RICKETS

Presenter: Dr Suzanna MwanzaModerator: Dr Pandey

02.10.13

HISTORYCC, F/4 years, from Serenje

First presented to UTH on 15 Feb 2013

Referred from Beit Cure hospital for management of Sickle Cell Disease (SCD)

Referral note said that patient was admitted at Beit Cure for orthopedic surgery for Right genu valgum in SCD.

HISTORY

PRESENTING COMPLAINTS• Inability to walk X 2 yrs

HoPC• Started limping at 2 years of age • Mother says patient seemed weak• Gradual developed deformity of legs• Then eventually started failing to walk• Patient complained of pain in the legs• Slowly enlarging head since 3 years of age

HISTORY

• No convulsion• History of jaundice• No history of pain passing urine or change in

frequency of passing urine

HISTORY

PAST MEDICAL HISTORY• Diagnosed with SCD at 2 yrs of age in Serenje• No history of stroke or trauma• No history of fractures• No history of Pnuemonia or recurrent

respiratory infections• HIV neg

HISTORY

DRUG HISTORY• On Folic acid• Did not take any vitamin supplements• Did not take any anticonvulsants or anti-acids

ANTENATAL HISTORY• Mother spent time outdoors for significant part

of a day• Had a varied diet that included local fish and eggs

HISTORY

BIRTH HISTORY• Born at term at local clinic in Serenje, cried at birth, BWt- 2.7kg

IMMUNISATION HISTORY• Fully immunised

DEVELOPMENTAL HISTORY• Sat at 6 months• Crawled at – cannot remember• Stood at about 11 months• Walked at about 1 year 2 months

HISTORYNUTRITIONAL HISTORY• Breastfed exclusively till about 5 months of age till about 1 year and

6 months• Weaned on mealie meal porridge with groundnuts at 5 months• Did not receive formula milk• Started taking nshima with varied goods mainly vegetables – with

local fish, eggs sometimes • Does not take cow milk• Ate 3 meals a day and one late afternoon snack

• Following birth, was taken outside from about 4-6 weeks of age• Patient comes outside everyday and does not wear clothing that

covers the whole body• Mother is a housewife and spends a significant part of her day

outside

HISTORY

FAMILY HISTORY• 2nd child in family of 2; first child died at birth

following prolonged labour• No known history of SCD• No history of anyone with similar deformities,

or of Rickets

EXAMINATION

• Small for age, alert• P+, tinge of jaundice, Co, LNo

• Afebrile• Oral cavity – dental caries• Ht – 86cm (below -3 SD)• Wt – 12.7kg (below -1 SD)• Wt/Ht – above median• HC – 55cm ( above +3 SD)

EXAMINATIONMusculoskeletal:

Head• Enlarged head - Caput quadratum• No craniotabes• No separated sutures and AF was closed• BossingChest• No rachitic rosary or harrison groovesBack• No spinal deformity – scoliosis or kyphosisLimbs• No widening of wrist and ankles• No anterior bowing of the tibia and femur• Able to stand unsupported, but walking with a limp with support• Genu valgus of right knee and genu varum of left knee (wind swept

deformity)

EXAMINATION

Cardiovascular:• tachycardia, haemic murmur

Per abdomen:• Moderately distended, soft, non-tender, enlarged liver of 5cm,

spleen not palpable

Chest:• Vesicular breath sounds

Central nervous system: • Neck supple, kernig’s negative• Normal tone in all limbs, power of 4 and normal reflexes

EXAMINATION

• Urinalysis– Leukocytes – negative– Nitrites – negative– Urobilinogen – normal– Blood – negative– Bilirubin – negative– Protein – negative– Glucose – negative– Ketones - negative– pH – 6.0– Specific gravity – 1.015

EXAMINATION

EXAMINATION

Right genu valgus and left genu varus (windswept deformity)

Anterior deviation of right knee

EXAMINATION

No harrison grooves No rachitic rosary; protuberant abdomen

EXAMINATION

Macrocephaly – HC 55cm (+3 SD)Bossing; caput quadratum

EXAMINATION

Short stature Height – 86cm (-3 SD)

DIAGNOSIS

• Rickets in• Sickle Cell Disease

INVESTIGATIONS

• FBC, Diff• Urea, creatinine, Sodium, Potassium, LFTs• Calcium, Phosphate, ALP, PTH, 25 Vit D, 1,25 Vit D• High performance liquid chromatography (HPLC)• X-ray of skull and upper and lower limbs• Folic acid• Deltaprim• Vitamin D3 – 5000U/day

