Hypoparathyroidism, Familial Isolated

A number sign (#) is used with this entry because familial isolated hypoparathyroidism can be caused by mutation in the parathyroid hormone gene (PTH; 168450), or in the GCM2 gene (603716), a homolog of the Drosophila glial cells missing gene.

There is also an X-linked form of hypoparathyroidism (307700).

Description

Garfield and Karaplis (2001) reviewed the various causes and clinical forms of hypoparathyroidism. They noted that hypoparathyroidism is a clinical disorder characterized by hypocalcemia and hyperphosphatemia. It manifests when parathyroid hormone (PTH; 168450) secreted from the parathyroid glands is insufficient to maintain normal extracellular fluid calcium concentrations or, less commonly, when PTH is unable to function optimally in target tissues, despite adequate circulating levels.

Congenital absence of the parathyroid and thymus glands (III and IV pharyngeal pouch syndrome, or DiGeorge syndrome, 188400) is usually a sporadic condition (Taitz et al., 1966).

Clinical Features

Garfield and Karaplis (2001) stated that the predominant clinical manifestations of hypoparathyroidism are those related to hypocalcemia. In the acute setting, neuromuscular irritability, including perioral paresthesias, tingling of the fingers and toes, and spontaneous or latent tetany with grand mal seizures and laryngeal spasm can be evident. Chronically, hypocalcemia can be asymptomatic and only become apparent after routine blood screening. Alternatively, it can manifest with mild neuromuscular irritability, calcification of the basal ganglia, extrapyramidal disorders, cataracts, alopecia, abnormal dentition, coarse brittle hair, mental retardation, or personality disorders. Biochemically, hypoparathyroidism is characterized by low serum calcium and raised serum phosphorus in the presence of normal renal function. Serum concentrations of immunoreactive PTH are low or undetectable, except in the setting of PTH resistance, where levels can be high-normal or elevated. Circulating levels of 1,25-dihydroxyvitamin D are usually low or low-normal. The 24-hour urinary excretion of calcium is decreased. Nephrogenous cAMP excretion is low, whereas renal tubular reabsorption of phosphorus is elevated.

Some reports of idiopathic hypoparathyroidism, in which affected sibs were born of consanguineous parents (Sutphin et al., 1943; Chaptal et al., 1960), suggest autosomal recessive inheritance. The familial cases of Sutphin et al. (1943) showed moniliasis also (see hypoadrenocorticism with hypoparathyroidism and superficial moniliasis, 240300). Bronsky et al. (1968) described 2 brothers who developed idiopathic hypoparathyroidism when 11 and 21 years old. A sister, who died when 19 years old, may also have been affected. Bronsky et al. (1968) cited 6 other reported families in which more than 1 member was affected.

Recessive inheritance was simulated in the family of Buchs (1961) in which 3 brothers had congenital hypoparathyroidism, apparently as a response to maternal hyperparathyroidism. Aceto et al. (1966) reported fetal and infantile hyperparathyroidism due to maternal hypoparathyroidism. The second and third offspring of the affected mother, a girl and a boy, had hypoparathyroidism. The fathers of at least 2 of the offspring were different. The report of Niklasson (1970) may concern autosomal recessive isolated hypoparathyroidism.

Benson and Parsons (1964) described hypoparathyroidism in a mother and 2 of her children. They found no circulating antibodies to parathyroid hormone. Barr et al. (1971) reported hypoparathyroidism in 2 generations of 2 unrelated kindreds. In 1 kindred there was father-to-son transmission.

Yumita et al. (1986) described 2 families with idiopathic hypoparathyroidism. In the first family, a brother and sister were affected; in the second family, 2 brothers and a sister were affected, although only 1 of the 3 was studied extensively. Yumita et al. (1986) suggested that progressive sensorineural deafness, which was present in both families, was an integral part of the hypoparathyroidism syndrome. However, in the second family, it appears to have been segregating, probably as an autosomal dominant, independently of the hypoparathyroidism.

