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A Novel Maturity-onset diabetes of the young (MODY) classically describes dominantly inherited forms of monogenic diabetes diagnosed before 25 years of age due to pancreatic β-cell dysfunction. In contrast, mutations in certain MODY genes can also present with transient or persistent hyperinsulinemic hypoglycemia in newborn infants, reflecting instead β-cell dysregulation. Of the MODY genes described to date, only hepatocyte nuclear factor-4-alpha (HNF4A; MODY1) and hepatocyte nuclear factor-1-alpha (HNF1A; MODY3) mutations may result in a biphasic phenotype of hypoglycemia in early life and hyperglycemia in later life. We report a family with a novel HNF4A mutation with diverse phenotypic presentations of glucose dysregulation. The proband was a term, appropriate-for-gestational age male infant with symptomatic hypoglycemia on day 3 of life needing high glucose infusion rate to maintain normoglycemia. He was born to a non-obese and non-diabetic mother. Glucose regulation was optimized using diazoxide upon confirmation of hyperinsulinism. Cascade genetic screening identified the same mutation in his father and elder sister, but mother was negative. Father was diagnosed with Type 1 diabetes at 15 years of age that required insulin therapy. Proband's elder sister, born at term appropriate for gestational age, presented with transient neonatal hypoglycemia needing parenteral glucose infusion for a week followed by spontaneous resolution. The paternal grandparents were negative for this mutation, confirming a paternal de novo mutation and autosomal dominant inheritance in this family. This pedigree suggests that the presence of early-onset paternal diabetes should prompt molecular testing in infants presenting in the newborn period with diazoxide-responsive hyperinsulinemic hypoglycemia, even in the absence of maternal diabetes and macrosomia.

A Novel Background: Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is an autosomal recessive and skeletal disorder included wide spectrum of clinical abnormalities such as fetal growth restriction, disproportionate face, microcephaly, post-natal growth retardation, adult height under 100 cm, abnormal skin pigmentation, insulin resistance, and susceptibility to cerebrovascular and hematologic abnormalities. Due to heterogeneous feature of MOPDs diseases and common clinical features among the different subtypes, mutation analysis can be considered as fundamental in the accurate diagnosis and confirmation of the MOPD II disease. Some studies revealed that, variants of gene encoding Pericentrin protein, PCNT, were associated with MOPD II. Methods: We performed whole exome sequencing based on the next generation sequencing (Illumina platform), to perform correct diagnosis in a 17-year-old girl with an unknown disease who was referred to the Diabetes Research Center in Yazd, Iran. The clinical features of the patient were short stature, generalized brachydactyly, gradual deterioration of brain functioning, menstrual irregularity, clitoromegaly, acanthosis nigricans, diabetes mellitus, hyperinsulinemia, insulin resistance, and dyslipidemia. Accordingly, her parents were also first cousin with no background disease. After identifying the novel variant, it was confirmed in the proband and her family using bi-directional Sanger sequencing, and its pathogenicity was also checked by different online tools. Results: Our study revealed a novel frame-shift variant in PCNT gene (c.7511delA, p.K2504Sfs*27), which causes premature termination of Pericentrin protein. The result disclosed that, the proband was affected by MOPD II disease. In addition, the Sanger sequencing confirmed the novel homozygote variant in the proband and heterozygote one in her parents, and the extended family perfectly segregated among them. Online tools such as Varsome and MutationTaster also showed a high level of pathogenicity for the variant identified. Conclusion: A novel variant was identified in the proband and her extended family, which emphasized the importance of PCNT gene mutations analysis in the screening and accurate identification of MOPD II disease, especially in prenatal diagnosis.

A Novel Autosomal dominant hyper-IgE syndrome caused by mutations in the transcription factor STAT3 (AD-HIES) is characterized by a collection of immunologic and non-immune features including eczema, recurrent infections, elevated IgE levels, and connective tissue anomalies. We report the case of a Qatari child with a history of recurrent staphylococcal skin infections since infancy, who was found to have a novel, de novo mutation in STAT3 (c.1934T>A, p.L645Q). The absence of mucocutaneous candidiasis and undetectable IgE levels until the age of 7 years prolonged the time to molecular confirmation of the cause for the patient's immune deficiency. STAT3 p.L645Q was found to have decreased transcriptional capacity. The patient also had low levels of Th17 cells and STAT3 phosphorylation was impaired in patient-derived cells. Nearly 100 unique mutations in STAT3 have been reported in association with AD-HIES.

A Novel Mutations in the CD40 ligand (CD40L) gene (CD40LG) lead to X-linked hyper-IgM syndrome (X-HIGM), which is a primary immunodeficiency (PID) characterized by decreased serum levels of IgG and IgA and normal or elevated IgM levels. Although most X-HIGM patients become symptomatic during the first or second year of life, during which they exhibit recurrent infections, some patients exhibit mild phenotypes, which are usually associated with hypomorphic mutations that do not abrogate protein expression or function. Here, we describe a 28-year-old man who initially presented with recurrent infections since the age of 7 years, when he exhibited meningitis caused by Cryptococcus neoformans. The patient had no family history of immunodeficiency, and based on clinical and laboratory presentation, he was initially diagnosed with common variable immunodeficiency (CVID). In subsequent years, he displayed several sporadic episodes of infection, including pneumonia, pharyngotonsillitis, acute otitis media, rhinosinusitis, fungal dermatosis, and intestinal helminthiasis. The evaluation of CD40L expression on the surface of activated CD3+CD4+ T cells from the patient showed decreased expression of CD40L. Genetic analysis revealed a novel de novo mutation consisting of a 6-nucleotide insertion in exon 1 of CD40LG, which confirmed the diagnosis of X-HIGM. In this report, we describe a novel mutation in the CD40L gene and highlight the complexities of PID diagnosis in light of atypical phenotypes and hypomorphic mutations as well as the importance of the differential diagnosis of PIDs.