Rickets

1. Rickets

4. • LAB TESTS:
• Initial laboratory tests in Rickets should include:
• Serum calcium;
• Phosphorus;
• Alkaline phosphatase;
• Parathyroid hormone (PTH);
• 25-hydroxyvitamin D;
• 1,25-dihydroxyvitamin D3;
• Creatinine; and
• Electrolytes.

5. • Urinalysis: Useful for detecting glycosuria and aminoaciduria
(positive dipstick for protein) in Fanconi syndrome.
• Evaluation of urinary excretion of calcium (24 hr collection for
calcium or calcium-creatinine ratio) : If hereditary hypophosphatemic
rickets with hypercalciuria or Fanconi syndrome is suspected.
• Direct measurement of other fat-soluble vitamins (A, E, and K) or
indirect assessment of deficiency (prothrombin time for vitamin K
deficiency) : if malabsorption is a consideration.

6. • Laboratory Findings in Disorders Causing Rickets:

7. • CAUSES OF RICKETS:
• 1. VITAMIN D DISORDERS
• 2. CALCIUM DEFICIENCY
• 3. PHOSPHORUS DEFICIENCY
• 4. RENAL LOSSES
• 5. DISTAL RTA

8. • VITAMIN D:
7-DEHYDROCHOLESTEROL
UV radiation in sunlight Inhibited by melanin
VITAMIN D3
Bound to Vit D binding protein Transported to liver
25-Hydroxylase
25-D
1 α Hydroxylase Kidney
1,25 D
Binds to intracellular receptor
and forms a COMPLEX
PTH secrn
CALCIUM
absorption
PHOSPHORUS
absorption
BONE
resorption
Inhibits its own
synthesis in kidney

9. • NOTE:
• PTH  Increased Calcium, Decreased Phosphate
• 1,25 D  Increased Calcium, Increased Phosphate
• Calcitonin  Decreased Calcium

10. • NUTRITIONAL VIT D DEFICIENCY:
• Laboratory Findings.
• Elevated PTH Hypophosphatemia
• Variable hypocalcemia
• Hypophosphatemia & hyperparathyroidism  Upregulation of renal
1α-hydroxylase  Wide variation in 1,25-D levels (low, normal, or
high)
• 1,25-D is only low when there is severe vitamin D deficiency.
• Some have metabolic acidosis secondary to PTH-induced renal
bicarbonate-wasting.
• There may be generalized aminoaciduria.

11. • VITAMIN D:
7-DEHYDROCHOLESTEROL
UV radiation in sunlight Inhibited by melanin
VITAMIN D3
Bound to Vit D binding protein Transported to liver
25-Hydroxylase
25-D
1 α Hydroxylase Kidney
1,25 D
Binds to intracellular receptor
and forms a COMPLEX
PTH secrn
CALCIUM
absorption
PHOSPHORUS
absorption
BONE
resorption
Inhibits its own
synthesis in kidney

12. • SECONDARY VIT D DEFICIENCY:
• Etiology.
-inadequate intake,
-inadequate absorption,
-decreased hydroxylation in liver &
-increased degradation.
Liver & gastrointestinal
diseases:
-Cholestatic liver disease,
-Defects in bile acid metabolism
-Cystic fibrosis
-Other causes of pancreatic
dysfunction,
-Celiac disease,
-Crohn disease.
-Intestinal lymphangiectasia
-After intestinal resection.

13. • SECONDARY VIT D DEFICIENCY:
• Etiology.
-inadequate intake,
-inadequate absorption,
-decreased hydroxylation in liver
-increased degradation.
Severe Liver disease:
-Insufficient enzyme axn
(25 hydroxylase)

14. • SECONDARY VIT D DEFICIENCY:
• Etiology.
-inadequate intake,
-inadequate absorption,
-decreased hydroxylation in liver &
-increased degradation.
-Drugs by inducing P450
-Anticonvulsants: Phenobarb,
Phenytoin.
-ATT : Isoniazid,
Rifampin

15. • VITAMIN D–DEPENDENT RICKETS, TYPE 1.
• Autosomal Recessive.
• Mutations in gene encoding renal 1α-hydroxylase.
• Prevent conversion of 25-D into 1,25-D.
• Normally present during 1st 2 yr of life.
• Can have any features of rickets, including symptomatic
hypocalcemia.

