A 2-year-old Girl with Poor Growth and Inability to Stand

A 2-year-old girl presents to the primary care office for a health supervision visit and is found to have poor growth and rickets. Her parents report poor oral intake, increased fussiness and sweating, and refusal to bear weight. She was able to crawl and pull to stand by 12 months but had regression of these milestones after 18 months. She consumes 15 to 18 oz of cow milk each day and eats a variety of table foods. She has had no vomiting, diarrhea, or dehydration. The family recently moved from another country, and previous growth charts are not available. Family history is notable for short stature in her mother, but accurate parental height measurements could not be provided. There are no family members with rickets, poor growth, osteopenia, or recurrent fractures. Initial laboratory testing reveals a low serum bicarbonate level, hypocalcemia, and hypophosphatemia (Table 1). Concern for an underlying renal tubular disorder led to a referral to pediatric nephrology for further evaluation.The patient is seen in the nephrology clinic 5 days later. She has a temperature of 98.1°F (36.7°C), a heart rate of 100 beats/min, blood pressure of 104/60 mm Hg (>95th percentile for age, sex, height), a respiratory rate of 32 breaths/min, and oxygen saturation of 99%. On physical examination she is small for age, with a height of 27.2 in (69 cm) (z score, −4.64) and weight of 20 lb (9.06 kg) (z score, −3.02). She is fussy, difficult to console, and diaphoretic. She has closed fontanelles without palpable sutures and has no craniofacial dysmorphisms, including scaphocephaly. Her cardiopulmonary examination reveals normal S1 and S2 heart sounds, without murmur or gallop, and her lungs are clear to auscultation. Her abdomen is soft, nontender, and without hepatosplenomegaly or palpable masses. She has normal female external genitalia, Tanner stage 1. There is a palpable rachitic rosary bilaterally; marked widening of the wrists, knees, and ankles; and symmetrical lower extremity bowing. She has 2+ peripheral pulses. There are no acute rashes or birthmarks. Aside from fussiness during the examination, which improves when held by her parents, her neurologic examination is nonfocal. A manual blood pressure obtained while the patient was calm is normal.She is directly admitted from the nephrology clinic to the hospital for further evaluation. Additional laboratory testing shows a 25-hydroxyvitamin D level of 65 ng/mL (162.24 nmol/L) (reference range, 20–100 ng/mL [49.92–249.60 nmol/L]), a 1,25-dihydroxyvitamin D level of 24 pg/mL (57.60 pmol/L) (reference range, 24–86 pg/mL [57.60–206.40 pmol/L]), a parathyroid hormone (PTH) level of 503 pg/mL (503 ng/L) (reference range, 14–72 pg/mL [14–72 ng/L]), and an alkaline phosphatase level greater than 5,500 U/L (>91.85 µkat/L) (reference range, 31–152 U/L [0.52–2.54 µkat/L]). Her urinalysis has 1+ protein, without other abnormalities, and her urine calcium excretion for age was not elevated (spot urine calcium-to-creatinine ratio, 0.14 mg/mg; reference range, <0.5 mg/mg). (1) Renal ultrasonography findings are normal. A skeletal survey reveals generalized osteopenia, subperiosteal resorption and thinning of the cortices, several vertebral body compression fractures and wedging, and multiple pathologic long bone fractures in different stages of healing (Fig 1). Her chest radiograph shows distal bony rib flaring (Fig 2). With concern for increased urinary phosphate wasting driving her hypophosphatemia, a serum fibroblast growth factor (FGF23) level is sent and is undetectable (<14 pg/mL) (reference range, <52 pg/mL). Genetic testing is performed and confirms her diagnosis.Rickets has a worldwide prevalence in children and is caused by impaired mineralization of newly formed osteoid adjacent to growth plate cartilage. (2) The bony changes associated with ineffective mineralization or demineralization lead to poor skeletal growth, as children with rickets are at increased risk for recurrent fractures and bony deformities, with significant effects on quality of life. Rickets is categorized based on the presence of hypocalcemia (ie, calcipenic rickets) and/or