ClinVar Genomic variation as it relates to human health

In 2 unrelated patients, Francomano et al. (1996) found the same novel FGFR3 mutation as the cause of a previously undescribed skeletal dysplasia characterized by extreme short stature, severe tibial bowing, profound developmental delay, and acanthosis nigricans (SADDAN; 616482). The mutation, a 1949A-T transversion causing a lys650-to-met (K650M) substitution, occurs in the distal tyrosine kinase domain. (A change at the adjacent nucleotide in FGFR3 (1948A-G) causes a substitution at the same codon (K650E; 134934.0004) and results in thanatophoric dysplasia type II (187601).) Both individuals with the K650M mutation, one aged 5 years and the other aged 29 years, had skeletal findings distinct from both TD1 (187600) and TD2. These included absence of craniosynostosis or cloverleaf skull anomaly and presence of moderate bowing of the femurs with reverse bowing of the tibia and fibula. The older patient had bilateral tibial pseudoarthroses. Other clinical and physical features common to both patients included survival past infancy; periods of respiratory compromise during infancy but without the need for prolonged mechanical ventilation; development of acanthosis nigricans in the cervical and flexural areas; and seizures and hydrocephalus during infancy with severe limitation of motor and intellectual development. The younger patient had structural anomalies of the brain, including a hypoplastic corpus callosum and abnormal development of the cerebellum. Tavormina et al. (1999) referred to the distinctive syndrome described by Francomano et al. (1996) as SADDAN dysplasia, an acronym derived from 'severe achondroplasia with developmental delay and acanthosis nigricans.' They reported 4 unrelated individuals with this syndrome (2 of whom were reported by Francomano et al., 1996) approaching the severity observed in thanatophoric dysplasia type I. Different from thanatophoric dysplasia was the development of extensive areas of acanthosis nigricans beginning in early childhood in 3 patients, severe neurologic impairments, and survival past infancy without prolonged life-support measures. Lys650 is highly conserved in the kinase domain activation loop. Transient transfection studies with FGFR3 mutant constructs showed that the lys650-to-met mutation caused a dramatic increase in constitutive receptor kinase activity, approximately 3 times greater than that observed with the lys650-to-glu mutation. Zankl et al. (2008) reported a patient with the SADDAN phenotype associated with a K650M substitution resulting from a de novo 1949A-T transversion in exon 15 of the FGFR3 gene. The patient 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, while 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. The K650M mutation due to a 1988A-T transversion was found in cell lines and tumors of multiple myeloma (254500) containing a karyotypically silent translocation between t(4;14) and the IgH. Chesi et al. (1997) proposed that after the t(4;14) translocation, somatic mutation during tumor progression generated an FGFR3 protein that was active in the absence of ligand. FGFR is, then, another example of a gene that can be both an oncogene and a 'teratogene.' Kitoh et al. (1998) reported the lys650-to-met mutation as the cause of thanatophoric dysplasia type I. (less)

In 2 unrelated patients, Francomano et al. (1996) found the same novel FGFR3 mutation as the cause of a previously undescribed skeletal dysplasia characterized by extreme short stature, severe tibial bowing, profound developmental delay, and acanthosis nigricans (SADDAN; 616482). The mutation, a 1949A-T transversion causing a lys650-to-met (K650M) substitution, occurs in the distal tyrosine kinase domain. (A change at the adjacent nucleotide in FGFR3 (1948A-G) causes a substitution at the same codon (K650E; 134934.0004) and results in thanatophoric dysplasia type II (187601).) Both individuals with the K650M mutation, one aged 5 years and the other aged 29 years, had skeletal findings distinct from both TD1 (187600) and TD2. These included absence of craniosynostosis or cloverleaf skull anomaly and presence of moderate bowing of the femurs with reverse bowing of the tibia and fibula. The older patient had bilateral tibial pseudoarthroses. Other clinical and physical features common to both patients included survival past infancy; periods of respiratory compromise during infancy but without the need for prolonged mechanical ventilation; development of acanthosis nigricans in the cervical and flexural areas; and seizures and hydrocephalus during infancy with severe limitation of motor and intellectual development. The younger patient had structural anomalies of the brain, including a hypoplastic corpus callosum and abnormal development of the cerebellum. Tavormina et al. (1999) referred to the distinctive syndrome described by Francomano et al. (1996) as SADDAN dysplasia, an acronym derived from 'severe achondroplasia with developmental delay and acanthosis nigricans.' They reported 4 unrelated individuals with this syndrome (2 of whom were reported by Francomano et al., 1996) approaching the severity observed in thanatophoric dysplasia type I. Different from thanatophoric dysplasia was the development of extensive areas of acanthosis nigricans beginning in early childhood in 3 patients, severe neurologic impairments, and survival past infancy without prolonged life-support measures. Lys650 is highly conserved in the kinase domain activation loop. Transient transfection studies with FGFR3 mutant constructs showed that the lys650-to-met mutation caused a dramatic increase in constitutive receptor kinase activity, approximately 3 times greater than that observed with the lys650-to-glu mutation. Zankl et al. (2008) reported a patient with the SADDAN phenotype associated with a K650M substitution resulting from a de novo 1949A-T transversion in exon 15 of the FGFR3 gene. The patient 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, while 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. The K650M mutation due to a 1988A-T transversion was found in cell lines and tumors of multiple myeloma (254500) containing a karyotypically silent translocation between t(4;14) and the IgH. Chesi et al. (1997) proposed that after the t(4;14) translocation, somatic mutation during tumor progression generated an FGFR3 protein that was active in the absence of ligand. FGFR is, then, another example of a gene that can be both an oncogene and a 'teratogene.' Kitoh et al. (1998) reported the lys650-to-met mutation as the cause of thanatophoric dysplasia type I. (less)