ickets.
The child should undergo careful clinical examination, including documentation of growth and pubertal status. The clinical signs to look for on examination are shown in Table 10.3.
Rickets causes abnormal bone mineralization which may be evident on X‐ray. Additional radiological features commonly include a characteristic widening of the growth plate with cupping, splaying and fraying of an irregularly margined metaphysis (Figure 10.4). The characteristic clinical signs of vitamin D‐deficient and hypophosphataemic rickets are detailed in Table 10.3 and Figure 10.5 and Figure 10.6.
Figure 10.4 X‐ray of the wrist of a child with rickets caused by vitamin D deficiency.
Figure 10.5 Rachitic rosary.
Source: Courtesy of Dr Nina Ma.
Figure 10.6 Bowing of the legs in a child with hypophosphataemic rickets.
The lowered renal threshold for resorption of phosphate, which is associated with hypophosphataemic rickets, can be calculated from simultaneous serum and urinary biochemical measurements by reference to Kruse et al. (1982) or Shaw et al. (1990), which also contains details of age‐appropriate reference ranges. The presence of glycosuria, amino‐aciduria, or a metabolic acidosis with inappropriately alkaline urine is suggestive of a wider defect of tubular function, such as Fanconi’s syndrome or renal tubular acidosis.
Depending on the cause of the rickets, different preparations of vitamin D are required for effective treatment, as shown in Table 10.5. Where renal dysfunction is associated with metabolic bone disease, treatment of the wider systemic metabolic abnormality is required. Detailed guidance for this is beyond the scope of this volume and the reader is advised to consult appropriate textbooks on paediatric nephrology. Children with Fanconi’s syndrome may require phosphate therapy, whereas those with renal tubular acidosis require treatment with bicarbonate.
Table 10.5 Treatment of rickets.
Calcitriol 15–20 ng/kg per day increased to 30–60 ng/kg per day subdivided into one or two daily doses orally.
Unlike in adults, osteoporosis in childhood is not clearly defined but is caused by reduced bone mass per unit volume with a normal ratio of mineral to matrix. The possibility of osteoporosis should be considered in a child who presents with fractures following minimal trauma in whom there is also evidence of decreased bone mineral density (usually more than three standard deviations below the mean for age, size, and puberty). This may occur as a result of an imbalance between bone formation and bone resorption because of a variety of reasons or as a result of abnormalities of type 1 collagen synthesis (e.g. osteogenesis imperfecta). The causes of decreased bone mineral density, which may predispose to osteoporosis and present in childhood, are shown in Table 10.6.
Table 10.6 Causes of osteoporosis and other disorders which may lead to decreased bone mineral density.
Figure 10.7 X‐rays showing vertebral compression in a child with osteoporosis.
Clinical examination should include a careful assessment of growth, nutritional state, pubertal development, and the clinical signs of osteogenesis imperfecta listed in Table 10.3. The presence of unexplained bone tenderness and pain, particularly in the spinal region, and in association with a spinal deformity, such as a kyphosis or scoliosis, might suggest previously unsuspected fractures. These may occur with severe osteoporosis or osteogenesis imperfecta.
Distinguishing between osteogenesis imperfecta and idiopathic juvenile osteoporosis may prove difficult. Osteogenesis imperfecta should be considered in the presence of the clinical signs listed in Table 10.3. A skull X‐ray for the presence of wormian bones and a blood sample for genetic testing (e.g. the type 1 collagen genes COL1A1 or COL1A2) may assist in the diagnosis of osteogenesis imperfecta (for classification, see Table 10.7). Idiopathic juvenile osteoporosis may be suggested by X‐ray evidence of metaphyseal compression fractures at the knee. Histomorphometric examination of bone biopsy material may also help distinguish between these two conditions.
Table 10.7 Classification of osteogenesis imperfecta.
Bone mineral density may be measured by dual energy X‐ray absorptiometry (DEXA) scanning of the lumbar spine or hip. This method involves minimal radiation exposure and is based on the measurement of the attenuation of X‐rays of differing energy intensity as they pass through bone. However, these characteristics are influenced by the width of bone through which the X‐rays pass, which in children may vary as a consequence of age, body size, or puberty, in addition to illness. Interpretation of the data needs to take these factors into account and appropriate paediatric reference values must be used to interpret the results. It is recommended that bone mineral density should only be measured in children with risk factors for low bone density associated with low trauma or recurrent fractures, back pain, spinal deformity or loss of height, change in mobility status, or malnutrition.
