Comprehensive Guide to Pediatric Parathyroid Disorders

1. . Common Parathyroid Disorders in Children Dr Sarar Mohamed FRCPCH (UK), MRCP (UK), CCST (Ire), CPT (Ire), DCH (Ire), MD Consultant Paediatric Endocrinologist & Metabolic Physician Associate Professor of Pediatrics King Saud University

2. . Agenda • Calcium homeostasis • Causes of hypocalcaemia • Rickets • hypercalcaemia

3. Key-players of calcium metabolism • Calcium & Phosphates • Parathyroid hormone (PTH). • Cholecalciferol (Vit.D3) and Calcitriol ( active form of vit D and it produced by the kidney ) • Estrogen and other Sex hormones. ( in adults only ) • Calcitonin.

4. PARATHYROID HORMONE • Function of PTH • 1-raises the level of calcium in the blood • 2-decreases levels of blood phosphate. • 3-Partially antagonistic to calcitonin

5. PARATHYROID HORMONE • Secreation stimulated by fall in serum Ca. • mobilize calcium from bone • Increases renal reabsorption of ca • decreases renal clearance of calcium •  increase calcium absorption - intestine Calcium homeostasis

6. Vitamin D • Fat soluble ‘vitamin’ • Synthesised in skin • Food sources include fish oils

7. NB : Calcitriol ( active form of vit D and it produced by the kidney )

8. Vitamin D The active hormone is 1,25(OH)2D3 It increases absorption of calcium from gut. It increases reabsorption of ca from kidney. .

9. Calcitonin • It is a calcium lowering hormone • Secreted by Thyroid C cells Anti - PTH

10. Target Organs Kidney G.I.Tract Bone

11. Dysfunction of parathyroid Gland - MCQ 1. Too little parathyroid hormone – hypoparahypothyroidism causes low serum calcium and high phosphate 2. Too much parathyroid hormone– hyperparahyperthyroidism causes high calcium and low phosphate.

12. Newborn Screening Hyperparathyroidism • Main symptom is hypercalcemia, and hypophosphatemia also occurs but not always. • Normal or elevated PTH (intact pituitary function), the problem is that end organ is resistant. • Leading to decreased calcium and increased phosphate levels with normal ALP. • Clinical presentation: short stature, and obese. • Radiology: x-ray shows short 4th metacarpal and delayed development. • Occur in End organ insensitivity  occur in obese childrens Pseudohypoparathyroidism مهم

13. Calcium profile • To diagnose a metabolic bone disease • calcium • Phosphate • Alkaline phosphatase • Parathyroid hormone • Vitamin D • Urinary calcium and phospherus

14. Newborn Screening • Elevated ALP on calcium profile, think of rickets. • For vitamin D deficiency, measure the 25 hydroxy-cholecalciferol(which is normally formed in the liver). • Prolonged breast feeding without supplementation can lead to nutritional deficiency in the infants.

15. . Causes of hypocalcaemia • Rickets • Hypopararthyroidism • Psuedohypopararthyroidism • Familial hypocalcaemia • Renal failure • Drugs: phenytoin • Maternal diabetes: newborn to diabetic mothers have decreased insulin, hyperglycemia, and pancreatic atrophy. Insulin is required for PTH. This condition subsides with time and patient is taken for counseling. • Prematurity • DiGoerge syndrome CATCH 22 • Cardiac abnormality (tertaolgy of Fallot). • Abnormal facies. • Thymus aplasia. • Cleft palate. • Hypoparathyroidism/hypocalceamia.

16. اولا: Rickets • Reduced mineralization of bone matrix due to calcium deficiency. Rickets results when the osteoid does not have mineral. This can also happen quickly, depending on the severity of mineral deficiency. In adolescents or adults it is called osteomalacia because they are not growing bones. Calcium deficiency/Vit D deficiency

17. Newborn Screening • Commonest cause of vitamin D deficiency is decreased sun exposure overall, but in infancy it is mainly from diet; therefore, if patient is on breast milk switch to supplement. • All types of rickets leads to decreased phosphate level except renal rickets because of renal failure (renal osteodystrophy).

18. Etiology : Deficiency of Vit. D • Dietary lack of the vitamin  like in baby who is breastfeeding dependant - MCQمهمه • Insufficient ultraviolet skin exposure • Malabsorption of fats and fat-soluble vitamins- A, D, E, & K. • Abnormal metabolism of vitamin D chronic renal failure. .

19. Rickets: Non renal causes – • Nutritional • Intestinal – malabsorption • Hepatobiliary • Metabolic – anticonvulsant therapy • Rickets of prematurity (happens in the first weeks of life).

20. Renal causes • Renal osteodystrophy: CRF • Familial hypophosphataemic rickets • Renal tubular acidosis • Fanconi syndrome (the loss of phosphate leads to rickets). • Primary • Secondary - cystinosis (abnormal accumulation of amino acid cystine, autosomal recessive, commonest cause of Fanconi), Wilson’s disease, Lowe’s syndrome (x-linked recessive), tyrosinemia. • Vitamin D dependent type 1 rickets (Deficiency of 1-hydroxyvitamin-D-25-hydrolase). مهم • Vitamin D dependent type 2 rickets (End-organ insensitivity to autogenous 1,25-dihydroxyvitamin D). Type 2 is associated with alopecia. مهم • Both are autosomal recessive.

