Hyperparathyroidism in children

An overview of hyperparathyroidism in children.

1. Hyperparathyroidism in children Dr Joyce MWATONOKA Resident, Pediatrics and Child Health

2. Introduction Excessive production of PTH P rimary hyperparathyroidism ; defect of the parathyroid glands such as an adenoma (80%) or hyperplasia, rarely carcinoma Secondary hyperparathyroidism ; compensatory, usually aimed at correcting hypocalcemic states of diverse origins eg ; CKD, Vit D deficiency, malabsorption Tertialy hyperparathyroidism; hyperlasia due to intense and protracted stimulation

3. Epidemiology Childhood hyperparathyroidism is uncommon Estimated incidence in children is 1 per 200-300,000 Prevalence is 2-5 in 100,000 Higher predominance in adolescence, although still very low compared to adults

4. PTH physiology When serum levels of calcium fall, the signal is transduced through the calcium-sensing receptor , and secretion of PTH increases PTH stimulates activity of 1α-hydroxylase in the kidney, enhancing production of 1,25-dihydroxycholecalciferol Which induces synthesis of a calcium-binding protein ( calbindin -D) in the intestinal mucosa, with resultant absorption of calcium

5. Cont… PTH also mobilizes calcium by directly enhancing bone resorption , an effect that requires 1,25(OH)2D3

6. Etiology Onset during childhood is usually the result of a single benign adenoma (Familial isolated hyperparathyroidism) It usually becomes manifested after 10 yr of age AD. Mostly affect adults, but children have been involved in approximately 30% of the pedigrees Can be caused by mutations in the MEN1 , CDC73 or CASR gene

7. Cont… In other kindreds , hyperparathyroidism occurs as part of the constellation known as the multiple endocrine neoplasia (MEN) syndromes or of the hyperparathyroidism–jaw tumor syndrome

8. MEN type I I s an AD disorder characterized by hyperplasia or neoplasia of the endocrine pancreas , the anterior pituitary , and the parathyroid glands Hyperparathyroidism is usually the presenting manifestation, with a prevalence approaching 100% by 50yr Rarely occurs in children <18 yr

9. Cont…

10. Hyperparathyroidism–jaw tumor syndrome It is an AD disorder characterized by parathyroid adenomas and fibro-osseous jaw tumors ( osteitis fibrosa cystica ) Affected patients can also have polycystic kidney disease, renal hamartomas , and Wilms tumor Although the condition affects adults primarily, it has been diagnosed as early as age 10 yr

11. Familial hypocalciuric hypercalcemia (FHH) Rare benign, genetic condition, AD Loss of function mutations in the CASR gene Generally asymptomatic Low urinary calcium (<0.02 mmol /L) Increased serum calcium levels (usually 10.5-12mg/dl), mild to moderate Hypermagnesemia , hypophosphatemia PTH, usually normal or mild elevated

12. N eonatal severe hyperparathyroidism It is a rare disorder May be homozygous or heterozygous for the mutation in the Ca2+-sensing receptor gene, whereas most persons with 1 copy of this mutation exhibit AD familial hypocalciuric hypercalcemia Histologically , the parathyroid glands show diffuse hyperplasia

13. Cont… Sxs develop shortly after birth and consist of anorexia, irritability, lethargy, hypotonia , constipation, and failure to thrive Radiographs reveal subperiosteal bone resorption , osteoporosis, and pathologic fractures Sxs may be mild, resolving without treatment, or can have a rapidly fatal course if dx and treatment are delayed

14. Transient neonatal hyperparathyroidism O ccurr in few infants born to mothers with hypoparathyroidism ( idiopathic/surgical ) or with pseudohypoparathyroidism In each case, the maternal disorder had been undiagnosed or inadequately treated during pregnancy Due to chronic intrauterine exposure to hypocalcemia with resultant hyperplasia of the fetal parathyroid glands. In the newborn, manifestations involve the bones primarily, and healing occurs between 4 - 7mo of age

15. Cont… In pseudohypoparathyroidism , PTH levels are elevated because a mutation in the Gsα protein interferes with response to PTH Hence resistance to PTH Elevated PTH, hyperphosphatemia , and hypocalcemia with normal Vit D levels and renal function

