PTPN11 – Cardiofaciocutaneous Syndrome

PTPN11 encodes the SHP-2 tyrosine phosphatase, a key positive regulator of RAS/MAPK signaling. Cardiofaciocutaneous (CFC) syndrome is an autosomal dominant RASopathy characterized by cardiac defects, ectodermal abnormalities, and developmental delay. Although PTPN11 mutations underlie ~50% of Noonan syndrome cases, their role in CFC has been minimally reported and remains distinct from classical CFC genes (BRAF, MEK1/2, KRAS).

Clinical Validity

A single family with three affected individuals carrying a heterozygous PTPN11 variant c.1232C>T (p.Thr411Met) was reported in a proband with overlapping Noonan and CFC features (sparse coarse hair, ectodermal involvement, developmental delay) that segregated to her mother and sister (PMID:15384080). Two cohort studies of rigorously phenotyped CFC patients (n=28 and n=10) found no PTPN11 coding mutations, indicating that PTPN11 is not a common cause of CFC (PMID:12384786; PMID:12529707).

Overall strength: Limited

Genetic Evidence

Inheritance mode: Autosomal dominant.
Segregation: The c.1232C>T (p.Thr411Met) variant co-segregated with CFC-like features in three family members (PMID:15384080). No additional unrelated PTPN11-associated CFC probands have been described.
Variant spectrum: One missense variant reported in CFC context.

Functional Evidence

Molecular dynamics and in vitro assays demonstrated that p.Thr411Met favors an active SHP-2 conformation, similar to other gain-of-function PTPN11 mutations, leading to prolonged RAS/MAPK pathway activation concordant with CFC phenotypes (PMID:15384080).

Conflicting Evidence

Two independent studies of 38 total CFC patients yielded no PTPN11 coding or deletion mutations, supporting genetic heterogeneity and arguing against a major role for PTPN11 in CFC (PMID:12384786; PMID:12529707).

Integration & Conclusion

PTPN11 mutations can rarely present with CFC-like clinical features, but evidence is limited to a single multigenerational family. Functional data support a pathogenic gain-of-function effect for p.Thr411Met on SHP-2 activity. However, the absence of PTPN11 variants in larger CFC cohorts underscores that PTPN11 is not a common etiological gene for classic CFC syndrome. Key take-home: PTPN11 testing may be considered in atypical CFC presentations, but negative results require testing of canonical CFC genes.

References

• American journal of medical genetics. Part A • 2004 • Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation. PMID:15384080
• Human genetics • 2002 • Absence of PTPN11 mutations in 28 cases of cardiofaciocutaneous (CFC) syndrome. PMID:12384786
• European journal of human genetics : EJHG • 2003 • PTPN11 mutations are not responsible for the Cardiofaciocutaneous (CFC) syndrome. PMID:12529707

Evidence Based Scoring (AI generated)