Endocrine Abstracts

JOINT3778

Introduction: Diphthamide-deficiency (DPH1) syndrome is a rare autosomal recessive neurodevelopmental disorder characterised by variable degrees of developmental delay, dysmorphic features, sparse hair, hand/foot and genital anomalies, short stature and central nervous system malformations. To date, less than 20 cases have been reported in the litterature. Here, we present a case of patient with two novel DPH1 gene variants.

Case presentation: A one year old boy was referred to the pediatric endocrinology clinic for non auto-immune hypothyroidism (TSH 13.8 μIU/ml). The patient was a full term infant presenting with mild psychomotor delay, sparse hair, strabismus, syndactyly, valgus deformity of the feet and a history of unilateral cryptorchidism and bilateral inguinal hernia. His growth development was normal. Thyroid ultrasound was unremarkable and treatment with levothyroxine was initiated. Neurologic evaluation after normalisation of thyroid function confirmed a mild psychomotor delay (mostly hypotonia). During followup, patient’s growth velocity progressively declined with his height falling below parental target. Bone age was delayed by one year. Laboratory testing confirmed growth hormone (GH) deficiency and GH treatment was started. Brain MRI revealed a mild ventricular dilatation, a thin corpus callosum and a small sized pituitary gland. As part of the investigation of the patient’s multiple pathologies, whole exome sequencing (WES) study was performed, detecting a maternally inherited heterozygous c.907-1delG intronic variant expected to lead to a loss of protein function (in silico analysis) and a paternally inherited c.284C>T (p. Thr95Met) variant) variant of unknown significance in the DPH1 gene.

Conclusion: Loss of function DPH1 gene variants affect diphtamide biosynthesis, a post-translationaly modified histidine residue crucial for cell division and embryonic development, leading to cell death and growth defects. We report two novel DPH1 variants, in a patient with clinical features consistent with those previously described in DPH1 syndrome. Although further studies are required to confirm the functional impact of these variants, this case highlights the expanding genotypic spectrum of DPH1 syndrome and emphasizes the importance of considering this diagnosis in patients with compatible clinical presentation.