PTHLH – Brachydactyly Type E

Parathyroid hormone-like hormone (PTHLH, PTHrP) plays a critical role in endochondral bone development via regulation of chondrocyte proliferation and hypertrophy. Heterozygous pathogenic variants in PTHLH cause autosomal dominant brachydactyly type E (BDE), characterized by shortening of metacarpals, metatarsals and/or phalanges often accompanied by short stature Gene Symbol; Disease Name.

Multiple unrelated families and individuals harbor rare PTHLH variants co-segregating with BDE. A four-member kindred (three siblings and affected mother) carried a novel missense variant c.25T>C (p.Trp9Arg) (PMID:37501674), while a four-generation pedigree with ten affected individuals exhibited a frameshift variant c.146dupA (p.Ser50ValfsTer22) (PMID:38407575). Additional heterozygous variants including c.2T>G (p.Met1Arg) in an AHO-like cohort (PMID:34897794) and c.44T>G (p.Leu15Arg) in a Chinese family (PMID:25801215) further support dominant inheritance and phenotypic consistency. In total, at least 14 affected relatives demonstrate segregation of PTHLH variants.

The variant spectrum includes three missense changes (p.Trp9Arg, p.Met1Arg, p.Leu15Arg), one frameshift (p.Ser50ValfsTer22), and a splice site alteration (c.524+2T>C). No recurrent or founder alleles have been described. Phenotypic variability extends to speech delay in some carriers, though the core features of metacarpal and metatarsal shortening with short stature remain consistent across reports.

Functional studies in cell and animal models elucidate a loss-of-function mechanism. Gene-trap disruption of Nfib in murine chondrocytes reduces PTHrP expression and impairs cartilage matrix formation (PMID:17904922). In vitro assays demonstrate that PTHrP prevents premature chondrocyte hypertrophy by promoting cyclin D1–dependent phosphorylation and proteasomal degradation of Runx2 and Runx3 (PMID:19351720), recapitulating the short limb phenotype when PTHrP is deficient.

No conflicting evidence has been reported. The convergence of multiple segregating variants, consistent autosomal dominant inheritance, and concordant functional data justify a Strong ClinGen clinical validity classification for the PTHLH–BDE association. Genetic evidence reaches a Strong tier (14 segregations across four pedigrees), and functional evidence is Moderate (cellular and murine models demonstrating PTHLH haploinsufficiency).

Key Take-home: Heterozygous loss-of-function variants in PTHLH cause autosomal dominant brachydactyly type E, and targeted genetic testing of PTHLH is recommended in individuals with metacarpal/ metatarsal shortening and short stature.

References

• Bone Reports | 2023 | A novel mutation in PTHLH in a family with a variable phenotype with brachydactyly, short stature, oligodontia and developmental delay. PMID:37501674
• Molecular Genetics & Genomic Medicine | 2024 | A novel heterozygous mutation in PTHLH causing autosomal dominant brachydactyly type E complicated with short stature. PMID:38407575
• Journal of Bone and Mineral Research | 2021 | Skeletal disorders with AHO-like features: novel PTHLH and TRPS1 variants identified by WES. PMID:34897794
• Clinica Chimica Acta | 2015 | Exome sequencing reveals a novel PTHLH mutation in a Chinese pedigree with brachydactyly type E and short stature. PMID:25801215
• Bone | 2007 | Involvement of nuclear factor I transcription/replication factor in the early stage of chondrocytic differentiation. PMID:17904922
• Journal of Cell Science | 2009 | PTHrP prevents chondrocyte premature hypertrophy by inducing cyclin-D1-dependent Runx2 and Runx3 phosphorylation, ubiquitylation and proteasomal degradation. PMID:19351720

Evidence Based Scoring (AI generated)