Achondroplasia, Severe, With Developmental Delay And Acanthosis Nigricans

A number sign (#) is used with this entry because of evidence that severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) is caused by heterozygous mutation in the gene encoding fibroblast growth factor receptor-3 (FGFR3; 134934) on chromosome 4p16.

Clinical Features

Tavormina et al. (1999) reported 4 unrelated individuals with a distinctive syndrome comprising severe achondroplasia with developmental delay and acanthosis nigricans, which they referred to as SADDAN dysplasia. Two of the patients had previously been reported in an abstract (Francomano et al., 1996). The severity approached that observed in thanatophoric dysplasia type I (TD1; 187600). Differences included the development of extensive areas of acanthosis nigricans beginning in early childhood in 3 of 4 patients, severe neurologic impairments, and survival past infancy without prolonged life-support measures. Bellus et al. (1999) described in detail the clinical and radiographic features of these patients.

Zankl et al. (2008) reported a patient with the SADDAN phenotype. He had severe micromelia, frontal bossing, large anterior fontanel, depressed nasal bridge, reverse tibial bowing, small thorax, and hypotonia. Acanthosis nigricans was not present. He died at age 21 days due to respiratory failure. Zankl et al. (2008) noted that about half of patients reported with the K650M mutation died before 21 days of age, whereas others have shown longer survival. The authors also noted that acanthosis nigricans has been reported in patients with other skeletal dysplasias due to FGFR3 mutations, and thus should be considered a long-term complication rather than a specific feature of SADDAN. In addition, mental retardation only becomes apparent in long-term survivors and thus cannot be used as a diagnostic criterion for SADDAN in the neonatal period.

Molecular Genetics

In 4 unrelated patients with SADDAN dysplasia, Tavormina et al. (1999) identified a heterozygous mutation in the FGFR3 gene (K650M; 134934.0015), resulting in a dramatic increase in constitutive receptor kinase activity.

In a patient with SADDAN dysplasia, Zankl et al. (2008) identified heterozygosity for the K650M mutation in the FGFR3 gene.

Animal Model

Iwata et al. (2001) introduced the murine equivalent (K644M) of the human SADDAN point mutation (K650M; 134934.0015) into the mouse Fgfr3 gene. Heterozygous mutant mice showed a phenotype similar to human SADDAN, e.g., the majority of the SADDAN mice survived the perinatal period. The long bone abnormalities in SADDAN mice were milder than the TDII model. In addition, overgrowth of the cartilaginous tissues was observed in the rib cartilage, trachea, and nasal septum. Unlike the TDII model, FGF ligands at low concentrations differentially activated Map kinase in primary chondrocyte cultures from wildtype and SADDAN mice.