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Link to original content: https://omim.org/entry/146200
ORPHA: 189466, 2238, 2239; DO: 0111387;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11p15.3 | Hypoparathyroidism, familial isolated 1 | 146200 | Autosomal dominant; Autosomal recessive | 3 | PTH | 168450 |
A number sign (#) is used with this entry because of evidence that familial isolated hypoparathyroidism-1 (FIH1) is caused by heterozygous, homozygous, or compound heterozygous mutation in the parathyroid hormone gene (PTH; 168450) on chromosome 11p15.
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.
Genetic Heterogeneity of Familial Isolated Hypoparathyroidism
FIH2 (618883) is caused by mutation in the GCM2 gene (603716). An X-linked form of familial hypoparathyroidism, HYPX (307700), is caused by interstitial deletion/insertion on chromosome Xq27.1, which may have a position effect on expression of SOX3 (313430).
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).
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.
The pattern of transmission of FIH1 in the family studied by Arnold et al. (1990), previously studied by Ahn et al. (1986) as family D, was consistent with autosomal dominant inheritance.
The pattern of transmission of FIH1 in the family studied by Parkinson and Thakker (1992) was consistent with autosomal recessive inheritance.
In a family with autosomal recessive inheritance of FIH, Parkinson et al. (1993) 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).
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.
In 1 of the families studied by Ahn et al. (1986), family D, Arnold et al. (1990) identified a heterozygous 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.
Exclusion Studies
Using a polymorphic tetranucleotide, AAAT(n), within the first intron of the PTH gene, Parkinson et al. (1993) excluded linkage with isolated hypoparathyroidism in 1 family with autosomal dominant inheritance. In a second family with autosomal recessive inheritance, linkage of the disorder with the PTH locus could not be excluded; DNA sequencing of the PTH gene coding and promoter regions from an affected individual revealed no differences from the published sequence.
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.
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Arnold, A., Horst, S. A., Gardella, T. J., Baba, H., Levine, M. A., Kronenberg, H. M. Mutation of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism. J. Clin. Invest. 86: 1084-1087, 1990. [PubMed: 2212001] [Full Text: https://doi.org/10.1172/JCI114811]
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