An approach to case of vitamin D resistant rickets

1. APPROACH TO A
CASE OF VITAMIN
D RESISTANT
RICKETS
PRESENTED BY:
DR. ADITI TULSIYAN
PG RESDIENT
PAEDIATRICS

2.  SOURCES OF VITAMIN D
Cutaneous synthesis
Dietary sources- animal source (Cholecalciferol D2) salmon, cod liver oil, egg yolk
plant source (Ergocalciferoll D3) orange juice, milk
Factors affecting synthesis of Vitamin D in skin
1. Timing of the day
2. Season
3. Skin pigmentation
4. Exposure of skin to UVB
Daily Requirement
Infants 400 IU (10ug)
Children 600 IU (15ug)
Breast milk is poor in Vitamin D (12-40 IU/L)
Dietary Ca Requirement
Infants(0-6 mnths)- 200mg/d
(6-12 mnths)- 260 mg/d
Children >12mnths – 500mg/day

3. VITAMIN D METABOLISM
290-315nm
Absorbed in duodenum
Peripheral conversions occurs in SKIN
COLON MACROPHAGES VASCULAR
SMOOTH MUSCLES BONE PARATHYROID
GLAND
-----INHIBITS ABSOPRTION
OF PHOS FROM DCT
INHIBITS ABSOPRTION
OF PHOS FROM DCT

4. Rickets is a disease of growing bone that is caused by
unmineralized matrix at the growth plate and occurs in
children only before fusion of the epiphyses.
It is derived from the word WRICKETS meaning
TWISTED referring to the characteristic BOW LEGS of
rickets.
 The most common cause of rickets is nutritional deficiency
although the incidence of rickets overall has decreased through
the public health measures

5. 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謀ependent rickets type 1 A and B
 Vitamin D謀ependent rickets type 2 A and B
 Chronic kidney disease
CALCIUM DEFICIENCY
Low intake
Diet
Premature infants (rickets of prematurity)
Malabsorption
Primary disease
Dietary inhibitors of calcium absorption
PHOSPHORUS DEFICIENCY
Inadequate intake
Premature infants (rickets of prematurity)
Aluminum-containing antacids

6. RENAL LOSSES
 X-linked hypophosphatemic rickets*
 Autosomal dominant hypophosphatemic rickets*
 Autosomal recessive hypophosphatemic rickets (1 and 2)*
 Hereditary hypophosphatemic rickets with hypercalciuria
 Overproduction of fibroblast growth factor-23
 Tumor-induced rickets*
 McCune-Albright syndrome*
 Epidermal nevus syndrome*
 Neurofibromatosis*
 Fanconi syndrome
 Dent disease
 Distal renal tubular acidosis

7. 290-315nm
-----INHIBITS ABSOPRTION OF
PHOS FROM DCT
Level is increased in
ADHR ARHR XLHR
INHIBITS ABSOPRTION
OF PHOS FROM DCTVDDR 1
Mutation in gene for vit D
receptor
VDDR2

9. HEAD
Craniotabes(ping pong skull) – occurs due to thinning of inner table
of occipital bone under the pressure
of intracranial contents with failure of mineralization
Can be elicited by gentle pressure with both thumbs
which produces dent with crackling sensation
elicited b/w 3-12 months of life
Frontal Bossing
Craniosyntosis
Delayed closure of fontanels
Delayed Dentition with enamel hypoplasia
Hot cross bun skull (CAPUT QUADRATUM)

10. CHEST
 Rachitic Rosary
 Harrison sulcus (11TH and 12th rib)
 Pigeon chest deformity
 Respiratory Tract infection
 Atelectasis
ABDOMEN
Visceroptosis d/t deformed chest and weak abdominal muscles
Protruded abdomen
PELVIS
Narrowed pelvic inlet d/t forward protrusion of sacral promontory

