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The ABC's of Pediatric Laboratory Medicine- R is for Rickets

By: Jumoke Oladipo, MD, DABCC, Clinical Chemist, Staten Island University Hospital, NY

Rickets is a disorder caused by inadequate mineralization of bone matrix at the growth plates that occurs in children before epiphyseal fusion. Decreased endochondrial ossification leads to excessive epiphyseal cartilage, growth failure and skeletal deformities. The growth plate continues to thicken despite the lack of mineralization due to continued growth of the cartilage of osteoid. There is also a general softening of the bones and widening of the metaphyses. Rickets and osteomalacia are often used interchangeably but osteomalacia is due to inadequate mineralization of bone matrix which can exist with or without rickets.

Rickets is thought to have its roots in Northern Europe in the 17th century although it was not well described till 16451,2. Subsequently, in 1650, Francis Glisson concluded that rickets was a disease of children with peak incidence between eighteen months of age and two and half years1,2. He also proposed that rickets was neither contagious nor heritable but suggested a mystic nature to the etiology of rickets. Names by which rickets was known in the 17th and 18th centuries included gibbosus or cyrtosis (meaning curve), rachitis and the English disease3.

Rickets was very common in the New England colonies of the United States and in Europe where its etiology was attributed to deficient diet, unhygienic environment, lack of exercise and lack of exposure to sunlight. 3 The late 19th and 20th centuries saw a tremendous expansion in the knowledge of rickets; early animal studies linked rickets to the absence of a dietary fat which was believed to be closely linked to vitamin A4. It was not until 1922 that McCollum et al characterized this dietary fat as vitamin D5. It was also discovered that sunlight and cod liver oil were essential in the prevention and treatment of rickets.

The association of rickets with seasonal variations (higher incidence in winter months), dietary deficiency, skin pigmentation and exclusive breastfeeding led to diet fortification and improved therapy with subsequent eradication of rickets in the United States by the mid 1900s. Thereafter, rickets was considered to be a disease of the developing countries until reports of its re-emergence in the United States in recent years with majority of the affected infants being dark skinned and residents of the northern latitudes5,6,7. Currently, rickets is considered not to be limited to developing countries nor a disease of the past.

Etiology and Epidemiology:

Rickets can be due to either predominant calcium or predominant phosphate deficiencies. The most common causes of calcium related rickets (Calcipenic) are due to vitamin D abnormalities with nutritional deficiency topping the list. Others include rickets of prematurity, vitamin D dependent rickets, chronic renal failure, congenital Vitamin D deficiency and intestinal malabsorption syndromes. Obesity has also been documented as an increasing cause of vitamin D deficiency due to sequestration of vitamin D in adipose tissue8.

Phosphopenic rickets results most commonly from renal phosphate wasting (phosphaturia). Causes could be hereditary (XLH - X-linked hypophosphatemia, ADHR - autosomal dominant, ARHR - autosomal recessive variants) or acquired (intrinsic renal tubular diseases and tumor induced rickets). Drug induced rickets due to prolonged use of antiepilepsy drugs (phenytoin, carbamazepine and phenobarbital) has been reported; these reports were mostly in institutionalized children9, while reports in ambulatory children have not found evidence of rickets10,11. Reports of more recent experience with the classic antiepileptic drugs are not available for children because, typically, these drugs are no longer used as first-line agents in pediatric epilepsy with the exception of neonatal seizures in which phenobarbital and phenytoin are still used.

Vitamin D deficiency is particularly prevalent among exclusively breastfed dark skinned babies, because in addition to the skin pigmentation, breast milk has very low levels of vitamin D. Surprisingly, rickets have been reported in sun rich areas with prevalence rates as high as 24%12. Dark skinned persons will require a higher amount of exposure to sunlight compared to light skinned persons for an equivalent amount of vitamin D. Urban environments also have challenges with obtaining adequate UV-B exposure due to fear of violence, work schedules, prolonged use of television, video games and computers by children and use of sunscreen to prevent skin cancer.

