Two Novel Variants and One Previously Reported Variant in the Insulin Receptor Gene in Two Cases with Severe Insulin Resistance Syndrome

Abstract

Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS) are rare diseases caused by biallelic variants within the insulin receptor gene (INSR). Here, we report 2 cases: one with DS and the other with RMS. The case with DS presented with intrauterine growth retardation, nipple hypertrophy, clitoromegaly, distended abdomen, hypertrichosis, and dysmorphic features. The second case showed severe acanthosis nigricans, hyperkeratosis, and hypertrichosis. In both cases, abnormal glucose homeostasis due to severe insulin resistance was observed. The diagnosis of DS and RMS was established based on clinical characteristics, abnormal glucose homeostasis, high serum insulin levels, and determination of pathogenic variants in the INSR gene. The first case with DS has 2 novel homozygous variants, NM_000208.3, c.3122delA (p.N1041Mfs*16) and c.3419C>G (p.A1140G), and the second case with RMS has a previously reported homozygous variant NM_000208.3, c.3529+5G>A (IVS19+5G>A) in the INSR gene.

A Novel Mutation in the INSR Gene Causes Severe Insulin Resistance and Rabson–Mendenhall Syndrome in a Paraguayan Patient

“…The nephrocalcinosis observed in this case is a known complication of RMS and reflects the underlying metabolic disruption [ 16 ]. Close monitoring of renal function is essential in these patients, and regular imaging studies are required to detect any changes in the renal structure [ 14 , 16 ]. The hypertrichosis and acanthosis nigricans are also typical features of this syndrome and reflect the underlying insulin resistance.…”

“…RMS can appear in a variety of ways, and the severity of the condition can vary from person to person [ 1 , 9 , 13 ]. While some patients present with milder forms of the disorder, others may have more severe manifestations such as early-onset diabetes, severe insulin resistance, and recurrent infections [ 12 , 14 , 15 ]. It can be difficult to make a diagnosis because RMS’s clinical features may also overlap with those of other metabolic and genetic disorders [ 16 , 17 , 18 ].…”

“…While insulin therapy proves limited in certain cases, prioritizing blood glucose control is paramount. Dyslipidemia and hypertension, typically less pronounced in younger patients with severe defects, become more pertinent in older individuals with higher residual INSR function [ 9 , 10 , 14 , 18 ]. Understanding the genetic basis of the disease guides effective management strategies for RMS, underscoring the significance of tailored approaches in addressing its complex metabolic components [ 13 , 17 ].…”

A Novel Mutation in the INSR Causes Severe Insulin Resistance and Rabson-Mendenhall Syndrome in a Paraguayan Patient

“…The management of RMS includes providing supportive care for dental and other systemic abnormalities, controlling hyperglycemia with insulin therapy, managing other associated conditions like hypertension and dyslipidemia. Individuals with RMS may have better long-term outcomes if they receive early diagnosis and treatment [9,10,14,18]. Further exploration is expected to grasp the metabolic components of RMS and foster more successful treatment methodologies for this perplexing problem [13,17].…”