De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review

TL;DR

This paper reports new KDM3B gene mutations in Diets-Jongmans syndrome and shows growth hormone treatment can help some patients.

Contribution

Expands the known KDM3B mutation spectrum and demonstrates rhGH therapy effectiveness in DIJOS for the first time.

Findings

Four patients had novel de novo KDM3B variants with growth retardation as a key feature.

One patient showed improved growth after recombinant human growth hormone treatment.

Clinical variability in neurodevelopment was observed among patients with DIJOS.

Abstract

Background: Pathogenic variants in KDM3B have been implicated as the cause of Diets-Jongmans syndrome (DIJOS), an autosomal-dominant disorder characterized by growth retardation, intellectual disability, facial dysmorphism and autism-spectrum disorder. However, only a limited number of cases have been reported. Methods: The general characteristics of four patients were recorded, including clinical features, child development, neuropsychological assessment and therapeutic interventions. Whole exome sequencing (WES) was performed for potential genetic causes and interpretation of variants was performed in accordance with ACMG guidelines. Results: All patients carried de novo variants in the KDM3B gene, namely, c.2832-3C>G, c.1188del p.(Glu397Argfs*21), c.4580T>C p.(Leu1527Pro), and c.3220dup p.(Glu1074Glyfs*48). Unlike other patients with DIJOS who presented with growth retardation, mild to moderate intellectual developmental disorder and facial dysmorphism, our patients mainly presented with growth retardation, while their neurodevelopment was either normal or mildly impaired. In addition, our patients received primarily supportive care. One patient treated with recombinant human growth hormone (rhGH) showed improvement in growth. Conclusions: Our results broaden the mutational spectrum of KDM3B-related disorder and highlight the inter-patient variability of the clinical phenotype. For the first time, we demonstrate that rhGH therapy can partially promote growth, providing novel evidence for genetic counseling.

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