Ahn et al. (1986) studied 8 families with a total of 23 affected persons fulfilling strict criteria for familial isolated hypoparathyroidism: no demonstrable anatomic cause, no evidence of candidiasis or autoimmune polyglandular failure, no antithyroid or antiadrenal autoantibodies, no developmental defects that might indicate an embryologic disorder such as familial branchial pouch dysgenesis, and, of course, undetectable or subnormal plasma levels of immunoreactive PTH. Inheritance was consistent with autosomal dominance in 5 and autosomal recessivity in 3; 1 of the 'dominant pedigrees' and 2 of the 'recessive pedigrees' were also consistent with X-linked inheritance (see 307700). In none of 23 affected persons was there absence of the PTH gene or abnormal restriction patterns to suggest recognizable deletions, insertions or rearrangements. Furthermore, in 4 families affected sibs inherited different PTH alleles, as marked by RFLPs, implying that hypoparathyroidism was not due to an abnormality in the PTH gene. In 2 families concordance was found between the inheritance of hypoparathyroidism and specific PTH alleles, a finding consistent with but of course not proving the possibility that the FIH in these families was caused by mutation in or near the PTH structural gene.

Nusynowitz and Klein (1973) described a 20-year-old male college student with hypocalcemia, hyperphosphatemia, chronic tetany, and cataracts. Normal to high levels of immunoreactive parathyroid hormone were found. Renal responsiveness to exogenous PTH was demonstrated. The authors suggested that this patient suffered from a defect in conversion of proparathyroid hormone to its active form. The parents were not related and no other affected persons were found in the family (Nusynowitz, 1973). Ahn et al. (1986) restudied this family and found that the proband had markedly reduced or absent plasma PTH by radioimmunoassays that are midmolecule specific or carboxy-terminal specific despite symptomatic hypocalcemia. In addition an affected son had low plasma PTH. Thus, this is an instance of autosomal dominant hypoparathyroidism. Linkage analysis with the RFLPs used was uninformative because both parents were homozygous for the same haplotype.

Schmidtke et al. (1986) described a family in which 2 brothers and their mother had hypoparathyroidism. No gross abnormality of the PTH gene was found on Southern blotting. Linkage of the PTH gene to the hypoparathyroidism was excluded by the finding that the mother had passed a different PTH allele (as marked by a RFLP) to each of her sons. De Campo et al. (1988) described a 3-generation family in which 6 of 13 members were affected by primary hypoparathyroidism. In this family, male-to-male, female-to-female, and female-to-male transmission was demonstrated, confirming the autosomal dominant hypothesis.

McLeod et al. (1989) described a mother and 2 sons with clinical hypoparathyroidism and no detectable serum parathyroid hormone on radioimmunoassay. The propositus presented with seizures and on CT scan had bilateral basal ganglion calcification and calcification in the frontal lobes. His similarly affected mother had even more extensive intracerebral calcification.

Mapping

Using a polymorphic tetranucleotide, AAAT(n), within the first intron of the PTH gene, Parkinson et al. (1993) excluded linkage with autosomal dominant isolated hypoparathyroidism in 1 family with dominant inheritance and a second family with autosomal recessive inheritance. In another family with autosomal recessive inheritance, they demonstrated linkage to the PTH gene, which was not unexpected because the same family was found by Parkinson and Thakker (1992) to have a donor splice site mutation in the PTH gene (168450.0002). Thus, both autosomal dominant and autosomal recessive forms of familial isolated hypoparathyroidism have been related to mutations in the PTH gene.

Cytogenetics

Scire et al. (1994) reported clinical features of 2 adolescent males illustrating that the main manifestation of 22q11 deletion can be chronic symptomatic hypocalcemia secondary to hypoparathyroidism, together with seizures and cerebral calcifications. The patients had no cardiac abnormality or T-cell deficiency and had no cleft palate, features that occur in the DiGeorge syndrome (188400) and the velocardiofacial syndrome (VCFS; 192430). The patients did have facial features of VCFS, and one in particular had a hypernasal voice.

Makita et al. (1995) reported 2 further cases of isolated hypoparathyroidism in whom they demonstrated a 22q11 deletion by fluorescence in situ hybridization.

