Approach to a child presenting with rickets

Introduction Rickets is a disease of growing bones due to defective mineralization at growth plates in growing children. Defective mineralization of bone matrix is referred to as osteomalacia and is seen in children with rickets. Adequate calcium and phosphate levels are required for bone mineralization and vitamin D is critical for calcium homeostasis. Prevalence of nutritional rickets is rising in the developing as well as the developed countries due to changing lifestyles and globalization 1,2 .


Introduction
Rickets is a disease of growing bones due to defective mineralization at growth plates in growing children.Defective mineralization of bone matrix is referred to as osteomalacia and is seen in children with rickets.Adequate calcium and phosphate levels are required for bone mineralization and vitamin D is critical for calcium homeostasis.Prevalence of nutritional rickets is rising in the developing as well as the developed countries due to changing lifestyles and globalization 1,2 .

Vitamin D deficiency rickets
The serum level of 25OHD is currently considered to be the most appropriate marker of the Vitamin D status of an individual.25OHD level of less than 50nmol/l is considered as deficiency according to Institute of Medicine Guidelines 3 .There are three stages of vitamin D deficiency: 1. Hypocalcaemia due to poor intestinal absorption and reduced bone resorption.2. Normal calcium and low phosphate state due to secondary hyperparathyroidism 3. Severe bone disease with recurrence of hypocalcaemia.
Measurement of 25OHD is not available in the state sector in Sri Lanka.Based on the clinical history and in the absence of a chronic underlying condition, a trial of treatment with vitamin D and calcium is considered rational in resource limited settings 4 .After 1-2 months of treatment a repeat x-ray should be done to look for the line of healing.Serum alkaline phosphatase also should show a downward trend at the end of one month.If biochemical or radiological evidence of response is present, nutritional rickets could be diagnosed and treatment continued for 2-3 months.Thereafter, maintenance with daily intake of vitamin D 400units is recommended at least for 6 months.Treatment of vitamin D deficiency should be with either ergocalciferol (D2) or cholecalciferol (D3).The dose regime is as follows 5 : < 6 months of age -3,000 units daily 6 months -12 years -6,000 units daily >12 years -10,000 units daily If malabsorption, liver disease or compliance is an issue, a single oral or intramuscular dose of vitamin D 150-300,000 units can be given every 3 months.
Other suggested treatment regimens are as follows: • Infants and toddlers -10,000U/kg (maximum 150, 000U) 6 • Adolescents -10,000U/kg (maximum 600,000U) 7 It is important that adequate calcium intake is given to these children with nutritional rickets as they are at risk of dietary calcium insufficiency 4 ..Intravenous calcium is the treatment of choice until healing occurs with attention to serum phosphate and magnesium levels.Subsequently high dose of calcium and calcitriol will be useful in the management.These patients need to be monitored for development of hypercalciuria and nephrocalcinosis.

Vitamin D resistant rickets
In the presence of hypercalciuria a thiazide diuretic needs to be started at a dose of 0.5-2mg/kg day.

Anticonvulsant induced rickets
All drugs used in seizure control predispose to vitamin D deficiency.Underlying mechanism is the activation of cytochrome P450 enzymes which also metabolises vitamin D. It has been recently recommended that children on anticonvulsants for more than 3 months should be provided supplements of vitamin D in a dosage of three times that used for normal children 10,11 .

Hypophosphataemic rickets
It must be emphasized that low phosphorus levels do not necessarily mean hypophosphataemic rickets.All causes of calcipenic rickets result in secondary hyperparathyroidism and phosphaturia.The most useful biochemical marker is the PTH which is normal or minimally raised in hypophosphataemic rickets.
Abnormalities in the sodium-phosphate cotransporter in the epithelial brush border of the proximal renal tubule result in hypophosphataemic rickets.Phosphaturia results in defective mineralization of the growth plate in the presence of normal calcium, vitamin D and PTH levels.

