Pediatric Hyperparathyroidism

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Hyperparathyroidism refers to a serum Parathyroid Hormone (PTH) level above the normal range. PTH secretion is regulated by the action of serum ionized calcium on the Calcium Sensing Receptor (CASR) in parathyroid chief cells. Physiologically, calcium level is maintained within normal limits mainly due to this calcium sensing mechanism. Hyperparathyroidism may be classified into three major subtypes based on pathophysiology; primary, secondary and tertiary hyperparathyroidism.

 

Primary hyperparathyroidism (PHPT) entails an abnormality in parathyroid cell function leading to hypercalcemia with an inappropriately normal or elevated PTH level.  The etiology and pathology of PHPT is very different in neonates and older children. Most neonatal cases are due to inactivating mutations of the Calcium Sensing Receptor (CASR) causing Severe Neonatal Hyperparathyroidism (NSHPT). On the other hand, in children and adolescents PHPT is most frequently (80-92%) due to a single benign parathyroid adenoma, and less commonly due to multiglandular disease (MGD). [1, 2, 3, 4, 5, 6, 7, 8]  MGD is more commonly observed in the Multiple Endocrine Neoplasia Syndromes MEN1 , MEN2A,  and MEN4 or as part of the Hyperparathyroidism Jaw Tumor Syndrome (HPT-JT). Germline mutations in several genes have been identified in MGD as well as in non-syndromic familial isolated hyperparathyroidism. Somatic mutations in different genes have been related to a minority of cases of sporadic parathyroid adenomas. [9, 10] The differential diagnosis for primary hyperparathyroidism includes a usually asymptomatic form of primary hyperparathyroidism due to heterozygous inactivating CASR mutations, Familial Hypocalciuric Hypercalcemia (FHH). Parathyroid carcinoma is very rare in adults and children(<1%).<ref>11</ref>

A meta-analysis by Roizen et al concluded that hypercalcemia and hypercalciuria is greater in juvenile primary hyperparathyroidism than adult primary hyperparathyroidism with serum intact PTH at similar concentrations which suggested a different pathophysiology between pediatric and adult cases. [12]

Secondary hyperparathyroidism refers to an elevated PTH level in the context of low or normal serum calcium levels. This disorder may be caused by hyperphosphatemia as observed in chronic renal failure, or by hypocalcemia as in malabsorption or Vitamin D deficiency. The elevated PTH level in these cases reflects a normal response to a stimulus, and it normalizes by treating the underlying pathology.

Tertiary hyperparathyroidism occurs when parathyroid hyperplasia becomes so severe that removal of the underlying cause does not eliminate the stimulus for PTH secretion and hypertrophic chief cells become autonomous. This usually presents as the progression of chronic secondary hyperparathyroidism

This chapter will focus on primary hyperparathyroidism.  In these cases, inappropriately elevated parathyroid hormone secretion leads to hypercalcemia and hypophosphatemia. PTH increases renal calcium reabsorption at the distal convoluted tubule and increases intestinal calcium absorption indirectly by increasing the production of 1,25 (OH)2 vitamin D by stimulating the 1 α hydroxylation of 25 OH Vitamin D in the proximal renal tubules. 1,25 (OH)2 Vitamin D in turn stimulates active intestinal calcium transport. PTH also leads to hypercalcemia by increasing bone resorption. PTH indirectly stimulates bone resorption by acting on the osteoblast PTH receptor, which then signals the osteoclast to produce various substances, among them is the ligand of the receptor activator of the nuclear transcription factor NF-kappa B (RANK), known as RANK ligand (RANKL), which can stimulate osteoclast differentiation and proliferation.  PTH leads to hypophosphatemia by decreasing renal phosphate reabsorption.

 

 

The estimated incidence of primary hyperparathyroidism (PHPT) in pediatric patients is 1 per 200-300,000 and its prevalence is 2-5 in 100,000. [1, 6]  It has a higher predominance in adolescents, but its incidence is still much lower in this population than in adults where it has been estimated at 1:500-2000. [13]   In adults PHPT is more frequent in females, while most pediatric series find no difference in distribution by sex. [4]

 

 

 

 

Prognosis depends on the etiology. For primary hyperparathyroidism due to a parathyroid adenoma, parathyroidectomy should be curative if the condition occurs in isolation. However, if it is associated with other tumors, prognosis would depend on the management of accompanying tumors. NSHPT has a high mortality rate if untreated. Secondary hyperparathyroidism is cured by treating the underlying pathology.

Patients with primary hyperparathyroidism must understand the following:

Location and function of parathyroid gland and PTH

Effects of hypercalcemia on the body (eg, dehydration, neurological symptoms, arrhythmia, stones, bone demineralization, increased fracture risk)

Lack of success in managing most cases of primary hyperparathyroidism medically, need for surgical consultation, and resection of one or more parathyroid glands

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Belcher R, Metrailer AM, Bodenner DL, Stack BC Jr. Characterization of hyperparathyroidism in youth and adolescents: a literature review. Int J Pediatr Otorhinolaryngol. 2013 Mar. 77 (3):318-22. [Medline].

