Endocrine Abstracts

Here we report a case of an adult patient (44y/o) followed for type-2 diabetes since he was 15 years, hypercholesterolemia treated with PCSK9 inhibitors and hypertension. At physical examination he presented: progeroid features, prominent forehead, hypertelorism, short palpebral fissures, broad nasal bridge, baldness, and hypotricosis. He was also affected by hearing loss with a jarring voice and lost teeth in early age. He showed developmental delay and ID, mild atrial septal defect, mild osteoporosis and a monolateral low testis volume, with subclinical hypergonadotroph hypogonadism. Diabetes was in control with metformin, and DPPIV-i, liver steatosis was in follow-up. The BMI was normal and subcutaneous fat was underrepresented in limbs, but increased in the abdomen. Since the abnormal distribution of fat and metabolic alterations at a young age, we suspected a progeroid lipodystrophy syndrome. Leptin (1.9 mg/l) was undetectable and the genes known to cause classical lypodistrophy syndromes were wild type as well as CGH-array. A whole genome sequencing (WES) of the proband and his parents was thus performed revealing a de novo pathogenic frameshift variant in HIST1H1E (MIM*142220), p.Ser150fs, c.447dupC, encoding the H1.4 histone protein. This protein is a member of the H1 histone family that acts as a structural component of the chromatin controlling DNA condensation, gene expression and DNA replication/repair. Mutations in these class of genes perturb cellular process resulting in cellular senescence and have been correlated to alteration of genome methylation. Truncating mutations in HIST1H1E are characteristic of the Rahman Syndrome (MIM#61743), a recently recognized developmental disorder characterized by mild to severe ID, a distinctive facial gestalt, variable somatic overgrowth which may manifest in early infancy, but not in adults, that often display decreasing height percentile over time, and an aging appearance. The WGS analysis also revealed a pathogenic variant in the LDLR gene explaining hypercholesterolemia and in OTOGL responsible for neurosensorial hearing loss. This case represented a complex phenotype that had remained for a long time without a clinical diagnosis and that reached it on the basis of the results obtained throught WGS with three genes explaining most of his phenotypic characteristics. It is remarkable that the patient also manifested lipodystrophy, characterized by a progressive metabolic impairment secondary to adipose tissue dysfunction, that might be explained by the pleiotropic effect of the HIST1H1E mutation. Trascriptomic analysis on the PBMC of proband and parents has been performed and is ongoing to detect molecular signaling specific of each mutation.