Rickets

Defect in proximal tubular reabsorption REF: Nelson’s 18^th ed page 2720

Familial Hypophosphatemia: (Vitamin D-Resistant Rickets, X-Linked Hypophosphatemia)

• The most commonly encountered non-nutritional form of rickets is familial hypophosphatemia. The usual mode of inheritance is X-linked dominant
• Pathogenic mechanisms involve defects in the proximal tubular reabsorption of phosphate and in the conversion of 25(OH)D to 1,25(OH)2 D. The latter defect is evidenced by low-normal serum 1,25(OH)2 D levels despite hypophosphatemia and by the finding that further phosphate depletion of subjects with familial hypophosphatemia does not stimulate 1,25 (OH)2 D synthesis as it does in normal subjects
• Patients have a normal or slightly reduced serum calcium level, a moderately reduced serum phosphate level, elevated alkaline phosphatase activity, and no evidence of secondary hyperparathyroidism. Urinary phosphate excretion is large, despite hypophosphatemia, indicating a defect in renal tubular phosphate

Increased acid phosphatase REF: Nelson Textbook of Paediatrics 17th edition page 186487 “Alkaline phosphatase not acid phosphatase is increased in rickets”

RICKETS is a softening of bones in children due to deficiency or impaired metabolism of vitamin D, magnesium, phosphorus or calcium, potentially leading to fractures and deformity. Types

• Nutritional Rickets
• Vitamin D Resistant Rickets
• Vitamin D Dependent Rickets (Type I & Type II)
• Congenital Rickets

Signs and symptoms:

• Bone pain or tenderness
• Dental problems
• Muscle weakness (rickety myopathy or “floppy baby syndrome” or “slinky baby” (such that the baby is floppy or slinky-like)
• Increased tendency for fractures (easily broken bones), especially greenstick fractures
• Skeletal deformity

            — Toddlers: Bowed legs (genu varum)

            — Older children: Knock-knees (genu valgum) or “windswept knees”

            — Cranial, pelvic, and spinal deformities (such as lumbar lordosis)

• Growth disturbance
• Hypocalcaemia (low level of calcium in the blood)
• Tetany (uncontrolled muscle spasms all over the body)
• Craniotabes (soft skull)
• Costochondral swelling (aka “rickety rosary” or “rachitic rosary”)
• Harrison’s groove
• Double malleoli sign due to metaphyseal hyperplasia
• Widening of wrist raises early suspicion, it is due to metaphyseal cartilage hyperplasia. 

Diagnosis:

Blood tests:

Serum calcium may show low levels of calcium, serum phosphorus may be low, and serum alkaline phosphatase may be high.

• Arterial blood gases may reveal metabolic acidosis
• An X-ray or radiograph of an advanced sufferer from rickets tends to present in a classic way:

bow legs (outward curve of long bone of the legs) and a deformed chest. Changes in the skull also occur causing a distinctive “square headed” appearance. These deformities persist into adult life if not treated. Long-term consequences include permanent bends or disfiguration of the long bones, and a curved back.

Bow legs Mel: Ghai Paediatrics 6/e, p 128. Nelson 17/e,p 183; Apley’s 8/e, p 119]

Ghai states – “Long bones of legs get deformed when the child starts bearing weight. Therefore deformities of legs are unusual before the age of 1 year. Anterior bowing of legs, knock knee and coxa vera are the usual deformities.”

• Clinical manifestation of Rickets:

The main factor responsible for pathogenesis in Rickets: –

• In rickets the abdomen is protuberant (pot belly) because of marked hypotonia of abdominal wall muscles. Visceral proptosis and lumbar lordosis also occurs in rickets.
• More Questions on rickets: ?
• Earliest manifestation of Rickets     Craniotabes
• Clinical manifestation of Rickets appears at       later half of first year or in T.’^d year. (Unusual below the age of 3 months)
• Questions on Radiological feature of Rickets: ?

– Earliest radiological changes appear in long bones of radius and ulna

– Cupping of inetaphyses

– Large gap b/w epiphyses and metaphyses (widening of the phy.vis i.e. growth plate)

– Irregular metaphyseal margins (ill-defined zone of provisional calcification)

–  Osteopenia

The earliest feature of healing in rickets is seen in X ray of growing end of the bones.

