10 Rickets

RicketsRicketsRickets is defined as the failure Rickets is defined as the failure of osteoid to calcify in a of osteoid to calcify in a growing person or animal. growing person or animal.

Defective mineralization of Defective mineralization of cartilage taking place in the cartilage taking place in the epiphyseal growth plate, leading epiphyseal growth plate, leading to widening of the long ends of to widening of the long ends of bones, growth retardation, and bones, growth retardation, and skeletal deformities in childrenskeletal deformities in children

Osteomalacia: disorder of Osteomalacia: disorder of mineralization of newly formed mineralization of newly formed matrix in adultsmatrix in adults

History of Rickets and vitamin DHistory of Rickets and vitamin D

1600 - In the mid 1600s, rickets 1600 - In the mid 1600s, rickets is first described. is first described.

1918 - Edward Mellanby induces 1918 - Edward Mellanby induces rickets in dogs and then cures the rickets in dogs and then cures the disease by feeding the animals disease by feeding the animals cod-liver oil. cod-liver oil.

1919 - K. Huldschinsky cures 1919 - K. Huldschinsky cures children of rickets using children of rickets using artificially produced ultraviolet artificially produced ultraviolet light. light.

HistoryHistory

1936 - Windaus deduces the chemical structure 1936 - Windaus deduces the chemical structure of vitamin D3 produced in the skin (now known of vitamin D3 produced in the skin (now known as cholecalciferol) and identifies the as cholecalciferol) and identifies the structure of its parent molecule, 7-structure of its parent molecule, 7-dehydrocholesteroldehydrocholesterol. .

1968 - Hector F. DeLuca and colleagues 1968 - Hector F. DeLuca and colleagues identify identify 25-hydroxyvitamin D325-hydroxyvitamin D3. .

1970, the existence of a second active 1970, the existence of a second active metabolite produced from 1 alfha D is metabolite produced from 1 alfha D is reported by Anthony W. Norman, and coworkers. reported by Anthony W. Norman, and coworkers.

1971 - Three research groups identify the 1971 - Three research groups identify the chemical/molecular structure of the final chemical/molecular structure of the final active form of vitamin D as active form of vitamin D as 1,25-1,25-dihydroxyvitamin D3dihydroxyvitamin D3,, which is soon which is soon reclassified as a hormone controlling calcium reclassified as a hormone controlling calcium metabolism. metabolism.

Incidence and High Risk Group Incidence and High Risk Group for Ricketsfor Rickets

Those at higher risk for developing rickets Those at higher risk for developing rickets includeinclude::

Dark-skinned children Dark-skinned children Breast-fed infants whom or there mothers Breast-fed infants whom or there mothers are not exposed to sunlight are not exposed to sunlight

Individuals on vegetarian or vegan diets Individuals on vegetarian or vegan diets who do not drink milk who do not drink milk

Lactose intolerant individuals Lactose intolerant individuals Living in an inner-city area also is a Living in an inner-city area also is a risk factor for rickets because of the risk factor for rickets because of the presence of smog.presence of smog.

(extremely pale skin that burns rather than (extremely pale skin that burns rather than tans) have a decreased risk for rickets tans) have a decreased risk for rickets due to their greater production of due to their greater production of vitamin D in sunlight.vitamin D in sunlight.

PathogenesisPathogenesis

Defective Defective mineralization of mineralization of cartilage taking cartilage taking place in the place in the epiphyseal growth epiphyseal growth plateplate, leading to , leading to widening of the widening of the long ends of long ends of bones, growth bones, growth retardation, and retardation, and skeletal skeletal deformities in deformities in childrenchildren

Causes of Causes of calcipeoniccalcipeonic ricketsrickets

1- vitamin D deficiency.1- vitamin D deficiency.

2- defect of 1-alph 2- defect of 1-alph hydroxylase.hydroxylase.

3- dietary ca deficiency.3- dietary ca deficiency.

4- chronic R F. 4- chronic R F.

Radiological findings:Radiological findings:

Widening of the epiphyseal plate. Widening of the epiphyseal plate. Broadning, cupping & fraying.Broadning, cupping & fraying. Shafts of long bones are osteopnic & Shafts of long bones are osteopnic & the cortex become thin.the cortex become thin.

The trabecular pattern is reduced & The trabecular pattern is reduced & becomes coarse.becomes coarse.

Fractures & deformities.Fractures & deformities. Periosteal elevation.Periosteal elevation. Psudofracture. Psudofracture.

CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONS

Skeletal findings:Skeletal findings:Skull:Skull: delay closure of the delay closure of the fontanelles fontanelles

wide suture.wide suture. parietal & frontal parietal & frontal bossing.bossing.

craniotabescraniotabes..

