1. Rickets Zulf Mughal Consultant in Paediatric Bone Disorders Department of Paediatric Endocriology Royal Manchester Children's HospitalManchester M13 0JH Bone Study Day, 28 th September 2012

2. Overview   What is Rickets?   Vitamin D Deficiency Rickets   Calcium Deficiency Rickets   Vitamin D Dependent Rickets type I & type II   X-Linked Hypophosphataemic Rickets

3. What is Rickets ?

4. Rickets – Historical Perspective Francis Glisson - "De Rachitide” 1650  19 th CENTURY - Rickets rampant among the poor children living in the industrialised & polluted northern cities  “Disappearance of Rickets” in early 20 th Century:  Cod-liver oil supplements in 1930s  Improvement in nutrition  Pollution control measures  Recent resurgence of Rickets

5. What is Rickets ? What is Rickets ?  Disease of the growing child  Impaired mineralisation of the growth plate & osteoid  Low serum phosphate is fundamental to pathogenesis of rickets Normal Growth Plate Rachitic Growth Plate Apoptosis of Hypertrophic Chondrocytes caused by PHOSPHATE ions HYPOPHOSPHATEMIA No Apoptosis of Hypertrophic Chondrocytes

6. What is Rickets ? What is Rickets ? Impaired Apoptosis of Terminally Differentiated Chondrocytes in the Growth Plate Responsible for Clinical & Radiological Signs of Rickets

7. What is Rickets ? What is Rickets ? Vitamin D Related Rickets - Vitamin D Deficiency - Impaired Hepatic 25-hydroxylation - Impaired Renal 1α-hydroxylation of 25(OH)D - End organ resistance to 1,25(OH) 2 D Rickets due to Dietary Calcium Deficiency Calcipaenic RicketsPhosphopaenic Rickets Hypophosphataemic Rickets - X-linked Dominant (PHEX gene mutation) - Autosomal Dominant (FGF23 mutation) - Autosomal Recessive Type 1 (DMP1mutation) - Autosomal Recessive Type 2 (ENPP1mutation) - With Hypercalciuria (SLC34A3 gene mutation) - Associated with: (a) McCune-Albright syndrome (b) Tumour induced osteomalacia (c) Linear nevus sebaceous syndrome - Raised PTH Renal Phosphate Wastage Hypophosphatemia Impaired Apoptosis of Terminally Differentiated Chondrocytes in the Growth Plate MughalCurr Osteoporos Rep. 2011;9(4):291-9 Mughal. Curr Osteoporos Rep. 2011;9(4):291-9

8. Calcipaenic Rickets Vitamin D Related Rickets   Vitamin D Deficiency Rickets   Impaired Hepatic 25-hydroxylation   Vitamin D Dependent Rickets Type I (Impaired Renal 1α-hydroxylation of 25(OH)D)   Vitamin D Dependent Rickets Type II (End organ resistance to 1,25(OH) 2 D) Rickets due to Dietary Calcium Deficiency

9. Vitamin D Deficiency Rickets

10. Vitamin D Deficiency in Adolescents   Tetany & Convulsions   Limb pains   Lower limb & pelvic deformities   Proximal myopathy

11. Biochemical Changes in Vitamin D Deficiency Early vitamin D deficiency: 25(OH)D ↓ Ca Normal PTH ↑P ↓ 1,25(OH) 2 D ↑ ALP ↑ Severe vitamin D deficiency: 25(OH)D ↓ ↓ Ca ↓ PTH ↑ ↑ P ↓ ↓ 1,25-(OH) 2 D ↓ ALP ↑ ↑ Occasionally PTH resistance: Ca ↓, P ↑, 25(OH)D ↓↓, PTH ↑↑ & 1,25-(OH) 2 D ↓↓ Archives of Disease in Childhood. 2009; 94:932-937