The true incidence of rickets in the US is unknown since this is not a reportable disease however; several studies have suggested the re-emergence of nutritional rickets in the US in recent years especially in areas with reduced sunlight6,8,13. There has also been a resurgence of rickets in the UK and major European countries especially among immigrants from South Asia, Africa, Afro-Caribbean and Middle East (figure I). In recent times, the promotion of breastfeeding has been associated with an increase in the incidence of rickets especially amongst breastfed dark skinned children14. The greatest burden of this disease however remains in Africa, the Middle East and Asia where disease prevalence are reported to be between 10 - 70%15.
http://2.bp.blogspot.com/_Jn-LeUC-BnU/TOEYT4wH9eI/AAAAAAAABko/ibgtOHRVJ_s/s400/rickets1.JPG 

Figure I: Resurgence of rickets made news headlines. This excerpt is from an article based on research conducted in Southampton, UK by Professor Nicholas Clarke, consultant orthopaedic surgeon at Southampton General Hospital and professor of paediatric orthopaedic surgery at the University of Southampton.

 

 

Summary of Ca and Vit D Homeostasis:

A proper balance between bone mineral deposition and resorption has to be maintained for adequate bone growth. The parathroid gland through its calcium sensing receptor is the major organ responsible for the maintenance of circulating calcium levels. Release of parathyroid hormone (PTH) leads to metabolic effects that include increase in osteoclastic bone resorption, increase in renal tubular reabsorption of calcium and increased excretion of phosphates. There is also up-regulation of 1,25-dihydroxycholecalciferol (1,25DHCC) which is responsible for producing active vitamin D. One of the most important actions of active vitamin D is to increase the intestinal absorption of calcium.

Vitamin D metabolism has been discussed extensively by Dr. V Grey in the 2006 online edition of the monitor16; in summary however, the major organs involved in vitamin D metabolism are the skin, parathyroids, intestines, kidneys and bone. Vitamin D is responsible for normal mineral ion concentrations and is required not only to prevent rickets but also for many cellular and neuromuscular functions. It also has skeletal and extraskeletal effects. It promotes the gene for calbidin, a calcium binding protein that transports calcium across the enterocyte. It also increases the production of calcium channels along the intestinal walls permitting calcium movement from the enterocyte into the circulation. Vitamin D is essential for the actions of PTH on osteoclasts and stimulates the production of osteocalcin and osteopontin (calcium binding proteins) by osteoblasts. It can be concluded that PTH is the early responder in controlling circulating calcium concentrations whereas vitamin D is the late responder in maintaining a normal mineralized skeleton.

Pathophysiology

A study by Fraser et al in 196717 concisely explains the three classic stages of rickets. In stage I, there is hypocalcemia caused by vitamin D deficiency, development of secondary hyperparathyroidism, upregulation of 1 α hydroxylase enzyme, and increase in calcium intestinal absorption. This stage may be asymptomatic or may manifest as convulsions. In stage II, normocalcemia, hyperaminoaciduria, hypophosphatemia and hyperphosphaturia with evident clinical rickets is present. Stage III is a progression of stage II but with recurrence of hypocalcemia, convulsions and severe skeletal manifestations. Bone disease starts in the late phase of stage I. The three stages may not be present in all patients.

Placental tranfer of 25OHD (25 hydroxyvitamin D) is protective for the first three months of life and symptoms begin to appear thereafter. Congenital rickets is very rare and is usually due to severe maternal calcium deficiency.

Vitamin D dependent rickets - 1 (VDDR-1, pseudo vitamin D deficiency) is caused by an autosomal recessive defect in 1-α hydroxylase. This is a very rare disorder with the exception of a French Canadian population in Quebec with a prevalence rate at birth of of 1 in 2916 and a carrier rate of 1 in 2718. Calcitriol (1,25OH2D) resistant rickets (CRR or vitamin D resistant rickets) is due to an autosomal recessive defect in the calcitriol receptor resulting in absent vitamin D signaling.

