Isolated Hypoparathyroidism

Types

Autosomal dominant hypocalcemia with hypercalciuria type 1 (HYPOC1)/Bartter syndrome subtype V (OMIM phenotype number #601198)

Autosomal dominant hypocalcemia with hypercalciuria type 2 (HYPOC2) (OMIM phenotype number and #615361)

Autosomal dominant hypocalcemia with hypercalciuria, also referred to as autosomal dominant hypercalciuric hypocalcemia or hypocalcemic hypercalciuria or familial hypocalcemia, is an inherited disorder of calcium metabolism, transmitted with a autosomal dominant pattern of inheritance. They belong to the group of isolated hypoparathyroidism, since no other alterations are present other than the abnormal parathyroid function.
In autosomal dominant hypocalcemia with hypercalciuria type 1 (HYPOC1), the abnormal regulation of PTH secretion is due to heterozygous mutations of calcium sensing receptor (CaSR, OMIM  gene/locus OMIM number #601199 on chromosome 3q21), a membrane protein mainly expressed in the parathyroids and in renal tubule, which is capable of sensing small changes in extracellular calcium concentration [Cao2+]. When activated by small increases of the [Cao2+], the wild type CaSR triggers responses mediated by second messengers leading to an increase in intracellular calcium [Cai2+] fluxes, which ultimately inhibit PTH secretion and modulate renal mineral ion handling. Therefore, activating mutations of the CaSR result in a decrease of PTH, with consequent hypocalcemia with relative or absolute hypercalciuria. This is demonstrated by values of the urinary calcium creatinine (Ca/Cr) ratios within or above the upper reference limit.
Gain-of-function mutations of the CaSR are mostly missense (almost 100 identified, so far) and clustered in hot spots of the gene coding for critical conformational changes of the receptor. It is likely that the functional activity of the CaSR correlates with disease severity. HYPOC1 biochemical phenotype has been reproduced in the Nuf/+ or Nuf/Nuf mice, expressing one or two copies of CaSR, respectively, with the activating mutation Leu723Glu.
HYPOC1 is one of the most frequent causes of non-surgical, genetically determined hypoparathyroidism, with an estimated prevalence of less than 1:70000, with a F:M ratio of 1:1. No dysmorphic features are present. Hypocalcemia does not manifest at birth, but later in life, usually in the second-third decade. Hypocalcemia is mild or asymptomatic in 50% of cases, symptomatic in the other half of patients, with neuromuscular symptoms such as parestesias, but few episodes of carpo-pedal spasms, and seizures. More than one third of patients develop ectopic and basal ganglia calcifications. PTH concentrations are usually in the low-normal range. Serum magnesium levels are in the low-normal range, while serum phosphate is high. Bone films are usually negative. Bone mineral density as measured by DXA is normal or even increased. Nonetheless, few member of an identified kindred heterozygous for CaSR activating mutation, showed short stature and early osteoarthritis. Urinary excretion of calcium can be normal, but with relative hypercalciuria for the observed serum calcium levels, in the case of untreated mild disease, but it typically increases to overt hypercalciuria especially under treatment with active vitamin D analogs. Some patients may experience polyuria and polydipsia, because of the impaired water resorption mediated by enhanced CaSR-inhibition of vasopressin-dependent aquaporin-2-expression in the apical renal collecting duct. In very few cases, severe activating mutations of the CaSR cause a phenotype resembling the salt-wasting Bartter syndrome (also referred to as Bartter syndrome subtype V), characterized by hypocalcemia, hypomagnesemia, hypokalemia, metabolic alkalosis, hyperreninemia, and hyperaldosteronemia.
The recently identified autosomal dominant hypocalcemia with hypercalciuria type 2 (HYPOC2) is caused by heterozygous gain-of-function missense mutations of the guanine nucleotide binding protein (G Protein) Alpha 11 (GNA11). The altered protein increases the sensitivity to changes in [Cao2+].
No bone-signs specific for FIH exist. Nonetheless, increases in trabecular bone volume and cortical thickness have been reported, as in other forms of hypoparathyroidism.

In patients with autosomal dominant hypocalcemia, treatment with calcium and vitamin D analogs are likely to exhacerbate hypercalciuria, thus easily leading to nephrolithiasis and nephrocalcinosis. Therefore, it is advisable to treat only symptomatic patients, with the lowest dose of calcium and calcitriol. The addition of a thiazide diuretic may help in increasing serum calcium and lowering calciuria, thus decreasing the risk of nephrolithiasis. Also therapy with recombinant PTH has been demonstrated to lower the risk of renal complications. Future therapies might employ calcilytics, which directly modulate the CaSR.

Genes

Activating mutations of CaSR (HYPOC1/Bartter Syndrome subtype V), GNA11 (HYPOC2).

Phenotype

Biochemical (see above in the main text); no radiological or physical signs, with the exception of signs of hypocalcemia in almost half of the cases.

Main biochemical alterations

Hypocalcemia, low or low-normal serum PTH levels, hyperphosphatemia, hypomagnesemia, high Ca/Cr ratio, low serum 1,25(OH)2 vitamin D.
 

References:

  1. Cianferotti L. and Brandi M.L.: The Molecular Genetics of Hypoparathyroidism. In: The Parathyroids: Basic and Clinical Concepts, Third Edition, Academic Press, 2015.
  2. Hendy G.N. and Cole D.E.C.: Familial Isolated Hypoparathyroidism. In: Hypoparathyroidism, Springer, 2015.
  3. Pearce S.H.S., Williamson C., Kifor O., Bai M., Coulthard M. G., Davies M., Lewis-Barned N., McCredie D., Powell H., Kendall-Taylor P., Brown E.M., Thakker R.V. A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor. New Eng. J. Med. 335: 1115-1122, 1996.
  4. Baron J., Winer K.K., Yanovski J.A., Cunningham A.W., Laue L., Zimmerman D., Cutler G.B., Jr. Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism. Hum. Molec. Genet. 5: 601-606, 1996.
  5. Brown E.M., MacLeod R.J. Extracellular calcium sensing and extracellular calcium signaling. Physiol. Rev. 81: 239-297, 2001.
  6. www.omim.org