16. Secondary hyperparathyroidism Early in CKD, hyperphosphatemia results in a reciprocal fall in the calcium concentration with a consequent increase in PTH But in advanced stages of renal failure, production of 1,25(OH)2D3 is also decreased, leading to worsening hypocalcemia and further stimulation of PTH

17. Clinical manifestations (of hypercalcemia ) M uscle weakness, fatigue, headache, anorexia, abdominal pain (pancreatitis, constipation), nausea, vomiting, constipation, polydipsia , polyuria , weight loss, and fever CVS; heart block, short QT interval, arrhythmias Renal; polyuria , nephrogenic DI, AKI, CKD, nephrocalcinosis

18. Bones, stones, moans & psychiatric overtone Bones ; fractures, weakness, bone pain Stones ; nephrolithiasis Groans/moans ; abdominal cramping, nausea, ileus , constipation Psychiatric overtone ; (neuronal hypoactivity ) hyporeflexia , depressed mood, confusion, lethargy, nephrogenic diabetes insipidus - dehydration -Ca is a competitive inhibitor of ADH

19. Laboratory findings Primary Increased serum PTH levels Elevated total serum calcium and ionized calcium levels Increase in urinary calcium excretion Serum phosphorus level is reduced to approximately 3 mg/ dL or less Mild hyperchloremic acidosis Measure Vit D levels Secondary Increased serum PTH levels Normal or low calcum levels Vitamin D deficincy Underlying renal failure (CKD)

20. Cont… Adenomas with skeletal involvement, serum ALP levels are elevated, but in hyperplasia the levels of ALP may be normal even when there is extensive involvement of bone Calcitonin levels are normal; Acute hypercalcemia can stimulate calcitonin release, but with prolonged hypercalcemia , hypercalcitoninemia does not occur

21. Radiography Subperiosteal bone resorption , best seen along the margins of the phalanges of the hands (laterally/along the radial) Pathognomonic for hyperparathyroidism

22. Cont… Distal clavicular resorption

23. Cont… Salt and pepper appearance -multiple punched out lesions on the skull Classical in primary hyperthyroidism

24. Cont… Rugger jersey sign -sclerotic superior and inferior endplates Diagnostic for osteoslerosis ass/c secondary hyperparathyroidism

25. Cont… In more advanced disease, there may be generalized rarefaction, cysts, tumors, fractures, and deformities Approximately 10% of patients have radiographic signs of rickets Abdominal X-ray can reveal renal calculi or nephrocalcinosis

26. Cont… Parathyroid maging ; -USS -CT -MRI -Radioisotope scanning using 99mTc-sestamibi Bone densitrometry (DXA)

27. Other causes of hypercalcemia Endocrine Idiopathic infantile hypercalcemia Vitamin D (intoxication, subcutaneous fat necross ) Drugs; thiazide diuretics, lithium Miscellaneous; hypophospatemia , vitamin A intoxication, blue-diaper syndrome Malignancy; bone metastases, breast, lung, bone cancer Granulomatous d’ses ; TB, sarcoidosis

28. Treatment Primary ; Adenoma – parathyroidectomy Secondary ; medical management, Vit D replacement, phosphate restriction/binding agents Tertiary ; total/subtotal parathyoidectomy Postoperatively observe for hypocalcemia and tetany ; IV calcium gluconate may be required for a few days. Calcium level gradually returns to normal, a diet high in calcium and phosphorus must be maintained for several months

29. Cont… Fluids; 0.9% NS Loop diuretics Bisphosphonates ; alendronate , ibandronate (reduce osteoclast activity) -Second line; Long term side effect-interferes with bone turnover. Short term; hypocalcemia IV calcitonin for more rapid reduction -side effect, hypocalcemia Dialysis; severe hypercalcemia >18mg/dl

30. Cont… Corticosteroids lower the serum calcium level to normal in patients with hypercalcemia from other causes but generally do not affect the calcium level in patients with hyperparathyroidism

31. Treating other causes of hypercalcemia Most neonates with severe hypercalcemia require total parathyroidectomy ; less-severe hypercalcemia remits spontaneously in others - calcimimetics Familial hypercalciuric hypercalcemia ; loop diuretics Malignancy (low PTH, high Ca); full work up including assay for PTHrP , ALP, calcitriol , femur xray /MM work up)

32. Px The prognosis is good if the disease is recognized early and there is appropriate surgical treatment When extensive osseous lesions are present, deformities may be permanent A search for other affected family members is indicated