VITAMIN-D RESISTANT RICKETS.ppt educationx

4/25/2024 1
DepartmentofPediatrics
L.N.MedicalCollege&ResearchCentre,

REFRACTORY RICKETS
MODERATOR :- Dr. RASHMI DWIVEDI
Dr. SWADESH VERMA
PRESENTER : Dr. RAJENDER SINGH

REFERENCE
An overview of rickets in children , kidney int rep (2020), published online 11 april 2020.
Ghai essential pediatrics , 9 edi.
Nelson textbook of pediatrics , 21 edi.
Nield ls, mahajan p, joshi a, kamat d. Rickets: not a disease of the past. Am fam physician. 2006 aug 15;74(4):619-
26. Pmid: 16939184.
Levine, michael. (2020). Diagnosis and management of vitamin D dependent rickets. Frontiers in pediatrics. 8.
10.3389/fped.2020.00315.
Pediatric nephrology , arvind bagga , 5 edi.
Image source – internet

DISCUSSION
PATHWAY OF VITAMIN D PRODUCTION
INTRODUCTION
BONE METABOLISM & RICKETS
PATHOGENESIS
 TYPES OF RICKETS
DIAGNOSIS
TREATMENT
CONCLUSION

7-dehydrocholesterol In skin
Cholecalciferol (vitamin D3)
25 hydroxycholecalciferol
Liver
kidney
1,25-Dihydroxycholecalciferol
Parathyroid hormone
inhibition
25 hydroxylase
1,25 hydroxylase

 Cholecalciferol (Vitamin D3) Is Formed in the Skin as a result of irradiation of 7-dehydrocholesterol, a
substance normally in the skin, by ultraviolet rays (UVB) from the Sun.
 The additional vitamin D compounds that we ingest in food are identical to the cholecalciferol formed in the
skin,
 Cholecalciferol gets converted it to 25- hydroxycholecalciferol, which occurs in the liver.
 25-hydroxycholecalciferol has a feedback inhibitory effect on the conversion reactions.
 In the proximal tubules of the kidneys 25-hydroxycholecalciferol converts to 1,25-dihydroxycholecalciferol.
 This conversion requires PTH.
 In the absence of PTH, almost none of the 1,25dihydroxycholecalciferol is formed.
 PTH exerts a potent influence in determining the functional effects of vitamin D in the body.

PATHWAY OF VITAMIN D PRODUCTION
NIELD LS, MAHAJAN P, JOSHI A, KAMAT D. RICKETS: NOT A DISEASE OF THE PAST. AM FAM PHYSICIAN. 2006 AUG 15;74(4):619-26. PMID: 16939184.

These actions increase the concentrations of calcium
and phosphorus in extracellular fluid.
• The increase of Ca and
P in extracellular fluid,
in turn, leads to the
calcification of osteoid,
primarily at the
metaphyseal growing
ends of bones but also
throughout all osteoid
in the skeleton.
• Parathyroid hormone
facilitates the 1-hydro-
xylation step in
vitamin D metabolism

OTHER EFFECTS OF VITAMIN D
• Cellular metabolism: citric acid oxidation
• Formation of soluble complex of citrate and Ca in the blood
• Skin differentiations in the local treatment of Psoriasis
• Pulmonary differentiation (Increases the surfactant in preterm infants)
• Immunomodulatory action in autoimmune disorders

MUSCLES
• Increases the muscular protein and the ATP in myocytes
• Tonicity and the normal contraction of the muscles

PARATHYROID HORMONE
• Controls parathyroid hormone synthesis
• In case of low plasma calcium, PTH secretion increases
• In response to secretion of PTH, increase synthesis of 1,25(OH)2D3
• PTH causes renal losses of phosphate, reducing the bone calcification
• Demineralization of bone, increase to normalize serum Ca.

How much is enough?
Guidelines for Vitamin D Intake
Age
RDA (recommended daily
allowance)
0 - 1 yr 400 IU or 10 mcg
1 – 3 yr 600 IU or 15 mcg
GHAI ESSENTIAL PEDIATRICS , 9 EDI.