11. EXTREMITIES
 Enlargement of wrists and ankles d/t physeal overgrowth
 Double malleoli
 Valgus or varus deformities
 Windswept deformity (combination of valgus deformity of 1 leg
with varus deformity of the other leg)
 Anterior bowing of the tibia and femur
 Coxa vara
 Leg pain
 Increase fractures (particularly green stick fracture)
 String of pearl deformity

13. BACK (RACITIC CAT BACK)
Scoliosis
Kyphosis
Lordosis
HYPOCALCEMIC SYMPTOMS
Tetany
Seizures
Stridor due to laryngeal spasm
Diarrhoea or Constipation
Anemia
GENERAL
Failure to thrive
Listlessness
Muscle Weakness

14. Radiological Findings
 Cupping of epiphyseal end
 Fraying
 Increase in distance between distal end of radius
and metacarpal bones
 Rarefaction of Diaphysis
 Coarse trabeculation

15. Investigation
 Vitamin D status
Based on 25OH level- Best measure to estimate circulating Vitamin D
level because of its minimal regulation
Sufficiency- >50nmol/l
Insufficiency- 30-50 nmol/l
Deficiency - <30nmol/l
1,25 OH LEVEL
S.Ca
S.PO4
ALP
PTH

17. TREATMENT FOR NUTRITIONAL
RICKETS
 STOSS THERAPY- 3,00,00-6,00,000 IU/day PO/IM as 2-4 doses over 1 day
 2,000-5,000 IU/day over 4-6 week
 Calcium supplemenattion (35mg/kg/day)
Followed by daily Vitamin D intake - <1yr- 400IU/day
>1yr- 600 IU/day
Oral calcium – 500mg/day
Calcitriol- 0.05ug/kg/day
Iv calcium- 20mg/kg of CaCl2
100mg/kg of CaGluconate

18.  Stoss therapy respond well in case of Vitamin D
deficiency Rickets
Biochemical recovery in few days (96hrs)
EARLIEST biochemical change after starting stoss
therapy- Increase in S.PO4 level
Radiological recovery in 6-7days

19. Response to therapy
 Improvement in pain symptoms
 Healing of bone malformation
 Radiological evidence of healing
zone of provisional calcification appears (WHITE LINE OF FRENKEL)
appears at the end of zone of degeneration
osteoid between this line and diaphysis gradually ossifies
HEALED RICKETS
Bone density returns to normal with slight cupping remains as a stigma of previous
rickets

21. HEALED RICKETS
ABSENT PRESENT
WHITE LINE OF CALCIFICATION
XRAY AFTER 2-4 WEEKS
REPEAT DOSE OF
CHOLECALCIFEROL
PRESENT
White line of calcification
X ray After 2-4 weeks
STOSS THERAPY
ABSENT
HEALED
RICKETS
REFRACTORY
RICKETS

22. CALCIUM DEFICIENCY
 Rickets secondary to inadequate dietary calcium
 Age of onset- Begins after 6 months of age when child is
being weaned off from breast milk.
 Diet rich in phytates, oxalates and phosphates (green
leafy vegetables) leads to decrease absorbtion of
calcium
 Risk factors
Malabsorption syndromes
Small bowel resection
Milk allergy

23. Diagnosis
 S. Ca - Normal/Decreased
 S.Pi - decreased
 PTH - Increased
 25(OH)D3- Normal
 1,25 (OH)D3 –Increased
 ALP- Increased
 Urinary ca/ pi – DECRERASED
TREATMENT
Calcium supplement
1-3 years (700mg/day)
4-8 years (1000mg/day)
9-18 years (1300mg/day)

24. PHOSPHORUS DEFICIENCY
ETIOLOGY
Inadequate intake
Malabsorption
Rickets of prematurity
Aluminum containing antacids (leads to phosphate chelation)
DIAGNOSIS
 S. Ca - Normal
 S.Pi - decreased
 PTH - N/decreased
 25(OH)D3- Normal
 1,25 (OH)D3 –Increased
 ALP- Increased
 Urinary ca/ pi – DECRERASED