Thorax:Thorax:

1-enlargement of the 1-enlargement of the costochondral costochondral junction.junction.

2- development of 2- development of harrison sulcus.harrison sulcus.

3- pectus carinatum. 3- pectus carinatum.

Extremities:Extremities:

1- increase 1- increase width of width of epiphyseal epiphyseal line at the line at the distal distal forearm & forearm & knee.knee.

2- swelling.2- swelling.3- genovarum.3- genovarum.4-genuvulgum.4-genuvulgum.5- wind swept.5- wind swept.

SpineSpine

1- scoliosis.1- scoliosis.

2-kyphosis.2-kyphosis.

In more advanced casesIn more advanced cases

• Thinning of the cortex.Thinning of the cortex.• Radiolucent transfer bands.Radiolucent transfer bands.• Green stick fractures.Green stick fractures.• Deformities.Deformities.

Extra skeletal findingExtra skeletal finding

1- dental1- dental hypoplasia .hypoplasia .2- dental abscesses.2- dental abscesses.3- hypotonia.3- hypotonia.4-seizure.4-seizure.5- acquire infection.5- acquire infection.

6- increase sweating.6- increase sweating.

7- tetany.7- tetany.

8- cataract.8- cataract.

9- Calcification of the Basal 9- Calcification of the Basal GangliaGanglia

10- extra pyramidal disorder.10- extra pyramidal disorder.

11- malnutrition. 11- malnutrition.

Laboratory FindingsLaboratory Findings

• ALP increase.ALP increase.• Serum phosphorus will be lowSerum phosphorus will be low• Serum calcium low / normalSerum calcium low / normal• Serum concentration of the PTH Serum concentration of the PTH increasedincreased

• TRP .TRP .• Serum 25-OH vit D Serum 25-OH vit D • 1,25-OH2 vit D .1,25-OH2 vit D .

Vitamin D Deficiency Vitamin D Deficiency RicketsRickets

Vitamin D deficiency Vitamin D deficiency RicketsRickets

• Vitamin deficiency rarely occurs Vitamin deficiency rarely occurs in newborns, but symptoms most in newborns, but symptoms most commonly develop bet 4 & 8mon.commonly develop bet 4 & 8mon.

The main reasons for inadequate The main reasons for inadequate vit D supply in infants are vit D supply in infants are

• prolonged breast feedingprolonged breast feeding without without vit D supplementation &vit D supplementation &

• concomitant avoidance of concomitant avoidance of sun sun exposure .exposure .

Dark skin is an additional Dark skin is an additional risk factor for developing risk factor for developing rickets in breast feed rickets in breast feed infants.infants.

Laboratory findingLaboratory finding::

• Serum calcium normal | low.Serum calcium normal | low.• Serum phosphate always low.Serum phosphate always low.• Serum ALP elevated.Serum ALP elevated.• Serum 25-OH vit D low.Serum 25-OH vit D low.• Serum concentration of the PTH Serum concentration of the PTH increasedincreased

A generalized aminoaciduria occurs from A generalized aminoaciduria occurs from the parathyroid activity; aminoaciduria the parathyroid activity; aminoaciduria does not occur in familial does not occur in familial hypophosphatemia rickets (FHR).hypophosphatemia rickets (FHR).

Treatment:Treatment: Vitamin D 5000 IU | day.Vitamin D 5000 IU | day. CA intake should be maintained at CA intake should be maintained at 1000 mg|day.1000 mg|day.

This regime should lead to the This regime should lead to the resolution of biochemical & resolution of biochemical & radiological abnormalities within 3 radiological abnormalities within 3 monnth.monnth.

Reappearance of urinary ca excretion Reappearance of urinary ca excretion shows that the bodys vit D & ca stores shows that the bodys vit D & ca stores have been refilled.have been refilled.

If the pt has no detectable calciurea If the pt has no detectable calciurea after 3 month of treatment , after 3 month of treatment , contiuation of the same Rx regimen for contiuation of the same Rx regimen for another 3mon is advisableanother 3mon is advisable. .