hypophosphatemia (ie, phosphopenic rickets) as the primary metabolic disturbance(s), and it can be caused by nutritional deficiencies or single gene defects related to vitamin D synthesis or phosphate handling by the kidneys. (3)In hypocalcemic rickets, patients have low serum calcium levels from impaired gastrointestinal calcium absorption, nutritional vitamin D deficiency, inability to form active vitamin D (1,25-dihydroxyvitamin D), or end-organ resistance to vitamin D. (4) Dietary calcium deficiency without concurrent vitamin D deficiency has been reported in developing countries. (5) Hypocalcemia is a strong stimulus for PTH secretion, which results from decreased binding of ionized calcium to the calcium-sensing receptor proteins abundantly found on the surface of parathyroid gland cells. Thus, PTH levels are commonly elevated in hypocalcemic rickets. (4) The most common cause of hypocalcemic rickets worldwide is nutritional vitamin D deficiency; other causes of hypocalcemic rickets include malabsorption syndromes (eg, celiac disease, inflammatory bowel disease), low sunlight exposure (decreased conversion of 7-deoxycholesterol in the skin to cholecalciferol), liver dysfunction (inability to convert cholecalciferol and ergocalciferol to 25-hydroxyvitamin D), vitamin D–dependent and vitamin D–resistant rickets, dietary calcium deficiency, and renal osteodystrophy.Hypophosphatemic rickets is most commonly related to inappropriate handling of phosphate reabsorption by the kidneys, either as an isolated genetic defect or as part of more global dysfunction of the proximal tubules. The most common hereditary cause of hypophosphatemic rickets worldwide is X-linked hypophosphatemia (XLH), which is associated with X-linked–dominant inactivating mutations in the phosphate-regulating gene PHEX. Mutation in PHEX results in upregulation of FGF23 production, a hormone derived by osteocytes that decreases proximal tubular reabsorption of phosphorus and inhibits 1,25-dihydroxyvitamin D synthesis. High circulating FGF23 levels lead to increased urinary phosphate loss in XLH through decreased production of the type 2a and 2c sodium-phosphate cotransporters in the proximal tubule, with resultant hypophosphatemia and inappropriately low or normal active vitamin D levels. Hypophosphatemic rickets is usually associated with normal or only marginally elevated PTH levels (eg, during early treatment of XLH) because the primary defect is phosphate deficiency. (6) Other causes of hypophosphatemic rickets include renal Fanconi syndrome (acquired and hereditary causes), other genetic defects associated with isolated urinary phosphate loss (eg, autosomal dominant and autosomal recessive hypophosphatemic rickets, hypophosphatemic rickets with hypercalciuria), and nutritional phosphate deficiency (eg, osteopenia of prematurity). (7)For our patient, the differential diagnosis was broad given her concurrent hypocalcemia and hypophosphatemia. Her history revealed no primary concern for malnutrition or malabsorption, and laboratory testing for nutritional vitamin D deficiency was normal. Although her initial serum bicarbonate level was low at 17 mEq/L (17 mmol/L), venous blood gas showed normal pH, and her other laboratory studies were not suggestive of proximal renal tubular acidosis.The patient’s 1,25-dihydroxyvitamin D level was at the low end of the reference range, and in conjunction with a family history of short stature in her mother she was initially suspected to have XLH. However, her tubular reabsorption of phosphate was 90%, which was appropriately elevated in the context of her hypophosphatemia and not suggestive of renal phosphate wasting (Table 1). Her undetectable serum FGF23 level eliminated XLH as the diagnosis, thus a hypophosphatemia molecular genetic panel was sent to further investigate the etiology of her rickets. Other diagnoses considered at this time included 1α-hydroxylase deficiency, leading to impaired synthesis of active vitamin D, and hereditary vitamin D resistance (previously vitamin D–dependent rickets [VDDR] type 2). However, classically, these conditions are associated with normal 25-hydroxyvitamin D levels along with decreased and increased 