Introduction Monogenic neonatal diabetes mellitus (NDM) is a rare form of diabetes, presenting within the first six months of life and caused by pathogenic variants affecting pancreatic β-cell development or function. Because its initial presentation may overlap with type 1 diabetes, molecular diagnosis is crucial, as it directly influences prognosis and treatment - particularly the potential responsiveness to sulfonylureas in ATP-sensitive potassium (KATP)-channel-related NDM. This study reports a retrospective descriptive case series and aims to characterize the clinical and genetic features of infants with NDM, to improve therapeutic management and long-term outcomes. Materials and methods We conducted a retrospective descriptive case series of infants diagnosed with diabetes before six months of age, hospitalized in the Pediatric Endocrinology Unit of the Abderrahim Harouchi Mother-Child Hospital, Casablanca, Morocco, between January 2018 and December 2025. Clinical presentation, biochemical data, insulin requirements, genetic results, and outcomes were extracted from medical records. Genetic testing was performed through next-generation sequencing (NGS), or targeted Sanger sequencing when financially feasible. Results Ten infants were included (nine males and one female), with a mean age at diagnosis of 71 days. Diabetic ketoacidosis (DKA) was the presenting feature in all cases. Consanguinity was reported in 55% of families. Pathogenic or likely pathogenic variants were identified in six infants (60%), involving ABCC8, INS, EIF2AK3, CASP10, and chromosome 6q23-24 duplication, including two syndromic forms. Two infants with ABCC8 mutations achieved insulin independence with sulfonylurea therapy. Syndromic etiologies - Wolcott-Rallison syndrome, Donohue syndrome, and autoimmune lymphoproliferative syndrome type IIA (ALPS-type IIA) - were associated with severe multisystemic involvement. Three children had no identifiable pathogenic variant, despite clinical features consistent with NDM. Long-term outcomes varied widely, ranging from normal neurodevelopment to early mortality in Donohue syndrome. Conclusion This retrospective descriptive case series highlights the marked genetic heterogeneity and clinical variability of neonatal diabetes in a resource-limited setting. Genetic testing enabled precision therapy in infants harboring KATP-channel mutations and clarified prognosis in syndromic forms. Expanding access to molecular diagnostics remains essential to improve equity in care, optimize metabolic outcomes, and support individualized management strategies.

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。.

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.

Donohue syndrome (DS) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous mutations in insulin receptor (INSR), leading to severe insulin resistance. It is characterized by extreme hyperinsulinemia, fasting hypoglycemia, postprandial hyperglycemia, severe growth restriction, and dysmorphic features, with a high mortality rate in the first year due to metabolic instability and infections. We report the case of a 3-month-old Honduran girl with a homozygous exon 14 deletion in INSR who presented with severe insulin resistance, metabolic dysregulation, and dysmorphic facial features. Despite treatment with octreotide, metformin, and maltodextrin, the patient's condition worsened, leading to septic shock, disseminated intravascular coagulation, and multiple organ failure. This case highlights the challenges in correlating genotype with phenotype in DS and emphasizes the importance of understanding how specific INSR mutations influence the treatment response and clinical outcomes.