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We retrospectively analyzed endocrine late effects in 81 childhood cancer survivor (CCS) patients who had been referred to our endocrinology department in Chiba Children's Hospital between January 1, 2008 and December 31, 2016. Among 69 eligible patients (33 male, 36 female), endocrine late effects were identified in 56 patients (81.1%). The median age at the last visit to our endocrinology department was 17.4 years (range: 7.1-35.3 years). The most common primary cancer was acute lymphoblastic leukemia (22 patients, 31.8%). Forty-four patients (64%) were treated using radiation therapy. A primary brain tumor and high doses (≥6 g/m2) of cyclophosphamide were significantly associated with growth hormone deficiency (GHD). Our present study suggests that high doses of cyclophosphamide is a risk factor for GHD. Adult heights and pubertal growth spurts of patients treated with radiation therapy were significantly lower than patients not treated with radiation therapy. Our retrospective study reconfirmed that hematopoietic stem cell transplantation and chronic graft versus host disease (GVHD) were associated with elevated risks of primary hypothyroidism. However, it is unclear whether GVHD induces thyroid dysfunction. Gonadal radiation and busulfan were associated with primary hypogonadism as reported in previous studies. We found high doses of cyclophosphamide to be involved in pituitary disorders. We suggest that pediatric endocrinologists should discuss the potential effects of radiation therapy on adult height and pubertal growth spurt in CCS patients. Moreover, patients who have been treated with high doses of cyclophosphamide or have chronic GVHD require long-term follow-up for endocrine late effects.

Thyroid dysfunction has been observed in childhood cancer survivors (CCSs) who have undergone hematopoietic stem cell transplantation (HSCT). We retrospectively analyzed the thyroid function of 54 CCSs who underwent HSCT and were referred to our endocrinology department at Chiba Children's Hospital between January 1, 2008, and December 31, 2019. Three patients developed autoimmune thyroid disease (AITD) after HSCT. Two of these patients had Graves' disease (GD), and the third had autoimmune thyroiditis. The association between HSCT and AITD remains unclear. All three patients had chronic graft versus host disease (GVHD). AITD was reported to be induced by the transmission of abnormal T or B lymphocyte clones from the donor to the recipient. One patient with GD was treated with a high dose of anti-thymocyte globulin (ATG). Some studies have reported that ATG is associated with a risk of severe T cell depletion and GD onset. In conclusion, CCSs who received HSCT rarely developed AITD. We suggest that CCSs treated with ATG and/or experiencing an onset of chronic GVHD should be carefully monitored for thyroid function because it might reveal AITD.

Fibroblast growth factor 23 (FGF-23), a hormone mainly secreted by osteocytes and osteoblasts, regulates phosphate and vitamin D levels. However, the in vivo significance of FGF-23 is not fully elucidated. This case report describes a 12-year-old girl with systemic lupus erythematosus (SLE), lupus nephritis, and an elevated serum FGF-23 level. The patient was treated with active vitamin D and oral sodium phosphate medications to manage low serum phosphate levels (2.2 mg/dL). Magnetic resonance imaging (MRI) revealed a high-intensity area in the left femur, but somatostatin receptor scintigraphy images did not indicate tumor-induced osteomalacia. SLE treatment using mycophenolate mofetil (1500 mg/day) was initiated, and serum complements levels increased as FGF-23 level increased. Serum FGF-23 level gradually decreased as urinary protein levels decreased after treatment with steroids; however, there was no change in the high-intensity area on MRI. Recent studies have reported that serum FGF-23 level is associated with iron deficiency and inflammation; yet, the mechanism related to these associations is not fully elucidated. The findings from this case suggest that elevated serum FGF-23 levels noted in our patient were related to silent lupus nephritis and lupus nephritis activity.

Summary Ammonium acid urate (AAU) crystals are rare in industrialized countries. Furthermore, the number of children with diabetic ketoacidosis (DKA) who develop severe acute kidney injury (AKI) after hospitalization is small. We encountered two patients with AKI caused by AAU crystals during the recovery phase of DKA upon admission. They were diagnosed with severe DKA and hyperuricemia. Their urine volume decreased and AKI developed several days after hospitalization; however, acidosis improved in both patients. Urine sediment analysis revealed AAU crystals. They were treated with urine alkalization and diuretics. Excretion of ammonia in the urine and urine pH levels increased after treatment of DKA, which resulted in the formation of AAU crystals. In patients with severe DKA, the urine and urine sediment should be carefully examined as AAU can form in the recovery phase of DKA. Learning points: Ammonium acid urate crystals could be formed in the recovery phase of diabetic ketoacidosis. Diabetic ketoacidosis patients may develop acute kidney injury caused by ammonium acid urate crystals. Urine and urine sediment should be carefully checked in patients with severe DKA who present with hyperuricemia and volume depletion.

