Hereditary hyperparathyroidism: Familial Hypercalcemia Hypocalciuria Syndrome

Familial Hypercalcemia Hypocalciuria Syndrome (FHH)/ Neonatal Severe Hyperparathyroidism (NSHPT)

FHH (OMIM 145980) (Table I) is a rare disorder inherited in au- tosomal dominant manner and characterized in the adult by the outcome of increased/normal levels of serum calcium, moderate hypophosphoremia, increased/normal circulating PTH levels, that are frequently inadequate when correlated to serum calcium levels and an inappropriately low urinary calcium excretion. The majority of patients with FHH are asymptomatic and do not benefit from surgical resection of their mildly enlarged parathyroid that cannot correct the calcium-dependent PTH secretion set-point abnormality. FHH-related hypercalcemia is highly penetrant at all ages. Generally, these patients show relative hypocalciuria (urinary calcium/creatinine ratio typically <001) in the presence of hypercalcemia and hyperparathyroidism due to inactivation of CaSR protein in renal tubules. Moreover, a mild hypermagnesemia can be found. NSHPT (OMIM 239200) (Table I) generally represents the ho- mozygous form of FHH, in which PHPT occurs at birth or within the first 6 months of life determining a severe symptomatic hy- percalcemia, with skeletal manifestations of PHPT and if neck surgery is not promptly performed a lethal outcome may occur.  

Pathology

PHPT in the setting of FHH is generally sustained by the presence of mildly enlarged parathyroid glands, whereas markedly hyperplastic parathyroid glands are a typical feature of NSHPT-related PHPT (Table III).

Molecular aspects

Inactivating mutations, with a loss of function, of CaSR gene, localized at chromosome 3q13-21, account for both the forms (92, 93) (Table II). CaSR protein is a membrane protein consisting of 1078 amino acids, mainly expressed by kidney and parathyroid cells, belongs to the G proteins-coupled receptor (GPCR) superfamily. The CaSR is able to sense small changes in circulating calcium concentration and when activated it inhibits PTH secretion and renal tubule calcium reabsorption. The described mutations in FHH and NSHPT subjects are prevalently localized in the calcium binding site of extracellular portion of receptor. Inactivation of this GPCR protein results in half-maximal inhibition of PTH secretion only at increased concentrations of serum calcium (calcium set-point), although the magnitude of PTH suppression by increased serum calcium concentrations is normal in patients with FHH. Somatic mutations within the CaSR gene, which would explain impaired function and altered receptor expression, have not been detected both in sporadic and familial forms of parathyroid tumors thus far.

Treatment of FHH/NSHPT-PHPT manifestations

Although it is generally accepted that FHH patients do not benefit from surgery of parathyroid lesions, subtotal parathyroidectomy can be performed in subjects developing symptomatic PHPT (Table III) who may have an underlying polyclonal parathyroid cell hyperproliferation due to a heterozygous inacti- vation of CaSR or to another hypothetical acquired genetic defect in a different gene. When performed the neck surgery in FHH subjects may include subtotal parathyroidectomy leaving 10-20 mg of parathyroid tissue in order to achieve normocalcemia (Table III). In all cases, cryopreservation of parathyroid tissue should be considered. Total parathy- roidectomy must be performed in the first months of life in NSHPT affected infants (Table III).
You can afford your medication buy your sale levitra online