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Editor—Over the past 12 years, 26 patients with an unusual syndrome of congenital hypoparathyroidism associated with severe prenatal and postnatal growth retardation and a pattern of facial anomalies have been seen at the King Faisal Specialist Hospital and Research Centre, Saudi Arabia.1 2 The disorder has been listed by McKusick in OMIM as “hypoparathyroidism-retardation-dysmorphism syndrome; HRD” as entry 241410. Recently, Parvari et al 3 reported the assignment of the gene for this disorder to chromosome 1 at 1q42-43. Their report was based on a study of consanguineous Bedouin families from Israel and their linkage analysis was based on homozygosity by descent.4 This reports describes a study of three consanguineous Saudi families, which yielded results consistent with the 1q42-43 location of the responsible gene.
Blood samples were collected and DNA extracted from three Saudi families consisting of first cousin parents and their 14 children, five of whom manifested the Sanjad-Sakati syndrome. DNA samples were pooled from the five affected children and a separate pooled sample prepared from the DNA of their nine unaffected sibs. The initial analysis included PCR amplified DNA markers linked to genes involved either in parathyroid structure or function.5 As no evidence of linkage was found, the analysis was expanded to the human genome screening set from Research Genetics (Huntsville, Alabama). The analysis proceeded from chromosome 22 to chromosome 1. A positive result was based on finding a single band in the pooled sample from the affected children indicating homozygosity, while the pooled sample from the unaffected sibs showed two or more bands. A positive result with marker DlS235 prompted analysis of all 20 samples separately with the additional markers D1S1656, D1S163, D1S179, D1S2712, D1S1540, D1S1680, D1S2678, D1S2680, D1S2850, D1S373, and D1S2670, all of which cluster around 1q42-43.
Multipoint lod scores were generated using MAPMAKER/HOMOZ.6 Analysis of the data assumed equal frequencies of the alleles at each marker. The order of the markers was taken from the maps published by Broman et al.7 The data showed that the affected sibs in the three families were homozygous for markers that clustered around the marker D1S235. A maximum lod score of 4.12 around D1S235 at 1q42-43 was obtained. Flanking markers D1S1656 and D1S2678 were consistent with those found by Parvari et al 3and suggest a candidate region maximally at 1 cM.
The initial report of Sanjad et al 1 in 1988 and their definitive report in 19912 clearly established this as a distinct disorder with autosomal recessive inheritance. The consistency with which hypocalcaemic tetany or seizures or both occur in intrauterine growth retarded infants suggests that this is not a diagnosis likely to be missed. That this disorder has only been reported in consanguineous Arabic families suggests that a founder effect of a long standing mutation is responsible for this disorder.
Kenny-Caffey syndrome type 1 is clinically manifest as growth retardation, craniofacial anomalies, small hands and feet, hypocalcaemia, hypoparathyroidism, and radiological evidence of cortical thickening in the long bones with medullary stenosis and absent diploic space in the skull. The original reports of Caffey8 and Kenny and Linarelli9 suggested autosomal dominant inheritance and the condition is now referred to as Kenny-Caffey syndrome type 2. In 1997 Khan et al 10 reported on 16 affected children with Kenny-Caffey syndrome type 1 in six unrelated sibships born to healthy, consanguineous, Bedouin parents from Kuwait. From this group of patients, Diaz et al 11 in 1998 mapped the locus for this disorder to 1q42-43. All of this information taken together suggests that the Sanjad-Sakati syndrome and type 1 Kenny-Caffey syndrome are at least allelic disorders if not the same condition. Despite the multiplicity of abnormalities, including intrauterine growth retardation, mental retardation, and facial dysmorphism with congenital hypoparathyroidism, there is currently no information about the nature of the underlying molecular defect in either disorder. Mapping of the locus responsible now offers promise for analysis of candidate genes or positional cloning as likely methods to delineate the molecular basis.
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