Thyroid nodules have been observed in childhood cancer survivors (CCS) treated with chemotherapy and radiotherapy. We report four patients with thyroid nodules identified during the long-term follow-up of children who underwent hematopoietic stem cell transplantation (HSCT). The thyroid nodules were diagnosed as adenomatous goiter in all four patients. The interval between the primary cancer diagnosis and the occurrence of the thyroid nodules was more than 10 yr. Furthermore, all four patients underwent HSCT in conditioning with total body irradiation (TBI) before the age of 10 yr. Two of four patients commenced treatment with levothyroxine due to elevated TSH levels. Only two patients showed elevated thyroglobulin levels (> 70 µg/L). In conclusion, we suggest that CCS who have undergone HSCT in conditioning with TBI more than 10 yr previously should be followed up carefully for thyroid nodules using ultrasound.

It is debatable whether Hajdu-Cheney syndrome (HCS) and serpentine fibula-polycystic kidney syndrome (SFPKS) represent a single clinical entity with a variable degree of expression or two different entities, because both disorders share common clinical and radiological manifestations, including similar craniofacial characteristics, and defective bone mineralization. Since it was shown that heterozygous truncating mutations in NOTCH2 are responsible for both HCS and SFPKS, 37 patients with HCS and four patients with SFPKS are reported. To elucidate the clinical consequences of NOTCH2 mutations, we present detailed clinical information for seven patients with truncating mutations in exon 34 of NOTCH2, six with HCS and one with SFPKS. In addition, we review all the reported patients whose clinical manifestations are available. We found 13 manifestations including craniofacial features, acroosteolysis, Wormian bones, and osteoporosis in >75% of NOTCH2-positive patients. Acroosteolysis was observed in two patients with SFPKS and bowing fibulae were found in two patients with HCS. These clinical and molecular data would support the notion that HCS and SFPKS are a single disorder.

Combined pituitary hormone deficiency (CPHD), isolated hypogonadotropic hypogonadism (IHH), Kallmann syndrome (KS), and septo-optic dysplasia (SOD) are genetically related conditions caused by abnormal development of the anterior midline in the forebrain. Although mutations in the fibroblast growth factor receptor 1 (FGFR1) gene have been implicated in the development of IHH, KS, and SOD, the relevance of FGFR1 abnormalities to CPHD remains to be elucidated. Here, we report a Japanese female patient with CPHD and FGFR1 haploinsufficiency. The patient was identified through copy-number analyses and direct sequencing of FGFR1 performed for 69 patients with CPHD. The patient presented with a combined deficiency of GH, LH and FSH, and multiple neurological abnormalities. In addition, normal TSH values along with a low free T4 level indicated the presence of central hypothyroidism. Molecular analyses identified a heterozygous ~ 8.5 Mb deletion involving 56 genes and pseudogenes. None of these genes except FGFR1 have been associated with brain development. No FGFR1 abnormalities were identified in the remaining 68 patients, although two patients carried nucleotide substitutions (p.V102I and p.S107L) that were assessed as benign polymorphism by in vitro functional assays. These results indicate a possible role of FGFR1 in anterior pituitary function and the rarity of FGFR1 abnormalities in patients with CPHD.

