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Disorders of the Calcium-Sensing Receptor

Disorders of the Calcium-Sensing Receptor. Hengameh Abdi , MD Endocrine Research Center Research Institute for Endocrine Sciences Shahid Beheshti University of Medical Sciences 14 April 2016. Agenda. Introduction Familial Hypocalciuric Hypercalcemia

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Disorders of the Calcium-Sensing Receptor

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  1. Disorders of the Calcium-Sensing Receptor HengamehAbdi, MD Endocrine Research Center Research Institute for Endocrine Sciences ShahidBeheshti University of Medical Sciences 14 April 2016

  2. Agenda • Introduction • Familial HypocalciuricHypercalcemia • Neonatal Severe Hyperparathyroidism • Acquired Hypercalcemic Disorders of the CaSR • Autosomal Dominant Hypocalcaemia with Hypercalciuria • Hypoparathyroidism due to CaSR Antibodies

  3. Introduction • Activating or inactivating mutations in the calcium-sensing receptor (CaSR) gene result in altered calcium sensing and therefore inappropriate PTH release with respect to the serum calcium concentration.

  4. Disorders of extracellular calcium sensing by the calcium-sensing receptor

  5. Familial HypocalciuricHypercalcemia(Familial Benign Hypercalcemia, FHH, FBHH) • First time in 1972. • Prevalence of 10% among unsuccessful parathyroidectomiesbefore the recognition of FHH. • Epidemiologic data from 3-year prospective studies of cases of hypercalcemia: Gunn IR. Ann Clin Biochem 2004; 41: 441–458 Marx SJ. Ann Int Med 1980; 92:351–356

  6. Familial HypocalciuricHypercalcemia(Genetic) • Autosomal dominant inheritance with high penetrance. • Genetically heterogeneous with 3 variants with similar clinical features: • FHH 1: loss-of-function mutations of the CaSR gene on 3q21.1. The most common form. • FHH 2: loss-of-function mutations in the GNA11 gene on 19p13. • FHH 3: loss-of-function mutations in the AP2S1 gene on 19q13. • The result of these mutations is fewer normally functioning receptors on the parathyroid or renal cell surface.

  7. Familial HypocalciuricHypercalcemia(Pathophysiology) • The relative insensitivity of the CaSR to calcium effectively "resets" not only parathyroid but also kidney to maintain mild to moderatehypercalcemia. • The net effect: • Hypercalcemia (mild, persistent, non-progressive) • Inappropriately normal (80%) or high serum PTH level • Hypocalciuria (Ca/Cr clearance ratio* <0.01) • Frequently high normal levels of serum magnesium or frank hypermagnesemia *Ca/Cr clearance ratio: urine Ca/urine creatinine x serum creatinine/serum Ca, performed on blood sample and random or 24-h urine specimen.

  8. Familial HypocalciuricHypercalcemia(Clinical findings) • Typically asymptomatic. • Benign clinical course. • Occasional cases of pancreatitis or chondrocalcinosis.

  9. Familial HypocalciuricHypercalcemia[Overlap with primary hyperparathyroidism (PHPT)] 10% of patients with PHPT have hypercalcemiawith "normal" serum PTH concentrations. 15 to 20% of patients with FHH may have a mildly elevated PTH concentration. Varghese J. EndocrPract. 2011;17[Suppl 1]:13-17)

  10. Familial HypocalciuricHypercalcemia(Overlap with primary hyperparathyroidism) • In patients with PHPT, the Ca/Cr clearance ratio is usually between 0.01 and 0.05 and most often >0.02. However, the Ca/Cr clearance ratio may be <0.01 in 10-20% of patients with PHPT, particularly those with concomitant vitamin D deficiency. • Affected family members in occasional FHH families are hypercalciuric.

  11. Phenotypic differences between FHH and primary hyperparathyroidism(Vargas-Poussou R, et al. JCEM 2016 Mar 10:jc20153442)

  12. Familial HypocalciuricHypercalcemia(Distinction from primary hyperparathyroidism) • The absence of symptoms. • Laboratory findings typical of FHH in the proband. • A history of familial hypercalcemiawith hypocalciuria, sometimes with previously unsuccessful parathyroid surgery, in other affected family members, including young children. • Even if the family history is negative, this does not rule out familial involvement and serum and urinary calcium determination should be performed in several first degree relatives, if possible.

  13. Familial HypocalciuricHypercalcemia(Distinction from primary hyperparathyroidism) • CaSR mutational analysis, although available, is not routinely performed. • Mutational analysis may be of benefit in distinguishing FHH from PHPT in the following clinical settings: • Families with familial isolated hyperparathyroidism • Patients with overlap in the Ca/Cr clearance ratio, namely between 0.01 and 0.02 • Patients with the phenotype of FHH whose parents are both normocalcemic (ie, FHH possibly caused by a de novo CaSR mutation) • Atypical cases where no family members are available for testing • Infants or children <10 y/o (in whom neonatal hyperparathyroidism and FHH are the most common causes of PTH-dependent hypercalcemia.)

  14. Clinical approach to distinguishing between PHPT and FHH in a hypercalcemicpatient Eastell R, et al. JCEM 2014; 99:3570-79

  15. Clinical approach to distinguishing between PHPT and FHH in a hypercalcemicpatient (cont.) • UCCR: Urine Ca/Cr clearance ratio • Urinary calcium excretion is highly variable and should be estimated on at least two or three occasions on different days. In addition, urinary calcium excretion may be low in patients of African-American origin or those with vitamin D deficiency or renal impairment. Eastell R, et al. JCEM 2014; 99:3570-79

  16. Familial HypocalciuricHypercalcemia(Management) • No intervention (failure of parathyroidectomy to normalize serum calcium concentration) • Affected family members should be identified and counseled to avoid parathyroid surgery, sometimes undertaken because of a mistaken diagnosis of primary hyperparathyroidism.