25. X LINKED HYPOPHOSPHATEMIC
RICKETS
 XLD
 ON Ch Xp22
 Prevalance-1/20,000
 Most common inherited form of rickets
 Mutation in PHEX gene

26.  PHEX GENE- PHosphate regulating gene with homology to Endopeptidase
on X chromoosome
Inactivates FGF 23
HYPOPHOSPHATEMIA DECREASED PRODUCTION OF 1,25D
DECREASED ACTIVITY OF 1a HYDROXYLASE
DECREASED RENAL TUBULAR ABSORBTION OF
PHOSPHATE
INCREASED LEVEL OF FGF 23
MUTATION PHEX GENE

27. CLILNICAL MANIFESTATION
 LOWER limb deformities are predominating
feature – COXA VARA
GENU VALGUM
GENU VARUM
 DENTAL ABNORMALITIES- Pulp deformities,
recurrent dental abscess
 Abnormalities of maxillofacial region
 Premature closure of sutures

28. DIAGNOSIS
 S. Ca - Normal
 S.Pi - Decreased
 FGF23- Increased
 PTH - Normal
 25(OH)D3- Normal
 1,25 (OH)D3 –Decreased
 ALP- Increased
 Urinary ca- Normal
 Urinary pi – DECRERASED

29. Treatment
Phosphorus
 1-3g /day in 4 divided doses.(frequent dosing reduces diarrhoea)
Calcitriol
 30-70 ng/kg /day in 2 divided doses
 Osteotomy required for severe bone deformities
 Short Stature- Growth Hormone

30. COMPLICATIONS OF TREATMENT
 OCCURS IF THE BALANCE BETWEEN PHOSPHORUS AND CALCIUM
IS INADEQUATE
WORSENS BONE LESIONS
SEC HYPERPARATHYROIDISM
DECREASED CALCIUM ABSORTION
INCREASED PHOSPHORUS
HYPERCALCIURIA
NEPHROCALCINOSIS
HYPERCALCEMIA
INCREASED CALCITRIOL

31. AUTOSOMAL DOMINANT
HYPOPHOSPHATEMIC RICKETS
HYPOPHOSPHATEMIA
DECREASED PRODUCTION OF 1,25D
DECREAED ACTIVITY OF 1a HYDROXYLASE
HYPOPHOSPHATEMIA
DECREASED RENAL TUBULAR ABSORBTION OF
PHOSPHATE
PREVENTS DEGRADATION OF FGF 23
MUTATION IN GENE ENCODING FGF 23

32. DIAGNOSIS
 S. Ca - Normal
 S.Pi - Decreased
 FGF23- Increased
 PTH - Normal
 25(OH)D3- Normal
 1,25 (OH)D3 –Decreased
 ALP- Increased
 Urinary ca- Normal
 Urinary pi – DECRERASED

33. AUTOSOMAL RECESSIVE
HYPOPHOSPHATEMIC RICKETS
TYPE 1 – MUTATION IN DENTIN MATRIX
PROTEIN (DMP1)
TYPE 2- MUTATION IN ENPP1 GENE
Causes arterial calcification of infancy
Both types lead to increase in level of FGF3

34. HEREDITARY
HYPOPHOSPHATEMIC RICKETS
WITH HYPERCALCIURIA AR
 Mutation in Sodium Phosphorus
cotransporter in proximal tubule (SLC34A3)
Leg abnormalities are the dominating
symptoms here
Short stature (upper segment>lower segment)
Muscle weakness
Bone Pain
Kidney stones
Hypercalcuria
Supression of PTH
Increased Intestinal absorption of Calcium
INCREASED PRODUCTION OF 1,25D
HYPOPHOSPHATEMIA
MUTATION IN SLC34A3

35. Diagnosis
 S. Ca - Increased
 S.Pi - Decreased
 FGF3- Normal
 PTH - Decreased
 25(OH)D3- Normal
 1,25 (OH)D3 –Increased
 ALP- Increased
 Urinary ca- Normal
 Urinary pi – DECRERASED

