Clinical polymorphism of primary hyperparathyroidism in children

BACKGROUND: Primary hyperparathyroidism (PHPT) in children is quite rare, with a prevalence of 2–5 cases per 100,000 children. Hypercalcemia in PHPT has a negative impact on the gastrointestinal tract, urinary, musculoskeletal and nervous systems. Timely diagnosis of the disease in children is difficult due to its rare occurrence and variety of clinical symptoms.

AIM: To study clinical manifestations of primary hyperparathyroidism in children depending on the degree of hypercalcemia.

MATERIALS AND METHODS: Retrospective observational study with a prospective component 50 patients with primary hyperparathyroidism. All patients underwent a comprehensive laboratory and instrumental study at the Institute of Pediatric Endocrinology, Endocrinology Research Center of Russia in the period 2014–2023.

RESULTS: The clinical manifestations of primary hyperparathyroidism in children are very diverse. Weakness and fatigue were observed in 36% of patients (CI (23; 51)). Frequent manifestations of the gastrointestinal tract were nausea — in 20% (CI (10; 34)), gastritis — in 38%, (CI (25; 53)), duodenogastric reflux - in 24%, CI (13; 38). Hypercalciuria was detected in 64% of patients (CI (49; 77)), urolithiasis - in 36% (CI (23; 51). Complaints of leg pain were observed in 24% of patients (CI (13; 38)) deformity of the lower extremities was present in 20% (CI (10; 34)). 16% of patients had a history of low-traumatic fractures (CI (7; 29)). The median age of onset of the first clinical symptoms of PHPT in children was 13.7 years [10.6; 15.2]. At the time of diagnosis of the disease, 12 patients (24%) had no complaints and were examined due to incidentally detected hypercalcemia (n=3), hypercalciuria (n=1), and detected formations of the parathyroid gland according to ultrasound (n=5), with a family history of multiple endocrine neoplasia syndrome type 1 (n=3). To identify the relationship between the clinical manifestations of PHPT and blood calcium levels, all patients were divided into 3 groups depending on the level of hypercalcemia: mild hypercalcemia — 29 patients, moderate — 16, severe — 5. According to the results of the study, a statistically significant relationship between the presence of individual clinical manifestations of PHPT and the degree of hypercalcemia was not identified, however, a statistical tendency was noted between the presence of individual symptoms of the disease (hypercalciuria, weight loss, vomiting, pain in abdomen, constipation, esophagitis, rib pain, gait disturbance) and blood calcium levels, and a positive association was found between hypercalciuria and hypercalcemia. In addition, it was noted that in patients with severe hypercalcemia, the number of clinical signs is significantly higher than in patients with mild or moderate hypercalcemia.

CONCLUSION: The study demonstrates the variety of clinical manifestations of PHPT, for which doctors of various specialties — pediatricians, gastroenterologists, nephrologists, neurologists, orthopedic traumatologists, can observe children. In the presence of symptoms and diseases such as fatigue, nausea, pain in the legs, deformation of the lower extremities, low-traumatic fractures, urolithiasis, gastritis, it is necessary to examine the level of calcium in the blood in children.

1. Mokrysheva NG, Eremkina AK, Mirnaya SS, et al. The clinical practice guidelines for primary hyperparathyroidism, short version. Problems of Endocrinology. 2021;67(4):94-124. (In Russ.). doi: https://doi.org/10.14341/probl12801

2. Soto-Pedre E, Newey PJ, Leese GP. Stable Incidence and Increasing Prevalence of Primary Hyperparathyroidism in a Population-based Study in Scotland. J Clin Endocrinol Metab. 2023;108(10):e1117-e1124. doi: https://doi.org/10.1210/clinem/dgad201

3. Khan AA, Hanley DA, Rizzoli R, et al. Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus. Osteoporos Int. 2017;28(1):1-19. doi: https://doi.org/10.1007/s00198-016-3716-2

4. Mokrysheva NG, Dobreva EA, Maganeva IS, et al. Primary hyperparathyroidism in Russia according to the registry. Problems of Endocrinology. 2019;65(5):300-310. (In Russ.). doi: https://doi.org/10.14341/probl10126

5. Lawson ML, Miller SF, Ellis G, Filler RM, Kooh SW. Primary hyperparathyroidism in a paediatric hospital. QJM. 1996;89(12):921-32. doi: https://doi.org/10.1093/qjmed/89.12.921