Alternative Recommended Alternative Recommended regiemsregiems

An alternative and recommended An alternative and recommended therapy is to administer the vitamin therapy is to administer the vitamin D in a single day, D in a single day, usually divided usually divided into 4 or 6 oral doses dose with into 4 or 6 oral doses dose with 15,000 mcg (600,000 U) of vitamin D15,000 mcg (600,000 U) of vitamin D

In this method Vitamin D is well stored In this method Vitamin D is well stored in the body and released gradually in the body and released gradually over many weeks and problem of over many weeks and problem of compliance can be solved by this waycompliance can be solved by this way

An intramuscular injection also is An intramuscular injection also is available and recommended available and recommended

Laurence Finberg, MD, Clinical Professor, Department of Pediatrics, University of California at San Francisco and Stanford University

Monitoring:Monitoring:

In nutritional rickets, the phosphate In nutritional rickets, the phosphate level rises in 96 hours and level rises in 96 hours and radiographic healing is visible in radiographic healing is visible in 6-7 days6-7 days (differentiating point (differentiating point with FHR)with FHR)

Serum ca, ph, ALP Serum ca, ph, ALP urinary ca | creatinine ratio urinary ca | creatinine ratio should be measured 4 wks after start should be measured 4 wks after start of therapy.of therapy.

Also repeated after 3mon of therapy Also repeated after 3mon of therapy & radiographs should be obtained. & radiographs should be obtained.

American Academy of pediatrics American Academy of pediatrics recommends that vit D recommends that vit D

supplementation (200IU | day) be supplementation (200IU | day) be provided to:provided to:

1)1) All breast fed infants unless All breast fed infants unless they are receiving at least they are receiving at least 500 ml of vit D fortified 500 ml of vit D fortified milk | day.milk | day.

Supplementation should start in Supplementation should start in the 1the 1stst 2mon of life. 2mon of life.

2) All non breast fed infants who 2) All non breast fed infants who are ingesting less than 500 ml are ingesting less than 500 ml of vitD fortified milk | day.of vitD fortified milk | day.

3) Children & adolescent who do 3) Children & adolescent who do not ingest at least 500 ml , & not ingest at least 500 ml , & do not get regular sunlight do not get regular sunlight exposure & do not take a exposure & do not take a multivitamin supplement that multivitamin supplement that contains at least 200 IU of vit contains at least 200 IU of vit D.D.

How Much Sun Exposure How Much Sun Exposure Necessary??Necessary??

Sensible sun exposure Sensible sun exposure

(usually 5–10 min of exposure of the (usually 5–10 min of exposure of the arms and legs or the hands, arms, arms and legs or the hands, arms, and face, 2 or 3 times per week) and face, 2 or 3 times per week)

In one study as little as 20 min/d In one study as little as 20 min/d of ultraviolet light to the face of ultraviolet light to the face of a light-skinned baby is of a light-skinned baby is sufficient; sufficient;

CALCIPEONIC RICKETSCALCIPEONIC RICKETS

Pseudo vitamin D deficiencyPseudo vitamin D deficiency

OrOr

Vitamin D Dependent type 1 Vitamin D Dependent type 1 RicketsRickets

OrOr

1 alpha hydroxylase 1 alpha hydroxylase deficiencydeficiency

Skindihydrotachysterol

Ultraviolet light

Vitamin D3

ErgosterolVitamin D2

Hydroxylation in liver25 hydroxycholecalciferol

cholecalciferol

calcidiol

1-25 Hydroxy

cholecalciferol

Hydroxylation in kidney

calcitriolPTH

Facilitate hydroxylation

kidney

Active metabolite

Pseudo vitamin D Pseudo vitamin D deficiency:deficiency:

It is AR disorder cause by It is AR disorder cause by defective conversion of defective conversion of calcidiol to calcitriol.calcidiol to calcitriol.

The gene encoding the enzyme The gene encoding the enzyme that is responsible for the that is responsible for the conversion has been mapped to conversion has been mapped to chromosome 12q14.chromosome 12q14.

The biochemical findings are The biochemical findings are normal serum level of calcidiol normal serum level of calcidiol & low calcitriol.& low calcitriol.

Treatment:Treatment:

Replacement therapy with Replacement therapy with calcitriol, an off-labeled use calcitriol, an off-labeled use of this drug.of this drug.

Wt < 10 kg (1 microgram | day)Wt < 10 kg (1 microgram | day)Wt > 10 Kg (2 microgram | day)Wt > 10 Kg (2 microgram | day)Rx is continued until the bone Rx is continued until the bone is healed.is healed.

There after the maintenance dose There after the maintenance dose varies bet 0.25 to 8 microgram | varies bet 0.25 to 8 microgram | day. day.

MonitoringMonitoring Closed supervision is needed during the Closed supervision is needed during the initial phase of Rx includes physical initial phase of Rx includes physical examination & biochemical evaluation examination & biochemical evaluation every 2 to 3 wks.every 2 to 3 wks.

Radiographs should show clear Radiographs should show clear improvement after 4 wks of therapy & improvement after 4 wks of therapy & repeated after 3mon.repeated after 3mon.

