Unmasking Acanthosis Nigricans Discloses a Rare Severe Insulin Resistance Disorder, a Case of Rabson-Mendenhall Syndrome

Dear Editor, Rabson-Mendenhall syndrome (RMS) is a rare autosomal recessive genetic syndrome characterised by severe insulin resistance, endogenous hyperinsulinemia with or without glucose intolerance, and distinctive phenotypic features. This syndrome results from mutations in the insulin receptor (INSR) gene located on chromosome 19p13.2, leading to a 90% reduction of insulin receptors on cell surfaces despite normal synthesis rates of insulin receptor precursors.[1] This leads to decreased insulin receptor density in plasma membranes, causing cellular insulin resistance. The pathophysiology involves elevated serum insulin stimulating insulin-like growth factor 1 (IGF-1) receptors on keratinocyte membranes. Prolonged exposure leads to upregulation of keratinocytes and fibroblasts, subsequently causing acanthosis nigricans. RMS is extremely rare, occurring in less than one in every million individuals worldwide, with most patients surviving only up to 15 years of age, although some may live into the third decade.[2] A 3-year-old male child, second-born to non-consanguineous parents, presented to our dermatology outpatient department with generalised skin pigmentation, excessive body hair, defective dentition, and features of premature secondary sexual characteristics. The child demonstrated significant global developmental delays including largely unintelligible speech, difficulty with parent separation, inability to follow simple two-step instructions, inability to walk stairs independently, and delays in self-care skills such as independent feeding. On examining, the child weighed 10 kg, had a height of 33 inches (short stature for age), and had dysmorphic features: coarse face, large low-set ears, wide nostrils, large mouth, thickened lips, macroglossia, increased head circumference, wide, short neck with low hairline, hoarseness of voice, and enlargement of external genitalia. Cutaneous findings revealed generalised hyperpigmentation with dark, thick, velvety appearance (acanthosis nigricans) particularly prominent at the nape of neck, axillae, groin, and sacral region. Large terminal hairs were present throughout the body. There was normal mucosa with large fissured tongue and dysplastic dentition showing multiple dental caries and enamel hypoplasia [Figure 1].Figure 1: (a) Generalised acanthosis nigricans more at the flexural folds of axilla, groin, and thighs, (b) Acanthosis nigricans at the nape of the neck with hypertrichosis and terminal hairs, (c) Thickened lips, multiple dental caries, dysplastic dentition, and enamel hypoplasia, and (d) Enlargement of external genitalia along with generalised acanthosis nigricans more at the flexural folds of groin and popliteal fossaLaboratory investigations revealed fasting blood sugar of 54 mg/dL, random blood sugar of 228, post-prandial blood sugar of 127 mg/dL, HbA1c of 7.1, and serum fasting insulin of 52.36 mcU/mL. The Homeostasis Model Assessment for insulin resistance (HOMA-IR) was 6.98, which indicates a significant insulin resistance. Complete blood counts, liver function test, renal function test, and urine routine microscopy revealed no abnormalities. The radiograph of skull showed multiple impacted teeth with incomplete development of their roots with no other abnormalities. Skin biopsy from the nape of the neck revealed orthokeratotic hyperkeratosis, papillomatosis, and hyperpigmentation of basal layer consistent with features of acanthosis nigricans [Figure 2].Figure 2: H & E stain 10×: The area between the dermal papillae is filled with keratotic material and stratum corneum shows basket weave appearanceBased on clinical findings and laboratory investigations, a diagnosis of RMS was made. Our patient received urea, lactic acid, and glycolic acid-based cream for acanthosis nigricans. Given the current glycaemic profile, anti-hyperglycaemic medications were not immediately warranted, but regular endocrinological follow-up was advised. In children, acanthosis nigricans serves as an important cutaneous marker of underlying metabolic disorders, endocrinopathies, and rarely malignancies, warranting thorough evaluation.[3] Our patient’s presentation is notable for the unusually early age of presentation and severity of global developmental delays, which are rarely detailed in RMS literature.[4] While mild developmental delay has been occasionally mentioned, comprehensive neurodevelopmental profiling is seldom reported. This case highlights an unusually early and severe presentation of RMS in a 3-year-old child, emphasising the importance of recognising acanthosis nigricans as a dermatological marker of serious underlying metabolic disorders. The significant global developmental delays observed in our patient underscore the need for incorporating routine developmental assessments and early intervention strategies into multidisciplinary RMS management. There is no specific treatment for RMS. Management mainly focusses on glycaemic control and complication prevention. Treatment may include insulin and insulin-sensitising agents such as metformin and glitazones. Promising future therapies include recombinant human IGF-1 for ketoacidosis management and recombinant methionyl human leptin for improving insulin tolerance.[5] Author Contributions BB: Concepts, design, definition of intellectual content, literature search, clinical studies, manuscript preparation, manuscript editing, manuscript review, guarantor. SC: Concepts, design, definition of intellectual content, clinical studies, data acquisition, data analysis, statistical analysis, manuscript preparation, manuscript editing, manuscript review, guarantor. MSK: Concepts, design, clinical studies, data acquisition, data analysis, statistical analysis, manuscript preparation, manuscript review. CKS: Concepts, design, definition of intellectual content, literature search, clinical studies, data acquisition, manuscript editing, manuscript review. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.