Early Multisystem Presentation of Frank-ter Haar Syndrome with a Novel Compound Heterozygous SH3PXD2B Variant: A Case Report

Abstract

Background: Frank-ter Haar syndrome (FTHS; OMIM #249420) is an ultra-rare autosomal recessive disorder caused by biallelic variants in SH3PXD2B, which encodes the podosome adaptor protein TKS4. Fewer than 50 molecularly confirmed cases have been reported.

Case presentation: We describe a 6-year-old girl, born at term to non-consanguineous parents, who had low-set ears and craniofacial dysmorphism at birth. A neonatal skull radiograph showed a copper-beaten calvarium and abdominal ultrasonography incidentally noted bowel-wall thickening; no diagnosis was reached at the time and echocardiography was normal. At 6 years she presented with global developmental delay, mild intellectual disability and recurrent lower respiratory tract infections. A repeat skeletal survey confirmed brachycephaly and a persistent copper-beaten skull, with an incidental asymmetry of carpal ossification not previously described in this condition. Paroxysmal inconsolable crying prompted ophthalmological review, which revealed bilateral glaucoma with significant refractive error. Chest radiography and CT thorax were normal. Whole-exome sequencing identified a novel missense variant in SH3PXD2B (exon 13; c.2690C>T, p.(Ser897Phe)) in trans with a paternally inherited nonsense variant (c.1219C>T, p.(Arg407*)), confirmed by segregation and consistent with autosomal recessive FTHS.

Conclusions: This case expands the mutational spectrum of SH3PXD2B and shows that non-specific neonatal radiological findings may antedate the recognisable FTHS phenotype by years. Paroxysmal crying as the presenting sign of occult glaucoma underscores the need for proactive ophthalmological screening in skeletal dysplasia syndromes.