36. Treatment
 Oral Phosphorus replacement
1-2.5g/day of elemental phosphorus in 5 divided
doses.

37. OVERPRODUCTION OF FGF23
 Tumor induced osteomalacia
 Mc Cune Albright Syndrome (Triad of polyosteotic fibrous dysplasia
Hypopigmented macules
Polyendocrinopathy
Neurofibromatosis
Epidermal Nevus Syndrome

38. Renal Tubular Acidosis
 PROXIMAL RTA(FANCONI SYNDROME)
RENAL LOSSES OF:
PHOSPHATES
AMINOACIDS
BICARBONATE
URIC ACID
LMW PROTEINUREA
Rickets due to hypophosphatemia
Bone dissolution d/t metabolic acidosis
DISTAL RTA
Metabolic acidosis
Hypercalciuria‘
Nephrocalcinosis

39. RICKETS OF PREMATURITY
Risk factors: Prematurity, birth weight<1000g,
complicated neonatal course
prolonged use of parenteral nutrition, use of diuretics and
corticosteroids
Age of presentation: 1-4 months
Presenting Features: Nontraumatic fractures
Respiratory distress d/t atelectatsis and poor ventilation
develops >5 weeks after birth
Enamel Hypoplasia
Dolichocephaly
Rachitic Findings

40. DIAGNOSIS:
 S. Ca - N/LOW/HIGH
 S.Pi - Decreased
 FGF3- Normal
 PTH - Decreased
 25(OH)D3- Normal
 1,25 (OH)D3 –Increased
 ALP- Increased (>5-6 times the upper limit of adults)
 Urinary ca- Normal
 Urinary pi – DECRERASED
SCREENING xray at 6-8 weeks of age for infants who are high risk for
rickets

41. Clinical Approach to A case of
RICKETS
Past History- H/O Recurrent pneumonia, tetanic episodes
H/o oily stool, bleeding or any other history s/o FAT MALABSORPTION
h/s/o chronic liver disease
h/o hematuria, proteinurea, UTI
h/s/o CKD
h/o polyuria (s/o FACONI SYNDROME)
Dietary History- H/o breastfeeding, fortified milk or cow milk
dietary fibres interferes with Calcium absorption

42. ANTENATAL HISTORY- Poor nutrition, inadequate sun exposure
BIRTH HISTORY- Prematurity, birth weight<1000g,
complicated neonatal course
prolonged use of parenteral nutrition, use of diuretics and
corticosteroids
TREATMENT HISTORY – Phenobarbital , Phenytoin- Increases degradation of Vitamin D
Al Containing antacid interferes with Phosphate absorption
Protease inhibitors inhibits cytochrome P450 and decreases production of
active form of Vitamin D
 FAMILY HISTORY- H/O previous sibling death (s/o CYSTINOSIS)
Important in many genetic cause of rickets

43. Rachitic Leg
Abnormalities
SKULL
DEFORMITIES
DELAYED
DENTITION
TOOTH ABSCESS
XLHR
GENERALIZED ARETERIAL
CALCIFICATIONOF
INFANCYARHR 2

44. Rachitic Leg
Abnormalities
Short Stature
Muscles Weakness
Bone Pain
Renal Stones
HEREDITARY
HYPOPHOSPHATEMIC
RICKETS WITH
HYPERCALCIURIA

45. Ca Pi PTH 25OH 1,25 0H2D FGF23 Urine
Pi Ca
VITAMIN D Def N/ N
DIETARY Pi Def N N/ N
DIETARY Ca Def N/ N
VDDR1 N N/HIGH NOT
DETECTABLE
V
VDDR2 N N/HIGH
XLH N N N V
ARHR N N N
ADHR N N N
HHRH N N N N

46. MANAGEMENT
 Baesd on the etiology
VITAMIN D Deficieny: vitamin D therapy
Calcium supplementation
Phosphorus
Calcitriol
Orthopedic intervention for bone deformities
Physiotherapy