Familial hypocalciuric hypercalcaemia was first described in 1966. The disorder was initially named ‘familial benign hypercalcaemia’ in the case description of a 7- year- old boy and his extended 11- member family by Foley et al. in 1972. The distinctive clinical features were lack of clinical symptoms, mild hypercalcaemia, normal levels of PTH, normal or low serum phosphate for age, and low urinary calcium excretion. The pattern of inheritance in that family was compatible with an autosomal dominant mode of trans mission. The authors postulated that there might be an abnormality in the calcium- sensing mechanism in the parathyroid glands. Marx et al. examined kindreds with the same syndrome and named it FHH to highlight the absolute to relative hypocalciuria for the degree of hypercalcaemia being demonstrated.
The prevalence of FHH is estimated to be 1% or less to that of primary hyperparathyroidism (PHPT). Given its benign clinical features which may lead to cases escaping medical detection, FHH may be more common than the estimated prevalence of ~1/ 78 000 from data from developed countries. FHH is inherited in an autosomal dominant manner and approaches a 100% penetrance of the trait.
Patients are usually asymptomatic despite chronic hyper calcaemia. Typical manifestations of hypercalcaemia (nausea, an orexia, constipation, nephrolithiasis, nephrocalcinosis) are usually not present. Even patients with FHH with the higher serum calcium levels, are often asymptomatic. Chondrocalcinosis with advanced age and cases of pancreatitis associated with FHH1 have been described. Patients with three most frequent FHH2 mutations (p.I200del, p.L135Q, p.T54M) display a mild FHH phenotype with serum adjusted calcium concentrations of less than 2.8 mmol/ L. FHH3 patients may experience symptomatic hypercalcaemia, reduced fractional excretion of calcium, low bone mineral density and cognitive dysfunction, and/ or behavioural disturbances in children with the p.R15C or p.R15L AP2σ mutations. Adults with FHH3 with the heterozygous germline p.R15C mutation display elevated PTH levels and mild hypophosphatemia, and even osteomalacia after the age of 30 has been reported in at least one family.
Biochemically, FHH1 is characterized by lifelong mild- to- moderate hypercalcaemia, inappropriately low urinary calcium excretion, a normal or mildly elevated circulating PTH level, and high- normal to elevated serum magnesium levels. Serum calcium levels for most affected families range from 2.6 to 2.9 mmol/ L and average at about 10% above the upper limit of normal. In some kindreds, the serum calcium levels can range from the upper half of the normal range to as high as 3.24– 3.49 mmol/ L. Serum calcium levels within a kindred are usually clustered within a relatively narrow range. Serum magnesium levels in FHH are measured at the upper half of normal or mildly elevated. Serum magnesium levels correlate positively with the serum calcium con centration. Serum phosphate levels in FHH are usually in the lower half of the normal range and rarely low. Renal function remains intact in FHH despite hypercalcaemia, and renal complications such as nephrocalcinosis are not present.
Inappropriately low urinary calcium excretion is found in 95% of patients. In a Danish study, 24- hour urinary calcium excretion was measured within the lower range of normal at approximately 2.7446 mmol/ 24 hours in FHH patients vs. a normal cohort in which it ranged from 1.996 to 7.984 mmol/ 24 hours [43]. Inappropriately low urinary calcium excretion demonstrates the enhanced renal tubular ab sorption of calcium. The calcium- to- creatinine clearance ratio (CCCR) which is also known as fractional excretion of calcium is defined by:
Approximately 80% of individuals with FHH demonstrate a CCCR of < 0.01 equivalent to less than 1%, whereas approximately 80% of patients with PHPT have a CCCR higher than 0.01 (Table 1). Patients with FHH are able to concentrate urine normally, while patients with PHPT show reduced urinary concentrating capacity if they are dehydrated.
Table1. Characteristics of patients with familial hypocalciuric hypercalcaemia type 1– 3 (FHH) and primary hyperparathyroidism (PHPT)
Approximately 80% of patients with FHH have normal plasma PTH levels, with the other 20% having mildly elevated levels. Elevated PTH levels may be mirroring the functional effect of a specific mutation. 25- hydroxyvitamin levels and 1,25- dihydroxyvitamin levels are generally within normal range. The elevated 1,25- dihyrdoxyvitamin levels of PHPT are usually not encountered and might be due to the generally normal PTH levels in FHH (Table 1). Bone mineral density is comparable to age- matched controls, even though markers of bone turnover can be mildly elevated. In patients with FHH, bone mineral density does not need to be measured, unless there are other reasons to consider excessive bone loss. The parathyroid glands are usually of normal size and histology in patients with FHH. In a few cases of FHH, a single or multiple parathyroid adenomas or mild chief cell proliferation were shown. Parathyroid localization studies need not be done, unless the case is one of NSHPT or NHPT or the rare patient with FHH with a coexistent superimposed parathyroid adenoma. Most cases of FHH that have gone to surgery demonstrate four- gland para thyroid hyperplasia. After an erroneous subtotal parathyroidectomy for FHH, hypercalcaemia will recur, despite normal appearing para thyroid glands in most affected individuals with FHH.
