A novel PAPSS2 pathogenic variant: expanding the mutational spectrum and genotype–phenotype landscape in skeletal dysplasia

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Abstract
Objectives: The biosynthesis of 3′-phosphoadenosine 5′-phosphosulfate (PAPS), a universal sulfate donor, is catalyzed by two isoenzymes: PAPS synthetase 1 (PAPSS1) and PAPS synthetase 2 (PAPSS2). While PAPSS1 is ubiquitously expressed, PAPSS2 shows tissue-specific expression and plays a key role in cartilage development and adrenal steroid metabolism. PAPSS2 deficiency impairs dehydroepiandrosterone sulfation (DHEA-S), leading to increased bioactive androgens and hyperandrogenism. Biallelic PAPSS2 variants cause skeletal dysplasias from brachyolmia (BO) to severe spondyloepimetaphyseal dysplasia (SEMD). This study aimed to expand the PAPSS2 mutational spectrum and explore potential genotype–phenotype correlations, including the distribution of variants across functional domains. Case presentation: Two siblings with disproportionate short stature underwent clinical, radiological, and biochemical evaluation. Targeted next-generation sequencing of skeletal dysplasia-associated genes was performed. Serum DHEA-S levels were measured to assess steroid sulfation. A literature review of previously reported PAPSS2 variants was conducted to explore genotype–phenotype correlations. A novel homozygous missense variant, c.1466C>G (p.Pro489Arg), in the ATP sulfurylase domain of PAPSS2, was identified in both siblings. The male proband exhibited a severe SEMD phenotype, while his sister presented with milder BO features. Both had markedly reduced DHEA-S levels (4.04 μg/dL and 31.8 μg/dL), consistent with impaired adrenal androgen sulfation. Review of the literature indicates an enrichment of SEMD-associated variants within the ATP sulfurylase domain, although phenotypic overlap with BO is evident, as also observed in the present family. Conclusions: This study expands the known PAPSS2 mutational spectrum by identifying a novel pathogenic variant. The observed intrafamilial variability highlights the complexity of genotype–phenotype relationships, particularly in the context of limited case numbers, while low DHEA-S levels represent a robust biochemical marker of impaired steroid sulfation.

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