Vomiting, hypotonia and failure to thrive in a 12-month-old female

A 12-month-old female presents to the Emergency Department with failure to thrive (FTT), irritability, frequent urination (>10 large voids/day) and 1 week of daily nonbloody, nonbilious vomiting. She is a previously healthy child who had been growing and developing normally until 6 months of age. Since this time, she has presented to the Emergency Department twice, both times being admitted for FTT. There has been no diarrhea or fever. Her only medications are Vitamin D (400 IU po once daily) and Lansoprazole (2 mg/kg/day). Physical examination reveals a nondysmorphic child. Her weight is 6.82 kg (first percentile). She is afebrile and tachycardic (184 beats/min). She has dry mucous membranes. Her cardiorespiratory, abdominal and genitourinary examinations are normal. She is not yet sitting independently or crawling. Her muscle tone is decreased peripherally. Urinalysis is isotonic (specific gravity = 1.010) with 11–20 wbc/hpf. An abdominal ultrasound shows bilaterally enlarged echogenic kidneys. An upper gastrointestinal (UGI) series is normal. Laboratory results reveal hypernatremia with serum sodium of 152 mmol/L (reference range [133–148 mmol/L]), hypokalemia with serum potassium of 3.2 mmol/L [3.6–5.2 mmol/L], hypophosphatemia with serum phosphate of 0.9 mmol/L [1.50–2.20 mmol/L] and hypercalcemia with serum calcium of 3.30 mmol/L [2.10–2.70 mmol/L]. FTT is most commonly the result of insufficient caloric intake. However, organic medical conditions causing poor nutrient absorption or increased metabolic demands must also be considered. Poor intake was initially favoured as the patient responded to fortified nasogastric feeding with appropriate weight gain during her first two admissions. During these admissions, her vomiting improved significantly. Her more subtle urinary symptoms were not carefully measured but did not resolve. Her sodium, potassium, chloride and creatinine were normal on both admissions and extended electrolytes were not completed. Intussusception and other structural causes of her vomiting were considered and were ruled out with an abdominal ultrasound. Gastroparesis was ruled out with a UGI series. A urinary tract infection was ruled out with a urinalysis as described above and negative urine culture. The patient was previously started on Lansoprazole for possible gastroesophageal reflux, which did not improve her symptoms. On her third admission, hypercalcemia and hypophosphatemia narrowed the differential diagnosis. The differential diagnosis for hypercalcemia includes hyperparathyroidism (primary and tertiary) and familial hypocalciuric hypercalcemia, in which a normal or high parathyroid hormone (PTH) level is expected. Malignancy, immobility, tuberculosis and vitamin D toxicity are also on the differential, with a low PTH expected. Williams Syndrome should also be considered, in which a normal or low PTH is expected. The patient's urine output was strictly measured and met criteria for polyuria during this admission. A nephrogenic tubulopathy profile including functional or nephrogenic diabetes insipidus (NDI) was suspected. An intact PTH level was ordered and returned low at <3.77 pg/mL [16.03–63.18 pg/mL] indicating appropriate suppression due to hypercalcemia. A 25-hydroxy vitamin D level was elevated at 221.1 nmol/L [50–200 nmol/L], representing elevated vitamin D stores. The patient's vitamin D supplement was confirmed to be dosed and administered correctly, ruling out exogenous vitamin D toxicity. The working diagnosis based on these findings was idiopathic infantile hypercalcemia (IIH), a rare genetic condition characterized by elevated serum calcium levels and suppressed serum PTH levels. Hypercalcemia can cause renal abnormalities including reversible NDI, as was the case for this patient. Other recognized symptoms of IIH include vomiting, hypotonia, FTT, gross motor delay and lethargy. A next generation sequencing panel confirmed a diagnosis of IIH with two heterozygous variants in the CYP24A1 gene. The CYP24A1 gene encodes an enzyme (25-hydroxyvitamin D3-24-hydroxylase) which has a role in calcium homeostasis (1). Patients with this mutation are unable to eliminate active vitamin D metabolites, which is why they can present with symptoms of vitamin D toxicity. The long-term sequelae of IIH include nephrolithiasis and nephrocalcinosis, which can impair renal function over time. The echogenicity on the patient's renal ultrasound was thought to represent early nephrocalcinosis secondary to hypercalcemia. Early diagnosis and treatment can limit the long-term effects of IIH. However, most children with IIH will have sequalae that persist into adulthood including nephrocalcinosis (88%) and chronic kidney disease (28%) (2). A smaller subset progress to end-stage renal disease requiring transplantation (2). Initial management of hypercalcemia secondary to IIH includes adequate hydration, low dietary calcium intake (both formula and solid foods) and minimization of oral vitamin D intake. Refractory responses to initial management or severe symptomatic hypercalcemia often require secondary medical management including intravenous volume expansion, medications to enhance urinary calcium excretion (i.e., loop diuretics), agents to increase skeletal calcium uptake (i.e., bisphosphonates) and cardiac monitoring. Our patient's vitamin D supplementation was held. She was started on a low calcium formula with a minimum daily total fluid intake and twice daily furosemide (1 mg/kg/dose). Her serum calcium normalized with these interventions leading to significant improvement of her vomiting, irritability and DI symptoms. Consider a broader workup for FTT including extended electrolytes, especially if uncommon symptoms such as hypotonia, developmental delay and polyuria are present or if symptoms persist despite adequate caloric supplementation. The differential diagnosis for hypercalcemia is broad but can be narrowed by ordering a parathyroid hormone level and vitamin D analog level. Suspect a nephrogenic tubulopathy profile including functional or NDI when excessive urination is present in the setting of electrolyte abnormalities (hypokalemia or hypercalcemia). Informed consent was obtained from the parents for publication of this manuscript.

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