Hypoparathyroidism, X-Linked

A number sign (#) is used with this entry because of evidence that X-linked hypoparathyroidism (HYPX) is caused by an interstitial deletion/insertion on chromosome Xq27.1, which may have a position effect on expression of SOX3 (313430).

Clinical Features

Peden (1960) reported a family in which multiple males had neonatal idiopathic hypoparathyroidism in an X-linked pattern of inheritance. No affected males reproduced. Peden (1960) suggested that most familial cases with early onset are of the X-linked type, the autosomal type (146200) having a later onset.

Whyte and Weldon (1981) performed extensive studies of a second kindred from Missouri (where Peden's family also lived) with neonatal or infantile onset of X-linked isolated hypoparathyroidism. No ancestor common to the 2 kindreds could be identified.

Whyte et al. (1986) reported the autopsy findings in a member of the family of Peden (1960) who had died as a teenager after an automobile crash. A careful search for parathyroid tissue was made. Dissection of the thyroid gland and tissue from elsewhere in the neck, including between the trachea and esophagus and in the retroesophageal space, and histologic study of the soft tissue from these areas showed no parathyroid tissue whatever; thus, the pathology appears to be agenesis of the parathyroid glands. The patient was receiving phenobarbital and diphenylhydantoin for treatment of seizures as well as calcium supplements and vitamin D.

Mumm et al. (1997) investigated the relatedness of the 2 seemingly unrelated Missouri kindreds. Both kindreds lived in eastern Missouri and were known to have migrated there from Kentucky in the 1880s. Despite genealogic studies of 5 generations, no common ancestor had been identified. Mumm et al. (1997) compared the DNA sequence of the mitochondrial D-loop among several individuals in both kindreds. The mtDNA sequence was identical among affected males and their maternal lineage for individuals in both kindreds. Conversely, the mtDNA sequence of the fathers of the affected males differed from that of the maternal lineage at 3 to 6 positions. These results demonstrated that the 2 kindreds exhibiting X-linked recessive hypoparathyroidism are indeed related and that an identical gene defect is responsible for the disease. Mumm et al. (1997) suggested that this approach may be important in investigating common ancestry in other X-linked disorders.

Buchs (1957) reported 3 affected brothers who presented with neonatal tetany. Although maternal hyperparathyroidism with fetal parathyroid suppression was not excluded, it is unlikely because subsequent children were normal.

Teebi et al. (1992) reported a Bedouin family with 4 affected male sibs including a set of triplets. The mother had a brother who died in early infancy of unknown causes.

Mapping

In the family reported by Whyte and Weldon (1981), Thakker et al. (1988, 1989) established linkage of X-linked hypoparathyroidism with a RFLP located at Xq26-q27.

Zucchi et al. (1996) reported a YAC/STS map from the distal portion of Xq and suggested that the locus for X-linked hypoparathyroidism is in a segment 3 Mb telomeric to the factor IX locus (F9; 300746). Trump et al. (1998) performed further linkage analysis and suggested that the HYPX locus lies within a 1.5-Mb interval flanked centromerically by marker F9 and telomerically by DXS984.

Molecular Genetics

Nesbit et al. (2004) noted that the region on Xq26-q27 to which X-linked recessive hypoparathyroidism had been linked contained 3 genes: ATP11C (300516), U7snRNA, and SOX3 (313430). Sequence analyses of these 3 genes revealed no abnormalities. Nesbit et al. (2004) raised the possibility that other genomic abnormalities such as duplications or translocations, which could cause altered gene function (Kleinjan and van Heyningen, 2005), may underlie the etiology of X-linked recessive hypoparathyroidism.

In studies in the affected members of the Missouri family with X-linked hypoparathyroidism reported by Peden (1960), Bowl et al. (2005) undertook a detailed characterization of the genomic region containing the HYPX locus by combined analysis of single-nucleotide polymorphisms and sequence-tagged sites. This identified a 23- to 25-kb deletion, which did not contain genes. However, DNA fiber-FISH and pulsed-field gel electrophoresis revealed an approximately 340-kb insertion that replaced the deleted fragment. Use of flow-sorted X chromosome-specific libraries and DNA sequence analyses revealed that the telomeric and centromeric breakpoints on X were, respectively, approximately 67 kb downstream of SOX3 and within a repetitive sequence. Use of a monochromosomal somatic cell hybrid panel and metaphase-FISH mapping demonstrated that the insertion originated from 2p25 and contained a segment of the SNTG2 gene (608715) that lacked an open reading frame. However, the deletion-insertion, which represents a novel abnormality causing hypoparathyroidism, could result in a position effect on SOX3 expression. Indeed, Sox3 expression was demonstrated, by in situ hybridization, in the developing parathyroid tissue of mouse embryos between 10.5 and 15.5 days postcoitum. Thus, the results indicated a likely role for SOX3 in the embryonic development of the parathyroid glands.