CSNK2B Mutation: A Rare Cause of IGHD

Abstract

Objective: Poirier-Bienvenu neurodevelopmental syndrome (POBINDS) is a rare neurodevelopmental syndrome, resulting from germline heterozygous CSNKB2 pathogenic variants. The main presentations are severe epilepsy, delayed psychomotor development, and/or profound intellectual disability. More recently, CSNK2B pathogenic variants have been reported in patients with mild intellectual disability and no history of epileptic symptoms. Short stature is present in 66% of patients, in half of these cases due to proven growth hormone deficiency.

Methods: Whole genome sequencing (WGS) was performed through a French genomic program for a patient with isolated growth hormone deficiency after negative next generation sequencing (NGS) results. NGS panel analysis of CSNK2B and genes involved in isolated growth hormone deficiency (IGHD) was performed in 44 patients from the Genhypopit network (n = 2144) with growth hormone deficiency (GHD) and intellectual disability (ID) or epilepsy and in a convenience cohort of 68 GHD patients.

Results: We present the first case of POBINDS presenting mainly as growth delay due to GHD. Genome analysis revealed a de novo pathogenic variant in the translation initiation codon of CSNK2B (c.1 A > G, p.(Met1?)). The patient had mild intellectual disability and subsequent analysis of the patient's clinical history revealed that he had had febrile convulsions, compatible with POBINDS. No CSNK2B pathogenic variants were identified among the 44 selected patients with GHD and ID or epilepsy, or in a convenience cohort of 68 patients with GHD.

Conclusion: Although rare, pediatricians should be aware that POIBNDS syndrome may present as IGHD with mild ID.

Keywords: CSNK2B; Poirier–Bienvenu Syndrome; epilepsy; growth hormone deficiency; intellectual disability.

Figure 1

(a) Family pedigree of the patient (squares, male family members; circles, female family members; filled black symbols, affected; Genotypes: M/M, homozygous; N/M, heterozygous; N/N, normal; SDS at final height or at the age of index case diagnosis) (b, c) Sanger sequencing results (b) with the CSNK2B variant NM_001320.7:c.1 A > G (c) without the variant.