Subject 1, a 15-year-old man, was diagnosed as having severe aplastic anemia, and he was treated with antithymocyte globulin and cyclosporine. He also received multiple red blood cell transfusions (a total volume of 223 units over 7 years). An iron-chelating agent, deferoxamine (1,000 mg/day) was administered because of an increased serum ferritin level of 2,842.6 ng/mL after 1 year of the diagnosis, but his serum ferritin level was persistently high at regular follow-up visits.

At 21 years of age, hyperglycemia (serum glucose level, 358 mg/dL) was detected on routine laboratory tests with a high body mass index (36.5 kg/m²), and the glycated hemoglobin A1c level was 9.4%. The 24-hour urine C-peptide level was 24.8 µg/day (normal range, 23–148 µg/day) with negative antiglutamic acid decarboxylase (anti-GAD) antibody. He had no family history of diabetes or pancreatic diseases, and he did not take any medicine that interfered with glucose metabolism at that time. Results of the serum biochemical test indicated an aspartate aminotransferase level of 94 IU/L, alanine aminotransferase level of 157 IU/L, alkaline phosphatase level of 74 IU/L, and total bilirubin level of 1.7 mg/dL. The serum ferritin and iron levels were 11,106 ng/mL (normal range, 20–320 ng/mL) and 270 µg/dL (normal range, 65–157 µg/dL), respectively. The total iron binding capacity was 288 µg/dL (normal range, 256–426 µg/dL). An echocardiogram showed a normal ventricular chamber size and good ventricular function, indicating no evidence of cardiac involvement of hemochromatosis. However, an abdominal computed tomography scan showed hepatosplenomegaly and nonspecific, multiple small lymph node enlargement in the celiac and periportal regions. Subsequently, metformin was administered; however, his glucose level was poorly controlled, with the glycated hemoglobin A1c level increasing as high as 9%, which required an intensive insulin regimen (Fig. 1A).

At 22 years of age, he underwent the second allogeneic peripheral blood stem cell transplantation (PBSCT) after 3 months of the first allogenic PBSCT from his mother because of graft failure. During the follow-up period, mild sensory and motor neuropathies were observed at 24 years of age. Currently, he is 28 years old and has shown no evidence of cardiovascular complications with a normal blood pressure and low-density lipoprotein cholesterol level. Although his peripheral neuropathy did not progress, his urine albumin/creatinine ratio has gradually increased to 582.5 mg/g causing him to require angiotensin-converting-enzyme inhibitor medication. Results of endocrine tests were normal: thyroid-stimulating hormone (TSH) level of 3.2 µU/mL, free thyroxine (T4) level of 1.5 ng/dL, luteinizing hormone (LH) level of 2.3 mIU/mL, follicle-stimulating hormone (FSH) level of 3.2 mIU/mL, testosterone level of 2.5 ng/mL, and insulin-like growth factor-I (IGF-I) level of 164 ng/mL (Table 1). His height and weight were 181.1 cm (1.36 standard deviation score [SDS]) and 96 kg (2.29 SDS), respectively. The sexual maturity rating of the testis and pubic hair was Tanner stage V, and the testicular volume of both of his testes was 8 mL. As his physical sign of puberty progress, dynamic studies evaluating hypothalamic-pituitary-gonadal axis were not performed.

Subject 2 was diagnosed as having severe aplastic anemia at 2 years of age, and she received multiple red blood cell transfusions before she underwent haploidentical PBSCT. Diabetes mellitus developed at 11 years of age with a high serum ferritin level (12,559.8 ng/mL). An intensive insulin regimen was initiated, and her blood glucose level was well controlled; her hemoglobin A1c level was less than 7% until she was referred to our pediatric hemato-oncology clinic at 13 years of age. Laboratory data obtained before she was referred were unavailable. At the time of admission, her skin was relatively dark with pale conjunctiva, and the examination of the lungs, heart, and abdomen was unremarkable. Peripheral blood test results showed a white blood cell count of 1,500/mm³ (absolute neutrophil count, 150/mm³), hemoglobin level of 10.1 g/dL, and platelet count of 39,000/mm³. The glycated hemoglobin A1c level was 6.6%, and the 24-hour urine C-peptide level was 107 µg/day with a negative anti-GAD antibody. The amount of transfused red blood cells could not be estimated because of inadequate data from the previous hospital. Liver and renal function was normal. At 13 years of age, she underwent haploidentical PBSCT from her mother after a conditioning regimen composed of antilymphocyte globulin, cyclophosphamide, and fludarabine with total body irradiation was administered. At 14 years of age, endocrine test results showed the following: TSH level of 0.96 µU/mL, free T4 level of 1.1 ng/dL, LH level of 2.5 mIU/mL, FSH level of 2.5 mIU/mL, estradiol level of 16.4 pg/mL, cortisol level of 2.5 µg/dL, and IGF-I level of 200 ng/mL (Table 1). On physical examination, height and weight were 150.5 cm (−1.57 SDS) and 45.8 kg (−0.81 SDS), respectively. The sexual maturity rating of breast and pubic hair was Tanner stage II. A combined anterior pituitary hormone test was performed at 14 years of age because of her short stature and delayed puberty. Peak levels of LH and the growth hormone (GH) were 3.1 mIU/mL and 0.79 ng/mL, respectively. Other pituitary hormone responses were normal. Her bone age was 13 years according to the Greulich and Pyle method⁵⁾. Magnetic resonance imaging of the pituitary gland was not performed. However, the combination of hypogonadotropic hypogonadism and GH deficiency indicated damage in the pituitary gland, and both total body irradiation and iron accumulation could be considered as causes of pituitary dysfunction. After confirming the diagnosis, estropipate (0.16 mg/day, Esgen) was started, and the dose was gradually increased to 0.94 mg/day.

Additionally, bone mineral densitometry results showed osteoporosis, with a z-score of −3.7 in the femur and −2.8 in the spine, thus calcium carbonate/cholecalciferol (1,500 mg/day, Cal-D-vita, Roche). Supplementation therapy was also initiated. As iron overload caused organ dysfunction, we performed phlebotomy 4 times instead of administering iron-chelating agents, and the serum ferritin level gradually decreased to 2,763.2 ng/mL. Her blood glucose level was initially well controlled, and the glycated hemoglobin A1c level remained lower than 7% with a conventional split-mixed insulin regimen until 6 years after the diagnosis of diabetes (Fig. 1B). However, frequent blood glucose excursions and gradually increasing levels of glycated hemoglobin A1c were observed, so multiple daily insulin injections were initiated to control hyperglycemia at 17 years of age. She is currently 18 years old, and she has been receiving treatment with multiple insulin injections and fenofibrate (160 mg/day) for hypertriglyceridemia, and estrogen/progesterone replacement therapy. Microvascular complications were not observed.