The rare osteosclerotic bone dysplasia Kenny-Caffey syndrome (KCS) is one of few syndromes associated with neonatal hypoparathyroidism. The recent description of a number of consanguineous Kuwaiti autosomal recessive KCS pedigrees made possible a genome-wide scan for linkage to the KCS disease gene by homozygosity mapping. Significant linkage was obtained to a locus situated at chromosome 1q42-q43 with a maximal two-point LOD score of 13.30 at marker D1S2649. Haplotype analysis of flanking markers defined the KCS critical region to a 4-cM interval interval between the centromeric marker D1S1540 and the telomeric marker D1S2850. All affected individuals in these unrelated kindreds were homozygous for identical alleles at markers D1S2649 and D1S235, suggesting a single ancestral mutation underlying the disease in these families. Interestingly, the Sanjad-Sakati syndrome (SSS), an autosomal recessive trait associated with congenital hypoparathyroidism without skeletal involvement, also was recently linked to chromosome 1q42-q43. Given the phenotypic similarity, the possibility that SSS is allelic with KCS was considered and Saudi Arabian SSS families were genotyped with markers from the KCS critical region. A maximum multipoint LOD score of 14.32 was obtained at a marker D1S2649, confirming linkage of SSS to the same region as autosomal recessive KCS. Haplotype analysis of SSS alleles identified the same rare haplotype seen in the KCS alleles. These results suggested a common ancestral founder for these two disorders and narrowed the critical region to a 2.6-cM interval between markers D1S1540 and D1S235. In a case of genotype informing phenotype, reevaluation of SSS patients has demonstrated the occurrence of osteosclerosis as these patients age. The genetic data, combined with the overlapping clinical phenotype, suggests that the two syndromes are not only allelic, but are caused by the same ancestral mutation. Localization of the KCS/SSS gene at 1q42-q43 rules out an etiologic role for mutation in the parathyroid hormone (PTH), PTH receptors-1 and 2, and the calcium-sensing receptor genes in these disorders.
|Journal of Investigative Medicine
|Published - Feb 1999