Flaring of the anterior ends of the ribs is characteristically seen in rickets.

In children, prior to epiphyseal fusion, vitamin-D deficiency results in growth retardation associated with an expansion of the growth plate known as rickets.

Though flaring of the ribs  can also be seen in scurvy, it is more characteristic of rickets.

Ref: Harrison’s Principle of Internal Medicine, 16th Edition, Page 2247; Abnormal Skeletal Phenotypes: From Simple Signs to Complex Diagnosis By Alessandro Castriota-Scanderbeg, Bruno Dallapiccola, Page 140

Hypophosphatasia is a rare autosomal recessive condition characterized by deficiency of alkaline phosphatase activity in serum, bone, and tissues.

Enzyme deficiency leads to poor skeletal mineralization with clinical and radiographic features similar to rickets.

Diagnosis is made by demonstrating elevated urinary phosphoethanolamine associated with low serum alkaline phosphatase.

• Obstructive hepatobiliary disease
• Bone disease (physiologic bone growth, Paget disease, osteomalacia, osteogenic sarcoma, bone metastases)
• Hyperparathyroidism
• Rickets
• Benign familial hyperphosphatasemia
• Pregnancy (third trimester)
• GI disease (perforated ulcer or bowel infarct)
• Hepatotoxic drugs

Osteomalacia is found within the same spectrum of rickets, affects trabecular bone, and results in undermineralization of osteoid bone. By definition, rickets is found only in children prior to the closure of the growth plates, while osteomalacia occurs in persons of any age.

Hypophosphatemic rickets (vitamin D–resistant rickets) is an dominant X-linked condition in which vitamin D production and metabolism are normal but renal tubular loss of phosphate interferes with skeletal ossification.

The major manifestations are a mild-to-moderate decrease in stature and bowing of the lower extremities. 

Ans. is a i.e. Rickets

Contracted pelvis is alteration in size and / or shape of pelvis of sufficient degree so as to alter the normal mechanism of labour in an average size baby. It can be a result of malnutrition, diseases or injuries affecting the bone of pelvis or it can be due to any developmental defect.

Ans. is ‘b’ i.e., Alkaline phosphatase

o Amongst the given options, alkaline phosphatase is best because it is raised in all type of rickets.

o The primary (Basic) investigations in a child of rickets are :‑

1. Serum calcium
2. Serum phosphorus
3. Alkaline phosphatase

o If patient does not respond to calcium and Vit D therapy, secondry investigations are done :‑

1. Vit D level
2. Serum PTH
3. Urinary calcium and phosphorus.

Ans. is ‘c’ i.e., Decreased absorption of calcium

Rickets is a metabolic disorder characterized by deficient mineralization of bone.

o Rickets may be due to : –

i)         Vit D deficient —> absorption of calcium (Vit D dependent rickets).

ii)       Increased phosphate excretion due to defective reabsorption —) Vit D resistant rickets.

Ans. is ‘b’ i.e., Defect in mineralization

o To know the pathophysiology of rickets, one should know the structure of bone.

o Bone consists of ‑

1)      Protein matrix i.e. osteoid —–> also known as unmineralized bone.

2)      Mineral phase. principally composed of calcium and phosphate, mostly in the form of hydroxyapatite.

o In rickets osteoid (protein matrix) is formed normally but mineralization of this osteoid does not occur i.e. there is defective mineralization.

o Rickets is a syndrome of diverse etiology characterized by defective mineralization of bone and epiphyseal cartilage (growth plate) of growing bones.

Ans. is ‘c’ i.e., Epiphyseal dysgenesis

o In rickets osteoid (protein matrix) is formed normally but mineralization of this osteoid does not occur i.e. there is defective mineralization.

o Epiphyseal plate (growth plate) has following five zones (moving from epiphysis towards metaphysis) –

i)        Resting zone

ii)       Proliferative zone

iii)      Maturation zone

iv)      Zone of hypertrophy

v)       Zone of provisional calcification

o Normally, capillaries grow from metaphysis to epiphysis via tunnels in the zone of provisional calcification. This ingrowth of capillaries destroy the cartilagenous cells in zone of hypertrophy, thereby limiting the growth of epiphyseal plate.