The past few years has broadened our knowledge of phosphate metabolism, now we know that intestinal absorption of phosphate is independent of vitamin D. The renal system is responsible for phosphate balance by tubular reabsorption and excretion controlled by phosphatonins and PTH. Fibroblast growth factor 23 (FGF23) has been recognized as a major phosphatonin that regulates renal phosphate reabsorption. FGF23 is produced mainly by osteocytes and acts on the renal tubular cells to prevent the reabsorption of phosphate thereby leading to increased phosphate excretion. Increased FGF23 signaling leads to excess renal phosphate loss and down regulation of 1 α hydroxylase while deficient signaling leads to phosphate retention19,20. One of the common mutations in XLH involves the phosphate regulating gene on the X chromosome (PHEX gene), which increases FGF23 levels and promotes phosphate wasting; there is usually no associated hypocalcemia. Autosomal dominant hypophosphatemic rickets (ADHR) was the first disease associated with FGF23 abnormalities and this is due to amino acid substitutions at the cleavage sites making the molecule resistant to cleavage, having a longer half life and increased circulating levels promoting phosphate wasting. Autosomal recessive hypophosphatemic rickets (ARHR) is rare and is due to a defect in the DMP 1 gene (Dentin Matrix Protein 1), which is highly expressed in osteoblasts and osteocytes. Aquired renal phosphate wasting in children with mesenchymal tumors is also linked to the secretion of FGF23 by these tumors21.

Non-phosphatonin causing phosphaturic conditions include hereditary hypophosphatemic rickets with hypercalciuria (HHRH), Fanconi syndrome and isolated intrinsic renal tubular diseases like cystinosis and tyrosinemia. HHRH is caused by a primary defect in phosphate transport involving mutations in the SLC34A3 gene which encodes for NaPi-IIc protein (Na dependent phosphate co-transporter in the proximal convoluted tubule)22. The body responds appropriately by increasing 1 α hydroxylase and active vitamin D concentrations. The importance of this comes to play in the treatment of this condition in which phosphate supplementation is all that is needed for correction.

Clinical Features (refer to Figure 2):

rickets

Figure 2

Most of the features of rickets are skeletal in nature. The deformities found largely depend on the age at presentation and the severity of the disease. Craniotabes (softening of the cranial bones) is a common finding. A characteristic finding in the chest is the rachitic rosary finding which is widening of the costrochondral junctions giving it a beadlike feel on palpation. There is enlargement of the wrists and ankles and the characteristic Harrison groove, which is a horizontal depression along the lower anterior chest wall due to pulling in of the softened ribs by the diaphragm on inspiration. Other bony deformities are frontal bossing, scoliosis, lordosis, kyphosis, genu valgum symptoms include failure to thrive, muscle weakness, fractures and listlessness. Children may present with tetany, seizures and cardiac failure23,24.

 

Diagnosis

Diagnosis of rickets is usually based on the clinical features, biochemical analysis and radiologic studies. Radiologic findings are beyond the scope of this review, but is important to evaluate the skull, limbs and joints.

Biochemical and genetic tests are carried out to determine the etiology of rickets which are important to determine treatment modalities. The initial laboratory tests usually carried out in a child with rickets would include serum calcium, phosphorus, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, creatinine and electrolytes. Serum 25-hydroxyvitamin D levels are the best indicator of vitamin D status. 1,25-dihydroxyvitamin D is not a useful test to determine if a child is vitamin D deficient and is frequently misordered. Vitamin D insufficiency and deficiency states have been defined as levels between 20 and 29 ng/mL and below 20 ng/mL respectively. Levels below 10 ng/mL indicates severe deficiency states. Studies suggest that peak calcium absorption occurs at levels of 32 ng/mL and maximal PTH suppression is not reached until levels of 30-40 ng/mL23.  In 2011, the Institute of Medicine (IOM) committee concluded that serum 25-hydroxyvitamin D levels of 16 ng/mL cover the requirements of half of the population and levels of 20 ng/mL cover 97.5% of the population26.  This created some controversy, as the levels were lower than those previously recommended.

Other investigations may be carried out depending on the suspected etiology of the rickets. Measurement of urinary calcium may be important in hereditary hypophosphatemic rickets with hypercalciuria. Amino acids and glucose in urine should be ordered if fanconi syndrome is suspected. Measurement of FGF23 has been proposed as a routine laboratory investigation to assist in determination of the etiology of hypophosphatemic rickets. Even though there are many commercial kits available for the assay of FGF23, none is FDA approved yet. Renal phosphate wasting is confirmed by very low total phosphate reabsorption and TmP/GFR ratio (Maximal tubular reabsorption of phosphorus per glomerular filtration rate).