12. Radiological Changes R x Vitamin D 3 +Calcium

13. Treatment of Vitamin D Deficiency Rickets   Oral vitamin D 2 or D 3, 3000 - 6000 i.u./day for 6 to 8 weeks   Oral calcium supplements if necessary   Monitoring:  Improvement in symptoms (~ 2weeks)  ↓ in serum PTH & alkaline phosphatase  ↑ in serum phosphate, calcium & 25(OH)vitamin D  Radiological healing (~ 3 months)  Improvement of bow legs or knock-knees (~ 2 years)  Provide vitamin D supplements (~ 400 iu/day) after the rickets has healed has healed

14. Armas, L. A. G. et al. J Clin Endocrinol Metab 2004;89:5387-5391 Time course of the rise in serum 25OHD after a single oral dose of 50,000 IU of either cholecalciferol (vitamin D3) or ergocalciferol (vitamin D2) to two groups of 10 normal men each Vitamin D 3 or Vitamin D 2 ?

15. Prevention of Vitamin D Deficiency

16. Vitamin D supplementation During Pregnancy, Lactation & Infancy DOH   All 0 to 6 months – 340 i.u/day or 8.5 mcg/day (Not necessary for formula fed infants unless volume < 500 mls/day)   All 7 months to 5 years – 280 i.u/day or 7 mcg/day   Adolescents at risk of vitamin D deficiency - 400 i.u/day or 10 mcg/day   All pregnant & lactating mothers - 400 i.u/day or 10 mcg/day

17. (www.healthystart.nhs.uk) Children’s Healthy Start Vitamin drops contain (5 drops daily): 233 micrograms of vitamin A 20 milligrams of vitamin C 7.5 micrograms of vitamin D3

18. Calcium Deficiency Rickets

19. Rickets Due to Calcium Deficiency Wind-swept Abnormality due to Calcium Deficiency Rickets – taken from a review by Dr John Pettifor Oginni et al Archives of Disease in Childhood. 2003;88:812-817

20. Severe Calcium Deficiency Rickets 16 th March 2012 Age 19 months 23 months 20 12 2011 04 04 2012 Ca mmol/l 2.36 2.39 ALP iu/l 1023 1301 P mmol/l 1.01 0.79 PTH pg/ml (11-35) 192 465 25OHD2nmol/l70.6 25OHD3nmol/l <15 Male infant born to Somali parents Breast fed from birth Allergic to dairy, eggs & fish Weaned mainly on pasta, rice, Weaned mainly on pasta, rice, potatoes & small amount of meat potatoes & small amount of meat Dalivit 0.6 mls daily Calcium supplements prescribed Calcium supplements prescribed Presented with delayed walking Presented with delayed walking

21. Severe Calcium Deficiency Rickets 16 th March 201211 th June 2012   Ca 2.35 mmol/l (2.2 – 2.7)   P 0.98 mmol/l (1.05-1.95)   ALP 538 IU/l (60 -300)   PTH 35 pg/ml (10 - 60)   25(OH)D2 46 nmol/ml   25(OH)D3 6.9 nmol/ml   Total 25(OH)D 52.9 nmol/ml R x CalciumSandoz

22. Vitamin D Dependent Rickets (VDDR) Type I & Type II

23. VDDR Type I  Corr Ca 2.02 mmol/l  P 0.59 mmol/l (1.1 – 2.0)  ALP 3636 IU/l (100 - 733)  PTH 1087 pg/ml (10 - 60)  25(OH)D 31 ng/ml  2 D < 10 pg/ml (20 - 50)  1,25(OH) 2 D < 10 pg/ml (20 - 50) September 2005 - 16 month old child with severe Rickets Known inactivating mutations in the CYP27B1 gene

24. Vitamin D Dependent Rickets Type I & Type II VDDR Type I  Physiological doses of calcitriol (1,25(OH)2D) or alphacalcidiol VDDR Type II  Pharmacological doses of calcitriol or alphacalcidiol (e.g. 3-6 mcg/day) (e.g. 3-6 mcg/day)+ Oral calcium – 2 to 3 grams/day Oral calcium – 2 to 3 grams/day  Long ‑ term treatment calcium infusions (especially patients with alopecia ) with alopecia )

25. Thank You Email: zulf.mughal@cmft.nhs.uk