Changes in Rickets

o In rickets, tunnels are not formed in zone of provisional calcification because there is defective mineralization No capillary ingrowth from metaphysis to epiphysis —> cartilagenous cells continue to proliferate but do not die —> Thickening of growth plate.

o Proliferating cells in growth plate extend beyond the normal width of bone —> widning of growth plate (clinically presents as palpable enlargement at wrist, elbow and ankle, also at costochondral junction -4 rachitic rosary).

o As there is softening of metaphysis, axial pressure pushes the epiphysis into the metaphysis cupping or flaring of metaphysis (In normal bones, metaphysis is rigid so cupping does not occur).

o As there is irregular calcification (mineralization), the edge of the metaphysis loses its sharp border —> fraying of metaphysis.

In subperiosteal region, calcium deposition in the osteoid surrounding the shaft is impaired —> softening and deformity of long bones.

Ans. is ‘a’ i.e., Rickets

Ans. is ‘b^‘ i.e., Hyphosphatemic rickets

Clues in this question are ‑

1. Normal calcium                                            3. Low phosphate

2. Normal paratharmone                                 4. Elevated alkaline phosphatase

o All these suggest the diagnosis of hypophosphatemic rickets.

Ans. is ‘b’ i.e., Hypophosphatemic rickets

Ans. is ‘a’ i.e., Craniotabes, ‘c’ i.e., Widening of wrist

Clinical features of rickets

o Clinical manifestations of rickets are usually manifested by 6 months of age.

o Rickets is unusual below the age of 3 months.

A.Reginal manifestations

1. Skull

 Craniotabes (softening of cranial bones)

o It is the earliest manifestation of rickets.

o Pressure over occipital and parietal bones gives ping pong ball like feel.

               Frontal bossing –> Prominent frontal bones.

               Parietal bossing

               Widned sutures

               Delayed closure of anterior fontanel.

              Caput quadratum or hot cross – bun skull The widned suture & thickening of bone around sutures create a cruciate pattern.

2. Chest

              Rachitic rosary —> Prominent costochondral junction.

              Pectus craniatum (pigeon breast) sternum projects forward.

              Harrison ‘s groove —> A horizontal depression along lower border of chest corresponding to the insertion of diaphram. It occurs due to pulling of the softened ribs by the diaphragm during inspiration.

3. Teeth

               Delayed eruption

               Enamel hypoplasia and dental caries.

4. Spine

               Thoracic kyphosis —> Rachitic Cat back

               Accentuation of lumbar lordosis

               Scoliosis (uncommon)

5. Limbs & joints

               Bone pain & Tenderness —> most common manifestation.

               Coxa vara

               Genu valgus or Genu varus

              Bowing of tibia, femur, radius & ulna

              Widening of wrist, elbow, knee & ankle because of enlargement of ends of long bones.

               Rachitic saber shins

              Sawsage – like enlargements of ends of the phalanges and metacarpals, with regular constrictions corresponding to the joints —> string-of-pearls deformity.

                   Windswept deformity

                  Double malleoli sign —> on palpation of medial malleoli two malleoli are palpable instead of one.

6. Abdomen

             Abdomen becomes protuberant —> Rachitic pot – belly.

              This is because of marked hypotonia of abdominal muscles.

B.Systemic manifestations

                         Growth retardation

                         Apathy, listlessness & irritability

                         Hypotonia and muscle weakness

                         Ligament laxity

                         Tetany, laryngeal stridor and convulsions, when there is hypocalcemia or Alkalosis which predisposes to hypocalcemia.

Note ‑

Deficiency of vitamin D in early infancy may result in bilateral lamellar cataract.

Ans. is ‘d’ i.e., Bow legs

o Long bones of legs gets deformed when the child starts bearing weight. Therefore deformities of legs are unusual before the age of one year.

Ans. is ‘b’ i.e., Gustock deformity

o Gunstock deformity is seen in malunited supracondylar fracture of humerus.

Note ‑

o Dont get confuse between option ‘a’ and answer of previous question. In this question the age of the child has not been mentioned. Bow legs can occur, once the child starts walking.

Ans. is ‘b’ i.e., Rickets

o Genu valgum (also known as knock knee) is a condition where knees are abnormally approximated and ankles are abnormally divergent.

o It is caused due to softening of bones or damage to lateral Femoral epiphysis

Out of given options ‑

o Most common cause in children is Rickets.

o Other diseases given in option are seen in elderly.