Pseudohypoparathyroidism type Ib (PHP1B) is caused by proximal tubular resistance to parathyroid hormone that occurs in most cases in the absence of Albright's Hereditary Osteodystrophy (AHO). Familial forms of PHP1B are caused by maternally inherited microdeletions within STX16, the gene encoding syntaxin 16, or within GNAS, a complex genetic locus on chromosome 20q13.3 encoding Gsα and several splice variants thereof. These deletions lead either to a loss-of-methylation affecting GNAS exon A/B alone or to epigenetic changes involving multiple differentially methylated regions (DMRs) within GNAS. Broad GNAS methylation abnormalities are also observed in most sporadic PHP1B (sporPHP1B) cases. However, with the exception of paternal uniparental disomy involving chromosome 20q (patUPD20q), the molecular mechanism leading to this disease variant remains unknown. We now investigated 23 Japanese sporPHP1B cases, who presented with hypocalcemia, hyperphosphatemia, elevated PTH levels, and occasionally with TSH elevations and mild AHO features. Age at diagnosis was 10.6 ± 1.45 years. Calcium, phosphate, and PTH were 6.3 ± 0.23 mg/dL, 7.7 ± 0.33 mg/dL, and 305 ± 34.5 pg/mL, respectively, i.e. laboratory findings that are indistinguishable from those previously observed for Caucasian sporPHP1B cases. All investigated patients showed broad GNAS methylation changes. Eleven individuals were homozygous for SNPs within exon NESP and a pentanucleotide repeat in exon A/B. Two of these patients furthermore revealed homozygosity for numerous microsatellite markers on chromosome 20q raising the possibility of patUPD20q, which was confirmed through the analysis of parental DNA. Based on this and our previous reports, paternal duplication of the chromosomal region comprising the GNAS locus appears to be a fairly common cause of sporPHP1B that is likely to occur with equal frequency in Caucasians and Asians.

OBJECTIVE The aim of this study was to evaluate clinical manifestations, laboratory findings, and effects of antithyroid drugs in younger children with Graves' disease (GD). DESIGN A retrospective and collaborative study. SETTING Nine facilities in Chiba prefecture, Japan. PATIENTS We analyzed 132 children and adolescents with GD. The subjects were divided according to the median age into a group of young children (group I, 4.1-12.4 years, n=66) and an adolescent group (group II, 12.5-15.9 years, n=66). MAIN OUTCOME MEASURES Clinical manifestations, laboratory findings, incidence of adverse effects, and remission rates 5 years after initial therapy were assessed. RESULTS The mean height SD score of group I (1.0) was higher than that of group II (0.3, p

We examined clinical, endocrinological and molecular biological aspects of an estrogen-secreting adrenal carcinoma in an 18-month-old male to clarify the pathogenesis of this condition. An 18-month-old boy was referred for evaluation of progressive bilateral gynecomastia and appearance of pubic hair. The patient had elevated plasma estradiol (349 pg/ml) and testosterone (260 ng/dl) levels that completely suppressed FSH and LH levels, and was subsequently diagnosed with an adrenal tumor on the right side. After removal of a 300-g adenocarcinoma, gynecomastia regressed and essentially normal hormone levels were restored. Aromatase activity in the tumor tissue determined by the 3H-water method was 71.0-104.4 pmol/min/mg protein. High levels of aromatase protein and mRNA in the tumor tissue were also demonstrated, while neither aromatase activity nor protein was detected in normal adrenal glands. To investigate the regulation of aromatase expression in the adrenal carcinoma, we examined the usage of alternate promoters responsible for aromatase gene transcription. In the present case, the amounts of aromatase mRNA utilizing gonadal types of exon 1c (1.3) and 1d (II) were significantly higher than those that using other exon 1s. This result suggested that the utilization of a gonadal-type exon 1 might be involved in the over-production of aromatase in estrogen-secreting adrenal carcinoma.

Oral sodium phosphate formulations indicated for hypophosphatemia are commercially available worldwide. In Japan, however, many medical institutes have used hospital dispensary or foreign over-the-counter formulations because no such medication with an indication covered by the health insurance system is domestically available. To address this problem, we initiated the development of Phosribbon(®). The present study evaluated the efficacy and safety of Phosribbon(®) in 16 patients with hereditary hypophosphatemic rickets. The optimal dosage and an administration pattern were also investigated. Administration of the agent resulted in an increase in the level of serum phosphorus in all patients, which implied that the employed dosage was appropriate. The dosage and administration pattern were adjusted based on comprehensive considerations, including changes in clinical laboratory values such as serum phosphorus, alkaline phosphatase and intact PTH, the dosage of a concomitantly administered activated vitamin D formulation and characteristics of individual patients. Adverse drug reactions were observed in 2 patients, neither of which were serious or necessitated therapy dose reduction or discontinuation. We conclude that Phosribbon(®) is a safe and effective treatment for patients with hypophosphatemic rickets and that dose adjustment in this therapy can be guided by the results of regular clinical examination and renal ultrasonography. (ClinicalTrials.gov Identifier: NCT01237288).