Hsu SC, Levine MA. Primary hyperparathyroidism in children and adolescents: the Johns Hopkins Children’s Center experience 1984-2001. J Bone Miner Res. 2002 Nov. 17 Suppl 2:N44-50. [Medline].

Roizen J, Levine MA. Primary hyperparathyroidism in children and adolescents. J Chin Med Assoc. 2012 Sep. 75 (9):425-34. [Medline].

Kollars J, Zarroug AE, van Heerden J, Lteif A, Stavlo P, Suarez L, et al. Primary hyperparathyroidism in pediatric patients. Pediatrics. 2005 Apr. 115 (4):974-80. [Medline].

Lawson ML, Miller SF, Ellis G, Filler RM, Kooh SW. Primary hyperparathyroidism in a paediatric hospital. QJM. 1996 Dec. 89 (12):921-32. [Medline].

Alagaratnam S, Brain C, Spoudeas H, Dattani MT, Hindmarsh P, Allgrove J, et al. Surgical treatment of children with hyperparathyroidism: single centre experience. J Pediatr Surg. 2014 Nov. 49 (11):1539-43. [Medline].

Mancilla EE, Levine MA, Adzick NS. Outcomes of minimally invasive parathyroidectomy in pediatric patients with primary hyperparathyroidism owing to parathyroid adenoma: A single institution experience. J Pediatr Surg. 2016 Feb 4. [Medline].

Thakker RV. Genetics of parathyroid tumours. J Intern Med. 2016 Jun 16. [Medline].

Starker LF, Akerström T, Long WD, Delgado-Verdugo A, Donovan P, Udelsman R, et al. Frequent germ-line mutations of the MEN1, CASR, and HRPT2/CDC73 genes in young patients with clinically non-familial primary hyperparathyroidism. Horm Cancer. 2012 Apr. 3 (1-2):44-51. [Medline].

Davidson JT, Lam CG, McGee RB, Bahrami A, Diaz-Thomas A. Parathyroid Cancer in the Pediatric Patient. J Pediatr Hematol Oncol. 2016 Jan. 38 (1):32-7. [Medline].

Roizen J, Levine MA. A meta-analysis comparing the biochemistry of primary hyperparathyroidism in youths to the biochemistry of primary hyperparathyroidism in adults. J Clin Endocrinol Metab. 2014 Dec. 99 (12):4555-64. [Medline].

Ruda JM, Hollenbeak CS, Stack BC Jr. A systematic review of the diagnosis and treatment of primary hyperparathyroidism from 1995 to 2003. Otolaryngol Head Neck Surg. 2005 Mar. 132 (3):359-72. [Medline].

Reh CM, Hendy GN, Cole DE, Jeandron DD. Neonatal hyperparathyroidism with a heterozygous calcium-sensing receptor (CASR) R185Q mutation: clinical benefit from cinacalcet. J Clin Endocrinol Metab. 2011 Apr. 96 (4):E707-12. [Medline].

Nesbit MA, Hannan FM, Howles SA, Babinsky VN, Head RA, Cranston T, et al. Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia. N Engl J Med. 2013 Jun 27. 368 (26):2476-86. [Medline].

Nesbit MA, Hannan FM, Howles SA, Reed AA, Cranston T, Thakker CE, et al. Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. Nat Genet. 2013 Jan. 45 (1):93-7. [Medline].

Nicholson KJ, McCoy KL, Witchel SF, Stang MT, Carty SE, Yip L. Comparative characteristics of primary hyperparathyroidism in pediatric and young adult patients. Surgery. 2016 Oct. 160 (4):1008-16. [Medline].

Christensen SE, Nissen PH, Vestergaard P, Mosekilde L. Familial hypocalciuric hypercalcaemia: a review. Curr Opin Endocrinol Diabetes Obes. 2011 Dec. 18 (6):359-70. [Medline].

Benaderet AD, Burton AM, Clifton-Bligh R, Ashraf AP. Primary hyperparathyroidism with low intact PTH levels in a 14-year-old girl. J Clin Endocrinol Metab. 2011 Aug. 96(8):2325-9. [Medline]. [Full Text].

Yao K, Singer FR, Roth SI, Sassoon A, Ye C, Giuliano AE. Weight of normal parathyroid glands in patients with parathyroid adenomas. J Clin Endocrinol Metab. 2004 Jul. 89 (7):3208-13. [Medline].

Wilhelm-Bals A, Parvex P, Magdelaine C, Girardin E. Successful use of bisphosphonate and calcimimetic in neonatal severe primary hyperparathyroidism. Pediatrics. 2012 Mar. 129(3):e812-6. [Medline].

Gannon AW, Monk HM, Levine MA. Cinacalcet monotherapy in neonatal severe hyperparathyroidism: a case study and review. J Clin Endocrinol Metab. 2014 Jan. 99 (1):7-11. [Medline].