Ans. is ‘b’ i.e., Rickets

Windswept deformity

o A valgus deformity of one in association of varus deformity of other knee is known as windswept deformity.

Causes of windswept deformity

o Rickets              

o Physeal osteochondromatosis      

o Hereditary dysplasia (epiphyseal dysplasia) of bone.

Ans. is ‘b’ i.e., X-ray knee joint is diagnostic

Treatment of Vit D deficiency rickets

o There are two startgies for administration of vitamin D ‑

A) Startgy 1 (stoss regimen)

               6 lac IU (15,000 g or 15 mg) Vit D3 is administered every 2 weekly.

               At every follow up monitoring is done by X-rays and blood investigations.

               Once healing is started, children are further put on 400 IU or 10 g of vitamin B₃ per day.

B) Startgy 2

               2,000 – 5,000 IU (50 – 125 g) of vit D₃ is given every day for 4-6 weeks.

Radiological changes of Rickets

o Earliest radiological changes are seen around the wrist, i.e. at lower end of radius & ulna.

o Later on, similar changes may also be seen around knee, elbow & ankle.

o X-ray findings are –

             Cupping & flaring of metaphysis

             Large gap between epiphysis and metaphysis because of widening of physis (growth plate).

             Fraying of metaphysis due to irregular calcification at metaphyseal margins.

             Generalized osteopenia

             Cortical thinning

             Coarse & fuzzy trabeculation

            White line of calcification (frenkels line) at physeal region —> It is the first radiological sign of healing and appears after administration of Vit D.

About other options

o Rachitic rosary is nontender (in contrast rosary of scurvy, i.e. scorbutic rosary is tender).

o Softening of ribs impairs air movement and predisposes patient to chest infection (pneumonia) and atelectasis. o Hyponatremia may be seen in rickets due to renal tubular acidosis (not in Vit D deficiency rickets).

Ans. is `a’ i.e., Craniotabes

Craniotobes is the earliest manifestation of Rickets.

Ans. is ‘a’ i.e., Rickets

Ans. is ‘d’ i.e., All of the above

Ans. is ‘c’ i.e., Saddle nose

o Saddle nose is not seen in rickets

Ans. is ‘a’ i.e., Rickets; ‘b’ i.e., CMV infection

Bulging anterior fontanel

o The fontanel is normally flat or slightly depressed relative to the frontal and parietal bones and is pulsatile. o Bulging fontanel is a reliable sign of raised ICT during infancy.

o The pulsations may disappear when fontanel becomes tense due to marked elevation of ICT.

B, C i.e. Cupping of metaphysis, Ricketic rosary

 Radiological features of bone

Rickets

 Metaphysis: indistinct, frayed, splaying, and cupping of marginQ. Patchy sclerosis in case of intermittent dietary deficiency

• Widened epiphysis with hazed cortical margin
• Generalized reduction in bone density
• Looser’s zone (less common)
• Severe cases show Genu valgum, bow legs, thoracic kyphosis, pigeon chest, ricketic rosaryQ, skull bossing, cox vera.

A i.e. Rickets

C i.e. Rickets

• Flaring of anterior ends of rib is charcteristically seen in ricketsQ and beaded ribs are found in osteogenesis imperfectaQ.
• Other causes of multiple anterior rib flaring are – achondroplasia, scurvy, thanatophoric dysplasia & normal variants.

Ans. is ‘c’ i.e., Rickets 

Answer is C (Ricket’s)

III. Shifts of extracellular phosphate into cells

1. Intravenous glucose
2. Insulin therapy of prolonged hyperglycemia or diabetic ketoacidosis
3. Catecholamines (epinephrine, dopamine, albuterol)
4. Acute respiratory alkalosis
5. Gram negative sepsis, toxic shock syndrome
6. Recovery from starvation or acidosis
7. Rapid cellular proliferation
   1. Leukemic blast crisis
   2. Intensive erythropoietin, other CSF therapy

IV. Accelerated net bone formation

1. Following parathyroidectomy
2. Treatment of Vitamin D deficiency, Paget disease
3. Osteoblstic metastases

Answer : B.) Hypophosphatemia.