INTRODUCTION
Derived from the word 'wrickets' meaning 'twisted' referring to
the characteristic bony deformities or 'bow legs of rickets.
Rickets is a common bone disease worldwide that is
associated with disturbances in calcium and phosphate
homeostasis.
Calcium and phosphate homeostasis is maintained through
vitamin D.
AN OVERVIEW OF RICKETS IN CHILDREN , KIDNEY INT REP (2020), PUBLISHED ONLINE 11 APRIL 2020.

CONTINUE……………..
It can be classified into 2 major groups based on phosphate or calcium levels: phosphopenic and calcipenic.
Nutritional rickets is a preventable disease through adequate intake of vitamin D through both dietary and sunlight
Exposure.
Other subtypes of rickets, such as vitamin D–dependent type 1 rickets and vitamin D– dependent type 2 rickets
(due to defects in vitamin D metabolism), renal rickets (due to poor kidney function), and hypophosphatemic
rickets (vitamin D–resistant rickets secondary to renal phosphate Wasting).
An important development has been the introduction of burosumab, a human monoclonal antibody to FGF- 23,
which is approved for the treatment of X-linked hypophosphatemia among children 1 year and older.

BONE METABOLISM & RICKETS
• Bones consist of cells that have various specific roles during the bone formation process.
• Osteoblasts are bone-forming cells that secrete the extracellular matrix and mineralize the
osteoid, whereas osteoclasts break down the bone matrix during the stage of remodeling, disease
conditions, or aging.
• For bone maturation, the organic component of the bone matrix, the osteoid, must be
mineralized by calcium salts.
• In rickets, this process is hampered and results in amassing of osteoid beneath the growth plate
leading to softness in the bone over a gradual period of time.

WHAT IS RICKETS ?
 Disease of the ( growing bone )
 Impaired mineralisation of the growth plate & osteoid
 Low serum phosphate is fundamental to pathogenesis of rickets
Normal Growth Plate Rachitic Growth Plate
Apoptosis of
Hypertrophic
Chondrocytes
caused by
PHOSPHATE ions
HYPOPHOSPHATEMIA
No Apoptosis of
Hypertrophic
Chondrocytes

WHAT IS RICKETS ?
Impaired Apoptosis of Terminally Differentiated Chondrocytes in the Growth Plate
Responsible for Clinical & Radiological Signs of Rickets

Hands and forearms of a young child with rickets show
prominence above the wrist, resulting from flaring and poor mineralization
of lower end of the radius and ulna.

Pathogenesis
Vitamin D deficiency
•
• Absorption of Ca, P
Serum Ca
Function of Parathyroid

Pathogenesis
PTH
High secretion
P in urine loss Decalcification of old bone
P in blood Ca in blood normal or low slightly
disturbance in homeostasis Ca, P
Rickets

ALP LEVELS
• Alkaline phosphatase, which is produced by overactive osteoblast cells, leaks to the
extracellular fluids so that its concentration rises to anywhere from moderate elevation to
very high levels.

REFRACTORY RICKETS
• Rickets that does not respond to the usual treatment of Nutritional rickets is called
refractory rickets.
• Diagnosis is made in patients with no radiological healing after vitamin D therapy.
• It can be broadly classified into two categories: Defects in vitamin D metabolism
and low phosphate disorders.
• Refractory rickets is often inherited.
GHAI ESSENTIAL PEDIATRICS , 9 EDI.

BIOCHEMICAL EVALUATION OF A CHILD WITH REFRACTORY RICKETS
PEDIATRIC NEPHROLOGY , ARVIND BAGGA , 5 EDI.

VITAMIN D–DEPENDENT TYPE 1 RICKETS
• Children with vitamin D–dependent rickets type 1A, an autosomal recessive
disorder, have mutations in the gene encoding renal 1α-hydroxylase, preventing
conversion of 25-D into 1,25-D.
• patients normally present during the 1st 2 yr of life and can have any of the
classic features of rickets , including symptomatic hypocalcemia.
• They have normal levels of 25-D but low levels of 1,25-D .
NELSON TEXTBOOK OF PEDIATRICS , 21 EDI.