• X-linked hypophosphataemic rickets (XLH)
Inactivating mutation of PHEX gene results in XLH.Increased expression of fibroblast growth factor 23 (FGF23) results in inhibition of phosphate reabsorption and impaired production of 1 alpha hydroxylase.Affected patients usually present with bowing of legs with characteristic anterior bowing of tibia.Defective dentine can result in dental pulp abscess formation.Biochemical investigations reveal reduced plasma phosphate, increased alkaline phosphatase and low renal tubular reabsorption of phosphate (TRP %).TRP <85% is regarded as abnormal.To correct the nonlinear relationships of TRP, Tubular maximum for phosphate reabsorption (TmPO4/GFR) is derived from the normogram or calculated for the newborns and toddlers to improve the accuracy 12 .
Treatment is with phosphate supplementation at a dose of 70-100mg/kg/day in 4-6 divided doses.Alfacalcidol at a dose of 25-50ng/kg once daily is given to prevent secondary hyperparathyroidism.
During follow up it is necessary to look for evidence of hypercalciuria, nephrocalcinosis and secondary hyperparathyroidism.If hyperparathyroidism is detected it is necessary to adjust the dose of alfacalcidol.Orthopaedic follow up will also needed to correct deformities.Treatment of hypophosphataemic rickets does not improve the growth optimally and there is no place for growth hormone according to recent Cochrane review 13 .
• Autosomal dominant hypophosphataemic rickets (ADHR).Lower limb deformities, tooth abscesses and fractures are commonly seen.Both sexes are equally affected and some women can present in second to fourth decade of life.The clinical cause is similar to mild form of XLH.Treatment is similar to XLH.
• Hereditary hypophosphataemic rickets with hypercalciuria (HHRH) Mutation in sodium-phosphate co-transporter gene SLC34A3 results in this condition.They have hypercalciuria in addition to hypophosphataemia.In the absence of readily available genetic tests it is important to delineate the type of hypophosphataemic rickets.However it is cheaper to look for hypercalciuria before commencing treatment for patients with hypophosphataemic rickets.Treatment includes high dose phosphate at 1-2.5g/d in 5 divided doses.
• X linked recessive hypophosphataemic rickets(Dent disease) Boys present with features similar to XLH but associated proteinuria, hypercalciuria and nephrocalcinosis will differentiate from other subtypes.They can progress to renal failure.Treatment is only with phosphate supplement.
• Autosomal recessive hypophosphataemic rickets.Biochemical and clinical features are similar to XLH and ADHR and treatment is similar to XLH.

Tumour induced osteomalacia (TIO)
TIO is an acquired cause of FGF23 excess mainly seen in adults.They present with fractures, bone pain or muscle weakness.Mostly mixed connective tissue tumours give rise to this condition.Removal of tumour results in biochemical and radiological improvement.

Fibrous dysplasia
Fibrous dysplasia is caused by somatic activating mutations in the alpha subunit of the stimulatory Gprotein.Non mineralizing bone lesions secrete FGF23 leading to hypophosphataemic rickets or osteomalacia.Phosphate levels need to be corrected with phosphate solutions.

Conditions associated with radiological features of rickets
Metaphyseal chondrodysplasia, Schmid, Jansen, Schwachman skeletal dysplasias and Blount disease will have similar radiological features but not the typical biochemistry.It is necessary to evaluate a child presenting with clinical and radiological features of rickets carefully before commencing on treatment.

Orthopaedic treatment
Orthopaedic treatment should only be considered after complete biochemical and radiological healing of rickets which may take 18-24 months.Mild to moderate deformities normalize by remodelling over years.If deformities interfere with mobilization surgical correction may need to be considered.

Conclusion
Rickets is a seemingly easy diagnosis in paediatric practice.However to manage a patient with rickets a careful clinical and biochemical evaluation is needed to decide on the most appropriate treatment.Once treatment is started it is difficult to re-evaluate.

Key points
• Vitamin D deficiency is common.
• Calcium deficiency can co-exist with vitamin D deficiency • Treat vitamin D deficiency with ergocalciferol or cholecalciferol NOT calcitriol or 1 alfa calcidol.
• Do serial PTH when hypophosphataemic rickets patients are on treatment to titrate 1 alfa calcidol dose.
• In hypophosphataemic rickets, in addition to phosphate buffer treatment add 1 alfa calcidol if there is no hypercalciuria.
• Look for evidence of hypercalciuria (patients with VDDR and hypophosphataemic rickets) and treat appropriately.
• Take the second void urine sample in the morning for calcium creatinine ratio.
• Do biochemical investigations at least after 4 hours of fasting, preferably 8 hours.
8itamin D resistant rickets type 1 (VDDR1) is due to 1 alpha hydroxylase deficiency.They usually present during the toddler age group.Biochemical features are similar to vitamin D deficiency rickets: hypocalcaemia, hypophosphataemia, raised PTH and high alkaline phosphatase levels.VDDR1 is treated with alfacalcidol or calcitriol 30-70ng/kg.Initially it may require supra-physiological doses till healing of rickets.Alfacalcidol has a long half-life and could be given as a daily dose but may need a larger dose as it is less potent.Calcitriol is more potent but needs to be given in two divided doses.Vitamin D resistant rickets type 2 (VDDR 2) is due to a mutation in the vitamin D receptor.It typically presents during infancy or toddler age groups.Mild cases may present during adolescence8.It is a rare condition and 50% of affected patients can have alopecia.Presence of alopecia does not determine the severity of the disease.Supra-physiological doses of calcitriol or alfacalcidol are useful in the treatment.It has been reported that phosphate treatment was useful in the treatment of VDDR2