Symptom-Based Diagnosis in Pediatrics (CHOP Morning Report) 1st Ed.

CASE 16-5

One-Year-Old Boy

JEANINE RONAN

HISTORY OF PRESENT ILLNESS

A 1-year-old boy presented to the emergency department 1 day following a fall. His mother was carrying him when she tripped over a foot stool and fell with him in her arms. The child fell forward and landed on a carpet on his stomach and chest. There was no loss of consciousness and the toddler cried immediately. That day, he remained very fussy and refused to use his right leg. He would cry with all diaper changes. Soon she started to notice that there was some increased swelling over the right lower extremity. There was no history of any recent viral infections or skin changes.

MEDICAL HISTORY

The birth history was remarkable for a baby who was small for gestation age, born at 39 weeks via emergent cesarean section. The birth weight was 4 lb and 5 oz. He remained hospitalized for 1 week, in part due to a severe snowstorm that swept through the area in November, shortly after his birth. The child has been treated in the past with iron supplementation for anemia diagnosed at 10 months of age. His developmental history was appropriate. He crawled up steps and cruised while holding onto furniture. He was not walking by himself yet. He was able to take off his own socks. His current diet consisted of breast milk. He did not take many solid foods. He did not receive any medications.

PHYSICAL EXAMINATION

T 37.4°C; RR 24/min; HR 138 bpm; BP 90/50 mmHg; Height 63 cm (<5th percentile); Weight 8.26 kg (<5th percentile)

In general, the child appeared tearful but consolable. His forehead was prominent. His cardiorespiratory examination was normal. The abdominal examination was benign. The musculoskeletal examination revealed some swelling around the distal end of the right femur and some widening of the wrists. His neurologic examination was unremarkable, including normal strength and DTRs.

DIAGNOSTIC STUDIES

The boy’s complete blood cell count revealed a WBC of 11 400 cells/mm3 (16% segmented neutrophils, 71% lymphocytes, 3% eosinophils), a hemoglobin of 11.8 g/dL, and a platelet count of 260 000 cells/mm3. His serum electrolytes, blood urea nitrogen, and creatinine were normal. Calcium level was 8.4 mg/L, phosphorus 2.2 mg/dL, and magnesium 2.2 mg/dL. His liver function tests were remarkable for a low serum albumin at 3.3 mg/dL and an elevated serum alkaline phosphatase at 1077 U/L but with a normal AST and ALT.

COURSE OF ILLNESS

Radiograph of the swollen leg revealed both the primary and underlying diagnosis (Figure 16-4).

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FIGURE 16-4. Radiograph of the femur.

DISCUSSION CASE 16-5

DIFFERENTIAL DIAGNOSIS

In this case, the differential diagnosis is particularly narrow. The normal white blood cell count and absence of fever make acute osteomyelitis less likely. In this case, fracture following the trauma described was the most likely primary diagnosis.

DIAGNOSIS

Radiologic films of the right lower extremity showed osteopenia, widened metaphyses, irregular metaphyseal, and physeal borders, with an incomplete nondisplaced distal right femur fracture (Figure 16-4). After obtaining further history, it was discovered that the child received very little sunlight exposure and that his diet was very limited consisting only of juice and breast milk. He had not received any multivitamins. The findings on X-ray, in conjunction with an extremely elevated alkaline phosphatase raised the suspicion of rickets. The diagnosis of rickets was confirmed by a low 25-OH vitamin D level and a normal 1,25-OH vitamin D level. This child had a femur fracture precipitated by trauma in conjunction with nutritional rickets. There was no evidence of an underlying renal or hepatic disease that could have contributed to the development of rickets. An electrocardiogram revealed a normal sinus rhythm and normal intervals. He was placed on vitamin D and calcium supplements orally.