RESULTSPARAMETER

15.02.13 25.02.13 05.04.13 22.0513 31.05.13

Hb g/dL 6.8 6.6 5.7 5.9 11.4

MCV μm3 98 87 98 98 94

MCH pg 33.1 30.5 27.4 29.7 29.3

PLT103/mm3

147 300 280 234 250

WBC103/mm3

32.1 25.7 19.0 19.5 12.9

Neut 103/mm3

12.38 7.93 5.67 5.33 5.03

ESR mm/hr

- 20 -

RESULTS PARAMETER 05.04.13 22.05.13 Reference range

Chloride 104.7 - 97-104 mmol/L

Potassium 3.20 - 3.5-5.5 mmol/L

Sodium 136.8 - 135-145mmol/L

Albumin 43.5 39.2 36.0 – 46.0 g/L

ALT 12.0 1.9 5.0 – 37.0 U/L

AST 42.6 42.1 5.0 – 36.0 U/L

GGT - 48.8 7.0 – 52.0 U/L

Bili -D 13.66 12.5 0.8 – 5.1 micromol/L

Bili -T 48.84 48.0 3.4 – 17.0 micromol/L

Total protein 70.4 64.6 66.0 – 87.0 g/L

Urea 1.90 0.24 1.7 – 8.3 mmol/L

Creat - 15.2 63.0- 120.0 micromol/L

Ca, PO4

RESULTS – High performance liquid chromatography –

13.02.13

PARAMETER RESULT REFERENCE RANGE

Haemoglobin A2 2.9% 2.5 – 3.9

Haemoglobin F 6.4%

Haemoglobin S 90.7%

Comment Confirms homozygous Hb SS

X-rays

X-ray of lower limbs – AP viewReduced bone density (rarefication)Widening of distal ends of femur and proximal and proximal end of tibia

X-ray of ankle joints – AP viewCupping of distal end of tibia

X - rays

Right ankle joint – lateral viewSplaying of metaphyseal end of boneWidening of distal end of metaphysisFraying of metaphysis

Left ankle joint - lateral viewReduced bone density

X- rays

Wrist joints – lateral viewMild widening of the distal radius Wrist joints – AP view

Mild widening of distal radius

X-rays

Skull X-ray – AP viewNo hair-on-end appearance Skull X-ray – lateral view

No hair-on-end appearance

RESULTSPARAMETER 13.02.13 22.05.13 11.06.16 REFERENCE RANGE

Calcium 2.13 2.20 2.20 – 2.70 mmol/L

Phosphorus 0.95 1.36 1.45 – 1.78 mmol/L

Alkaline phosphatase

3441 1129.7 50-332 U/L

Parathyroid hormone

120.7 15 – 65 pg/ml

Vitamin D (25-Hydroxy cholecalciferol)

14.06 ng/ml Deficiency: < 10 ng/mlInsufficiency: 10-30Sufficiency: 30-100Toxicity: >100

Follow up

• Started on Vit D 400IU on day 11 post-adm(2 tablets daily of Osteocare – the only available

source of Vit D at UTH at the time)• Discharged on day 11 for review after 1 month• Folic acid, Deltaprim, Vit D

Review – one month later

• Mother had purchase Vit D and was giving 1000U/day

• Mother had noted improvement• Patient was walking without support• Changed to Vit D 5000U/day for 6 months• Orthopaedic surgical correction of limbs if

there was no improvement in 6 months• Review in 6 months

Final diagnosis

DIAGNOSIS• Vitamin D deficiency (nutritional) Rickets– High phytate diet (high fiber diet)– ? Low calcium diet

• Sickle Cell Anaemia

REVIEW OF RICKETS

REVIEW OF RICKETS

• Rickets is a disease of growing bones which occurs in children only before the fusion of epiphyses and is due to unmineralised matrix at the growth plates

• Osteomalacia is due to inadequate mineralization of bone osteoid and occurs in children and adults

Vitamin D metabolism

Hormones for calcium and phosphate homeostasis

HORMONE FUNCTION Stimulants Inhibitors

1,25 dihydroxy cholecalciferol (calcitriol)

-promotes intestinal absorption of calcium & phosphorus-increases renal reabsorption of phosphate & calcium -on bone, high amounts cause absorption; & low amounts cause calcification

Low plasma calcium

High plasma calcium

Parathyroid hormone

-increased intestinal absorption of calcium & phosphate by renal conversion of 25 Vit D to 1,25 Vit D -in bone, increased calcium & phosphate absorption-decreased renal reabsorption of phosphate-increases renal reabsorption of calcium

