Familial Hypocalciuric Hypercalcemia as an Atypical Form of Primary Hyperparathyroidism

Abstract

Familial hypocalciuric hypercalcemia (FHH) causes lifelong hypercalcemia with features that overlap with typical primary hyperparathyroidism (PHPT). The incompleteness of this overlap has led to divergent nomenclatures for FHH. I compare two nomenclatures. One sets FHH as an entity distinct from PHPT. The other groups FHH with PHPT but conditions FHH as atypical PHPT. I analyzed selected articles about calcium-sensing receptors, FHH, PHPT, CASR, GNA11, and AP2S1. FHH usually results from a heterozygous germline inactivating mutation of the CASR, and less frequently from mutation of GNA11 or AP2S1. The CASR encodes the calcium-sensing receptors. These are highly expressed on parathyroid cells, where they sense serum calcium concentration and regulate suppression of PTH secretion by serum calcium. Their mutated expression in the kidney in FHH causes increased renal tubular reabsorption of calcium (hypocalciuria). Many FHH features are shared with PHPT and thus support FHH as a form of PHPT. These include a driver mutation expressed mainly in the parathyroid cells. The mutation causes a parathyroid cell insensitivity to extracellular calcium in vivo and in vitro, a right-shift of the set point for suppression of PTH secretion by calcium. Serum PTH is normal or mildly elevated; ie, it is not appropriately suppressed by hypercalcemia. Total parathyroidectomy causes hypoparathyroidism and durable remission of hypercalcemia. Some other features are not shared with PHPT and could support FHH as a distinct entity. These include onset of hypercalcemia in the first week of life, frequent persistence of hypercalcemia after subtotal parathyroidectomy, and hypocalciuria. The features supporting FHH as a form of PHPT are stronger than those favoring FHH as a distinct entity. Classifying FHH as an atypical form of PHPT represents compact nomenclature and supports current concepts of pathophysiology of FHH and PHPT. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Cinacalcet corrects biased allosteric modulation of CaSR by AHH autoantibody

“…The patient's calcium levels have been around 11 mg/dl without bisphosphonate treatment since then. Neither ultrasonography nor 99m Tc-MIBI scintigraphy identified adenoma/hyperplasia at the parathyroid sites (63)(64)(65)(66). He continued to show hypophosphatemia (iP 1.5 mg/dl) and hypocalciuria (FECa <1%).…”

Molecular and clinical insights from studies of calcium-sensing receptor mutations

“…Inactivating mutations in the CaSR also cause FHH1 (OMIM:145980), an autosomal dominant condition characterised by lifelong elevated serum calcium values, high or normal PTH concentrations and a low renal calcium excretion (Christensen et al 2008, Eastell et al 2014. FHH1 is usually benign and does not require treatment; however, its biochemical features have considerable overlap with typical primary hyperparathyroidism (PHPT), and often FHH is classified as a form of atypical PHPT (Marx 2018). However, unlike in typical PHPT, hypercalcaemia in FHH patients remains persistent following parathyroidectomy, and therefore, it is important to distinguish between typical PHPT and atypical forms (i.e.…”

A Novel Variant in the Calcium-Sensing Receptor Associated with Familial Hypocalciuric Hypercalcemia and Low-to-Normal PTH

“…This is consistent with prior reports describing overlapping symptoms in FHH and PHPT. In an early description of 15 kindreds with FHH, affected members reported significantly more frequent fatigue, weakness, headaches, and arthralgia, in comparison to those unaffected [ 3 , 14 ]. Given the absence of symptoms in the mother, we cannot argue that this particular variant is associated with symptom development, rather it may be a consequence of the inherent differences individuals possess in susceptibility to hypercalcemia-associated symptoms, perhaps independently of the cause.…”

“…Were it not for the inclusion of calcium in routine laboratory testing, most patients with mild primary hyperparathyroidism (PHPT) and FHH would not be identified given their largely asymptomatic nature, yet when mild hypercalcemia is detected, it is appropriate to exclude FHH, given that surgical management is rarely necessary. However, the phenotypes of FHH differ in their degree of calcium and PTH concentrations and even symptomatology, based on the particular variant in the CaSR, and can overlap clinically with PHPT [ 3 – 5 ]. Herein, we report two patients with FHH and a novel variant in the CaSR associated with low to normal PTH, elevated calcitriol, and symptoms associated with hypercalcemia that resolved after surgical parathyroidectomy in one patient.…”