ESPE Abstracts

Background: DNAJC3 is an endoplasmic reticulum (ER) co-chaperone involved in folding/processing of secretory and transmembrane proteins. The defect in the ER co-chaperone proteins impairs adaptive ER responses and leads to apoptosis, impairment of organ function with multisystemic involvement. Biallelic mutations in the DNAJC3, described in a limited number of cases cause multiple endocrine dysfunction and neurodegeneration of nervous system.

Herein, we report a new patient with severe growth retardation, microcephaly, early-onset hypothyroidism, hyperinsulinemic hypoglycemia and neuromotor retardation due to a novel homozygous mutation in the DNAJC3 gene.

Case Report: A 6.5 month-old boy was presented with growth retardation and hypothyroidism. The parents were first degree cousins. He was born at 27⁺³ gestational weeks because of preeclampsia with a birth weight of 610 g (-1.8 SDS) and had been hospitalized for 5 months in a neonatal care unit. At presentation, his height, weight and head circumference was 51 cm (-4.4 SDS), 3120 g (-4.3 SDS) and 33.5 cm (-6 SDS), respectively. He had a triangular face, antevert prominent ears, prognathism, clinodactyly, pectus carinatum and upturned eyebrows. Biochemistry, echocardiography and abdominal ultrasonography were normal. Anterior pituitary hormones were normal. Neurodevelopmental milestones were significantly delayed for age. Brain magnetic resonance imaging scan at 4.5 years of age showed cerebellar and brainstem atrophy and there were T2 hyperintensities in the frontoparietal area, as well as subcortical U fibers. Whole exome sequencing revealed a novel homozygous frameshift variant (c.1314dupG; p.F439Vfs*3) in DNAJC3 gene. An OGTT was performed after the molecular diagnosis revealed previously undiagnosed and clinically asymptomatic hyperinsulinemic hypoglycemia by a glucose level of 34 mg/dl and insulin 2.5 mIU/L at 180 minutes of the test. Blood glucose remained stable on frequent feeding and corn starch at night time without any other intervention.

Conclusion: We report a novel mutation in the DNAJC3 gene causing more severe growth and developmental delay compared to previously described cases. Hyperinsulinemic hypoglycemia is associated with increased morbidity and poor neurodevelopmental outcomes in patients with DNAJC3 gene mutations. Impaired glucose metabolism should be considered and investigated in patients with molecular defects affecting endoplasmic reticulum.