VITAMIN D–DEPENDENT TYPE 1 RICKETS
• Occasionally, 1,25-D levels are at the lower limit of normal, inappropriately low
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.
• Vitamin D–dependent rickets type 1B is secondary to a mutation in the gene for a
25-hydroxylase.
• Patients have low levels of 25-D but normal levels of 1,25-D .

TREATMENT
• Vitamin D–dependent rickets type 1A responds to long-term treatment with 1,25-D (calcitriol).
• Initial doses are 0.25-2 μg/day, and lower doses are used once the rickets has healed.
• Dose of calcitriol is adjusted to maintain a low-normal serum calcium level, a normal serum phosphorus level, and
a high-normal serum PTH level.
• Targeting a low-normal calcium concentration and a high-normal PTH level avoids excessive dosing of calcitriol,
which can cause hypercalciuria and nephrocalcinosis.
• Patient monitoring includes periodic assessment of urinary calcium excretion, with a target of <4 mg/kg/day.
• Vitamin D–dependent rickets type 1B may respond to pharmacologic doses of vitamin D2 (3,000 U/day) as a result
of alternative enzymes with 25-hydroxylase activity or residual activity of the mutant protein.

VITAMIN D–DEPENDENT RICKETS, TYPE 2
• Patients with vitamin D–dependent rickets type 2A have mutations in the gene encoding the
vitamin D receptor, preventing a normal physiologic response to 1,25-D.
• Levels of 1,25-D are extremely elevated in this autosomal recessive disorder .
• Most patients present during infancy, although rickets in less severely affected patients might
not be diagnosed until adulthood.

VITAMIN D–DEPENDENT RICKETS, TYPE 2
• Less severe disease is associated with a partially functional vitamin D
receptor.
• Approximately 50–70% of children have alopecia, can range from
alopecia areata to alopecia totalis.
• Epidermal cysts are a less common manifestation.
• Vitamin D–dependent rickets type 2B appears to result from
overexpression of a hormone response element–binding protein that
interferes with the actions of 1,25-D.
• Alopecia may be present. NELSON TEXTBOOK OF PEDIATRICS , 21 EDI.

TREATMENT
• Some patients respond to extremely high doses of vitamin D2 (25-D or 1,25-D), especially
patients without alopecia.
• This response is caused by a partially functional vitamin D receptor in patients with vitamin
D–dependent rickets type 2A, but may also occur in vitamin D–dependent rickets type 2B.
• All patients should be given a 3-6 mo trial of high-dose vitamin D and oral calcium.

TREATMENT
• The initial dose of 1,25-D should be 2 μg/ day, but some patients require doses as
high as 50-60 μg/day.
• Calcium doses are 1,000-3,000 mg/day.
• Patients who do not respond to high-dose vitamin D may be treated with long-
term IV calcium, with possible transition to very high dose oral calcium
supplements.
• Treatment of patients who do not respond to vitamin D is difficult.

CALCIUM DEFICIENCY
• Rickets secondary to inadequate dietary calcium is a significant problem in some countries in Africa.
• Because breast milk and formula are excellent sources of calcium, this form of rickets develops after children have
been weaned from breast milk or formula and is more likely to occur in children who are weaned early.
• Rickets develops because the diet has low calcium content, typically <200 mg/day if <12 mo old or <300 mg/day if
>12 mo old.
• In addition, because of reliance on grains and green leafy vegetables, the diet may be high in phytate, oxalate, and
phosphate, which decrease absorption of dietary calcium.
• This type of rickets can develop in children who receive intravenous nutrition without adequate calcium.
• Malabsorption of calcium can occur in celiac disease, intestinal abetalipoproteinemia, and after small bowel
resection.

CLINICAL MANIFESTATIONS
• Children with calcium deficiency have the classic signs and symptoms of rickets .
• Presentation can occur during infancy or early childhood, although some cases are diagnosed
in teenagers.
• Because calcium deficiency occurs after the cessation of breastfeeding, it tends to occur later
than the nutritional vitamin D deficiency that is associated with breastfeeding.