1,25-dihydroxyvitamin D, respectively. Her genetic testing ultimately revealed a homozygous pathogenic mutation in CYP27B1 (c.1375C>T, p.Arg49Cys), the causative gene associated with 1α-hydroxylase deficiency (previously VDDR type 1A).VDDR from 1α-hydroxylase deficiency is an autosomal recessive condition, a rare cause of rickets in children, and usually presents during infancy. It is caused by biallelic mutation of CYP27B1 located in chromosome 12q13.3, encoding the enzyme 1α-hydroxylase responsible for converting 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D in the kidney. (8) Although the worldwide prevalence of VDDR is unknown, a study in Denmark found a prevalence of 0.4 per 100,000 among children younger than 15 years. (9) Patients with 1α-hydroxylase deficiency commonly have hypocalcemia and hypophosphatemia (from impaired production of active vitamin D required for gastrointestinal absorption), with secondary hyperparathyroidism and elevated alkaline phosphatase activity. (10) The clinical presentation and biochemical profile in VDDR from 1α-hydroxylase deficiency can mimic nutritional rickets; however, unlike vitamin D deficiency there are normal or increased 25-hydroxyvitamin D and low 1,25-dihydroxyvitamin D levels. Hereditary vitamin D–resistant rickets (previously VDDR type 2), caused by inactivating mutations in the VDR gene that encodes the vitamin D receptor, may similarly present in infancy with hypocalcemia, secondary hyperparathyroidism, and rickets. However, unlike 1α-hydroxylase deficiency, this condition is associated with high 1,25-dihydroxyvitamin D levels. In addition, patients with hereditary vitamin D–resistant rickets may develop alopecia and ectodermal anomalies from absent vitamin D receptor activity in keratinocytes, (11) findings not encountered in 1α-hydroxylase deficiency.Treatment of VDDR consists of supplementation with activated forms of vitamin D, such as calcitriol (1–2 μg daily) to bypass this enzymatic block in vitamin D synthesis. Alfacalcidol (1–3 μg daily) may also be used as an alternative to calcitriol in countries where calcitriol is unavailable. (12) Once the rickets is healed, lower doses of calcitriol may be sufficient. Adequate intake of elemental calcium is recommended to meet dietary nutritional requirements; in the early phase of treatment, patients are at risk for developing “hungry bone” syndrome, a constellation of biochemical abnormalities that includes worsened hypocalcemia, hypophosphatemia, and hypomagnesemia as their bones begin remineralization. (13) Radiographic improvement in rickets may be seen as early as 6 to 8 weeks into therapy. Routine laboratory studies and renal sonography should be ordered to monitor for adverse effects of calcitriol therapy and calcium supplementation, including hypercalcemia, hypercalciuria, and nephrocalcinosis. In addition to annual ultrasonography, patients should have an annual eye examination to monitor for ocular calcifications. (14)Our patient began taking calcitriol and calcium carbonate, with close laboratory monitoring, and did not develop hungry bone syndrome or other adverse effects related to her therapy. She has had remarkable improvement in the radiographic appearance of her rickets (Fig 3), with return of her ability to bear weight while standing and the new ability to walk without assistance. Her laboratory values have also largely normalized after 12 months of therapy (Table 1), and her growth has improved (Figs 4 and 5).Clinicians should think of less common causes of hypophosphatemic rickets than vitamin D deficiency in patients presenting with a normal or elevated 25-hydroxyvitamin D level.X-linked hypophosphatemia (XLH) is the most common hereditary form of hypophosphatemic rickets. Patients with XLH commonly present with hypophosphatemia with inappropriately low or normal active vitamin D levels.Vitamin D–dependent rickets should be considered in patients with hypophosphatemic rickets who have a normal or elevated 25-hydroxyvitamin D level and a low 1,25-dihydroxyvitamin D level. Because these patients are unable to synthesize 1,25-hydroxyvitamin D, treatment requires supplementation with active vitamin D (eg, calcitriol).