Rickets

• Failure of osteoid calcification (rickets) in children is because of a disruption in the pathway of either vitamin D or phosphate metabolism.
• Types of rickets include the following:
  • Nutritional rickets
  • Congenital rickets
  • Rickets of prematurity
  • Vitamin D resistance (type I and type II)
  • Neoplastic rickets
  • Hypophosphatemic rickets
  • Drug-induced rickets.
• Low phosphate and high alkaline phosphatase levels characterize most of the disorders

Answer is C (Hypoparathyroidism) :

Raised alkaline phosphatase levels are associated with hyperparathyroidism and not with hypoparathyroidi.sm. Serum alkaline phosphatase levels may be raised in hyperparathyroidism depending upon degree of involvement of bone. Q

Ans. A i.e. Rickets

Rickets

• Pathology: Defective mineralization of osteoid/ bones & cartilage
• Features:

–        Craniotabes,

–        Wide open fontanelle,

–        Rachitic rosary (Enlargement of costochondral junction)

• X-ray appearances:

–        Widening & thickening of epiphysis,

Cupping & fraying of metaphysis

Ans. A: Frenkels Line

In rickets, the skeletal effects are due to lack of calcification of osteoid.

The first changes of rickets appear in rapidly growing distal ends of ulna & radius (wrist & knee are commonly involved due to more use).

Rarefaction of provisional zone of calcification with widening of epiphysis- diaphysis distance is first to appear. The most obvious change are at ‘metaphysis’- where rapid growth is occurring.

First change to appear is a ‘loss of normal zone of provisional calcification’ adjacent to metaphysis.

This begins as an indistinctness of the metaphyseal margin, progressing to a ‘frayed’ appearance with widening of the growth plate, due to lack of calcification of metaphyseal bone.

Weight bearing & stress on uncalcified bone gives rise to ‘splaying’ Sr ‘cupping’ of metaphysis.

A similar but less marked effect occurs in subperiosteal layer, which may cause lack of distinctness of cortical margin.

Eventually a generalized reduction in bone density is seen.

In the epiphysis – there may be some haziness of cortical margin.

Thus all findings in Rickets occur due to failure of calcification & abnormal demineralization

i. Skull changes

–        Pronounced calvarial demineralization

–        Basilar Invagination

–        Indistinct sutural margin

–        Delayed tooth eruption Premature craniostenosis

–        Craniotabes

–        Calvarial thickening following treatment

ii. Spine changes

–       Scoliosis

–        Biconcave vertebral bodies

–        Triradiatic pelvis.

Ans. D: Hypertonia

The history in patients with rickets may include the following:

• Generalized muscular hypotonia of an unknown mechanism is observed in most patients with clinical (as opposed to biochemical and radiographic) signs of rickets.
• Craniotabes manifests early in infants with vitamin D deficiency, although this feature may be normal in infants, especially for those born prematurely.
• If rickets occurs at a later age, thickening of the skull develops. This produces frontal bossing and delays the closure of the anterior fontanelle.

In the long bones, laying down of uncalcified osteoid at the metaphases leads to spreading of those areas, producing knobby deformity, which is visualized on radiography as cupping and flaring of the metaphyses.

• Weight bearing produces deformities such as bowlegs and knock-knees.
• In the chest, knobby deformities results in the rachitic rosary along the costochondral junctions. The weakened ribs pulled by muscles also produce flaring over the diaphragm, which is known as Harrison groove. The sternum may be pulled into a pigeon-breast deformity.

In more severe instances in children older than 2 years, vertebral softening leads to kyphoscoliosis. The ends of the long bones demonstrate that same knobby thickening. At the ankle, palpation of the tibial malleolus gives the impression of a double epiphysis (Marfan sign). Because the softened long bones may bend, they may fracture one side of the cortex (i.e., greenstick fracture).

Ans. C: Frenkel’s Line

Ans. C: Vitamin D dependent rickets-II

Hyperphosphatemia alters calcium and phosphate ion solubility products, and calcium deposition in soft tissue may occur. The lower circulating concentrations of 1, 25 (OH)2D may further aggravate the hypocalcemia by impairing intestinal absorption of calcium.

Hyperphosphatemic-induced hypocalcemia inhibits vitamin D synthesis and results in an increase in PTH secretion. Secondary hyperparathyroidism from long-term hyperphosphatemia is usually associated with renal insufficiency. Treatment should be directed towards the hyperphosphatemia in order to correct the hypocalcemia.

