Rabson-Mendenhall syndrome (RMS) is an extremely rare monogenic form of diabetes caused by mutations in the insulin receptor (INSR) gene, with only about 50 cases reported worldwide to date. Here, we report a case of RMS caused by a previously unreported c.1123+2 T>C splice mutation. The patient was diagnosed with acanthosis nigricans and hypertrichosis at birth, and the growth rate was slower than that of normal children. At age 5, the patient had severe hyperinsulinemia, congenital heart abnormalities, and pineal cysts. At age 13, he was diagnosed with diabetes and exhibited symptoms of hyperinsulinemia, low body weight, growth retardation, acanthosis nigricans, dental anomalies, an oversized penis, and a pineal cyst. Sequencing results indicated an INSR c.1123+2 T>C mutation, and bioinformatic analysis suggested that this mutation led to splicing abnormalities, thereby affecting INSR function. Both parents carried the mutated gene, whereas his brother had a normal genotype. Genetic diagnosis is vital in RMS; c.1123+2 T>C mutation of INSR causes pancreatic decline; current treatments show limited effectiveness.

Donohue syndrome and Rabson-Mendenhall syndrome are extreme forms of insulin resistance caused by biallelic mutations in the insulin receptor gene. Recombinant human IGF1 (rhIGF-1) treatment is often used but its long-term benefits and risks are still poorly delineated. We describe rhIGF-I treatment outcomes of a cohort of patients with Donohue syndrome and Rabson-Mendenhall syndrome, and compare them to previously published patients. Single-centre retrospective observational study. Case note review. Literature search for previously published Donohue syndrome and Rabson-Mendenhall syndrome patients treated with rhIGF-1. rhIGF1 outcomes beyond 4 months have been reported for only 11 patients with Donohue syndrome and Rabson-Mendenhall syndrome to date. We provide outcome data for three more males, and report the long-term clinical course of a patient already described. Metabolic benefits of rhIGF-1 included improved glycaemic control and fasting tolerance in early years of life, and some growth enhancement. Two patients exhibited poor response or intolerance to rhIGF-1 and died in infancy. The two longest-lived patients had progressive decompensation to diabetes mellitus, in one case despite long-term uninterrupted rhIGF-1 therapy. We also describe new features associated with severe insulin receptoropathies, such as cataract, liver haemangioma, and impaired hepatic protein synthesis. The phenotypes of Donohue and Rabson-Mendenhall syndromes are heterogeneous. Current treatment options remain unsatisfactory as high dose rhIGF-1 exerts only limited beneficial effects and does not prevent decompensation to diabetes mellitus. More research is needed to identify alternative treatment strategies for extreme forms of insulin resistance.

患儿，男，6岁8月龄，因生长速度缓慢伴皮肤黑6年余就诊。体格检查发现身高、体重均明显落后，有特殊面容（大耳朵、低耳位、上翘的鼻孔、厚嘴唇、牙列不齐），皮肤严重黑棘皮，伴有乳头突出、多毛、皮下脂肪薄、腹部膨隆，检查发现存在空腹低血糖及餐后高血糖，合并严重胰岛素抵抗，基因检测发现INSR基因变异。患儿诊断为Rabson-Mendenhall综合征。恩格列净联合二甲双胍治疗1年6个月效果良好。.

Rabson-Mendenhall Syndrome (RMS), a rare hereditary form of insulin resistance, is marked by severe hyperinsulinemia and early-onset acanthosis nigricans (AN) during childhood. A case of a 15-month-old girl was reported, presenting with widespread acanthosis nigricans, growth retardation, dysmorphic facial features, and hypertrichosis. Laboratory results indicated fasting hypoglycemia and hyperinsulinemia, while her oral glucose tolerance test (OGTT) remained normal. Whole-exome sequencing revealed two novel mutations in the insulin receptor gene (INSR): a c.3392 C > G missense/frameshift mutation in exon 19 and a c.4007_4010delAGAG deletion in exon 22. Acanthosis nigricans (AN) can serve as a clinical marker that strongly suggests underlying metabolic syndromes, making genetic analysis essential for confirming the diagnosis.

INSR encodes the insulin receptor, the essential entrainer of growth and metabolism to nutritional cues. INSR variants cause a spectrum of monogenic insulin resistance (IR) syndromes, namely, type A insulin resistance, Rabson-Mendenhall, and Donohue syndromes. However, to our knowledge, no large cohort studies focused on variant classification and its diagnostic value have been described. This multicentric cohort study included 73 patients carrying INSR variants, referred for IR by 52 centers from 6 countries. Variants were classified using new bioinformatic tools relying on different prediction mechanisms and the American College of Medical Genetics and Genomics guidelines. Besides expanding the INSR mutational spectrum, this study suggested a semidominant inheritance in several Donohue/Rabson-Mendenhall syndrome families. Questioning strictly Mendelian inheritance, heterozygous loss-of-function (LoF) variants were mostly found in overweight patients, with a higher LoF frequency in IR patients than in the general population (odds ratio 5.77). Diagnostic challenges arose when trying to refine classification criteria for variants of uncertain significance. Among the variant effect predictors assessed, MISTIC and AlphaMissense outperformed REVEL. The spectrum of INSR-related disorders extends beyond traditional entities. Heterozygous INSR LoF variants may increase IR susceptibility. International collaboration and functional assays are needed to drive precision medicine forward. While most patients with diabetes have Type 1 diabetes (T1D) or Type 2 diabetes (T2D) there are other etiologies of diabetes that occur less frequently. In this chapter we will discuss a number of these less common causes of diabetes. It is clinically very important to recognize these uncommon causes of diabetes as treatment directed towards the underlying etiology can at times result in the remission of diabetes (for example Cushing’s Syndrome) or be required to avoid other complications of the underlying disorder (for example hemochromatosis, which in addition to causing diabetes can lead to severe liver disease and congestive heart failure). In this chapter the following disorders that are associated with diabetes are discussed: 1) genetic disorders of insulin action (Type A insulin resistance, Donohue Syndrome/Leprechaunism, Rabson-Mendenhall syndrome); 2) maternally inherited diabetes mellitus and deafness syndrome; 3) disorders of the exocrine pancreas (pancreatitis, trauma/pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis); 4) endocrinopathies (acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma, primary hyperaldosteronism); 5) drug induced; 6) infections; 7) immune mediated (stiff-man syndrome, anti-insulin receptor antibodies); 8) ketosis prone diabetes (Flatbush diabetes); and 9) genetic disorders sometimes associated with diabetes (Down syndrome, Klinefelter syndrome, Turner syndrome, Wilsons syndrome, Wolfram syndrome, Friedreich ataxia, Bardet-Biedl syndrome [Laurence-Moon-Biedl syndrome], myotonic dystrophy, Prader-Willi syndrome, Alström syndrome, and Werner syndrome). Gestational diabetes, monogenic diabetes (maturity onset diabetes of the young (MODY) and neonatal diabetes), lipodystrophy, fibrocalculous pancreatic disease, diabetes associated with HIV infection, diabetes due to the autoimmune polyglandular syndromes, and post-transplant diabetes are not discussed in this chapter as they are discussed in other Endotext chapters. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.