SAT-231 - A De Novo CUL3 Loss-of-Function Variant in Severe Pediatric Short Stature: A Case Report

Background: Loss-of-function (LoF) and gain-of-function variants in CUL3 are an established cause of syndromic neurodevelopmental disorders and pseudohypoaldosteronism; however, their contribution to impaired linear growth is poorly defined.

Case: We describe a male child of Bangladeshi etnicity born preterm at 35 weeks with intrauterine growth restriction (birthweight -2 SDS) and postnatal growth failure. He presented with proportionate severe short stature (height -3.5 SDS), microcephaly, learning disability, eczema, and whorled hypo- and hyperpigmented skin alterations. Motor milestones were at the lower end of normal. Skeletal manifestations included a hairline upper limb fracture at 3 years and a femoral fracture at 4 years. Skeletal survey demonstrated mild coxa valga without features of a defined skeletal dysplasia. Brain MRI showed subtle posterior corpus callosum thinning. Since he was born small for gestational age without catch-up growth, he commenced growth hormone (GH) therapy at 8 years. IGF-1 was elevated prior to GH therapy and during treatment. potassium was intermittently elevated with normal sodium, renin and aldosterone. He presented an initial robust growth response (growth velocity increase from 5.9 to 11.9 cm/year; height SDS −3.5 to −1.7), followed by attenuation associated with missed injections. Extensive genetic investigations, including chromosomal microarray, imprinting disorder testing, chromosome breakage studies, targeted gene panels, and whole-genome sequencing (WGS) data, were initially non-diagnostic. Reanalysis of 100,000 Genomes Project WGS data identified a de novo frameshift variant in exon 9 of CUL3 [CUL3 NM_003590.5:c.1213_1214delGA p.(Glu405Thrfs*9)], predicted to cause LoF via nonsense-mediated decay or truncation. As exon 9 is prone to splice-altering variants linked to pseudohypoaldosteronism, cDNA splice-site PCR was performed which showed normal splicing.

Discussion: CUL3 encodes a scaffolding component of Cullin-RING E3 ubiquitin ligase complexes and belongs to a highly conserved protein family involved in cell cycle regulation and neurodevelopment. CUL3 is expressed in most tissues. LoF CUL3 variants have been associated with syndromic neurodevelopmental disorders, and animal models demonstrate reduced body and brain size. This case suggests that impaired linear growth and GH-responsive short stature may represent underrecognized features of CUL3 haploinsufficiency.

Conclusion: This case supports CUL3 as a candidate gene for a growth disorder with severe short stature and neurodevelopmental impairment. Ongoing studies aim to expand the cohort, refine the phenotype, and assess genotype-phenotype correlations, focusing on skeletal development and GH–IGF1 regulation. This may improve diagnosis and management of syndromic short stature.

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