Available at http://www.fda.gov/Drugs/DrugSafety/ucm340551.html.

Blair JW, Carachi R. Neonatal primary hyperparathyroidism–a case report and review of the literature. Eur J Pediatr Surg. 1991 Apr. 1 (2):110-4. [Medline].

Mancilla EE, Levine MA, Adzick NS. Outcomes of minimally invasive parathyroidectomy in pediatric patients with primary hyperparathyroidism owing to parathyroid adenoma: A single institution experience. J Pediatr Surg. 2017 Jan. 52 (1):188-191. [Medline].

Nussbaum SR, Thompson AR, Hutcheson KA, Gaz RD, Wang CA. Intraoperative measurement of parathyroid hormone in the surgical management of hyperparathyroidism. Surgery. 1988 Dec. 104 (6):1121-7. [Medline].

Carneiro DM, Solorzano CC, Nader MC, Ramirez M, Irvin GL 3rd. Comparison of intraoperative iPTH assay (QPTH) criteria in guiding parathyroidectomy: which criterion is the most accurate?. Surgery. 2003 Dec. 134 (6):973-9; discussion 979-81. [Medline].

Bilezikian JP, Brandi ML, Eastell R, Silverberg SJ, Udelsman R, Marcocci C, et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin Endocrinol Metab. 2014 Oct. 99 (10):3561-9. [Medline].

Udelsman R, Åkerström G, Biagini C, Duh QY, Miccoli P, Niederle B, et al. The surgical management of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab. 2014 Oct. 99 (10):3595-606. [Medline].

Cause

Gene

OMIM

1.      Neonate/Infant

             – Familial hypocalciuric hypercalcemia

Heterozygous inactivating CASR mutations

145980

             – Neonatal severe hyperparathyroidism

Homozygous inactivating CASR mutations

239200

             – Maternal hypoparathyroidism     

             – Maternal pseudohypoparathyroidism

             – Maternal Vitamin D deficiency

2.      Child/adolescent

             – Sporadic adenomas

             – Familial

                    * Familial hypocalciuric   

                       hypercalcemia (FHH)

CASR

145980

                    * Multiple Endocrine Neoplasia

                       type 1 (MEN1)

MEN1   

131100

                    * Multiple Endocrine Neoplasia

                       type 2a

RET   

171400

                    * Multiple Endocrine Neoplasia

                       type 4

CDKN1B

610755

                    * Familial hyperparathyroidism 

                       jaw tumor syndrome (HRPT2)

 

             – Autoantibodies to the CASR

             – Renal failure/post renal transplant

             – Chronic hyperphosphatemia

             – Vitamin D deficiency

                    * Nutritional

                    * Malabsorption

              -Vitamin D dependent rickets

                       type 1 VDDR1

              

 

 

              – Vitamin D dependent rickets    

                       type 2 VDDR2

                     

             

 

              -Other causes of hypocalcemia

                     Poor intake

                     Drugs

Edna E Mancilla, MD Associate Professor of Clinical Pediatrics, University of Pennsylvania School of Medicine; Attending Physician in Pediatric Endocrinology, The Children’s Hospital of Philadelphia

Edna E Mancilla, MD is a member of the following medical societies: American Society for Bone and Mineral Research, Chilean Society of Endocrinology and Diabetes, Chilean Society of Osteology and Mineral Metabolism, Endocrine Society, Latin American Society of Pediatric Endocrinology, Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children’s Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, American College of Endocrinology

Disclosure: Nothing to disclose.

Sasigarn A Bowden, MD Associate Professor of Pediatrics, Section of Pediatric Endocrinology, Metabolism and Diabetes, Department of Pediatrics, Ohio State University College of Medicine; Pediatric Endocrinologist, Associate Fellowship Program Director, Division of Endocrinology, Nationwide Children’s Hospital; Affiliate Faculty/Principal Investigator, Center for Clinical Translational Research, Research Institute at Nationwide Children’s Hospital

Sasigarn A Bowden, MD is a member of the following medical societies: American Society for Bone and Mineral Research, Central Ohio Pediatric Society, Endocrine Society, International Society for Pediatric and Adolescent Diabetes, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Gordon L Klein, MD, MPH Clinical Professor of Orthopedic Surgery and Rehabilitation, University of Texas Medical Branch School of Medicine

Gordon L Klein, MD, MPH is a member of the following medical societies: American Academy of Pediatrics, American Society for Nutrition, American Gastroenterological Association, American Pediatric Society, American Society for Bone and Mineral Research, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, Society for Pediatric Research

Disclosure: Nothing to disclose.

Phyllis W Speiser, MD Chief, Division of Pediatric Endocrinology, Steven and Alexandra Cohen Children’s Medical Center of New York; Professor of Pediatrics, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell

Phyllis W Speiser, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Pediatric Hyperparathyroidism

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