DIAGNOSIS
Laboratory findings include increased levels of ALP, PTH, and 1,25-D
Calcium levels may be normal or low, although symptomatic hypocalcemia is
uncommon.
There is decreased urinary excretion of calcium, and serum phosphorus levels may
be low as a result of renal wasting of phosphate from secondary
hyperparathyroidism.
In some children, there is coexisting nutritional vitamin D deficiency, with low
25-D levels.

TREATMENT
Treatment focuses on providing adequate calcium, typically as a dietary supplement (doses of 700
[age 1-3 yr], 1,000 [4-8 yr], and 1,300 [9-18 yr] system.
 Rickets from vitamin D deficiency can develop in children receiving anticonvulsants (e.g.,
phenobarbital, phenytoin) or antituberculosis medications (e.g., isoniazid, rifampin).

RENAL RICKETS SEC. TO (CKD)
 Term renal rickets is usually restricted to those with chronic kidney disease.
CKD results in the deficiency of the enzyme 1 alphahydroxylase, which decreases the
production of 1,25 hydroxy vitamin D (calcitriol).
 A history of renal failure will be evident that excludes the disorder from other bone diseases.
Laboratory findings usually show low calcitriol levels, but 25- hydroxyvitamin D levels may
even be normal.
The most characteristic finding is the elevated phosphate level secondary to poor renal
function of chronic kidney disease.

TREATMENT
Patients with chronic kidney disease cannot convert the calcidiol into
the active form calcitriol.
Vitamin D supplementation alone is therefore ineffective for renal
rickets.
So, a low phosphate diet, dietary phosphate binders, and oral
administration of 1 alfacalcidol or calcitriol is advised, along with
maintaining normal 25-hydroxyvitamin D level.

HYPOPHOSPHATEMIC RICKETS
• Main defect in these forms of rickets is the increased loss of phosphate through the urine.
• Hypophosphatemic rickets should not be confused with hypophosphatesia, which is a rare
inborn error of metabolism due to the dysfunction of the tissue nonspecific alkaline phosphatase
enzyme.
• Childhood hypophosphatesia has onset of symptoms between 6 months and 18 years and can
present as rickets, reduced mobility, fractures, and poor growth.

HYPOPHOSPHATEMIC RICKETS
• Characterized by low alkaline phosphatase levels, which is paradoxical because
other forms of rickets are associated with high alkaline phosphatase levels.
• Isolated malabsorption of phosphorus occurs in patients with long term use of
aluminum-containing antacids.
• This entity responds to discontinuation of the antacid and short-term phosphorus
supplementation.

Levine, Michael. (2020). Diagnosis and Management of Vitamin D Dependent Rickets. Frontiers in Pediatrics. 8. 10.3389/fped.2020.00315.

TYPES
• X-LINKED HYPOPHOSPHATEMIC RICKETS
• AUTOSOMAL DOMINANT HYPOPHOSPHATEMIC RICKETS
• AUTOSOMAL RECESSIVE HYPOPHOSPHATEMIC RICKETS
• HEREDITARY HYPOPHOSPHATEMIC RICKETS WITH HYPERCALCIURIA

• Sodium-phosphate (Na-Pi) cotransporter is responsible for phosphate reabsorption in the proximal tubule.
• Hormones including PTH and insulin like growth factor-1 regulate this transport system.
• Another important regulator of phosphate and vitamin D homeostasis is a recently discovered member of the
fibroblast growth factor (FGF) family, FGF-23, a circulating peptide secreted by the bone.
• FGF-23 binds with high affinity to its FGF receptor (FGFR) R1(IIIc) in the presence of klotho, a membrane
bound protein.
Fibroblast growth factor-23 (FGF-23) is a humoral mediator that decreases renal tubular reabsorption of
phosphate and therefore decreases serum phosphorus.
FGF-23, synthesized by osteocytes, also decreases the activity of renal 1α-hydroxylase, resulting in a decrease in
the production of 1,25-D.
• Animal studies suggest that FGF- 23 excess leads to phosphaturia and hypophosphatemia, by
decreasing the number of renal sodium phosphate transporter, NPT2a expressed in proximal renal
tubular cells, thus inhibiting sodium phosphate cotransport.

