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

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 Rickets

Normal Growth Plate Rachitic 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 ?

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 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

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 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

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

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,

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

(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 Rickets

16th 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/l 70.6

25OHD3nmol/l <15

• Male infant born to Somali parents

• Breast fed from birth

• 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

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)

� 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

Rx

Calcium

Sandoz

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)

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 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: zulf.mughal@cmft.nhs.uk