OBJECTIVE Methimazole (MMI) is used as a first-line antithyroid drug in children and adolescents with Graves' disease (GD). The aim of this study was to evaluate the correlation between the initial dose of MMI and the clinical course of GD after treatment. DESIGN Retrospective and collaborative study. SETTING Nine facilities in Chiba prefecture, Japan. PATIENTS Sixty-four children and adolescents with GD were analyzed. The subjects were divided into three groups by the initial daily dose of MMI: group A, 0.4±0.1 mg/kg (mean±SD, n=11); group B, 0.7±0.2 (n=37); group C, 0.9±0.2 (n=16). MAIN OUTCOME MEASURES The duration of time required for normalization of serum free T4 on initial treatment and the incidence of adverse effects for 1 year after the start of MMI were compared. Outcomes were compared among patients who were followed more than 3 years (group A, n=7; group B, n=24; group C, n=12). RESULTS Mean duration of times for normalization of T4 was 1.9±1.5 months in group A, 1.6±0.9 in group B and 1.9±1.5 in group C (NS). No major adverse reactions were observed. Minor adverse effects occurred in 9.1% of cases in group A, 13.5% in group B and 62.0% in group C (p

Objective The aim of this study was to compare the efficacy and adverse reactions during initial treatment and long-term outcome between children and adolescents with Graves' disease (GD) treated with propylthiouracil (PTU) and those treated with methimazole (MMI). Design, setting and participants Retrospective and collaborative study. Children and adolescents with GD were divided into group M (MMI: n=64) and group P (PTU: n=69) and into four subgroups by initial dose: group M1 ( or = 0.75 mg/kg, n=30), group P1 ( or = 7.5 mg/kg, n=45). Main outcome measures The duration for normalization of serum T4 on initial treatment, the incidence of adverse effects for one year and outcomes at 10 years after were compared. Results Mean durations for normalization of T4 (+/- SD) were 1.7 +/- 1.0 months in group M and 2.3 +/- 2.4 in group P [not significant (NS)], while the mean duration in group P1 (3.1 +/- 3.3) was significantly longer than those in the other subgroups (M1: 1.9 +/- 1.2; M2: 1.4 +/- 0.7; P2; 1.7 +/- 1.3). No major adverse reaction was observed. Minor adverse effects occurred in 25.0% of cases in group M and 31.9% in group P (NS). The incidence in group P2 (44.4%) was significantly higher than those in group M1 (20.6%) and group P1 (8.3%). Remission rates did not differ between the MMI-treated group (35.0%, n=20) and PTU-treated group (50.0%, n=40). Conclusions PTU may not be suitable for initial use in children and adolescents with GD, even with the risk of major adverse reactions such as liver failure excluded.

We evaluated the developmental prognosis of 31 infants born to mothers with autoimmune thyroiditis. Four of the babies developed transient neonatal hypothyroidism. Their mothers all had low thyroid hormone concentrations during pregnancy. Neonatal thyroid function tended to correlate with maternal thyroid function at delivery in babies born to mothers with Graves';disease who were taking antithyroid drugs. Since severe fetal hypothyroidism sometimes results in neurological damage, it is important to maintain normal maternal thyroid function during pregnancy.

We report herein a case of prenatally detected neonatal adrenocortical tumor (ACT). The patient was an otherwise healthy newborn girl. No signs of Beckwith-Wiedemann syndrome were identified, and her family medical history did not suggest predisposition to cancer. Computed tomography and ultrasonography after birth revealed a round solid tumor 40 mm in diameter in the right suprarenal area. The precise diagnosis of ACT was unexpectedly obtained based on results from the Japanese neonatal mass screening program. Blood 17-hydroxyprogesterone is routinely measured as a part of this program for early detection of congenital adrenal hyperplasia in Japan. Abnormally elevated level of 17-hydroxyprogesterone was reported in the patient and, thus, led to the diagnosis of ACT. Surgical resection was safely performed with perioperative steroid replacement. Adrenocortical tumors are extremely rare in childhood, particularly in the neonatal period. Some of these tumors secrete abnormally high levels of cortisol, suppressing function of the contralateral adrenal gland and, thus, leading to life-threatening postoperative adrenal insufficiency. Scheduled steroid replacement enables safe perioperative management in such cases. Adrenocortical tumor should always be considered among the differential diagnoses for neonatal suprarenal mass because precise diagnosis will enable the physician to develop appropriate treatment strategies.