X-LINKED HYPOPHOSPHATEMIC RICKETS
• Among the genetic disorders causing rickets because of hypophosphatemia, X-
linked hypophosphatemic rickets (XLH) is the most common, with a prevalence of
1/20,000.
• Defective gene is on the X chromosome, but female carriers are affected, so it is
an X-linked dominant disorder.

PATHOPHYSIOLOGY
• Defective gene is called PHEX because it is a phosphate-regulating gene with homology to
endopeptidases on the X chromosome.
• The product of this gene appears to have an indirect role in inactivating FGF-23.
• Mutations in PHEX lead to increased levels of FGF-23.
• Because the actions of FGF-23 include inhibition of phosphate reabsorption in the proximal
tubule, phosphate excretion is increased.
• FGF-23 also inhibits renal 1α-hydroxylase, leading to decreased production of 1,25-D.

One of the initial clinical findings is frontal bossing, which may appear as early as 6 months of age.
As the child starts walking, progressive limb deformities become evident, leading to disproportionate short
stature with shorter limbs.
Lower limbs are more affected, leading to coxa vara, genu valgum, or genu varum.
Dental abnormalities are common and may often be the presenting complaints. abnormalities include abscessed
noncarious. teeth, enamel defects, and enlarged pulp chambers.
Inadequate dentin mineralization results in cracks that allow penetration of systemic bacteria, leading to dental
abscess and severe infections, like facial cellulitis from dental focus in some patients.
 In addition, recent studies have shown higher incidence of craniovertebral and cranial vault anomalies,
especially early closure of the cranial sutures (craniosynostosis) and Chiari type 1 malformation.

LABORATORY FINDINGS
• Patients have high renal excretion of phosphate, hypophosphatemia, and increased ALP; 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 of 1,25-D.

TREATMENT
Patients respond well to a combination of oral phosphorus and 1,25-D (calcitriol).
The daily need for phosphorus supplementation is 1-3 g of elemental phosphorus divided into 4 or 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.
Calcitriol is administered at 30-70 ng/kg/day in 2 doses.
Burosumab-twza is a monoclonal antibody to FGF-23 that is an approved alternative approach for treating XLH in
children >1 yr.

• For children with significant short stature, growth hormone is an effective option.
• Children with severe deformities might need osteotomies, but these procedures should be done
only when treatment has led to resolution of the bone disease.

COMPLICATIONS
• Complications of treatment occur when there is not an adequate balance between phosphorus supplementation and
calcitriol.
• Excess phosphorus, by decreasing enteral calcium absorption, leads to secondary hyperparathyroidism, with
worsening of the bone lesions.
• In contrast, excess calcitriol causes hypercalciuria and nephrocalcinosis and can even cause hypercalcemia.
• Therefore, laboratory monitoring of treatment includes serum calcium, phosphorus, ALP, PTH, and urinary
calcium, as well as periodic renal ultrasound to evaluate patients for nephrocalcinosis.
• Because of variation in the serum phosphorus level and the importance of avoiding excessive phosphorus dosing,
normalization of ALP levels is a more useful method of assessing the therapeutic response than measuring serum
phosphorus.

PROGNOSIS
• The response to therapy is usually good, although frequent dosing can lead to problems with
compliance.
• Girls generally have less severe disease than boys, probably because of the X-linked inheritance.
• Short stature can persist despite healing of the rickets.
• Adults generally do well with less aggressive treatment, and some receive calcitriol alone.
• Adults with bone pain or other symptoms improve with oral phosphorus supplementation and
calcitriol.

AUTOSOMAL DOMINANT HYPOPHOSPHATEMIC RICKETS
Autosomal dominant hypophosphatemic rickets (ADHR) is much less common than XLH.
There is incomplete penetrance and variable age of onset.
 Patients with ADHR have a mutation in the gene encoding FGF-23 (FGF23).
The mutation prevents degradation of FGF-23 by proteases, leading its level to increase.

