A previously healthy, normally developing girl without familial obesity was evaluated at age 4 years for a sudden weight gain of 15 pounds in less than 1 year (25th to 95th percentile for weight) and decreased linear growth (25th to 10th percentile for height; Fig. 1b). She displayed no features of lipodystrophy. The medical history of the patient revealed that she was born to non-consanguineous healthy parents with a birth weight of 4 pounds 13 oz (2.14 Kg) by c-section at 37 weeks (3 weeks preterm) due to pre-eclampsia. Her growth in the first year of life included a height at the 75th percentile and weight at the 25th percentile. She never had any concerns about developmental delays or cognitive impairment. However, her parents noted fear and anxiety about routine daily activities, entering crowded spaces as well as decision making, starting around age 4 years. Ophthalmic exam did not show any vision abnormalities other than myopia and astigmatism. Given her mother’s history of hearing impairment, hearing test was done but did not show any abnormality.
During the initial evaluation, her sodium was 156 mEq/L with undetectable antidiuretic hormone (ADH), consistent with diabetes insipidus and disrupted thirst regulation. She was also found to have central hypothyroidism, elevated prolactin, and growth hormone deficiency (Table 1). Her baseline cortisol levels were normal to high with normal ACTH. A hypothalamic tumor was suspected, but brain MRI was normal (Fig. 1c). Due to the rapid weight gain, she was also worked up for Cushing’s syndrome, however, abdominal CT revealed no adrenal masses and overnight dexamethasone suppression test was normal.
She was originally started on subcutaneous DDAVP, and then transitioned to intranasal spray. She was very closely monitored with weekly blood draws, tight fluid instructions and close weight tracking. Despite this tight monitoring, she still required hospitalizations for hypernatremia at the time of infections. Given these difficulties, she never tried oral DDAVP. She was simultaneously treated with levothyroxine replacement.
After age 10, she was diagnosed with nonalcoholic fatty liver disease (NAFLD) with evidence of progressive fibrosis over time, resulting in hypersplenism and pancytopenia. Her liver function tests (LFTs) were noted to be elevated starting at age 10. At age 11, she underwent a liver US showing the presence of increased fat as well as splenomegaly. During the same period, she was noted to have autonomic dysfunction, abnormal thermoregulation, and profuse sweating.
She was treated with growth hormone from age 10 to age 14 years to assist with linear growth and it was discontinued due to increased swelling and weight gain. At age 10, she was diagnosed with sleep apnea and insulin resistance. She was started on metformin, but developed clinical diabetes by age 14. She did not achieve spontaneous menarche despite the development of oily skin and acne and was started on female hormone replacement with cyclic estrogen and progesterone therapy at the age of 14.
At age 15, she developed respiratory failure and shock from an upper respiratory tract infection, requiring intubation, oscillator, and vasopressors. She was able to recover after a prolonged hospitalization. Shortly after at age 16, she underwent a thorough evaluation at the Lurie Children’s Hospital that documented her autonomic dysfunction and hypoventilation (Additional file 1: Table S1). Management with overnight ventilator, oxygen supplementation and oscillator use were recommended. Home continuous overnight monitoring for oxygen saturation and heart rate were also initiated. At that time, she underwent PHOX2B gene testing due to the presence of autonomic dysfunction and this testing was negative.
Between the ages of 18–23, she was transitioned to adult endocrine care where her diabetes control was noted to become more challenging. She was started on insulin, with insulin requirement increasing to > 310 international units (IU) while her HbA1c increased to numbers above 9%. Poor diabetes control made management of sodium balance very difficult due to polyuria and absence of thirst. She developed severe acanthosis nigricans and lymphedema. Her weight increased to BMI over 40 kg/m2. Over time, she was started on U500 insulin. She also developed hypertriglyceridemia at this time with the highest value at 1062 mg/dL. Of note, given the hypertriglyceridemia, low adiponectin levels and the lack of a commercial test, she was never tested for presence of the insulin receptor auto-antibody.
She was started on liraglutide 0.6 mg daily with the hope of improving control and sparing insulin to improve acanthosis nigricans, hyperandrogenism, weight and fatty liver. Her insulin requirements dropped precipitously to less than 30% of baseline doses within 8 to 12 h of initiation (Fig. 1d). She was managed with liraglutide 1.2 mg daily on and off for about 2 years. Initiation of liraglutide did not cause worsening of her diabetes insipidus, hypernatremia, or pancytopenia. She did, however, experience worsened diarrhea due to the use of liraglutide leading to treatment interruption. Her acanthosis nigricans, facial acne and coarsening of facial features improved due to dose reduction in insulin.
With increased weight gain, swelling, worsening acanthosis nigricans, a weight reduction diet was attempted with meal replacement and caloric restriction. She lost 15 lbs. with this attempt. At the age of 26, she was noted to have a 1.6 cm Barcelona Clinic Liver Cancer (BCLC) Stage 0 (T1N0M0 Stage 1) liver lesion on routine semi-annual liver surveillance because of the presence of clinical cirrhosis and hypersplenism. The biopsy of the lesion favored the diagnosis of a well differentiated hepatocellular carcinoma (Fig. 2). A radiofrequency ablation procedure for this was successfully completed on 8/30/2018.
In addition, other comorbidities that developed over the years include cholelithiasis, chronic kidney disease with nephrotic range proteinuria (no biopsy performed to date to determine the underlying pathological mechanisms but being contemplated), hypertension, anemia and thrombocytopenia, splenomegaly, irritable bowel syndrome, vitamin D deficiency, and mild tricuspid regurgitation.