Pseudohypoparathyroidism (PHP) is a metabolic disorder characterized by organ resistance to the action of parathyroid hormone. PHP type 1 is subclassified into two apparent disorders, type 1a (PHP1a) and type 1b (PHP1b). Patients with PHP1a show Albright hereditary osteodystrophy including short stature. Patients with PHP1b have no such skeletal defects, however, literature regarding the growth of PHP1b is not currently available. We evaluated growth charts of PHP patients, including four PHP1a patients and six PHP1b patients. Growth patterns were different between PHP type 1a and 1b. Adult height was abnormally low in all PHP1a patients. The growth pattern of PHP1a was characterized by mild growth impairment in the prepubertal period, a blunted growth spurt and premature cessation of the growth spurt. The adult height of male PHP1b was slightly lower than average. An early growth spurt was observed only in male patients with PHP1b and it may reduce the adult height of male patients with PHP1b. This warrants further investigation into the growth and pubertal development of PHP1b patients.

Purpose: GH replacement therapy is required in the majority of children with OH deficiency after treatment of sellar and suprasellar tumors. Owing to the high cell proliferative ability of human GH (hGH), its influence on tumor recurrence has been debated. We retrospectively studied the immunohistochemical expression of the GH receptor in various tumor tissues, in order to investigate the relation between tumor recurrence and hGH replacement. Methods: GH replacement therapy was performed in 25 patients (8 boys and 17 girls) after the treatment. Tumor recurrence was noted in 4 patients (craniopharyngioma: 2 patients, pilocytic astrocytoma and germinoma: 1 each). Immunohistochemical study of GH receptor in tumor tissue was carried out in those recurrent and recurrence-free cases, by using MAb 263 as a primary antibody. Results: Two patients with recurrent craniopharyngioma were positive for MAb 263, but 1 recurrence-free patient was negative. Patients with pilocytic astrocytoma (recurrent and recurrence-free: 1 each) were all positive. Five patients with germinoma (1 with recurrence and 4 without recurrence) were all negative. Conclusion: In the patients with craniopharyngioma treated with GH, a positive immunohistochemical expression of GH receptor in tumor tissue may indicate a high probability of recurrence. In our cases, GH receptor was positive in astrocytomas and negative in germinomas, with or without recurrence. It is therefore speculated that each brain tumor may have its specificity in GH receptor expression.

“Clinical consequences in truncating mutations in exon 34 of NOTCH2: report of six patients with Hajdu-Cheney syndrome and a patient with serpentine fibula polycystic kidney syndrome” Am J Med Genet. 161:518–526, 2013 Yoko Narumi,* Byung-Joo Min, Kenji Shimizu, Itsuro Kazukawa, Kiyoko Sameshima, Koichi Nakamura, Tomoki Kosho, Yumie Rhee, Yoon-Sok Chung, Ok-Hwa Kim, Yoshimitsu Fukushima, Woong-Yang Park, and Gen Nishimura Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan Departments of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea Division of Medical Genetics, Saitama Children’s Medical Center, Saitama, Japan Division of Endocrinology, Chiba Children’s Hospital, Chiba, Japan Division of Medical Genetics, Gunma Children’s Medical Center, Shibukawa, Japan Department of Orthopedics, Shinshu University School of Medicine, Matsumoto, Japan Department of Endocrinology and Metabolism, Yonsei University College of Medicine, Seoul, Korea Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Korea Department of Radiology, Ajou University School of Medicine, Suwon, Korea Department of Radiology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan

We report a 3-yr-old male with short stature, speech delay, episodes of convulsion, and right morning glory syndrome. He had four episodes of febrile convulsion from the age of 1 yr 6 mo, and two episodes of afebrile convulsion with hypoglycemia. His height was 90.2 cm (-2.3 SD) and his growth rate was decreased from about 2 yr of age. Magnetic resonance imaging of the brain showed an atrophic anterior pituitary lobe, invisible stalk, and ectopic posterior lobe. Septo-optic dysplasia was deniable. We tested pituitary function. Cortisol response to CRH was normal (peak: 21.0 μg/dl). TSH response to TRH was prolonged and exaggerated (peak: 33.0 μU/ml at 120 min), and FT4 response was absent (peak: 0.74 ng/dl). After supplement of l-T4, GH response to arginine was decreased (peak: 5.1 ng/ml). We diagnosed hypothalamic hypopituitarism. We started treatment with l-T4 and growth hormone. Patients with congenital ocular anomaly including morning glory syndrome should be evaluated for brain and pituitary structure with MRI, and further endocrinological examinations should also be considered.