The actions of FGF-23 include decreased reabsorption of phosphate
in the renal proximal tubule, which results in hypophosphatemia, and
inhibition of the 1α-hydroxylase in the kidney, causing a decrease in
1,25-D synthesis.
In ADHR, as in XLH, abnormal laboratory findings are
hypophosphatemia, elevated ALP level, and a low or inappropriately
normal 1,25-D level .
 Treatment is similar to the approach used in XLH.

AUTOSOMAL RECESSIVE HYPOPHOSPHATEMIC RICKETS
(ARHR) type 1 is an extremely rare disorder caused by mutations in the gene encoding dentin matrix protein 1
(DMP1).
ARHR type 2 occurs in patients with mutations in the ENPP1 gene.
Mutations in ENPP1 also cause generalized arterial calcification of infancy.
Both types of ARHR are associated with elevated levels of FGF-23, leading to renal phosphate wasting,
hypophosphatemia, and low or inappropriately normal levels of 1,25-D.
 Treatment is similar to the approach used in XLH, although monitoring for arterial calcification is prudent in
patients with ENPP1 mutations.

HEREDITARY HYPOPHOSPHATEMIC RICKETS WITH HYPERCALCIURIA
• (HHRH) is a rare disorder that is mainly found in the Middle East.
• PATHOPHYSIOLOGY- Autosomal recessive disorder is caused by mutations in the gene for a sodium-phosphate co-
transporter in the proximal tubule (SLC34A3).
• The renal phosphate leak causes hypophosphatemia, which then stimulates production of 1,25-D.
• The high level of 1,25-D increases intestinal absorption of calcium, suppressing PTH.
• Hypercalciuria ensues as a result of the high absorption of calcium and the low level of PTH, which normally decreases renal
excretion of calcium.

CLINICAL FINDING & LAB. FINDING
• CLINICAL MANIFESTATIONS include , dominant symptoms of HHRH are rachitic leg abnormalities , muscle
weakness, and bone pain.
• Patients can have short stature, with a disproportionate decrease in the length of the lower extremities.
• The severity of the disease varies, and some family members have no evidence of rickets but have kidney stones
secondary to hypercalciuria.
• LABORATORY FINDINGS include hypophosphatemia, renal phosphate wasting, elevated serum ALP levels, and
elevated 1,25-D levels.
• PTH levels are low

TREATMENT
Therapy for HHRH patients relies on oral phosphorus replacement (1-2.5 g/day of
elemental phosphorus in 5 divided doses).
 Treatment of the hypophosphatemia decreases serum levels of 1,25-D and
corrects the hypercalciuria.
 The response to therapy is usually excellent, with resolution of pain, weakness,
and radiographic evidence of rickets.

FANCONI SYNDROME
Fanconi syndrome is secondary to generalized dysfunction of the renal proximal tubule .
 There are renal losses of phosphate, amino acids, bicarbonate, glucose, urate, and other molecules that are
normally reabsorbed in the proximal tubule.
 Some patients have partial dysfunction, with less generalized losses.
 The most clinically relevant consequences are hypophosphatemia caused by phosphate losses and proximal renal
tubular acidosis caused by bicarbonate losses.
Patients have rickets as a result of hypophosphatemia, with exacerbation from the chronic metabolic acidosis,
which causes bone dissolution.
 Failure to thrive (malnutrition) is a consequence of both rickets and renal tubular acidosis.

X-LINKED RECESSIVE HYPERCALCIURIAAND NEPHROLITHIASIS (DENT’S DISEASE)
Dent disease is an X-linked disorder usually caused by mutations in the gene encoding a chloride channel
expressed in the kidney (CLCN5).
 Affected males have variable manifestations, including hematuria, nephrolithiasis, nephrocalcinosis, rickets, and
chronic kidney disease.
Almost all patients have low molecular- weight proteinuria and hypercalciuria.
 Other, less abnormalities are aminoaciduria, glycosuria, hypophosphatemia, and hypokalemia.
Rickets occurs in approximately 25% of patients, and it responds to oral phosphorus supplements.
 Some patients also need 1,25-D, but this treatment should be used cautiously because it can worsen the
hypercalciuria.