Molecular Genetics

In 1 of the families studied by Ahn et al. (1986), family D, Arnold et al. (1990) identified a point mutation in the signal peptide-encoding region of the PTH gene (C18R; 168450.0001).

In 2 sisters and a brother with isolated hypoparathyroidism, the offspring of a first-cousin marriage, Parkinson and Thakker (1992) identified homozygosity for a mutation in the PTH gene (168450.0002).

Sunthornthepvarakul et al. (1999) identified a mutation in the PTH gene (168450.0003) in a patient with neonatal hypocalcemic seizures who was born to consanguineous parents. Serum calcium was 1.5 mmol/L (normal, 2.0-2.5); phosphate was 3.6 mmol/L (normal, 0.9-1.5). A few years later, 2 younger sisters and her niece presented with neonatal hypocalcemic seizures. Their intact PTH levels were undetectable during severe hypocalcemia. Only affected family members were homozygous for the mutant allele, whereas the parents were heterozygous, supporting autosomal recessive inheritance.

In the proband of an extensive kindred with familial isolated hypoparathyroidism, Ding et al. (2001) identified homozygosity for a large intragenic deletion in the GCM2 gene (603716.0001). The nonconsanguineous, asymptomatic parents were heterozygous for the deletion. Haplotype analysis revealed shared genotypes that flanked the GCM2 gene over 5 cM, suggesting a founder effect with homozygosity by descent of the chromosomal segment containing the GCM2 deletion. Ding et al. (2001) concluded that homozygous loss of function of the GCM2 gene impairs normal parathyroid gland embryology and is responsible for isolated hypoparathyroidism in a subset of patients.

In affected members of a consanguineous Pakistani family with familial isolated hypoparathyroidism, Baumber et al. (2005) identified homozygosity for a missense mutation in the GCM2 gene (603716.0002).

Pathogenesis

In HEK293 cells transfected with C18R-mutant preproPTH cDNA, Datta et al. (2007) demonstrated that the expressed mutant hormone was trapped intracellularly, predominantly in the endoplasmic reticulum (ER), resulting in apoptosis. The C18R-expressing cells also showed marked upregulation of the ER stress-responsive hormones BIP (HSPA5; 138120) and PERK (EIF2AK3; 604032) and the proapoptotic transcription factor CHOP (DDIT3; 126337). When C18R-mutant PTH was expressed in the presence of the pharmacologic chaperone 4-phenylbutyric acid, intracellular accumulation was reduced and normal secretion was restored. Datta et al. (2007) suggested that ER stress-induced cell death is the underlying mechanism for autosomal dominant hypoparathyroidism.

The studies of Winer et al. (2003) suggested that treatment with synthetic human PTH can be a safe and effective alternative to calcitriol therapy and can maintain normal serum calcium levels without hypercalciuria for at least 3 years in patients with hypoparathyroidism.

Animal Model

Glial cells missing-2 (Gcm2), a mouse homolog of Drosophila Gcm, is the only transcription factor with expression restricted to the parathyroid glands (see 603716). Gunther et al. (2000) generated mice deficient in Gcm2 by targeted disruption. The Gcm2-deficient mice lacked parathyroid glands but, unlike PTH-receptor-deficient mice, were viable and fertile and had only a mildly abnormal bone phenotype. The conditionally deleted mice exhibited hypocalcemia associated with hyperphosphatemia and increased calcium elimination in the urine without evidence of renal failure, features characteristic of hypoparathyroidism. Despite their lack of parathyroid glands, the Gcm2-deficient mice had PTH serum levels identical to those of wildtype mice, as did parathyroidectomized wildtype mice. Expression and ablation studies identified the thymus, where Gcm1 (603715), another Gcm homolog, is expressed, as an additional, downregulatable source of PTH. Thus, Gcm2 deletion uncovered an auxiliary mechanism for the regulation of calcium homeostasis in the absence of parathyroid glands. Gunther et al. (2000) suggested that this backup mechanism may be a general feature of endocrine regulation.