SFRP4 – Pyle disease

Pyle disease is a rare autosomal recessive skeletal dysplasia characterized by metaphyseal widening, cortical bone thinning, and genu valgum. The disorder results from biallelic loss-of-function mutations in the secreted frizzled-related protein 4 gene (SFRP4). Clinical diagnosis is supported by radiographic Erlenmeyer-flask deformity of the long bones and Wormian bones (HP:0002645).

Autosomal recessive inheritance is established through segregation in multiple families. A novel homozygous nonsense variant, c.183C>G (p.Tyr61Ter), was identified in an 11-year-old female with Pyle disease (PMID:28100910). A second homozygous splice-region deletion (c.855+4delAGTA) was reported in a South African patient (PMID:36138002). Compound heterozygous missense variants (c.161C>A (p.Ala54Asp) and c.373T>A (p.Cys125Ser)) were found in two affected siblings (PMID:33193738), and four additional probands with truncating alleles were described in an independent cohort (PMID:27355534).

The variant spectrum includes at least six protein-truncating alleles and two missense changes impairing Wnt-ligand binding. All reported mutations segregate with disease in affected families, with at least 8 unrelated probands and 2 additional affected siblings demonstrating biallelic inheritance.

Functional studies in Sfrp4-knockout mice recapitulate the human phenotype, showing increased trabecular bone mass alongside pronounced cortical thinning due to dysregulated Wnt and BMP signaling. Treatment with a soluble BMP2 receptor fusion protein or anti-sclerostin antibody restores cortical thickness, supporting a haploinsufficiency mechanism (PMID:27355534).

Overall, the strong genetic and experimental concordance between human mutations and mouse models definitively establishes SFRP4 deficiency as the cause of Pyle disease. Identification of biallelic SFRP4 variants informs molecular diagnosis, genetic counseling, and potential therapeutic targeting of Wnt/BMP pathways in cortical bone disorders.

References

• Journal of human genetics • 2017 • A novel sequence variant in SFRP4 causing Pyle disease. PMID:28100910
• BDJ open • 2022 • Craniofacial, dental, and molecular features of Pyle disease in a South African child. PMID:36138002
• Frontiers in genetics • 2020 • The First Report of Biallelic Missense Mutations in the SFRP4 Gene Causing Pyle Disease in Two Siblings. PMID:33193738
• The New England journal of medicine • 2016 • Cortical-Bone Fragility--Insights from sFRP4 Deficiency in Pyle's Disease. PMID:27355534

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