During administration of maintenance During administration of maintenance therapy , pts therapy , pts evaluated at 3mon evaluated at 3mon intervalsintervals , hand x-ray performed , hand x-ray performed once|once|yearyear to check for appearance of ricketic to check for appearance of ricketic changes.changes.

Vitamin D Resistant Vitamin D Resistant RicketsRickets

Or Or Vitamin D Dependent Rickets Vitamin D Dependent Rickets

type 2type 2

ororhereditary vit D – hereditary vit D –

resistantresistant

Known as hereditary vit D – Known as hereditary vit D – resistant receptor.resistant receptor.

It is a It is a very rarevery rare form of rickets. form of rickets.Reflecting the type of mutation Reflecting the type of mutation within the vit D receptor & the within the vit D receptor & the amount of residual vit D receptor amount of residual vit D receptor activityactivity. .

It is It is AR disorderAR disorder caused by the caused by the mutation in the gene encoding the mutation in the gene encoding the vit D receptor.& the defect in the vit D receptor.& the defect in the Receptor interferes with binding Receptor interferes with binding of hormone R complex to DNA threby of hormone R complex to DNA threby preventing preventing calcitriol calcitriol action.action.

Affected children appear Affected children appear normal at birth but develop normal at birth but develop rickets within the rickets within the 11stst 2year 2year of life.of life.

Alopecia Alopecia in 2\3 of cases & in 2\3 of cases & is a marker of D severity.is a marker of D severity.

Rx (Rx (2 microgram| day of 2 microgram| day of calcitriolcalcitriol) & 1000mg of ca.) & 1000mg of ca.

MonitoringMonitoring

Should be evaluated initially Should be evaluated initially at least once | day.at least once | day.

If not respond , dosage of If not respond , dosage of calcitriol increased gradually calcitriol increased gradually to reach to reach serum concentrationserum concentration of of up to 100 times the normal up to 100 times the normal mean.mean.

Repeated 3-4 months of Rx.Repeated 3-4 months of Rx.

Calcium deficiencyCalcium deficiency

Insufficient caInsufficient ca intake rather than intake rather than primary vitamin D def is the main primary vitamin D def is the main causative factor.causative factor.

Most the children had normal serum Most the children had normal serum calcidiol (25OH D)& high serum calcidiol (25OH D)& high serum calcitriol ( 1,25-OH vit D conc.) calcitriol ( 1,25-OH vit D conc.) indicating adequate intake of indicating adequate intake of vitamin D .vitamin D .

Those pts respond to Rx with ca Those pts respond to Rx with ca alone or combined with vitamin D .alone or combined with vitamin D .

Rx with Rx with 1000 mg of ca1000 mg of ca & & maintenancemaintenance of vit Dof vit D 400IU\day.400IU\day.

What Other Causes??What Other Causes??

MCQMCQ

CP child with seizure CP child with seizure disorder having good disorder having good nutrition and care by nutrition and care by

parentsparents

Presented with fractures Presented with fractures what will be the what will be the

possibility?possibility?

Child abuseChild abuseVitamin D deficiencyVitamin D deficiency

Drugs………….Anticonvulsant Drugs………….Anticonvulsant therapy can be the reasontherapy can be the reason

Other causes of vit D Other causes of vit D deficiencydeficiency

1- diminished absorption by 1- diminished absorption by gastrectomy.gastrectomy.

2- celiac disease.2- celiac disease.

3- malabsoption.3- malabsoption.

4- extensive bowel surgery.4- extensive bowel surgery.

5- IBD.5- IBD.

6- cystic fibrosis. 6- cystic fibrosis.

Phosphopenic ricketsPhosphopenic rickets

DefinitionDefinition

Rickets caused by phosphate Rickets caused by phosphate deficiency.deficiency.

Causes:Causes:

1- inadequate nutrition.1- inadequate nutrition.

2- increase renal loss.2- increase renal loss.

Classifications:Classifications:

NutritionNutrition

Parentral Parentral nutrition. nutrition.

Prematurity.Prematurity.

Increase renal Increase renal loss:loss:

familial familial hypophosphatemia hypophosphatemia ..

Renal tubular Renal tubular acidosis.acidosis.

Fanconi syndrome.Fanconi syndrome. Oncogenesis.Oncogenesis.

Rickets of PrematurityRickets of Prematurity

1)1) Increase risk in premature babies Increase risk in premature babies with birth weight < 1,500kg with with birth weight < 1,500kg with breast feeding.breast feeding.

