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.

Protein kinase RNA-like endoplasmic reticulum kinase (PERK) is an endoplasmic reticulum stress kinase whose loss of function disturbs human development, leading to skeletal dysplasia and permanent neonatal diabetes, as in the Wolcott-Rallison Syndrome (WRS). The lack of effective, less invasive therapies for developmental diseases highlights the need for animal models that replicate complex pathological phenotypes, while allowing scalable drug screening. Zebrafish high fecundity and rapid development enable efficient in vivo drug testing. We assessed zebrafish’s potential for studying PERK and its pharmacological modulation in developmental diseases like WRS. To assess the similarity between human and zebrafish PERK we used bioinformatic analyses. To inhibit PERK we used GSK2606414. To evaluate effects on skeletal, neuromuscular, and cardiac development we combined behavioural and functional assays. To assess diabetic-like phenotypes we used fluorescent pancreatic markers and a glucose probe. Zebrafish PERK conserves 11 of 12 critical GSK2606414‑binding residues (predicted 3D structures highly similar). Functionally, GSK2606414 (10 µM) decreased levels of PERK pathway markers and induced WRS-relevant phenotypes: reduced body length, increased trunk–tail curvature, decreased cranial cartilage staining; neuromuscular impairment (altered reflexes, reduced muscle birefringence) and cardiac dysfunction (pericardial oedema, reduced stroke volume and cardiac output). However, parameters not associated with WRS like otolith area and eye/body ratio remained unaffected. Moreover, GSK2606414 decreased 𝛽-cell mass and lowered 2-NBDG-glucose uptake in neuromasts, consistent with diabetic-like phenotypes. These findings evidence zebrafish’s potential for studying PERK function and its pharmacological modulation in developmental disorders like WRS, aiding research on pathophysiology and experimental treatments. The online version contains supplementary material available at 10.1007/s43440-026-00837-7.

Monogenic diabetes (MD) is a group of diabetes subtypes caused by defects in single genes. We report phenotypes and genotypes of MD among Sudanese children. Referred patients (from birth to 18 years of age) with diabetes and a clinical diagnosis of MD to Gaafar Ibnauf Pediatric Tertiary Hospital or the Sudan Childhood Diabetes Center between January 2006 and April 2023 were included. Patients were divided into two groups based on onset of diabetes before six months of age (Group 1, or neonatal diabetes mellitus) or after (Group 2, or non-neonatal diabetes mellitus). Genetic testing was performed for 87 patients at the Exeter Genomics laboratory and for one patient at the University of Cambridge, Metabolic Research Laboratories, UK. Out of 88 patients, 50 were from Group 1 and 38 from Group 2. We reported consanguinity in 63.6 % of the cohort and identified disease-causing variants for 18 genes in 43.2 % (Group 1) and 37.5 % (Group 2) of patients from the total cohort. The commonest causes in Group 1 and Group 2 were pathogenic variants in the EIF2AK3 and WFS1 genes, respectively. Pathogenic variants in recently reported novel genes ZNF808, NARS2, and FICD were detected in 8.5 %, 4.2%, and 1.4 % of patients, respectively. Patients with a disrupted WFS1 gene were found to have deafness (92.8 %) and optic atrophy (64 %). While skeletal deformities and liver disease were both seen in 28.6 % of patients with pathogenic variants in the ElF2AK3 gene. Hepatomegaly and hypophosphatemic rickets were uniformly seen in patients with pathogenic variants in the SLC2A2 gene. Generalized subcutaneous tissue loss and acanthosis nigricans were main features in AGPAT2 and INSR variants, respectively. Characterization of MD in Sudan showed a predominance of syndromic forms. Genetic studies conducted on consanguineous populations may raise higher probabilities in identifying rare genes.

To report an unusual case of Wolcott-Rallison syndrome (WRS) due to a novel homozygous missense mutation c.1805G>T (p.Gly602Val) in the Exon 11 of eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3) gene. A 2-month-old infant, born to a consanguineous marriage presented to PICU with the manifestation of severe diabetic ketoacidosis (severe hyperglycemia, pH 6.984 + ketones in urine). Genomic sequencing analyses detected a novel homozygous missense variation in the Exon 11 of the EIF2AK3 gene that resulted in the amino acid substitution of valine for glycine at codon 602 (p.Gly602Val). A diagnosis of Wolcott-Rallison syndrome was confirmed. He was treated with fluid therapy and regular insulin infusion. The purpose of this case report is to highlight the novel mutation in the Exon 11 of the EIF2AK3 gene and to raise awareness for screening of pathogenic genetic variants in the EIF2AK3 gene in all patients with neonatal diabetes mellitus. In the evaluation of infants with diabetic ketoacidosis, genomic DNA sequencing analyses should be performed in all cases of neonatal diabetes mellitus for early diagnosis of Wolcott-Rallison syndrome.

Wolcott-Rallison syndrome (WRS) is a rare genetic autosomal recessive inherited disorder with three main clinical features: neonatal diabetes mellitus (NDM), bone dysplasia, and acute liver dysfunction. The aim of the study is to report a rare case of WRS with genetic analysis. We report a 1-year-old male patient with consanguineous parents who was referred due to weakness and vomiting at 3 months old and was admitted due to diabetic ketoacidosis with severe acidosis and hyperglycemia without any other skeletal, hepatic, or renal presentations and a novel homozygous c.2825A>C (p.Asn942Thr) variant in exon 14 of the EIF2AK3 gene on chromosome 2. Genetic testing is recommended for distinguishing WRS from other causes of neonatal insulin-dependent diabetes, and early diagnosis in order to develop timely and appropriate treatment, especially rapid detection of the acute liver failure as the most life-threatening complication.