Vitamin D and Rickets
Clinical manifestation
Craniotabes - softening of skull bones
Can also be due to hydrocephalus, osteogenesis or syphilis
Rachitic rosery
Harrison grove - pulling of softened ribs by diaphragm
Valgus and varus deformity , wind swipe deformity
Failure to thrive
Symptomatic hypocalcemia
Radiological features
Rachitic rosery
Fraying - edge of metaphysis loses its sharp border
Cupping - edge of metaphysis changes from convex to concave
Widening of distal end of metaphysis
Dietary history
| Main source of vitamin D | Formulas Fortified milk Cutaneous synthesis |
|---|---|
| Less in | Breastfed infants (breast milk has low Vit D - 12-60 IU/L) Soy milk fed infants Use of anticonvulsants like phenobarbital and phenytoin |
| Defects of absorption | Look for history of liver and intestinal disease Fat malabsorption syndromes History of renal diseases |
Familial history for genetic clues
| In parents look for | Leg deformities Short statures |
|---|---|
| In sibling look for | Unexplained death - cystinosis (MC cause of Fanconi's syndrome) |
other features
Alopecia - Vit D dependent rickets type 2
Can cause
- Pneumonia
- Waddling gain
- Dental caries
- Hypocalcemic symptoms
Laboratory Investigations
- Calcium
- Phosphate
- ALP
- PTH
- 25 D
- 1,25 D
- Creatinine
- Electrolytes
- Urine glucose (Fanconi's anemia/dent's disease)
- Measurement for other fat soluble vitamins (for malabsorption)
VITAMIN D physiology
- 7 dehydrocholesterol to 3 cholecalciferol (by UVB light) - this process is decreased by melanin
- Vit D transported to liver by vit D binding protein
- In liver it is converted to 25 hydroxyl vitamin D (by 25 hydroxylase)
- In kidney 25 D is converted to 1,25 D by (1α hydroxylase)
- 1,25 D acts on the intercellular vit D response elements - increase in calcium and phosphorous absorption, suppress PTH
VIT D sources
-
Fish liver oil
-
Egg yolk
-
Fortified foods like oils
-
Formula milk
-
First 1-2 months of vitamin D is dependent on the maternal supply
-
Deficiency is more common in the winter seasons
-
Also more common in dark skinned people
Treatment
- Stoss regimen
- 600,000 IU administered in 2 to 4 doses over 1 day
- Alternative 2000 IU/day for 3 months
- Symptomatic hypocalcemia needs IV calcium
- Transient use of 1,25D may be necessary (0.05μg/kg/day)
Specific conditions related to vitamin D deficiency
Congenital vitamin D deficiency
Maternal vitamin D deficiency
- Symptomatic hypocalcemia
- Intrauterine growth retardation
- Decreased bone ossification
- Can predispose to tetany
Secondary vitamin D deficiency
| Inadequate absorption | Cholestatic liver disease Cystic fibrosis Defects in bile acid metabolism Chron's disease Intestinal lymph ectasia Intestinal resection |
Large doses of vitamin D 25 D at 5-7 μg/kg/day |
|---|---|---|
| Decreased hydroxylation | >90% loss of liver function | |
| Increased degradation | Cyp 450 inducers | Stoss regimen Stop the offending agent |
Vitamin D dependent rickets
Type 1
| 1A | - Problem with gene encoding 1α hydroxylase - Present in the 2nd year of life - LllNormal 25 D and low 1,25 D - Renal tubular dysfunction can be present and cause acidemia |
- Long term treatment with 25 D - 0.25-2μg/kg/day - Target should be low normal levels of calcitriol and high normal levels of PTH - Target urinary calcium excretion should be less than 4 mg/kg/day |
|---|---|---|
| 1B | Defect in 25 hydroxylase | Respond to 3000 IU/day of Vit D2 as a result of alternate enzymes with 25 hydroxylase activity |
Type 2
| 2A | - Mutation in the gene encoding the vitamin D2 receptor - Less severe disease is associated with partially functioning enzyme - Associated with alopecia (areata to totalis) - Epidermal cyst can be less common manifestation |
- 3-6 month trial of high dose vitamin D - From 2μg/kg/day - Calcium doses 3000 mg/kg/day - Respond to treatment if partially responding receptor is present - If not responding to high dose vit D then treatment is difficult |
|---|---|---|
| 2B | - Over expression of a hormone response element binding protein that interferes with the action of 1,25 D |
Chronic kidney disease
- Decreased activity of 1α hydroxylase in kidney
- Hyperphosphatemia can occur due to impaired phosphate excretion
Treatment - dietary phosphate restriction, oral phosphate binders, 1,25 D
Calcium deficiency
Can occur if dietary intake is <200mg/kg/day if <12 months or <300mg/kg/day if >12 months
Occur later than the nutritional deficiency of vitamin D
Diagnosis
- Urinary excretion of calcium is reduced
