rickets zulf mughal consultant in paediatric bone disorders department of paediatric endocriology...
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Rickets
Zulf MughalZulf Mughal
Consultant in Paediatric Bone Disorders
Department of Paediatric Endocriology
Royal Manchester Children's Hospital
ManchesterManchester
M13 0JHM13 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 PerspectiveRickets – Historical Perspective
Francis Glisson - "De Rachitide” 1650
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 RicketsRecent resurgence of Rickets
What is Rickets ?What is Rickets ?
Disease of the growing child Impaired mineralisation of the growth plate & osteoidImpaired mineralisation of the growth plate & osteoid Low serum phosphate is fundamental to pathogenesis of ricketsLow serum phosphate is fundamental to pathogenesis of rickets
Normal Growth Plate Rachitic Growth Plate
Apoptosis of Hypertrophic
Chondrocytes caused by
PHOSPHATE ions
HYPOPHOSPHATEMIANo Apoptosis of
Hypertrophic Chondrocytes
What is Rickets ?What is Rickets ?
Impaired Apoptosis of Terminally Differentiated Chondrocytes in the Growth PlateResponsible for Clinical & Radiological Signs of Rickets
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)2D
Rickets due to Dietary Calcium Deficiency
Calcipaenic Rickets Phosphopaenic RicketsHypophosphataemic 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
MughalMughal. Curr Osteoporos Rep. 2011;9(4):291-9Curr 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 AdolescentsVitamin D Deficiency in Adolescents
Tetany & Convulsions Limb pains Lower limb & pelvic deformities Proximal myopathy
Biochemical Changes in Vitamin D DeficiencyBiochemical Changes in Vitamin D DeficiencyEarly vitamin D deficiency:
25(OH)D ↓ Ca Normal
PTH ↑ P ↓
1,25(OH)2D ↑ ALP ↑
Severe vitamin D deficiency:25(OH)D ↓ ↓ Ca ↓
PTH ↑ ↑ P ↓ ↓
1,25-(OH)2D ↓ ALP ↑ ↑
Occasionally PTH resistance: Ca ↓, P ↑, 25(OH)D ↓↓,
PTH ↑↑ & 1,25-(OH)2D ↓↓
Archives of Disease in Childhood. 2009; 94:932-937
Radiological Changes
RRx x Vitamin DVitamin D33
+ + Calcium Calcium
Treatment of Vitamin D Deficiency RicketsTreatment 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 Improvement in symptoms (~ 2weeks)(~ 2weeks)
↓ ↓ in serum PTH & alkaline phosphatase in serum PTH & alkaline phosphatase
↑↑ in serum phosphate, calcium & 25(OH)vitamin Din serum phosphate, calcium & 25(OH)vitamin D
Radiological healing Radiological healing (~ 3 months)(~ 3 months)
Improvement of bow legs or knock-knees Improvement of bow legs or knock-knees (~ 2 years)(~ 2 years)
Provide vitamin D supplements (~ 400 iu/day) after the ricketsProvide vitamin D supplements (~ 400 iu/day) after the rickets
has healedhas healed
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 D3 or Vitamin D2 ?
Prevention of Vitamin D Deficiency
Vitamin D supplementation During Pregnancy, Vitamin D supplementation During Pregnancy, Lactation & InfancyLactation & 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
(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
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
Severe Calcium Deficiency RicketsSevere Calcium Deficiency Rickets
16th March 2012
Age 19 months 23 months 20 12 201120 12 2011 04 04 201204 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/l 70.625OHD3nmol/l <15
• Male infant born to Somali parents
• Breast fed from birthBreast fed from birth
• Allergic to dairy, eggs & fish
• Weaned mainly on pasta, rice,Weaned mainly on pasta, rice, potatoes & small amount of meatpotatoes & small amount of meat
• Dalivit 0.6 mls dailyDalivit 0.6 mls daily
• Calcium supplements prescribedCalcium supplements prescribed
• Presented with delayed walking Presented with delayed walking
Severe Calcium Deficiency RicketsSevere 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)
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
RRxx Calcium Calcium SandozSandoz
Vitamin D Dependent Rickets (VDDR) Type I & Type II
VDDR Type IVDDR Type I
Corr Ca 2.02 mmol/lCorr Ca 2.02 mmol/l
P 0.59 mmol/l (1.1 – 2.0) P 0.59 mmol/l (1.1 – 2.0) ALP 3636 IU/l (100 - 733) ALP 3636 IU/l (100 - 733)
PTH 1087 pg/ml (10 - 60)PTH 1087 pg/ml (10 - 60)
25(OH)D 31 ng/ml25(OH)D 31 ng/ml
1,25(OH)22D < 10 pg/ml (20 - 50)D < 10 pg/ml (20 - 50)
September 2005 - 16 month old child with severe Rickets
Known inactivating mutations in
the CYP27B1 gene
Vitamin D Dependent Rickets Type I & Type II
VDDR Type IVDDR Type I
Physiological doses of calcitriol (1,25(OH)2D) or alphacalcidiolPhysiological doses of calcitriol (1,25(OH)2D) or alphacalcidiol
VDDR Type IIVDDR Type II
Pharmacological doses of calcitriol or alphacalcidiol Pharmacological doses of calcitriol or alphacalcidiol (e.g. 3-6 mcg/day)(e.g. 3-6 mcg/day)
++ Oral calcium – 2 to 3 grams/dayOral calcium – 2 to 3 grams/day
Long‑term treatment calcium infusions (especially patientsLong‑term treatment calcium infusions (especially patients with alopeciawith alopecia ))