16. • VITAMIN D–DEPENDENT RICKETS, TYPE 1.
• Normal levels of 25-D, but low levels of 1,25-D.
• Occasionally, 1,25-D levels may be low normal.
• High PTH.
• Low serum phosphorus levels.
• Metabolic acidosis & generalized aminoaciduria.
(Due to renal tubular dysfunction)

17. • VITAMIN D:
7-DEHYDROCHOLESTEROL
UV radiation in sunlight Inhibited by melanin
VITAMIN D3
Bound to Vit D binding protein Transported to liver
25-Hydroxylase
25-D
1 α Hydroxylase Kidney
1,25 D
Binds to intracellular receptor
and forms a COMPLEX
PTH secrn
CALCIUM
absorption
PHOSPHORUS
absorption
BONE
resorption

18. • VITAMIN D–DEPENDENT RICKETS, TYPE 1.
• Normal levels of 25-D, but low levels of 1,25-D.
• Occasionally, 1,25-D levels may be at the lower limit of normal, but
this is inappropriate, given the high PTH and low serum phosphorus
levels, both of which should increase the activity of renal 1α-
hydroxylase and cause elevated levels of 1,25-D.
• As in nutritional vitamin D deficiency, renal tubular dysfunction may
cause a metabolic acidosis and generalized aminoaciduria.

19. • VITAMIN D–DEPENDENT RICKETS, TYPE 1.
• TREATMENT:
• Long-term treatment with 1,25-D (calcitriol).
• Initial: 0.25–2 μmg/day, with lower doses used once the rickets has
healed.
• During initial therapy, ensure adequate intake of calcium.
• Periodic monitoring of urinary calcium excretion,
with target of <4 mg/kg/day.

20. • VITAMIN D–DEPENDENT RICKETS, TYPE 2.
• Autosomal Recessive.
• Mutations in gene encoding the vitamin D receptor.
• Prevents a normal physiologic response to 1,25-D.
• Levels of 1,25-D are extremely elevated.
• Less severe disease is associated with a partially functional vitamin
D receptor.

21. • VITAMIN D–DEPENDENT RICKETS, TYPE 2.
• Treatment.
• The initial dose of 1,25-D should be 2 μmg/day, but some patients
require doses as high as 50–60 μmg/day.
• Calcium doses range from 1,000–3,000 mg/day.

22. • CHRONIC RENAL FAILURE:
• Decreased activity of 1α-hydroxylase in kidney  diminished
production of 1,25-D.
• In chronic renal failure, unlike the other causes of vitamin D
deficiency, patients have hyperphosphatemia as a result of
decreased renal excretion.
• Along with inadequate calcium absorption and secondary
hyperparathyroidism, the rickets may be worsened by the
metabolic acidosis of chronic renal failure.

23. • VITAMIN D:
7-DEHYDROCHOLESTEROL
UV radiation in sunlight Inhibited by melanin
VITAMIN D3
Bound to Vit D binding protein Transported to liver
25-Hydroxylase
25-D
1 α Hydroxylase Kidney
1,25 D
Binds to intracellular receptor
and forms a COMPLEX
PTH secrn
CALCIUM
absorption
PHOSPHORUS
absorption
BONE
resorption

24. • CHRONIC RENAL FAILURE:
• Treatment.
• A form of vitamin D which can act without 1-hydroxylation by
kidney should be used for therapy (Calcitriol).
• Calcitriol permits both adequate absorption of calcium and directly
suppresses the parathyroid gland.
• Dietary phosphorus restriction & Oral phosphate binders.
(Because hyperphosphatemia is a stimulus for PTH secretion)
• Chronic metabolic acidosis should be corrected with alkali.

25. • CAUSES OF RICKETS:
• 1. VITAMIN D DISORDERS
• 2. CALCIUM DEFICIENCY
• 3. PHOSPHORUS DEFICIENCY
• 4. RENAL LOSSES
• 5. DISTAL RTA

26. • CALCIUM DEFICIENCY:
• Diagnosis.
• Laboratory findings:
• Increased levels of Alkaline phosphatase, PTH, and 1,25-D.
• Calcium levels may be normal or low, although symptomatic
hypocalcemia is uncommon.
• Decreased urinary excretion of calcium.
• Secondary hyperparathyroidism  Low Serum phosphorus levels.
• In some children, there is coexisting nutritional vitamin D deficiency
 Low 25-D.

