Rabson-Mendenhall syndrome (RMS) is an extremely rare autosomal recessive disorder caused by pathogenic variants in the insulin receptor gene that produce profound insulin resistance with compensatory hyperinsulinemia. Classical RMS presentations typically include acanthosis nigricans, a non-obese or underweight body habitus, hirsutism, dental abnormalities, dysmorphic features, and growth abnormalities. However, early recognition can be difficult when patients present with non-specific complaints rather than with overt metabolic symptoms of diabetes.
In this report, a 10-year-old Saudi girl attended a family medicine clinic with intermittent bilateral leg pain and excessive hunger. She did not report polyuria or polydipsia, the classical symptoms that often prompt diabetes evaluation. The absence of those cardinal diabetic symptoms posed a diagnostic challenge and could have delayed recognition of a genetic insulin resistance syndrome if phenotypic clues had been overlooked.
Physical examination revealed several stigmata supportive of an insulin resistance disorder. The patient had extensive acanthosis nigricans, moderate hirsutism, a deepened voice, a high-arched palate, and dental enamel defects. Although RMS is classically associated with growth restriction, this patient was tall for age; interpretation of growth findings was complicated by a family history of tall stature. These discordant growth data emphasize the need to integrate family history and phenotype rather than rely solely on expected growth patterns for diagnosis.
Laboratory evaluation demonstrated severe biochemical insulin resistance. The documented insulin level was markedly elevated at 3522.5 µU/mL, consistent with profound compensatory hyperinsulinemia. Glycemic control was impaired, with an elevated HbA1c of 8.4% (68 mmol/mol). Biochemical hyperandrogenism was also present, aligning with the observed hirsutism and other androgenic features. Together, these laboratory abnormalities—very high insulin, elevated HbA1c, and hyperandrogenism—supported assessment for an underlying genetic insulin receptor defect rather than typical type 1 or type 2 diabetes alone.
Whole-exome sequencing established the molecular diagnosis. Testing identified a homozygous pathogenic variant in the insulin receptor gene: c.433C>T, p.Arg145Cys. This genotype confirmed Rabson-Mendenhall syndrome in this patient. The molecular finding provides a clear etiologic explanation for the severe receptor-level insulin resistance and the constellation of clinical and biochemical findings recorded on presentation.
Management for this patient combined metabolic, educational, and multidisciplinary approaches. Interventions reported included vitamin D supplementation, initiation of metformin, basal-bolus insulin therapy, and addition of dapagliflozin. The care plan also incorporated home glucose monitoring, diabetes education, dietary counseling, and ongoing multidisciplinary follow-up. Despite escalation of therapy, glycemic control remained suboptimal, underscoring the limited responsiveness of receptor-level insulin resistance to conventional glucose-lowering strategies.
This treatment summary reflects pragmatic management choices in severe genetic insulin resistance: insulin-sensitizing agents when feasible, high-dose or intensified insulin regimens acknowledging diminished receptor response, and adjunctive therapies such as sodium–glucose cotransporter 2 (SGLT2) inhibition to address hyperglycemia by insulin-independent mechanisms. The report does not provide detailed dosing, duration, or specific glycemic outcomes after each intervention beyond stating continued suboptimal control.
This case emphasizes several practical lessons for primary care clinicians. First, pronounced acanthosis nigricans, extreme hyperinsulinemia, hyperglycemia, and hyperandrogenic features should trigger consideration of a genetic insulin resistance syndrome, even in the absence of classic diabetic symptoms like polyuria or polydipsia. Second, family history and atypical growth patterns must be interpreted cautiously; a familial tendency toward tall stature can mask the growth restriction often associated with RMS.
Third, confirming the diagnosis requires molecular testing; whole-exome sequencing in this patient identified a homozygous insulin receptor pathogenic variant (c.433C>T, p.Arg145Cys). Finally, management demands a multidisciplinary approach and realistic expectations: receptor-level defects frequently produce poor glycemic response to standard therapies, necessitating combined pharmacologic, educational, and supportive measures.
Primary care clinicians play a critical role in early recognition by noting specific phenotypic signs and initiating appropriate workup and referrals for genetic testing and specialist care. Early identification permits targeted counseling, anticipatory monitoring for metabolic and endocrine complications, and coordination of multidisciplinary management for patients with rare genetic insulin resistance syndromes.