperinsulinemia, growth retardation, dental anomalies, and characteristic dysmorphic features including acanthosis nigricans.

Clinical Validity

Extensive evidence from case reports and series supports a Definitive gene–disease association: at least 42 unrelated RMS patients with biallelic INSR variants across multiple families, autosomal recessive segregation, and concordant functional data ([PMID:38957655]).

Genetic Evidence

INSR-related RMS follows autosomal recessive inheritance. Compound heterozygous or homozygous variants have been identified in affected probands, with parental carrier segregation confirmed by parental sequencing ([PMID:8270132]). Across 33 articles, over 42 cases exhibit pathogenic variants including nonsense, frameshift, missense, splice-site, and intragenic deletions. A representative variant is c.712G>A (p.Glu238Lys), detected in a Korean RMS patient and segregating with disease ([PMID:22563226]).

Variant Spectrum & Phenotype

The variant spectrum includes missense substitutions in extracellular and kinase domains, premature stop codons, splice-site disruptions, and small deletions. Recurrent and population-specific alleles have not been reported, indicating high allelic heterogeneity. Phenotypic hallmarks are severe hyperinsulinemia, growth delay, dental dysplasia, and acanthosis nigricans, often manifesting within the first year of life.

Functional Evidence

In vitro studies demonstrate that RMS-associated INSR variants impair receptor processing, cell-surface expression, insulin binding, and autophosphorylation. For example, the Gly359Ser variant reduces mature receptor levels to 10–30% of normal and abrogates kinase activity ([PMID:17201797]). The Ala1162Glu mutation similarly disrupts proreceptor processing and tyrosine kinase function ([PMID:8096518]). These findings corroborate haploinsufficiency as the principal mechanism.

Conclusion

Biallelic loss-of-function mutations in INSR are conclusively linked to Rabson-Mendenhall syndrome. Genetic testing for INSR variants should be pursued in infants presenting with extreme insulin resistance and characteristic dysmorphism. Functional assays of novel variants further enhance diagnostic confidence and inform family counseling.

Key take-home: INSR mutation testing provides definitive molecular diagnosis and guides management of Rabson-Mendenhall syndrome.

References

• Diabetologia • 1993 • An in-frame insertion in exon 3 and a nonsense mutation in exon 2 of the insulin receptor gene associated with severe insulin resistance in a patient with Rabson-Mendenhall syndrome PMID:8270132
• Journal of clinical endocrinology and metabolism • 2012 • Two novel insulin receptor gene mutations in a patient with Rabson-Mendenhall syndrome: the first Korean case confirmed by biochemical, and molecular evidence PMID:22563226
• Journal of the Endocrine Society • 2024 • Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients PMID:38957655
• Clinical endocrinology • 2007 • Functional characterization of a novel insulin receptor mutation contributing to Rabson-Mendenhall syndrome PMID:17201797
• The Journal of biological chemistry • 1993 • Substitution of glutamic acid for alanine 1135 in the putative "catalytic loop" of the tyrosine kinase domain of the human insulin receptor PMID:8096518

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