BPD and chronic lung BPD and chronic lung diseasedisease

2) Pt develop rickets even if the 2) Pt develop rickets even if the vitamin D intake adequate.vitamin D intake adequate.

DiagnosisDiagnosis

HistoryHistoryPhysical examination usually Physical examination usually revealsreveals few or no sign of rickets few or no sign of rickets except for craiotabes. except for craiotabes.

lab studies show:lab studies show:low P with normal ca serum.low P with normal ca serum.Decrease P in urine with increase Decrease P in urine with increase ca.ca.

x-ray with severe osteopenia x-ray with severe osteopenia with typical metaphyseal fracture with typical metaphyseal fracture of rickets & fractures rib.of rickets & fractures rib.

PreventionPrevention

1- daily intake of (10-15 mg) 1- daily intake of (10-15 mg) vitaminD in 1vitaminD in 1stst wk of life. wk of life.

2- elemental ca (50-60 mg | kg |2- elemental ca (50-60 mg | kg |day)day)

3- inorganic phosphorus (30-40mg 3- inorganic phosphorus (30-40mg | kg| day) | kg| day)

Familial hypophosphatemicFamilial hypophosphatemic

The kidneys fail to reabsorb The kidneys fail to reabsorb sufficient phosphate, sufficient phosphate,

leading to low levels of serum leading to low levels of serum phosphatephosphate

.Defect in the proximal tubule .Defect in the proximal tubule reabsorption reabsorption

This usually begins after age This usually begins after age 6-10 months.6-10 months.

IncidenceIncidence

1|20-25,ooo .1|20-25,ooo .

Clinical featuresClinical features

1- Usually occurs between end of 1- Usually occurs between end of the 1the 1stst year to 3 years. year to 3 years.

2- slow growth & deformities in 2- slow growth & deformities in lower extremities.lower extremities.

3- Poor dental development & 3- Poor dental development & tooth abscesses.tooth abscesses.

Clinical findingsClinical findings

Similar to those of nutritional Similar to those of nutritional rickets, but without proximal rickets, but without proximal myopathy. myopathy.

have high bone density. have high bone density. infantile skull defects are not infantile skull defects are not apparent as hypophosphatemia is apparent as hypophosphatemia is usually clinically evident at a usually clinically evident at a later age. later age.

calcium levels normal, calcium levels normal, NO tetany nor secondary NO tetany nor secondary hyperparathyroidism hyperparathyroidism

How to differentiate How to differentiate it from calcipeonic it from calcipeonic

rickets ?? rickets ??

InvestigationsInvestigations

1- low serum phosphate.1- low serum phosphate.

2- normal calcium.2- normal calcium.

3- normal PTH3- normal PTH

4- 4- 1,25-(OH )2 D in low normal 1,25-(OH )2 D in low normal

TreatmentTreatment

In Older children In Older children Oral elemental Oral elemental phosphate to provide 1-3 gphosphate to provide 1-3 g PO per PO per day in 5 divided dosesday in 5 divided doses

In Young children In Young children 0.2-1 gm/ day0.2-1 gm/ dayCalcitriol (1 25 hydroxy vitamin D) Calcitriol (1 25 hydroxy vitamin D) 0.5-1.5 mcg/d PO.0.5-1.5 mcg/d PO.

(Calcitriol prevents increases in (Calcitriol prevents increases in parathyroid hormone caused by parathyroid hormone caused by phosphate therapy)phosphate therapy)

TreatmentTreatment::

1)1) Vit D (20-60 ng|kg|d)Vit D (20-60 ng|kg|d)2)2) Phosphate (0.2- 1 g|d) in Phosphate (0.2- 1 g|d) in

young children young children (1-4 g|d) in older children.(1-4 g|d) in older children.3) Minor serum ca, p, ALP & 3) Minor serum ca, p, ALP &

urine excretion of ca to avoid urine excretion of ca to avoid nephrocalcinosis)nephrocalcinosis)

MonitoringMonitoring

Calcitriol dose may produce Calcitriol dose may produce hypercalcemia and renal damage. hypercalcemia and renal damage.

The calcium-creatinine (mg/mg) The calcium-creatinine (mg/mg) ratio in urine must be monitored ratio in urine must be monitored closely at first, and then every 3-closely at first, and then every 3-6 months to avoid renal 6 months to avoid renal complicationscomplications

Elevated phosphate intake may Elevated phosphate intake may produce secondary produce secondary hyperparathyroidismhyperparathyroidism

Differential DXDifferential DX

1- Fanconi syndrome1- Fanconi syndrome

2- Renal tubular acidosis2- Renal tubular acidosis

3-Oncogenic Rickets3-Oncogenic Rickets