INCIDENCE AND EPIDEMIOLOGY

Rickets is defined as inadequate mineralization of growing bone or osteoid tissue due to a deficiency of vitamin D. Vitamin D receptors are found on the kidney, intestine, bone osteoblasts, and parathyroid gland. Vitamin D2(ergocalciferol) is synthesized primarily in plants and with some limited availability in the diet. Vitamin D3 (cholecalciferol) is made by mammals. It is also found in some foods, but in humans it is naturally synthesized from provitamin form in its skin. Vitamin D3 is hydroxylated in the liver (25-hydroxylation) forming calcidiol (25-hydroxycholecalciferol or 25(OH)D3) and again in the renal cortical cells (1-hydroxylation) to produce calcitriol (1,25-dihydroxyvitamin D3 or 1,25(OH)2D3). Rickets develops due to nutritional deficiency of vitamin D or vitamin D transport or metabolism defects (“vitamin D-dependent rickets”).

In the past, it was thought that nutritional rickets was seen only in exclusively breastfed infants. Typically, breastmilk has low levels of vitamin D. These infants are not fed other foods rich in vitamin D. In addition, infants have a limited exposure to sunlight which also increases the risk of rickets. However, it has now become known that even formula-fed infants, as well as healthy children, and adolescents can be at risk for vitamin D deficiency. Nutritional rickets may be seen in patients on vegetarian diets. Dietary vitamin D may be found in liver, fish oils, and fatty fish. Many cereals and milk are fortified with vitamin D. In 2003, the American Academy of Pediatrics recommended a daily intake of 400 IU/day of vitamin D for all infants, children, and adolescents. Besides being essential for bone health, vitamin D has also been shown to have an important role in maintaining innate immunity and thereby preventing infection, autoimmune disease, cancer, and diabetes.

For some patients, impaired absorption of vita-min D deficiency may result from malabsorption, including celiac sprue or cystic fibrosis. Also, abnormalities in bile salt metabolism will decrease the absorption of vitamin D.

Nutritional rickets develops because the body tries to maintain a normal serum calcium level. When vitamin D is not present, less calcium is absorbed through the intestine. A lower calcium level causes the secretion of parathyroid hormone and the mobilization of calcium from the bone. Thus, as the body tries to preserve a normal calcium level, the parathyroid hormone becomes elevated, the serum phosphorus level is low, and the alkaline phosphatase enzyme is extremely elevated.

Other causes of rickets occur when there is difficulty with the metabolism of vitamin D. Liver disease may decrease the production of 25-OH cholecalciferol. Certain medications, including phenobarbital, can cause rickets by affecting the liver metabolism of vitamin D. Vitamin D-dependent rickets type I develops from absence of renal hydroxylase. Laboratory data are similar to nutritional rickets with the exception of low calcitriol levels. Symptoms can be overcome with high doses of vitamin D. Vitamin D-dependent rickets type II (vitamin D receptor mutations) occurs when there is a low affinity for vitamin D at the level of receptor. In this case, the calcitriol levels are very high. This too can be overcome by higher doses of vitamin D.

Rickets may also occur in conditions causing chronic acidosis since bone is resorbed to buffer the acid load. Excess phosphate excretion due to defects in renal tubular resorption of phosphate, such as X-linked hyperphosphaturia and Fanconi syndrome, may also lead to rickets.

CLINICAL PRESENTATION

Children with vitamin D deficiency can have a variable presentation. Infants may be asymptomatic, present with signs of hypocalcemia or present with overt signs of rickets and bone demineralization. Clinical signs of hypocalcemia include hypocalcemic seizures, stridor (laryngospasm), tetany, carpopedal spasm, and apnea. The presence of profound hypocalcemia should alert the clinician to vitamin D deficiency, but hypoparathyroidism, 22q11.2 deletion, and pseudohypoparathyroidism should also be considered.

A thorough social and dietary history allows the clinician to identify children who may be at risk of developing rickets. Detailed information regarding the infant feeding method, the timing of solid food introduction, and the use of vitamin D supplements should be collected. It is also necessary to ask about sunlight exposure, medications, family history, and stool consistency to assess for concerns about malabsorption.