Table I: Biochemical findings in common causes of rickets


Disorder

 Ca

Pi

PTH

25-(OH)D

1,25-(OH)2D

ALP

Urine Ca

Urine Pi

Vitamin D Deficiency

 ↔,↓

   ↓

    ↑

   ↓ 

↔,↓

     ↑

   ↓

    ↑

VDDR - 1

 ↔,↓

   ↓

    ↑

  ↔

   ↓

     ↑

   ↓

    ↑

CRR (VDDR -2)

 ↔,↓

   ↓

    ↑

  ↔

  ↑↑

     ↑

   ↓

    ↑

XLH

   ↔

   ↓

   ↔

  ↔

   R↓

     ↑

   ↓

    ↑

Tumor Induced Rickets

   ↔

   ↓

   ↔

  ↔

   R↓

     ↑

   ↓

    ↑

Fanconi Syndrome

   ↔

  ↓

   ↔

  ↔

   R↑

     ↑

   ↓,↑

    ↑

HHRH

   ↔

   ↓↓

  ↔,↓

  ↔

↑, R↓

     ↑

     ↑

     ↑

↔, Normal;↓, decreased; ↑ increased; R↓, relatively decreased; ↑↑, extremely increased; R↑, relatively increased; VDDR, vitamin D dependent rickets; CRR, calcitriol resistant rickets; XLH, X linked hypophosphatemic rickets; HHRH, hereditary hypophosphatemic rickets with hypercalcemia.

Ca, serum calcium; Pi, serum phosphate; PTH, parathyroid hormone; ALP, Serum Alkaline phosphatase.

Prevention of Vitamin D deficiency Rickets

Vitamin D deficiency rickets is preventable but remains a challenge. It is still uncertain if the prevention is due to the direct effects of vitamin D on the skeleton or indirectly through the correction of mineral ion concentration, the overall effect of adequate vitamin D levels remains very beneficial.

Most foods except for oily fish contain very little vitamin D unless artificially added. Prevention of vitamin D deficient rickets boils down to two approaches, adequate UV-B exposure and oral intake. There is still controversy as to how much exposure to sunlight should be allowed since sunlight exposure has been known to be a major risk factor for the development of skin cancer. Adequate dietary supplementation is about the only safe way to prevent this disease. The latest revision of requirements by the IOM in 2011 recommends 400 IU/day during the first year of life and 600 IU/L beyond the first year. In North America, fortification of cereals and infant formula with vitamin D is enforced and vitamin D supplementation is required for all breastfed babies. Increase in calcium intake is a factor that needs to be considered especially in areas where calcium deficiency has been identified as a major cause of rickets. Public health programs in the UK have recorded success in public awareness and a reduction in the incidence of symptomatic vitamin D deficiency25.

The resurgence in the diagnosis of rickets is multifactorial, these include greater awareness among pediatricians, better laboratory methods for vitamin D assessment with an upsurge in the laboratory diagnosis of vitamin D insufficiency/deficiency, lack or block to sunlight exposure and increased breastfeeding. Since rickets occurs in children less than two years of age, optimizing vitamin D status of women in child bearing age and in their young offsprings is the method of choice.

References

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  2. Rajakumar K, Thomas SB. Reemerging nutritional rickets: a historical perspective. Arch Pediatr Adolesc Med2005;159:335-41.
  3. Rajakumar K. Vitamin D, cod-liver oil, sunlight, and rickets: a historical perspective. Pediatrics 2003;112:e132-e135
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  5. McCollum EV, Simmonds N, Becker JE, Shipley PG. Studies on experimental rickets. XXI. An experimental demonstration of the existence of a vitamin which promotes calcium deposition. J Biol Chem 1922;53:293-312
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  21. Farrow EG, White KE. Tumor induced osteomalacia. Exp Rev Endocrinol Metab 2009;4.5:435
  22.  Pettifor JM. What's new In hypophosphatemic rickets? Eur J Pediatr 2008;167:493-499
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