Hypophosphatemia is more severe than hypocalcemia in vitamin D deficiency states because of the increased secretion of PTH, which is only partly active in elevating blood calcium but is capable of phosphaturia.

Ans. D: Rickets

The dietary risk factors for rickets include abstaining from animal foods.

Vitamin D deficiency remains the main cause of rickets among young infants in most countries, because breast milk is low in vitamin D and social customs and climatic conditions can prevent adequate UVB exposure.

Osteomalacia, occurs exclusively in adults and is characterized by proximal muscle weakness and bone fragility.

Ans. Rickets

Ans. Narrowing or absence of the normal zone of provisional calcification

Ans. Radiological examination of growing end of bone

Ans. Rickets

Ans. is ‘a’ i.e., Epidemic typhus

Weil felix reaction

• This reaction is an agglutination test in which sera are tested for agglutinins to 0 antigens of certain nonmotile proteus strains OX – 19, OX – 2 and OX – K.
• The basis of the test is the sharing of an alkali – stable carbohydrate antigen by some rickettsiae and by certain strains of proteus, P. vulgaris OX – 19 and OX – 2 and P. mirabilis OX – K.
• The test is usually done as a tube agglutination, though rapid slide agglutination methods have been employed for screening.

Ans. is ‘d’ i.e., Medial compartment osteoarthritis

Genu valgum (knock knee)

Genu valgum is a condition in which the lower legs are positioned at an outward angle with abnormal approximation of knees and abnormally divergent ankles. Genu valgum is a condition in which the knees touch, but the ankles do not touch. Normally, a child is born with genu varum. Therefore, neonates and infants normally have genu varum. When the infant begins to stand and walk, the lower limb straighten and this physiological genu varus disappear at around years of age. The leg become straight. Then, between the age of 2-3 years genu valgum starts developing gradually with maximum genu – valgum of 12° at the age of 31/4 years. Finally genu-valgum spontaneously get corrected by the age of 7 years to that of normal adult genu valgum of 7 – 8°. So upto 7 years, exagerated genu valgum is physiological. If this exaggerated genu valgum persists after 8 years, then it is pathological genu valgum.

Ans. is ‘d’ i.e., Medial compartment osteoarthritis

Ans. is ‘a’ i.e., Fibrous dysplasia

Wormian bones

• Wormian bones are extra bone pieces that occur within a suture in the cranium.
• These are irregular isolated bones which appear in addition to the usual centers of ossification of the cranium.
• They occur most frequently in the course of the lambdoid suture.
• Causes of wormian bones (Mnemonic – PORKCHOPS)

1. Pyknodysostosis
2. Osteogenesis imperfecta
3. Rickets
4. Kinky hair syndrome
5. Cleidocranial dysostosis
6. Hypothyroidism (cretinism) / Hypophosphatasia

• Otopalatodigital syndrome
• Progeria

1. Syndrome of Downs

• Wormian bone appears radiographically as islands of ossification in the skull in nonossified membranous bone.
• To be diagnostic value, the wormian bones should be 4 mm by 6 mm in size, 10 in number and arranged in a mosaic pattern.
• Wormian bones are not present in normal skull.

 The condition of the lower limbs as shown in photograph above represents Knock knees (Genu valgum).

Knock knees are angular deformities at the knee, in which the head of the deformity points inward. A standing child whose knees touch, but whose ankles do not, is usually said to have knock knees. During early childhood, knock knees are a part of normal growth and development.

CAUSES-

Knock knees are usually part of the normal growth and development of the lower extremities

.•   Some cases, especially in a child who’s 6 or older, may be a sign of an underlying bone disease, such as osteomalacia or rickets. 

•   Obesity can contribute to knock knees—or can cause gait (walking) problems that resemble, but aren’t actually, knock knees. 

•   The condition can occasionally result from an injury to the growth area of the shin bone (tibia), which may result  in just one knocked knee.

The underlying metabolic disorder as seen in the  X-ray wrist above represents Rickets (Appearance, cupping,Fraying,Splaying).

Rickets is a disease of growing bone that is unique to children and adolescents. It is caused by a failure of osteoid to calcify in a growing person.