27. • VITAMIN D:
7-DEHYDROCHOLESTEROL
UV radiation in sunlight Inhibited by melanin
VITAMIN D3
Bound to Vit D binding protein Transported to liver
25-Hydroxylase
25-D
1 α Hydroxylase Kidney
1,25 D
Binds to intracellular receptor
and forms a COMPLEX
PTH secrn
CALCIUM
absorption
PHOSPHORUS
absorption
BONE
resorption
Inhibits its own
synthesis in kidney

28. • CALCIUM DEFICIENCY:
• Treatment.
• Calcium supplement (350–1,000 mg/day of elemental calcium).
• Vitamin D supplementation if concurrent vitamin D deficiency.
• Prevention:
-Discourage early cessation of breast-feeding.
-Increase dietary sources of calcium.

29. • CAUSES OF RICKETS:
• 1. VITAMIN D DISORDERS
• 2. CALCIUM DEFICIENCY
• 3. PHOSPHORUS DEFICIENCY
• 4. RENAL LOSSES
• 5. DISTAL RTA

30. • PHOSPHATONIN.
Phosphatonin (a humoral mediator)
Decreases renal tubular reabsorption
of phosphate
Decreases activity of renal
1α-hydroxylase
Increased excretion of Phosphorus Decrease in production of 1,25-D.
Decreases S.phosphorus
• Fibroblast growth factor-23 (FGF-23) is the most well characterized phosphatonin.

31. • X-LINKED HYPOPHOSPHATEMIC RICKETS.
• X-linked hypophosphatemic rickets (XLH) is the most common
genetic cause of Rickets.
• Defective gene is on X chromosome.
• Female carriers are affected, so it is X-linked dominant.
• Pathophysiology.
• Defective gene: ‘PHEX’ (PHosphate-regulating gene with homology
to Endopeptidases on X chromosome)

32. PHEX GENE
Product of this gene
inactivates phosphatonin
Increased Phosphatonin
Decreased Phosphorus

33. • X-LINKED HYPOPHOSPHATEMIC RICKETS.
PHEX GENE
Product of this gene
inactivates phosphatonin
Increased Phosphatonin
Decreased Phosphorus

34. • X-LINKED HYPOPHOSPHATEMIC RICKETS.
• Clinical Manifestations.
• Rickets.
• Abnormalities of lower extremities and poor growth are the
dominant features.
• Short stature
• Delayed dentition, tooth abscesses.

35. • X-LINKED HYPOPHOSPHATEMIC RICKETS.
• Laboratory Findings.
• High renal excretion of phosphate,
• Hypophosphatemia,
• Increased alkaline phosphatase,
• PTH and serum calcium levels are normal.
• Hypophosphatemia normally upregulates renal 1α-
hydroxylase, and should lead to an increase in 1,25-D, but
these patients have low or inappropriately normal levels.

36. • X-LINKED HYPOPHOSPHATEMIC RICKETS.
• Treatment.
• Patients respond well to combination of oral phosphorus
and 1,25-D (calcitriol).
• Daily : 1–3 g of elemental phosphorus divided into 4–5
doses.
• Frequent dosing helps to prevent prolonged decrements in
serum phosphorus because there is a rapid decline after
each dose.
• In addition, frequent dosing decreases diarrhea, a
complication of high-dose oral phosphorus.
• Calcitrol : 30–70 ng/kg/day divided into 2 doses.

37. • X-LINKED HYPOPHOSPHATEMIC RICKETS.
• Complications of treatment occur when there is no balance
between phosphorus supplementation and calcitriol.
• Excess phosphorus  decrease enteral calcium absorption 
secondary hyperparathyroidism  worsening of bone lesions.
• Excess calcitriol  hypercalciuria and nephrocalcinosis; it may
even cause hypercalcemia.
• Hence, laboratory monitoring of treatment includes :
Serum calcium, phosphorus, alkaline phosphatase, PTH, and
urinary calcium; Periodic renal ultrasounds to evaluate
nephrocalcinosis.

38. • X-LINKED HYPOPHOSPHATEMIC RICKETS.
• Normalization of alkaline phosphatase levels is a more
useful method of assessing therapeutic response than
measuring serum phosphorus.
• For children with significant short stature, growth hormone
is an effective option.
• Children with severe deformities may need osteotomies,
but done only when treatment has led to resolution of the
bone disease.