6. Wang W, Kong J, Nie M, et al. Primary hyperparathyroidism in Chinese children and adolescents: A single‐centre experience at Peking Union Medical College Hospital. Clin Endocrinol (Oxf ). 2017;87(6):865-873. doi: https://doi.org/10.1111/cen.13453

7. Kollars J, Zarroug AE, van Heerden J, et al. Primary hyperparathyroidism in pediatric patients. Pediatrics. 2005;115(4):974-80. doi: https://doi.org/10.1542/peds.2004-0804

8. Mamedova E, Kolodkina A, Vasilyev EV, et al. Successful Use of Denosumab for Life-Threatening Hypercalcemia in a Pediatric Patient with Primary Hyperparathyroidism. Horm Res Paediatr. 2020;93(4):272-278. doi: https://doi.org/10.1159/000510625

9. Mamedova E, Mokrysheva N, Vasilyev E, et al. Primary hyperparathyroidism in young patients in Russia: high frequency of hyperparathyroidism-jaw tumor syndrome. Endocr Connect. 2017;6(8):557-565. doi: https://doi.org/10.1530/EC-17-0126

10. Orekhova E.A., Chugunova O.L., Blokh S.P., et al. Primary hyperparathyroidism as a cause of nephrocalcinosis and nephrolithiasis in an adolescent patient: a clinical case. Pediatria n.a. G.N. Speransky. 2023; 102 (4): 186-193. (In Russ.). doi: https://doi.org/10.24110/0031-403X-2023-102-4-186-193

11. Gostimsky AV, Matveeva ZS, Romanchishen AF, et al. Primary hyperparathyroidism in childhood. Pediatrician (St. Petersburg). 2017;8(5):20-24 (In Russ.). doi: https://doi.org/10.17816/PED8520-24

12. Gostimskiy A.V., et al. Features of the diagnosis of primary hyperparathyroidism in children. Endocrine Surgery. 2021;15(4):32-37. (In Russ.). doi: https://doi.org/10.14341/serg12758

13. Stokes VJ, Nielsen MF, Hannan FM, Thakker RV. Hypercalcemic Disorders in Children. J Bone Miner Res. 2017;32(11):2157-2170. doi: https://doi.org/10.1002/jbmr.3296

14. Boone D, Politz D, Lopez J, Mitchell J, Parrack K, Norman J. Concentration of serum calcium is not correlated with symptoms or severity of primary hyperparathyroidism: An examination of 20,081 consecutive adults. Surgery. 2017 Jan;161(1):98-106. doi: https://10.1016/j.surg.2016.09.012.

15. Yan H, Calcatera N, Moo-Young TA, Prinz RA, Winchester DJ. Degree of hypercalcemia correlates with parathyroidectomy but not with symptoms. Am J Surg. 2019 Mar;217(3):437-440. doi: https://10.1016/j.amjsurg.2018.09.010.

16. Bin Yahib SM, Algarni B, Alghamdi A, Nassan S. Primary Hyperparathyroidism as a Rare Cause of Unexplained Recurrent Abdominal Pain: Case Presentation and Literature Review. Cureus. October 2021. doi: https://doi.org/10.7759/cureus.19155

17. A. Skolarikos et al., EAU Guidelines. Edn. presented at the EAU Annual Congress Milan 2023. ISBN 978-94-92671-19-6. http://uroweb.org/guidelines/compilations-of-all-guidelines/

18. Velásquez-Forero F, Esparza M, Salas A, Medeiros M, Toussaint G, Llach F. Risk factors evaluation for urolithiasis among children. Bol Med Hosp Infant Mex. 2016. doi: https://doi.org/10.1016/j.bmhimx.2016.05.006

19. Boro H, Khatiwada S, Alam S, Kubihal S, Dogra V, et al. The spectrum of manifestations of primary hyperparathyroidism in children and adolescents. Pediatr Endocrinol Diabetes Metab. 2022;28(3):178-187. doi: https://doi.org/10.5114/pedm.2022.118315

20. El Allali Y, Hermetet C, Bacchetta J, et al Presenting features and molecular genetics of primary hyperparathyroidism in the paediatric population. Eur J Endocrinol. 2021;184(2):347-355. doi: https://doi.org/10.1530/EJE-20-1119

21. Szabo Yamashita T, Gudmundsdottir H, Foster TR, et al Pediatric primary hyperparathyroidism: Surgical pathology and long-term outcomes in sporadic and familial cases. Am J Surg. 2023;225(4):699-702. doi: https://doi.org/10.1016/j.amjsurg.2022.10.018