Low plasma calcium

High plasma calcium

Calcitonin -in bones, decreases calcium absorption and bone deposition of calcium-decreases formation of new osteoclasts

Increased plasma calcium

Risk factors for nutritional Rickets

• Exclusive breastfeeding – (insufficient Vit D concentrations 20-60 IU/L as opposed to 200

IU/L recommended in infants)• Maternal vitamin D deficiency• Living in temperate climates• Lack of sunlight exposure• Darkly pigmented skin• Social and religious customs that prevent sunlight exposure• Low dietary calcium intake• High phytate content in diet (unrefined cereal; impairs

intestinal calcium absorption)

Phytate in diet• Grains and leafy vegetables are high in phytate and oxalate which decrease

intestinal absorption of dietary calcium

• In rats, high phytate diet results in increased catabolism of 25-Vit D to inactive metabolites and increased excretion of these products in stool resulting in reduction of 25-Vit D concentration

• In humans, half life of 25-Vit D reduced to nearly 40% among patients on high fiber diets

• Studies in South Africa, Nigeria, Bangaladesh and UK Asians show that rickets was due to low calcium diet and high phytate diets (unrefined cereals)

– Mean age of presentation around 4 year in calcium deficiency rickets; adolescence for vit D deficiency rickets

Pettifor JM, 2004, Nutritional rickets: deficiency of vitamin D, calcium or both?, Am J Clin Nutr; 80 (suppl):1725S-9S

9/21/10

Causes of RicketsVITAMIN D DISORDERS •Nutritional Vitamin D deficiency •Congenital Vitamin D deficiency •Secondary Vitamin D deficiency • Malabsorption • Increased degradation • Decreased Liver 25-hydroxylase •Vitamin D dependent ricket Type 1 •Vitamin D dependent ricket Type 2 •Chronic Renal Failure• PHOSPHORUS DEFICIENCY •Inadequate intake • Premature infants • Aluminium containing antacids

CALCIUM DEFICIENCY •Low intake • Diet • Premature Infant •Malabsorption • Primary Disease • Dietary inhibitors of calcium absorption

RENAL LOSSES •X- linked hypophosphatemic ricket •AD hypophosphatemic ricket •Hereditary hypophosphatemic ricket with hypercalcuria •Overproduction of phosphatonin • Tumors induced rickets • Mccunealbright syndrome • Epidermal nevus syndrome • Neurofibromatosis •Fanconi syndrome •Dent Disease

Phosphatonin

• Phosphatonin is a humoral mediator that decreases renal tubular reabsorption of phosphate and thus decreases serum phosphorus

• Also decreases activity of renal 1 alpha hydroxylase causing decreased production of 1,25 Vit D

• Fibroblast growth factor-23 (FGF-23) is the most well characterised phosphatonin

• Increased levels of phosphatonin cause many of the phosphate-wasting diseases

Causes of RicketsCONDITION MECHANISM OF RICKETS DESCRIPTION

Vitamin D dependent type 1

Prevention of conversion of 25-Vit D into 1,25-Vit D

Autosomal recessive disorder; mutations in gene coding renal 1 alpha hydroxylase

Vitamin D dependent type 2

Prevention of normal physiologic response to 1,25 Vit D

Autosomal recessive disorder; mutations in gene coding vitamin D receptor

X-linked hypophosphatemic rickets

Decreased degradation of phosphatonin leading to increased phosphate excretion; & inhibition of renal 1 alpha hydroxylase & thus decreased production of 1,25 Vit D

X-linked dominant; PHEX gene defect (PHosphate regulating gene with homolgy to Endopeptidates on the X chromosome). Gene product has role in inactivating a phosphatonin (FGF-23)

Autosomal dominant hypophosphatemic rickets

Increased level of phosphatonin FGF-23 causes decreased renal phosphate reabsorption; inhibition of renal 1 alpha hydroxylase & thus decreased production of 1,25 Vit D

Mutation in the gene coding FGF-23 preventing degradation of FGF-23 by proteases

Hereditary hypophosphatemic rickets with hypercalcinuria

Renal phosphate leak causing hypophosphatemia which stimulates 1,25 Vit D and thus increased intestinal calcium absorption suppressing PTH. High calcium and low PTH leads hypercalcinuria.

