Kenny-Caffey Syndrome, Type 1

A number sign (#) is used with this entry because the autosomal recessive form of Kenny-Caffey syndrome (KCS1) is caused by mutation in the gene encoding tubulin-specific chaperone E (TBCE; 604934).

Biallelic mutation in the TBCE gene can also cause Sanjad-Sakati syndrome (HRDS; 241410) and PEAMO (617207).

Inheritance of Kenny-Caffey syndrome is most often autosomal dominant (KCS2; 127000) (Franceschini et al., 1992).

Clinical Features

Franceschini et al. (1992) suggested autosomal recessive inheritance of Kenny-Caffey syndrome in female and male sibs, born of normal consanguineous parents. The sister died at 10 days of age with generalized hypertonic seizures associated with hypocalcemia. The later-born brother had neonatal hypoparathyroidism; at 1 year of age, he was short but intelligent. Both infants showed characteristic cortical thickening and medullary stenosis. Franceschini et al. (1992) noted that recessive inheritance was also suggested by the parental consanguinity in a family with a single affected child (Bergada et al., 1988) and by the family with 2 affected infants with the same normal father and different normal mothers who were sisters (Sarria et al., 1980).

Khan et al. (1997) reported 16 affected children in 6 unrelated sibships, born to healthy, consanguineous parents of Bedouin ancestry. They were able to assess clinically 11 of these 16 patients. All presented with marked growth retardation, craniofacial anomalies, small hands and feet, hypocalcemia, hypoparathyroidism, radiologic evidence of cortical thickening of long bones with medullary stenosis, and absent diploic space in the skull. There was a history of 6 other affected sibs dying in infancy with hypocalcemic convulsions. All cases had early psychomotor retardation and absence of macrocephaly.

Mapping

Using 8 consanguineous Kuwaiti kindreds, Diaz et al. (1998) performed a genomewide search for linkage to the gene causing the autosomal recessive form of KCS with polymorphic short tandem repeat markers. Significant linkage to a locus situated at 1q42-q43 with a maximum 2-point lod score of 13.30 with marker D1S2649 was obtained. Haplotype analysis of flanking markers identified recombination events defining the KCS1 locus to a region between markers D1S2800 on the centromeric boundary and D1S2850 on the telomeric boundary, an approximately 4-cM interval. All affected individuals in these unrelated kindreds were homozygous for identical alleles at D1S2649 and D1S235, suggesting a single ancestral mutation underlying the disease in these families. Haploinsufficiency at 22q11, reported in a consanguineous KCS kindred by Sabry et al. (1998), was not documented in these families. Sabry et al. (1998) had demonstrated an interstitial deletion at 22q11 by fluorescence in situ hybridization in 2 affected sibs and their unaffected mother. The clinical findings in affected individuals from 6 of the 8 pedigrees studied by Diaz et al. (1998) had previously been described by Khan et al. (1997).

Molecular Genetics

Parvari et al. (2002) demonstrated mutations in the TBCE gene in both Kenny-Caffey syndrome and Sanjad-Sakati syndrome (see 604934.0001).