39. • AUTOSOMAL DOMINANT HYPOPHOSPHATEMIC
RICKETS.
• Less common than XLH.
• Incomplete penetrance and variable age of onset.
• Mutation in gene encoding FGF-23.
• Mutation prevents degradation of FGF-23 by proteases, leading to
increased levels of this phosphatonin.
• In ADHR, as in XLH, abnormal laboratory findings are
hypophosphatemia, an elevated alkaline phosphatase level, and a low
or inappropriately normal 1,25-D level .
• Treatment is similar as in XLH.

40. • Rickets Associated with Renal Tubular Acidosis :
• Rickets may be present in RTA, particularly in type II or proximal RTA.
• Hypophosphatemia and phosphaturia are common.
(Also characterized by hyperchloremic metabolic acidosis, various
degrees of bicarbonaturia, and frequently, hypercalciuria and
hyperkaluria. )
• Proximal RTA is treated with both bicarbonate and oral phosphate
supplements to heal rickets.
• Vitamin D given to offset the secondary hyperparathyroidism that
complicates oral phosphate therapy.

41. • RICKETS OF PREMATURITY :
• Pathogenesis.
• Transfer of calcium and phosphorus from mother to fetus occurs
throughout pregnancy, but 80% occurs during the 3rd trimester.
• Premature birth interrupts this process  rickets develop.
• Most cases of rickets of prematurity occur in birthweight <1,000 g.
• More likely to develop in infants with lower birthweight and younger
gestational age.
• Rickets occurs because unsupplemented breast milk and standard
infant formula do not contain enough calcium and phosphorus to
supply the needs of the premature infant.

42. • RICKETS OF PREMATURITY
• Laboratory Findings.
• Due to inadequate intake: serum phosphorus level is low or low-
normal.
• Renal conservation of phosphate : Low urine phosphate level;
• Most patients have normal levels of 25-D, unless there has been
inadequate intake or poor absorption .
• Hypophosphatemia stimulates renal 1α-hydroxylase  1,25-D is
high or high-normal. These high levels may contribute to bone
demineralization because 1,25-D stimulates bone resorption.

43. • RICKETS OF PREMATURITY
• Laboratory Findings.
• Serum calcium is low, normal, or high, and patients often have
hypercalciuria.
• Elevated serum calcium levels and hypercalciuria are secondary to:
-increased intestinal absorption and bone dissolution due to
elevation of 1,25-D levels and
-the inability to deposit calcium in bone because of an
inadequate phosphorus supply.
• There is an inadequate supply of calcium and phosphorus, but the
deficiency in phosphorus is greater.

44. • RICKETS OF PREMATURITY
• Laboratory Findings.
• Alkaline phosphatase often elevated, but some have normal levels.
• No single blood test is 100% sensitive for the diagnosis of rickets.
• The diagnosis should be suspected in infants with :
-alkaline phosphatase level more than 5–6 times the upper
limit of normal for adults (unless there is concomitant liver
disease)
or
-phosphorus level <5.6 mg/dL.

45. • RICKETS OF PREMATURITY
• Laboratory Findings.
• Confirmed by radiologic evidence of rickets- best seen on films of1
wrists and ankles.
• Rachitic rosary may be visible on chest x-ray.
• Unfortunately, x-rays are not able to detect early demineralization
of bone because changes are not evident until there is >20–30%
reduction in bone mineral content.

46. • RICKETS OF PREMATURITY
• Diagnosis.
• Screening tests are recommended.
• Weekly measurements of calcium, phosphorus, and alkaline
phosphatase.
• Periodic measurement of serum bicarbonate is important because
metabolic acidosis causes dissolution of bone.
• At least 1 screening x-ray for rickets at 6–8 wk of age; additional
films in very high-risk infants.

47. • RICKETS OF PREMATURITY
• Prevention.
• Human milk fortified with calcium & phosphorus or preterm infant
formula, which has higher concentrations of calcium and
phosphorus than standard formula.
• Increased mineral feedings should continue until the infant weighs
3–3.5 kg.
• These infants should also receive approximately 400 IU/day of
vitamin D via formula and vitamin supplements.
• Treatment.
• Ensure adequate calcium, phosphorus, and vitamin D.