A 7-month-old ex-30-week preterm female infant presented to the emergency department of our hospital with a two-month history of worsening intermittent vomiting and failure to thrive despite nutritional optimization and trial of different infant formulas. Past medical history was notable for prolonged NICU stay mainly due to delays in oral feeding. She had no pulmonary, cardiac, or intestinal complications of prematurity. She did not require any surgical procedure or hospital admission following NICU discharge at around 6 weeks of age. History is also negative for recent fevers or recurrent infections.
On presentation, she was in no acute distress and had normal vital signs. Weight and height were both below the first percentile. Physical examination was significant for the presence of hepatosplenomegaly. Laboratory workup was notable for elevated transaminases and significant hypercalcemia (4.47 mmol/L; Normal Range: 2.12-2.74mmol/L). Baseline phosphorus level was normal and the parathyroid hormone level was appropriately suppressed as seen in Table 1. She was admitted to hospital for management and further workup.
Aggressive intravascular fluid resuscitation with normal saline only partially improved serum calcium levels. Furosemide and calcitonin were used in succession, but they also failed to have a noticeable impact on serum calcium levels. Two doses of pamidronate, 0.5 mg/kg each two days apart, were eventually successful in restoring normal calcium levels. She also switched to low calcium infant formula, Calcilo- XD.
An extensive workup for viral and fungal etiologies was negative, as was the evaluation for metabolic, genetic, and oncologic causes of hypercalcemia. The skeletal survey did not show any lytic lesions; CT scan of the chest, abdomen, and pelvis was negative for the presence of lymphadenopathy or pulmonary lesions. Hepatosplenomegaly was confirmed with a CT scan; however, the underlying pathology was not revealed until a liver biopsy was performed for persistently elevated liver enzymes and massive hepatomegaly. Liver biopsy showed lobular histiocytic infiltrate with well-formed granulomas, hemophagocytosis, and increased portal/periportal and pericellular fibrosis with bridging indicating chronicity, with no further evidence to indicate an underlying etiology of the granulomas.
She was discharged home after 3 weeks of hospitalization once adequate weight gain and normal and stable calcium levels were achieved. Liver enzymes were improved but remained elevated. She had required readmission after one month for the recurrence of vomiting and poor weight. She had no fevers. Workup on this admission showed leukopenia and return of hypercalcemia (Table 1). Chronic granulomatous disease, immunodeficiency, tuberculosis, and hemophagocytic lymphohistiocytosis (HLH) were considered in the differential; however, screening was negative. HLH genotyping showed only a single allele mutation on UNC13 gene, but this variant did not explain her findings. Despite the lack of a standard definition of infantile sarcoidosis, this disease was considered due to elevated levels of angiotensin-converting enzyme (ACE) at 108 U/L (18-90). In the light of negative results for a possible underlying immunodeficiency and malignancy, she was placed on prednisolone 1 mg/kg/day for hypercalcemia. She remained afebrile and was discharged home in stable condition with prednisolone.
After 5 weeks of prednisolone treatment, she presented with daily emesis and low-grade fevers. Complete blood count showed pancytopenia, peripheral smear showed fungal elements. She was admitted to the intensive care unit for disseminated fungal infection. Urine Histoplasma antigen was found to be positive. Systemic antifungal treatment was started. Of note, serum calcium and liver enzyme levels were normal during the third admission (Table 1). Because of disseminated fungal infection, prednisolone was discontinued and a hydrocortisone taper was initiated. She had an excellent response to antifungal treatment. Hepatosplenomegaly resolved and all other serum markers have improved. She remained on systemic antifungal treatment for 9 months. She made full-recovery and caught up with growth and development.