22. Belcher R, Metrailer AM, Bodenner DL, Stack BC. Characterization of hyperparathyroidism in youth and adolescents: A literature review. Int J Pediatr Otorhinolaryngol. 2013. doi: https://doi.org/10.1016/j.ijporl.2012.12.008

23. Abboud B, Daher R, Boujaoude J. Digestive manifestations of parathyroid disorders. World J Gastroenterol. 2011;17(36):4063-6. doi: https://doi.org/10.3748/wjg.v17.i36.4063

24. Husain SZ, et al. Toxic-metabolic Risk Factors in Pediatric Pancreatitis: Recommendations for Diagnosis, Management, and Future Research. J Pediatr Gastroenterol Nutr. 2016;62(4):609-17. doi: https://doi.org/10.1097/MPG.0000000000001035

25. Alghanmi YY, Sindi HH, Bader DE, Alraddadi SM. Ectopic parathyroid adenoma with acute pancreatitis in a pediatric patient. Med Case Reports Study Protoc. 2021;2(8):e0130. doi: https://doi.org/10.1097/MD9.0000000000000130

26. Reyes-Cerecedo A, Tapia-Brito LS, González-Ortiz B. Pancreatitis aguda, secundaria a hiperparatiroidismo primario. Rev Mex Pediatría. 2021;88(2):75-77. doi: https://doi.org/10.35366/101282

27. Marcocci C, Cianferotti L, Cetani F. Bone disease in primary hyperparathyrodism. Ther Adv Musculoskelet Dis. 2012;4(5):357-68. doi: https://doi.org/10.1177/1759720X12441869

28. S R, Kandasamy D, MK V, Tripathi M, VP J. Genu valgum and primary hyperparathyroidism in children. Int J Case Reports Images. 2014;5(6):401. doi: https://doi.org/10.5348/ijcri-201455-CS-10041

29. de Silva NL, Jayalath MD, Sampath WKC, Perera R, Karunathilake C. Primary hyperparathyroidism in an adolescent presenting with genu valgus progressing to extensive bone disease; a case report. BMC Endocr Disord. 2023;23(1):71. doi: https://doi.org/10.1186/s12902-023-01328-z

30. Rao KS, Agarwal P, Reddy J. Parathyroid adenoma presenting as genu valgum in a child: A rare case report. Int J Surg Case Rep. 2019. doi: https://doi.org/10.1016/j.ijscr.2019.03.063

31. Dutta D, Kumar M, Das RN, et al Primary hyperparathyroidism masquerading as rickets: diagnostic challenge and treatment outcomes. J Clin Res Pediatr Endocrinol. 2013;5(4):266-9. doi: https://doi.org/10.4274/Jcrpe.1060

32. Pitukcheewanont P, Numbenjapon N, Costin G. Ectopic thymic parathyroid adenoma and vitamin D deficiency rickets: a 5-year-follow-up case report and review of literature. Bone. 2008;42(4):819-24. doi: https://doi.org/10.1016/j.bone.2007.10.006

33. Khan K, Qureshi S. Primary Hyperparathyroidism Masquerading as Rickets. J Coll Physicians Surg Pakistan. 2019;29(09):891-894. doi: https://doi.org/10.29271/jcpsp.2019.09.891

34. Laurent MR, De Schepper J, Trouet D, et al. Consensus Recommendations for the Diagnosis and Management of X-Linked Hypophosphatemia in Belgium. Front Endocrinol (Lausanne). 2021. doi: https://doi.org/10.3389/fendo.2021.641543

35. K. J. Nicholson, K. L. Mccoy, S. F. Witchel, and M. T. Stang, “Comparative characteristics of primary hyperparathyroidism in pediatric and young adult patients,” Surgery, pp. 1008-1016, doi: https://10.1016/j.surg.2016.06.028.

36. Minelli R, Meoli A, Tiri A, et al. An Atypical Presentation of Primary Hyperparathyroidism in an Adolescent: A Case Report of Hypercalcaemia and Neuropsychiatric Symptoms Due to a Mediastinal Parathyroid Adenoma. Front Endocrinol (Lausanne). 2020. doi: https://doi.org/10.3389/fendo.2020.581765

37. Ricci J, Vlasschaert J, Salit IE. Prolonged fever associated with primary hyperparathyroidism. Can Med Assoc J. 1984;131(5):459-60

38. Blair DC, Fekety FR. Primary hyperparathyroidism presenting as fever of unknown origin with unremitting headache. Ann Intern Med. 1979;91(4):575-6. doi: https://doi.org/10.7326/0003-4819-91-4-575