The clinical findings will vary based on the child’s age, underlying disorder, and duration of the problem. Patients with rickets may present with multiple abnormalities of the musculoskeletal system. Infants and young children may have significant frontal bossing, since the head grows rapidly early in life. Delayed dentition and enamel disruption may be present. The upper extremities and ribs grow quickly during the first year of life, and are therefore the regions to assess for signs of rickets. The child may experience painful and tender bones. The wrists and ankles may be broad and swollen. A rachitic rosary occurs when there is enlargement of the costochondral junctions of the anterior lateral ribs. There will be a prominence of bowing of the lower extremities in an ambulatory child. Some children may have trouble reaching some gross motor milestones, including delayed ambulation. Children with underlying chronic acidosis may present with failure to thrive.

DIAGNOSTIC APPROACH

Radiographs. Rickets may be diagnosed based on radiographic findings. Radiographs of the wrists are usually the most revealing. The metaphysic demonstrates cupping and widening with an increase in the width of radiolucency between the metaphysic and epiphysis. Bone density is decreased and the cortical bone is thin. A Milkman pseudofracture is a ribbon-like radiolucency that extends transversely across the concave side of the long bones. Pathologic fractures may be present. Occasionally, children are diagnosed with rickets by incidental findings on chest radiograph during an evaluation for respiratory distress from bronchiolitis. Chest radiograph findings include demineralization of the skeleton with cupping of the distal end of the ribs and humerus.

Laboratory studies. They can be used to determine the etiology of rickets (Table 16-8). Some important values are discussed below.

TABLE 16-8. Classification of laboratory values in causes of rickets.

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Calcium, magnesium, and phosphorus. In vitamin D deficient rickets, the calcium is typically mildly depressed (7-8 mg/dL), but in some cases the calcium may be much lower resulting in symptoms of hypocalcemia; phosphorus levels are normal to low depending on the extent of disease. Other cases of rickets are associated with profoundly low levels of phosphorus. This is usually due to renal wasting of phosphorus as seen in X-linked hypophosphatemia. Hypomagnesemia is frequently seen when calcium levels are low.

Alkaline phosphatase. Alkaline phosphatase will be elevated even prior to development of hypocalcemia, due to the increase in bone turnover.

Vitamin D metabolites. Both 25(OH)D3 and 1,25(OH)2D3 can be sent. 25(OH)D3 is the most important clinical indicator of nutritional levels. In nutritional rickets, the 25(OH)D3 is low and the 1,25(OH)2D3may be low or normal depending on the severity of the rickets and the duration of symptoms.

Other studies. Intact parathyroid hormone and serum creatinine are helpful in determining other possible cause of rickets (Table 16-8). Urinary calcium, pH, creatinine, and amino acids can be used to exclude (or diagnose) Fanconi syndrome and proximal renal tubular acidosis.

TREATMENT

Depending on the etiology, the treatment of rickets is aimed at restoring the serum calcium and phosphorus levels and increasing the mineralization of bone. In the case of nutritional rickets, vitamin D and calcium supplementation is the treatment of choice.

Currently, emphasis is placed on prevention of nutritional rickets. All infants, children, and adolescents should take daily vitamin D supplementation. Other natural sources of vitamin D include liver and fish, as well as fortified breakfast cereals and dairy products. Sunlight remains another source to increase the amount of vitamin D; however, the skin cancer risks with sun exposure limit its use.

If the patient has signs of symptomatic hypocalcemia, correction should be carried out immediately in a hospitalized setting. It is important to also monitor the patient’s heart rate and rhythm and to evaluate for prolonged QT syndrome. This will improve as the calcium level is restored to normal.

SUGGESTED READINGS

1. Bergstrom WH. Twenty ways to get rickets in the 1990s. Contemp Pediatr. 1991;8:88-106.

2. Carpenter TO. Disorders of calcium and bone metabolism in infancy and childhood. In: Becker KL. Principles and Practice of Endocrinology and Metabolism. Philadelphia: Lippincott Williams & Wilkins; 1996:631-637.

3. Ryan S: Nutritional aspects of metabolic bone disease in the newborn. Arch Dis Child. 1996;74:145-148.

4. Wagner C and Greer F. Prevention of rickets and vitamin D deficiency in infants, children and adolescents. Pediatrics. 2008;122(5):1142-1152.

5. Rajah J, Thandrayen K, Pettifor J. Diagnostic approach to the rachititc child. Eur J Pediatr. 2011;170:1089-1096.