FGFR3 – Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN)

Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) is a rare, autosomal dominant skeletal dysplasia characterized by disproportionate short stature, progressive acanthosis nigricans, developmental delay, central nervous system anomalies, hearing loss, seizures, and respiratory insufficiency. The phenotype overlaps with thanatophoric dysplasia but allows survival into adulthood. FGFR3 variants are etiologically implicated across a spectrum of chondrodysplasias including achondroplasia, hypochondroplasia, thanatophoric dysplasia, and SADDAN.

SADDAN results from heterozygous missense mutations in FGFR3, most notably the Lys650Met substitution in the kinase activation loop. Four unrelated, de novo cases have been described harboring the c.1946A>T (p.Lys649Met) variant, establishing a dominant gain-of-function mechanism ([PMID:10053006]; [PMID:10377013]). No familial segregation beyond de novo occurrence has been reported.

In vitro studies demonstrate that Lys650Met induces a ~3-fold increase in constitutive FGFR3 kinase activity compared to the Lys650Glu mutation associated with thanatophoric dysplasia type II ([PMID:10053006]). Furthermore, double mutants with p.Thr651Pro in cis dramatically reduce receptor activation, suppressing the severe skeletal phenotype ([PMID:24352917]). In vivo, targeted overexpression of FGF9 in transgenic mice, a high-affinity ligand of FGFR3, recapitulates chondrodysplastic features seen in human achondroplasia spectrum disorders ([PMID:10571691]).

FGFR3 analysis is essential for differentiating SADDAN from lethal thanatophoric dysplasia in the neonatal period and guiding prognosis and management. Growth hormone therapy in a long-term SADDAN survivor demonstrated a sustained increase in height and reduction in respiratory complications, suggesting potential therapeutic benefit ([PMID:38993719]).

Overall, the strong genetic and functional evidence supports the causal association between FGFR3 Lys650Met mutations and SADDAN, informing diagnostic genetic testing and providing a framework for targeted interventions. Key Take-home: FGFR3 c.1946A>T (p.Lys649Met) is a validated diagnostic biomarker for SADDAN with direct implications for patient management.

References

• American Journal of Human Genetics • 1999 • A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in FGFR3 PMID:10053006
• American Journal of Medical Genetics • 1999 • Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN): phenotypic analysis of a new skeletal dysplasia caused by a Lys650Met mutation in fibroblast growth factor receptor 3 PMID:10377013
• American Journal of Medical Genetics Part A • 2014 • Suppression of severe achondroplasia with developmental delay and acanthosis nigricans by the p.Thr651Pro mutation PMID:24352917
• Journal of Bone and Mineral Research • 1999 • Skeletal dysplasia and defective chondrocyte differentiation by targeted overexpression of fibroblast growth factor 9 in transgenic mice PMID:10571691
• Clinical Pediatric Endocrinology • 2024 • A case of long-term survival of SADDAN treated with growth hormone for marked short stature PMID:38993719

Evidence Based Scoring (AI generated)