Transcript Rickets
Rickets Zulf Mughal Consultant in Paediatric Bone Disorders Department of Paediatric Endocriology Royal Manchester Children's Hospital Manchester M13 0JH Bone Study Day, 28th September 2012 Overview What is Rickets? Vitamin D Deficiency Rickets Calcium Deficiency Rickets Vitamin D Dependent Rickets type I & type II X-Linked Hypophosphataemic Rickets What is Rickets ? Rickets – Historical Perspective 19th CENTURY - Rickets rampant among the poor children living in the industrialised & polluted northern cities “Disappearance of Rickets” in early 20th Century: Cod-liver oil supplements in 1930s Improvement in nutrition Pollution control measures Recent resurgence of Rickets Francis Glisson - "De Rachitide” 1650 What is Rickets ? Disease of the growing child Impaired mineralisation of the growth plate & osteoid Low serum phosphate is fundamental to pathogenesis of rickets Rachitic Growth Plate Normal Growth Plate Apoptosis of Hypertrophic Chondrocytes caused by PHOSPHATE ions HYPOPHOSPHATEMIA No Apoptosis of Hypertrophic Chondrocytes What is Rickets ? Impaired Apoptosis of Terminally Differentiated Chondrocytes in the Growth Plate Responsible for Clinical & Radiological Signs of Rickets What is Rickets ? Calcipaenic Rickets Phosphopaenic Rickets Hypophosphataemic Rickets - X-linked Dominant (PHEX gene mutation) 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)2D Rickets due to Dietary Calcium Deficiency Raised PTH - 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 - Renal Phosphate Wastage Hypophosphatemia Impaired Apoptosis of Terminally Differentiated Chondrocytes in the Growth Plate Mughal. Curr Osteoporos Rep. 2011;9(4):291-9 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)2D) Rickets due to Dietary Calcium Deficiency Vitamin D Deficiency Rickets Vitamin D Deficiency in Adolescents Tetany & Convulsions Limb pains Lower limb & pelvic deformities Proximal myopathy Biochemical Changes in Vitamin D Deficiency Early vitamin D deficiency: 25(OH)D ↓ PTH ↑ 1,25(OH)2D ↑ Ca P ALP Normal ↓ ↑ Severe vitamin D deficiency: 25(OH)D ↓↓ PTH ↑↑ 1,25-(OH)2D ↓ Ca ↓ P ↓↓ Archives of Disease ALP ↑ in↑ Childhood. 2009; 94:932-937 Occasionally PTH resistance: Ca ↓, P ↑, 25(OH)D ↓↓, PTH ↑↑ & 1,25-(OH)2D ↓↓ Radiological Changes Rx Vitamin D3 + Calcium Treatment of Vitamin D Deficiency Rickets Oral vitamin D2 or D3, 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 Vitamin D3 or Vitamin D2 ? 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 Armas, L. A. G. et al. J Clin Endocrinol Metab 2004;89:5387-5391 Prevention of Vitamin D Deficiency 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 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 (www.healthystart.nhs.uk) Calcium Deficiency Rickets 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 • Male infant born to Somali parents • Breast fed from birth Severe Calcium Deficiency Rickets • Allergic to dairy, eggs & fish • Weaned mainly on pasta, rice, potatoes & small amount of meat • Dalivit 0.6 mls daily • Calcium supplements prescribed • Presented with delayed walking Age 19 months 20 12 2011 23 months 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 25OHD2nmol/l 25OHD3nmol/l 70.6 <15 465 16th March 2012 Severe Calcium Deficiency Rickets 16th March 2012 11th 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) Rx Calcium Sandoz 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 Vitamin D Dependent Rickets (VDDR) Type I & Type II 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 1,25(OH)2D < 10 pg/ml (20 - 50) Known inactivating mutations in the CYP27B1 gene September 2005 - 16 month old child with severe Rickets 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) + Oral calcium – 2 to 3 grams/day Long-term treatment calcium infusions (especially patients with alopecia ) Thank You Email: [email protected]