Autosomal Dominant Hypocalcemia Type 1: A Systematic Review

Abstract

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism due to activating variants of the calciumsensing receptor gene (CASR). Inherited or de novo activating variants of the CASR alter the set point for extracellular calcium, resulting in inadequate parathyroid hormone (PTH) secretion and inappropriate renal calcium excretion leading to hypocalcemia and hypercalciuria. Conventional therapy includes calcium and activated vitamin D, which can worsen hypercalciuria, resulting in renal complications. A systematic literature review, using published reports from 1994 to 2021, was conducted to catalog CASR variants, to define the ADH1 clinical spectrum, and to determine the effect of treatment on patients with ADH1. There were 113 unique CASR variants reported, with a general lack of genotype/phenotype correlation. Clinical data were available in 191 patients; 27% lacked symptoms, 32% had mild/moderate symptoms, and 41% had severe symptoms. Seizures, the most frequent clinical presentation, occurred in 39% of patients. In patients with blood and urine chemistries available at the time of diagnosis (n = 91), hypocalcemia (99%), hyperphosphatemia (59%), low PTH levels (57%), and hypercalciuria (34%) were observed. Blood calcium levels were significantly lower in patients with severe symptoms compared with asymptomatic patients (6.8 AE 0.7 versus 7.6 AE 0.7 mg/dL [mean AE SD]; p < 0.0001), and the age of presentation was significantly lower in severely symptomatic patients (9.1 AE 15.0 versus 19.3 AE 19.4 years; p < 0.01). Assessments for complications including nephrocalcinosis, nephrolithiasis, renal impairment, and brain calcifications in 57 patients on conventional therapy showed that 75% had at least one complication. Hypercalciuria was associated with nephrocalcinosis, nephrolithiasis, renal impairment, or brain calcifications (odds ratio [OR] = 9.3; 95% confidence interval [CI] 2.4-37.2; p < 0.01). In 27 patients with urine calcium measures before and after starting conventional therapy, the incidence of hypercalciuria increased by 91% (p < 0.05) after therapy initiation. ADH1 is a condition often associated with severe symptomatology at presentation with an increase in the risk of renal complications after initiation of conventional therapy.

Severe hypocalcaemia episodes in a patient of primary hypoparathyroidism precipitated by underlying stress due to haemophagocytic lymphohistiocytosis (HLH) secondary to pulmonary tuberculosis

“…Along with the parathyroid, other tissues, including the kidney, also expresses CaSR. Genetic studies have linked gain-of-function mutations in CaSR, and G 11 α protein to ADH types 1 and 2, respectively 2 4. ADH is the most prevalent inherited cause of isolated HP 13.…”

“…A calcium-sensing receptor (CaSR) activating (gain of function) mutation causes autosomal dominant hypocalcaemia (ADH), a subtype of primary hypoparathyroidism (HP) 1–4. These individuals exhibit abnormal biochemical profiles, including hypocalcaemia, hypomagnesaemia, hyperphosphataemia, inappropriately normal serum intact parathormone (iPTH) concentrations and high or high normal urine calcium excretion 1–3.…”

“…These individuals exhibit abnormal biochemical profiles, including hypocalcaemia, hypomagnesaemia, hyperphosphataemia, inappropriately normal serum intact parathormone (iPTH) concentrations and high or high normal urine calcium excretion 1–3. ADH was long considered to induce mild, asymptomatic hypocalcaemia that required no therapy; however, it is now evident that it can cause refractory hypocalcaemia and severe symptoms, such as convulsions, depending on the mutation and its impact on parathyroid cells 4 5. People with ADH often appear in their adult years since most patients initially receive a preliminary diagnosis of idiopathic HP or hypocalcaemia 4.…”

“…ADH was long considered to induce mild, asymptomatic hypocalcaemia that required no therapy; however, it is now evident that it can cause refractory hypocalcaemia and severe symptoms, such as convulsions, depending on the mutation and its impact on parathyroid cells 4 5. People with ADH often appear in their adult years since most patients initially receive a preliminary diagnosis of idiopathic HP or hypocalcaemia 4. They have prolonged hypocalcaemia and hyperphosphataemia with an elevated calcium phosphate product, leading to the development of intracranial calcification.…”

The calcium-sensing receptor in inflammation: Recent updates

“…Finally, the CaSR has also been associated to nephrocalcinosis and nephrolithiasis, common inflammatory renal defects, which are also recurrent morbidities in ADH patients and are strongly associated with hypercalciuria (Roszko et al, 2022). Moreover, single nucleotides CaSR polymorphisms have been associated to calcium nephrolithiasis, in particular the rs6776158 (A > G) polymorphism, resident on CaSR first promoter, which is associated with decreased transcriptional activity (Vezzoli et al, 2013;Vezzoli et al, 2019).…”