  17. Neonatal Severe Hyperparathyroidism(NSHPT) • A very rare autosomal recessive condition due to homozygous inactivating mutation in the CaSRgene. • Offspring of consanguineous FHH 1 families. • Serum PTH concentrations as much as 10-fold higher than normal. • Usually severe hypercalcemia (serum calcium >15 mg/dL). • Relative hypocalciuria.

  18. Neonatal Severe Hyperparathyroidism • Rachitic changes often occur and bone x-rays may reveal marked demineralization and subperiostealresorption with multiple fractures. • Respiratory failure, failure to thrive. • This disorder can be fatal without immediate parathyroidectomy, although case reports have described the use of pamidronate and cinacalcet as a "rescue" therapy to stabilize infants with NSHPT prior to surgery or after failed surgery.

  19. Acquired Hypercalcemic Disorders of the CaSR • Autoimmune hypocalciurichypercalcemia • Primary hyperparathyroidism • Secondary and tertiary hyperparathyroidism • Expression of the CaSR protein is commonly reduced in adenomas from patients with primary hyperparathyroidism and/or severe secondary hyperparathyroidism due to chronic kidney disease. Although the pathogenetic importance of this change is uncertain.

  20. Autoimmune HypocalciuricHypercalcemia • Clinical features of FHH without CaSRmutations. • Circulating antibodies to the extracellular domain of the CaSR that stimulate PTH release from dispersed human parathyroid cells in vitro. • Multiple clinical autoimmune manifestations, including anti-thyroid antibodies, anti-gliadin antibodies. • Variable effects of treatment with glucocorticoids.

  21. HypocalcemicDisorders of the CaSR • Autosomal dominant hypocalcemiatype 1 (ADH-1) • Bartter syndrome type 5 (i.e., ADH with a Bartter-like syndrome) • Autoimmune hypoparathyroidism(AH)

  22. Autosomal dominant hypocalcemia • An activating (or gain-of-function) mutation of the CaSRgene. • Estimated prevalence: 1/70,000. • A low serum calcium concentration is perceived as normal, leading to a downward resetting of the PTH-calcium relationship.

  23. Autosomal dominant hypocalcemia(Biochemical Features) • Serum calcium concentration usually in the range of 6 to 8 mg/dL, but as low as 5 mg/dL in occasional families. • Normal (or only slightly low) serum PTH concentrations. • High or high normal urinary calcium excretion. • Recurrent nephrolithiasis and nephrocalcinosis, particularly during treatment with vitamin D and calcium supplementation. • No previous normal serum calcium values. • Low serum magnesium concentration (in some).

  24. Autosomal dominant hypocalcemia(Clinical Findings) • The majority of patients areasymptomatic and therefore are not diagnosed until adulthood, when hypocalcemia is incidentally noted. • Children in particular may become symptomatic with seizures and neuromuscular irritability during periods of stress, such as a febrile illness, and may be mislabeled as having febrile seizures.

  25. Autosomal dominant hypocalcemia(Diagnosis) • Distinction from idiopathic hypoparathyroidismmay be difficult: • Familial nature. • High urinary calcium excretion. • Tendency of patients to develop renal complications during treatment with calcium and vitamin D supplementation.

  26. Autosomal dominant hypocalcemia(Treatment) • Only in symptomatic patients. • Treatment to the point where symptoms disappear. • Cautious calcium and vitamin D supplementation with monitoring of urinary calcium excretion. • Thiazide diuretic as a possible adjunct. • Oral CaSR antagonists (calcilytics)…in development

  27. Bartter Syndrome Type 5 • More marked gain-of-function in the CaSR than ADH. • Classical features of the Bartter syndrome (i.e., hypokalemic metabolic alkalosis, hyperreninemia, and hyperaldosteronism). • Additional hypocalcemia.

  28. Autoimmune Acquired Hypoparathyroidism • Autoimmune hypoparathyroidism is a common feature of polyglandular autoimmune syndrome type I. • Autoantibodies to the extracellular domain of the CaSRin 20% of patients who have acquired hypoparathyroidism in association with autoimmune hypothyroidism. • Mostly in women.

  29. Conclusion: • Inherited abnormalities of the CaSR gene can cause either hypercalcemiaor hypocalcemia. • It can be challenging in the clinical setting to distinguish FBHH from PHPT and ADHH from idiopathic hypoparathyroidismbecause of the common biochemical features. Nevertheless, it is important to make this distinction since clinical management may be dependent on knowledge of the underlying pathophysiology. • Careful clinical assessment combined with biochemical testing and family studies will result in a confident diagnosis in many cases.

  30. References: • Thakker RV, et al. Regulation of Calcium Homeostasis and Genetic Disorders that Affect Calcium Metabolism. In Endocrinology. 7th ed. Jameson JL, De Groot LJ, Ed. Elsevier Saunders, 2016. • www.omim.org • Edward M Brown. Disorders of the calcium-sensing receptor: Familial hypocalciurichypercalcemia and autosomal dominant hypocalcemia. UpToDate 21.6 • Gunn IR, Gaffney D. Clinical and laboratory features of calcium-sensing receptor disorders: a systematic review. Ann Clin Biochem 2004; 41: 441-458

  31. Thanks for Your Patience!

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