PTPN11 – Metachondromatosis

Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant skeletal disorder characterized by combined exostoses and enchondromas (MONDO:0007979). Patients present with osteochondroma-like lesions pointing toward adjacent joints and columnar enchondromas, some of which regress spontaneously.

Genetic evidence for PTPN11 involvement was first provided by whole-genome sequencing of a single proband and linkage in a small family, identifying a heterozygous 11 bp deletion in exon 4 that co-segregated with MC, confirmed by a nonsense mutation in a second family (PMID:20577567). Subsequent targeted capture and sequencing across 16 participants from 11 MC families revealed heterozygous putative loss-of-function variants in 10 families and a 15 kb deletion spanning exon 7 in another, giving a total of 11 affected families and 17 participants with PTPN11 mutations (PMID:21533187).

The variant spectrum comprises frameshift (e.g., c.971_972insGAGTTACAAGTGCAACAATTCAAAG (p.Lys325fs)), nonsense (c.745G>T (p.Glu249Ter)), splice-site (c.525+1G>A), and copy-number deletion mutations consistent with haploinsufficiency. No such truncating variants were observed in 469 population controls (PMID:20577567).

Functional studies of microdissected MC lesions demonstrated loss-of-heterozygosity for the wild-type PTPN11 allele, supporting a Knudson two-hit mechanism in lesion formation (PMID:21533187). PTPN11 encodes SHP-2, a tyrosine phosphatase whose loss of function abrogates negative regulation of chondrocyte proliferation.

Additional case reports describe heterozygous PTPN11 mutations in singleton probands with classic MC phenotypes, including a 9-year-old boy with osteochondromas without enchondromas (PMID:29252664) and a 5-year-old girl with both exostoses and enchondromas confirmed by a splice-site mutation in exon 11 (PMID:26984661). These cases reinforce the clinical spectrum and incomplete penetrance of MC.

Approximately 6 of the 17 MC families lacked PTPN11 mutations, suggesting possible locus heterogeneity. No conflicting evidence disputes PTPN11’s role in MC; rather, additional causative genes may exist.

Overall, heterozygous loss-of-function variants in PTPN11 demonstrate a strong association with metachondromatosis, supported by family co-segregation, diverse truncating variant spectrum, and concordant functional data. Genetic testing for PTPN11 should be included in diagnostic panels for combined exostoses and enchondromatosis syndromes.

Key Take-home: PTPN11 haploinsufficiency is a clinically actionable and molecularly validated cause of metachondromatosis.

References

• PLoS genetics • 2011 • Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome. PMID:21533187
• PLoS genetics • 2010 • Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene. PMID:20577567
• JBJS case connector • 2016 • Metachondromatosis without Enchondromas: A Case Report and Review of the Literature. PMID:29252664
• Acta orthopaedica Belgica • 2016 • Exostoses, enchondromatosis and metachondromatosis; diagnosis and management. PMID:26984661

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