Newer techniques for obtaining volumetric measures of bone mineral density that are not constrained by the limitations of DEXA, such as quantitative computed tomography, are now becoming available.
bisphosphonates (e.g. pamidronate) have been used in childhood, mostly to treat osteogenesis imperfecta. Despite residual uncertainty about their long‐term safety, there is growing evidence that they benefit children by reducing the pain associated with mini‐fractures, increasing bone mineral density and facilitating physical rehabilitation and mobility. There seem to be few side effects in the short to medium term apart from a transient rise in body temperature, fever, and influenza‐like symptoms during the initial course of infusions. It is advised to optimize dietary calcium and vitamin D intake during therapy to reduce to a minimum the risks of developing hypocalcaemia. Furthermore, after prolonged use, consideration should be given to tapering the dose down gradually to avoid the development of an abrupt junction between bone formed whilst receiving bisphosphonate therapy and that formed thereafter, as this may represent a point of weakness at increased risk of fracture.
Hypercalcaemia occurs when the serum calcium concentration exceeds 2.65 mmol/L. The causes of hypercalcaemia are shown in Table 10.8.
Table 10.8 Causes of hypercalcaemia.
Mild idiopathic hypercalcaemia of infancy presents with symptoms between the ages of two and nine months, but resolves spontaneously by the age of four years. When severe, it may present in the neonatal period in association with the dysmorphic features of Williams syndrome (Table 10.3 and Figure 10.8). Hypercalcaemia is associated with granulomatous disease (e.g. sarcoidosis and tuberculosis) as a result of the conversion of 25‐hydroxyvitamin D to 1,25‐dihydroxyvitamin D in granulomatous cells.
Figure 10.8 Williams syndrome.
Neonatal primary hyperparathyroidism is a serious disorder caused by homozygous mutations of the calcium‐sensing receptor gene, the product of which regulates PTH secretion. It causes anorexia, hypotonia, chest deformities, and respiratory distress. It is associated with a high mortality in the neonatal period and, to be successfully treated, requires urgent parathyroidectomy. Similar heterozygous mutations are responsible for autosomal dominant, familial hypocalciuric hypercalcaemia.
Primary hyperparathyroidism as seen in association with pituitary adenomas and gastrinomas or other pancreatic tumours (multiple endocrine neoplasia type 1) or in association with medullary thyroid cancer and phaeochromocytoma (multiple endocrine neoplasia type 2A) is exceptional in the paediatric age group. These two groups of disorders are inherited in an autosomal dominant fashion and all offspring of affected individuals should be screened for these endocrinopathies. The presence of elevated serum concentrations of PTH will distinguish hyperparathyroidism from hypercalcaemia caused by vitamin D intoxication, idiopathic infantile hypercalcaemia, granulomatous disease, and malignancy.
a family history of multiple endocrine neoplasia.
a sample should be stored for possible measurement of 1,25‐dihydroxyvitamin D concentration later, should this be indicated.
The treatment of hypercalcaemia involves promoting a low‐calcium diet and where relevant, stopping vitamin D, calcium supplements and other drugs, such as thiazides, which increase calcium concentrations. Patients should be encouraged to drink plenty of fluids. If significant dehydration is present, this should be corrected with IV 0.9% saline. Prednisolone may be helpful if hypercalcaemia is secondary to sarcoidosis or vitamin D intoxication. If hypercalcaemia persists, bisphosphonate therapy may help by inhibiting mobilization of calcium from the skeleton. A parathyroid adenoma may be located by careful ultrasound examination and treated by surgical removal of the affected gland. Hyperparathyroidism caused by diffuse hyperplasia requires surgical removal of all four glands.
Osteoporosis which is of sufficient severity that treatment with bisphosphonates is to be considered.
Osteoporosis secondary to other underlying disorders (e.g. inflammatory bowel disease, rheumatoid arthritis, or Cushing’s syndrome or disease) should have the treatment of their underlying disease discussed with the relevant specialists.
Many causes of hypocalcaemia, rickets, and hypercalcaemia are transient and resolve in childhood without the need for referral onto adult services. However, where the underlying cause has potential implications into adult life (e.g. hypoparathyroidism or pseudohypoparathyroidism), then referral through local transition arrangements should be organized. Of note, even if well and currently asymptomatic, children known to be at risk of multiple endocrine neoplasia require referral to adult services for the organization of ongoing monitoring. Where there is an underlying genetic cause for a disorder of bone or calcium biochemistry