Rare disorder; described in Middle East; autosomal recessive; genetic features unclear

Causes of RicketsCONDITION MECHANISM OF RICKETS DESCRIPTION

McCune Albright syndrome

Elevated phosphatonin FGF-23 from dysplastic bone causing renal phosphate wasting

Polyostotic fibrous dysplasia, hyperpigmented macules, polyendocrinopathy

Epidermal nevus syndrome

Excessive production of phosphatonin causing renal phosphate wasting

Rare; sporadic; congential epidemal nevi associated with anomalies of other organs esp skeleton & CNS

Neurofibromatosis Production of phosphatonin causing renal phosphate wasting

Extremely rare complication in children

Fanconi syndrome Hypophosphataemia, exacerbation from metabolic acidosis from bone dissolution, impaired Vit 1,25 Vit D synthesis

Generalised dysfunction of renal proximal tubule causing renal loses of phosphate, amino acid, bicarbonate, glucose, urate

Dent disease X-linked; mutation in gene coding a chloride channel in kidney

Functions of Vitamin D and causes of Rickets

Clinical featuresGENERAL •Failure To Thrive •Listlessness •Protruding Abdomen •Muscle Weakness (specially proximal) •Fractures

HYPOCALCAEMIC SYMPTOMS•Tetany•Seizures•Stidor due larngeal spasm

HEAD •Craniotabes •Frontal Bossing •Delayed Fontanelle Closure •Delayed Dentition •Craniosynostosis

Clinical features

CHEST• Rachitic rosary

• Harrison Groove • Pectus carinatum • Thoracic asymmetry • Widening of thoracic

bone • Respiratory Infections • Atelectasis impairment

of air movement

Clinical features

BACK• Scoliosis • Kyphosis• Lordosis

EXTREMITIES• Enlargement of wrist or

ankle • Valgus and varus

deformities

Investigations

INVESTIGATIONS

Edge of metaphysis loses its sharp border FRAYINGEdge of metaphysis changes from convex or flat surface to a more concave surface CUPPING (most easily seen at distal ends of radius, ulna and fibula)Widening of Metaphyseal end of bone SPLAYINGMetaphyseal lines spread laterally forming CORTICAL SPURSWidening of distal ends of metaphysis (A-Normal, B-Rickets)

Other Radiological Findings

Changes of diaphysis – appear a few weeks later

Coarse trabeculation

generalized rarefaction

Cortical thinning

Subperiosteal erosion

Treatment

Type of Rickets Medical treatment

Nutritional vitamin D deficiency

-Vitamin D by1. Stoss therapy 300,000-600,000 IU PO/IM as 2-4 doses over 1 day2. 2,000-5,000 IU/day over 4-6 weeks3. Followed by daily intake of 400 IU/day as multivitamin-Adequate nutritional intake of calcium and phosphate (milk, formula, other dairy products)-for hypocalcaemia, 4. IV calcium followed by oral calcium supplements (1000mg elemental)

tapered over 2-6 weeks5. Acutely, transient use of PO/IV 1,25 D (calcitriol) 0.05ug/kg/day

Secondary vit D deficiency eg due to malabsorption - liver, GI diseases

-25-Vit D 5-7ug/kg/day or 1,25 Vit D-Followed by long term administration of high dosese of Vit D eg 1,000 IU/day

Vit D dependent type 1

-Long term treatment with calcitriol (1,25 Vit D) 0.25-2 ug/day with lower doses used once the rickets has healed-Adequate intake of calcium

TreatmentType of Rickets Medical treatment

Vit D dependent type 2

-Extremely high doeses of Vit D2 (25 Vit D) or calcitriol (1,25 Vit D, 2ug/day initally to 50-60ug/day)- response due to partial function of Vit D receptor-3-6 month trial of hig dose of Vit D and oral calcium (1,000-3,000mg/day)-if no response to high dose Vit D, the long term IV calcium with possible transition to high dose oral calcium supplement

Chronic renal failure

-Calcitriol-dietary phosphate restriction and use of oral phosphate binders-alkali to correct metabolic acidosis

X-linked & AD hypophosphatemic rickets

-oral phosphorus 1-3 g daily of elemental phosphorus divided into 4-5 doses-Calcitriol (1,25 Vit D) 30-70ng/kg/day divided into 2 doses

Hereditary hypophosphatemic rickets with hyercalciuria

-oral phophorus replacement 1-2.5g/day of elemental phophorus PO in 5 divided doses

Treatment

Surgical correction of limb deformities• Orthopaedic correction of bone deformities

after healing of rickets (correction of laboratory values)

THE END