1. RICKETS Presenter: Dr Suzanna Mwanza Moderator: Dr Pandey 02.10.13

2. HISTORY CC, 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.

3. 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

4. HISTORY No convulsion History of jaundice No history of pain passing urine or change in frequency of passing urine

5. 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

6. 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

7. 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

8. HISTORY NUTRITIONAL 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

9. HISTORY FAMILY HISTORY 2 nd 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

10. EXAMINATION Small for age, alert P+, tinge of jaundice, C o, LN o 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)

11. EXAMINATION Musculoskeletal: Head Enlarged head - Caput quadratum No craniotabes No separated sutures and AF was closed Bossing Chest No rachitic rosary or harrison grooves Back No spinal deformity – scoliosis or kyphosis Limbs 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)

12. 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

13. 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

14. EXAMINATION

15. Right genu valgus and left genu varus (windswept deformity) Anterior deviation of right knee

16. EXAMINATION No harrison grooves No rachitic rosary; protuberant abdomen

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

18. EXAMINATION Short statureHeight – 86cm (-3 SD)

19. DIAGNOSIS Rickets in Sickle Cell Disease

20. 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

21. RESULTS PARAMET ER 15.02.1325.02.1305.04.1322.051331.05.13 Hb g/dL6.86.65.75.911.4 MCV μm 3 988798 94 MCH pg33.130.527.429.729.3 PLT 10 3 /mm 3 147300280234250 WBC 10 3 /mm 3 32.125.719.019.512.9 Neut 10 3 /mm 3 12.387.935.675.335.03 ESR mm/hr -20-

22. RESULTS PARAMETER05.04.1322.05.13Reference range Chloride104.7-97-104 mmol/L Potassium3.20-3.5-5.5 mmol/L Sodium136.8-135-145mmol/L Albumin43.539.236.0 – 46.0 g/L ALT12.01.95.0 – 37.0 U/L AST42.642.15.0 – 36.0 U/L GGT-48.87.0 – 52.0 U/L Bili -D13.6612.50.8 – 5.1 micromol/L Bili -T48.8448.03.4 – 17.0 micromol/L Total protein70.464.666.0 – 87.0 g/L Urea1.900.241.7 – 8.3 mmol/L Creat-15.263.0- 120.0 micromol/L Ca, PO4

23. RESULTS – High performance liquid chromatography – 13.02.13 PARAMETERRESULTREFERENCE RANGE Haemoglobin A22.9%2.5 – 3.9 Haemoglobin F6.4% Haemoglobin S90.7% CommentConfirms homozygous Hb SS

24. X-rays X-ray of lower limbs – AP view Reduced bone density (rarefication) Widening of distal ends of femur and proximal and proximal end of tibia X-ray of ankle joints – AP view Cupping of distal end of tibia

25. X - rays Right ankle joint – lateral view Splaying of metaphyseal end of bone Widening of distal end of metaphysis Fraying of metaphysis Left ankle joint - lateral view Reduced bone density

26. X- rays Wrist joints – lateral view Mild widening of the distal radius Wrist joints – AP view Mild widening of distal radius

27. X-rays Skull X-ray – AP view No hair-on-end appearance Skull X-ray – lateral view No hair-on-end appearance

28. RESULTS PARAMETER13.02.1322.05.1311.06.16REFERENCE RANGE Calcium2.132.202.20 – 2.70 mmol/L Phosphorus0.951.361.45 – 1.78 mmol/L Alkaline phosphatase 34411129.750-332 U/L Parathyroid hormone 120.715 – 65 pg/ml Vitamin D (25- Hydroxy cholecalciferol) 14.06 ng/mlDeficiency: < 10 ng/ml Insufficiency: 10-30 Sufficiency: 30-100 Toxicity: >100

29. 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

30. 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

31. Final diagnosis DIAGNOSIS Vitamin D deficiency (nutritional) Rickets – High phytate diet (high fiber diet) – ? Low calcium diet Sickle Cell Anaemia

32. REVIEW OF RICKETS

33. 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

34. Vitamin D metabolism

35. Hormones for calcium and phosphate homeostasis HORMONEFUNCTIONStimulantsInhibitors 1,25 dihydroxy cholecalcife rol (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

36. 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)

37. 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

38. 9/21/10 Causes of Rickets VITAMIN 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

39. 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

40. Causes of Rickets CONDITIONMECHANISM OF RICKETSDESCRIPTION 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

41. Causes of Rickets CONDITIONMECHANISM OF RICKETSDESCRIPTION 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 NeurofibromatosisProduction of phosphatonin causing renal phosphate wasting Extremely rare complication in children Fanconi syndromeHypophosphataemia, 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 diseaseX-linked; mutation in gene coding a chloride channel in kidney

42. Functions of Vitamin D and causes of Rickets

43. Clinical features GENERAL 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

44. Clinical features CHEST Rachitic rosary Harrison Groove Pectus carinatum Thoracic asymmetry Widening of thoracic bone Respiratory Infections Atelectasis impairment of air movement

45. Clinical features BACK Scoliosis Kyphosis Lordosis EXTREMITIES Enlargement of wrist or ankle Valgus and varus deformities

46. Investigations

47. INVESTIGATIONS Edge of metaphysis loses its sharp border FRAYING Edge 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 SPLAYING Metaphyseal lines spread laterally forming CORTICAL SPURS Widening of distal ends of metaphysis (A-Normal, B-Rickets)

48. Other Radiological Findings  Changes of diaphysis – appear a few weeks later  Coarse trabeculation  generalized rarefaction  Cortical thinning  Subperiosteal erosion

49. Treatment Type of RicketsMedical treatment Nutritional vitamin D deficiency -Vitamin D by 1.Stoss therapy 300,000-600,000 IU PO/IM as 2-4 doses over 1 day 2.2,000-5,000 IU/day over 4-6 weeks 3.Followed by daily intake of 400 IU/day as multivitamin -Adequate nutritional intake of calcium and phosphate (milk, formula, other dairy products) -for hypocalcaemia, 1.IV calcium followed by oral calcium supplements (1000mg elemental) tapered over 2-6 weeks 2.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

50. Treatment Type of RicketsMedical 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 hypophosphatem ic 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 hypophosphatem ic rickets with hyercalciuria -oral phophorus replacement 1-2.5g/day of elemental phophorus PO in 5 divided doses

51. Treatment Surgical correction of limb deformities Orthopaedic correction of bone deformities after healing of rickets (correction of laboratory values)

52. THE END