21. Rickets: Effect at growth end plate • Inadequate growth plate mineralization. • Defective calcification in the interstitial regions. • The growth plate increases in thickness. • The columns of cartilage cells are disorganized. • Hereditary type is associated with short stature.

22. Rickets Rickets • Cupping of the epiphyses. • Bones incapable of withstanding mechanical stresses and lead to bowing deformities. • Eventual length of the long bones is diminished (short stature).

23. Age of presentation • VITAMIN D DEFICIENCY RICKETS (nutritional) • 6 to 18 months (first 2 years of life). • NON NUTRITIONAL RICKETS • Beyond this age group. • VITAMIN D DEPENDENT RICKETS • Presents early in life.

24. Skeletal manifestations of Rickets • Craniotaes (depression when pressing on the skull  ping ball sign) • Delayed closure of anterior fontanelle • Frontal and parietal bossing • Delayed eruption of primary teeth • Chest for rickets Rosary (increase in size of costo-chondoral junction)

26. Skeletal manifestations • EXTREMITIES – • Enlargement of long bones around wrists and ankles due to increased size of distal bones (radius and ulna) • Bow legs, knock knees • Green stick fractures

29. Extra – skeletal manifestations • SEIZURES AND TETANY – Secondary to hypocalcaemia • HYPOTONIA AND DELAYED MOTOR DEVELOPMENT In rickets developing during infancy.

30. Investigations • BASIC INVESTIGATIONS TO CONFIRM RICKETS • Low or normal serum Ca • Low phosphorus (very early on in the disease may be normal) • High alkaline phosphatase • X rays of ends of long bones at knees or wrists • Shows Widening, fraying, cupping of the distal ends of shaft. • Vit D level low • Parathyroid hormone high is secondary due to hypocalcemia مهم

31. Newborn Screening Rickets • Radiology changes : Show : Widening + cupping + decrease Mineralization

33. Genu valgus Tri radiate pelvis Wrist widening Wrist cupping Looser’s zones Wide metaphysis

34. Vitamin D Resistant Rickets ( X linked hypocalcemia ) • In the renal tubular disorders, rickets develops in the presence of normal intestinal function and are not cured by normal doses of vitamin D. • Resistant or refractory rickets. • Commonest is x-linked hypophosphatemic rickets • Short stature and late presentation. مهمه • Vitamin D is normal but the pathology is in the kidney because it can not absorb phosphate Defective final conversion of Vit. D in to active form or End organ insensitivity.

35. Newborn Screening • Rickets is a clinical diagnosis, whereas vitamin D deficiency is a biochemical one.

36. Vitamin D Resistant Rickets

37. Vitamin D Resistant Rickets

38. Newborn Screening Inherited rickets اعرفها كاسماء فقط وكلها تم تفصيلها سابقا • 1- hypophotemic rickets : PHEX , FGF23 , DMP1 • 2- vit D dependant rickets : Type 1 : CYP27B1 gene Type 2 : VDR gene  present with alopecia • 3- 25 hydroxylase deficincy CYP2R1

39. Treatment of Rickets • Vitamin D supplement • Nutritional (commonest) we give vitamin D3. • Resistant rickets is treated by the active form of vitamin D. • Type and dose depends on underlying cause of Rickets

40. . Causes of hypercalcaemia • Hyperparathyroidism • Vitamin D intoxicity • William syndrome • Familial hypocalcuric hypercalcaemia: calcium is not excreted. • malignancy

41. Full term 1 year old boy who presented with afebrile tonic clonic convulsions. He has no chronic illnesses or medication. On examination he has no apparent dysmorphic features and his vital signs were normal. • Describe an abnormality. • List two important investigations to confirm your diagnosis. • What is the most likely diagnosis?

42. Full term 1 year old boy who presented with afebrile tonic clonic convulsions. He has no chronic illnesses or medication. On examination he has no apparent dysmorphic features and his vital signs were normal. • Describe an abnormality. • List two other important investigations to confirm your diagnosis. • Answer: • Bowing of legs • 1. Serum calcium level, serum alkaline phosphatase, 25 Vitamin D level, hand x-ray • 2. Possible diagnosis is nutritional Vitamin D deficiency due to the age of the baby.

43. Data interpretation . An obese 2 year old girl was found to be hypocalcemic and did not respond to vitamin D.These results were found. Plasma Calcuim 1.2 mmol/L , Plasma phosphate 2.8mmol/L ( N- 0.8-1.4) Alkaline Phosphatase 300 1u/L Urea 4mmol/L Magnesium 0.7 mmol/L Parathyroid hormone 20mg/ml ( n <1) What is the most likely diagnosis? Psudohyperparathyrodism what may radiological exams of hand reveal? Shorting of the 4th metacarbal bone علامه مميزه

44. Newborn Screening • This is a case of pseudohypoparathyroidism. What makes it more likely is that the ALP, urea is normal (excluding both renal and non-renal causes of rickets) and only calcium is low with high PTH.

45. An 8 ½ yr old girl followed by the Endocrine Clinic was apparently well until three years ago when she started to have muscle pains and difficulty in getting out of bed in the morning. • Describe two abnormalities. • Give the most likely diagnosis.

46. An 8 ½ yr old girl followed by the Endocrine Clinic was apparently well until three years ago when she started to have muscle pains and difficulty in getting out of bed in the morning. • Describe two abnormalities. • Give the most likely diagnosis. • Answer: • Short stature bony deformity in the form of bowing of legs • X-Linked Hypophosphatemic Rickets

47. Thank you !