- Serum phosphate is reduced due to secondary hyperparathyroidism
Treatment
- Calcium at 25mg/kg/day
Phosphorous deficiency
Inadequate intake
- Can occur with malabsorption syndromes
- Can occur secondary to vitamin D or calcium deficiency
- Use of aluminum containing antacids can reduce phosphate in diet
FGF23
- Decrease the renal resorption of phosphate
- Also decreases the activity of 1,25 hydroxylase
X linked hypophosphatemic rickets (XLH)
- PHEX gene - phosphate regulating gene
- Has role in inactivating FGF23
- Mutated and cause increased FGF23
Clinical manifestations
- Rickets
- Abnormalities of lower extremities
- Poor growth
- Delayed dentition
- Tooth abscesses
- Short stature
Labs
- Low phosphate and low 1,25 D
- Normal ALP, PTH, calcium
- Hypophosphatemia
- High renal excretion of phosphate
Treatment
- Oral phosphorous and 1,25 D
- 1-3 g of Phosphorus in 1-3 doses
- 30-70 ng/kg/day of calcitriol
- Borosumab-twza is monoclonal antibody that bind to FGF23
Complication
- Can occur when phosphate and 1,25 D are not properly supplemented
- Excess calcitriol - hypercalciuria and nephrocalcinosis
- Excess phosphorus - secondary hyperparathyroidism can lead to worsening of bone lesions
- Continuous monitoring of labs is necessary
AD hypophosphatemic rickets
- AD mutation in the gene encoding the FGF23
- Mutation prevents the degradation of FGF23
AR hypophosphatemic rickets
Type 1
- Mutation in the dentin matrix protein (DMP1)
Type 2
- Mutation in the ENPP1
- Can cause generalized arterial calcification in infancy
Both types associated with elevated levels of FGF23. Treatment is same. Monitoring for renal artery calcification should be done
Hereditary hypophosphatemic rickets with hypercalcemia
- Rare disorder of Middle East
- Mutation int gene encoding for sodium phosphate co-transporter
- Renal phosphate leak cause hypophosphatemia which in turn induces 1,25 D
- This increases calcium absorption and resorption and cause hypercalciuria
Clinical features
- Bone pain
- Short stature
- Nephrocalcinosis
Labs
- Hypophosphatemia
- Renal phosphate wasting
- Elevated serum ALP levels
- Elevated 1,25 D
- PTH low
Treatment
- Oral phosphate replacement
- 1-2.5g/day of elemental phosphate in 2 dived doses
Over production of FGF23
Tumor induced osteomalacia
- Similar to XLH
- Treatment is excision of the tumor
McCune Albright syndrome
- Renal phosphate wasting - hypophosphatemia
- Rickets
- Triad of
- Poly ostotic fibrous dysplasia
- Hyperpigmented macules
- Polyendocrinopathy
Labs
- Low levels of 1,25 D
- Elevated ALP
- Elevated FGF23
Treatment
- Same as XLH and bisphosphonates
Epidermal nevus syndrome
- Produce FGF23
- Hypophosphatemic rickets
Neurofibromatosis
Raine syndrome
- FAM20C gene
- Osteosclerotic bone dysplasia
- Most patients die in the neonatal period
Fanconi's syndrome
- Generalised dysfunction of the renal proximal tubule
- Loss of
- phosphate
- bicarbonates
- glucose
- urate
- amino acids
- Proximal RTA
- Chronic metabolic acidosis which can cause dissolution of bone
- Failure to thrive
- Treatment is by etiology
Dent disease
- X linked disorder caused by the defect in the chloride gene (CLCN5)
- Some patients can have OCRL1 gene defect which can cause lowe syndrome
Clincial features
-
Nephrocalcinosis
-
Nephrolithiasis
-
Chronic kidney disease
-
aminoaciduria
-
Glycosuria
-
Hypercalciuria
-
Hypokalemia
-
Rickets can occur in 25% of the people
-
Responds to oral phosphorous supplements
Rickets of prematurity
- Most of the calcium and phosphate transfer occurs in the 3rd trimester
- If child is born preterm this can cause rickets of prematurity
- Present after 1-3 months
Clinical features
- Non-traumatic fractures
- Decreased chest compliance due to multiple bone fractures in chest
- Rachitic respiratory distress after 5 weeks
- Enamel hypoplasia
- Poor bone mineralisation can lead to dolichocephaly
Lab findings
- Low phosphate
- Renal response is adequate
- Low urine phosphate
- Normal 25 d
- High 1,25 D
- Inadequate phosphorous to deposit calcium in bone - hypercalciuria
- Both calcium and phosphate supplementation should be provided for the bone development
- ALP raised 5-6x
Diagnosis
- Weekly monitoring of calcium phosphorus and ALP
- Screening radiograph at 6-8 weeks should be done
Prevention
- Early enteral feeding
- High phosphate and calcium containing parenteral feeds
- Avoid soy milk
Distal renal tubular acidosis
- Metabolic acidosis with inability to acidify the urine
- Hypercalciuria
- Nephrocalcinosis
- Respond to alkali therapy