RENAL TUBULAR ACIDOSIS
• Proximal and distal renal tubular acidosis (RTA) are important causes of refractory rickets in
children.
• The conditions are characterized by hyperchloremic metabolic acidosis with normal blood levels
of urea and creatinine.
• Most subjects with RTA show features of Fanconi syndrome (bicarbonaturia, phosphaturia,
glucosuria and aminoaciduria) and are capable of acidifying urine once plasma bicarbonate level
is below 15 mEq/l.
• Patients with distal RTA show relatively high urine pH (6.0-6.5) despite severe acidosis.
• Appropriate correction of acidosis with bicarbonate supplements and phosphate
supplementation (in proximal RTA) results in healing of rickets.
A. BAGGA 5TH EDITION

RICKETS OF PREMATURITY
• Rickets in very-low-birthweight infants has become a significant problem, as the survival rate for this group of
infants has increased.
• The transfer of calcium and phosphorus from mother to fetus occurs throughout pregnancy, but 80% occurs during
the 3rd trimester.
• Most cases of rickets of prematurity occur in infants with a birthweight <1,000 g.
• It is 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.
• Other risk factors include cholestatic jaundice, a complicated neonatal course, prolonged use of parenteral nutrition,
the use of soy formula, and medications such as diuretics and corticosteroids.

 Rickets of prematurity occurs 1-4 mo after birth.
 Non-traumatic fractures-legs, arms, ribs
 Respiratory distress and poor ventilation(>5weeks)
 Negative effects on growth-beyond 1yr
 Enamel hypoplasia
 Dolicocephaly
 Frontal bossing, rachitic rosary ,craniotabes, widened wrists and ankles

LABORATORY FINDINGS
• Because of inadequate intake, the serum phosphorus level is low or low-normal in patients with rickets of
prematurity
• 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, so levels of 1,25-D are high or high-normal.
• These high levels can contribute to bone demineralization because 1,25-D stimulates bone resorption.
• Serum levels of calcium are low, normal, or high, and patients often have hypercalciuria.
• Elevated serum calcium levels and hypercalciuria are secondary to increased intestinal absorption and bone
dissolution caused by elevated 1,25-D levels and inability to deposit calcium in bone because of an inadequate
phosphorus supply.

• Alkaline phosphatase levels are often elevated, but some affected infants have normal levels.
• No single blood test is 100% sensitive for the diagnosis of rickets.
• The diagnosis should be suspected in infants with ALP >5-6 times the upper limit of normal (UL) for adults (unless
there is concomitant liver disease) or phosphorus <5.6 mg/dL.
DIAGNOSIS-
• screening tests are recommended, tests should include weekly measurements of calcium, phosphorus, and ALP.
• Periodic measurement of the serum bicarbonate concentration is also important, because metabolic acidosis causes
dissolution of bone.
• At least 1 screening radiograph for rickets at 6-8 wk of age is appropriate in infants who are at high risk for rickets.

PREVENTION & TREATMENT
• Provision of adequate amounts of calcium, phosphorus, and vitamin D significantly decreases the risk of rickets of
prematurity.
• Infants should receive either human milk fortified with calcium and phosphorus or preterm infant formula, which
has higher concentrations of calcium and phosphorus than standard formula.
• Soy formula should be avoided because there is decreased bioavailability of calcium and phosphorus.
• 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 through formula and vitamin
supplements.

CONCLUSION
• Rickets is a disorder of growing children that arises from defective mineralization of the growth
plate.
• Nutritional rickets is a preventable disease by maintaining an adequate intake of vitamin D
through both dietary and sunlight exposure.
• Vitamin D supplementation will work in nutritional rickets secondary to vitamin D deficiency
but not in most of the non-nutritional variants of rickets.
• Knowledge of these conditions is essential for prompt diagnosis and proper management.

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