Two Japanese Infants With Hypothyroidism Following Exposure to Iodinated Contrast Media.

We report 2 Japanese infants with hypothyroidism requiring levothyroxine (LT4) replacement therapy following exposure to iodinated contrast media (ICM). Patient 1 was born at 32 weeks gestation. He had congenital heart disease and underwent contrast-enhanced computed tomography (CT) on day 22 (estimated amount of iodine: 600 mg/kg/dose). The newborn mass screening showed normal thyrotropin (thyroid-stimulating hormone; TSH) levels at day 4, but high TSH and low free thyroxine levels on retest at day 44. LT4 replacement therapy was administered on days 46 to 74. No hypothyroidism requiring LT4 replacement therapy was observed afterward. The ultrasonography showed a hypoplastic thyroid gland. Patient 2 was born full-term. She had congenital heart disease and underwent contrast-enhanced CT on day 52 (estimated amount of iodine: 1500 mg/kg/dose). The newborn mass screening showed normal TSH levels on day 4, but high TSH levels on retest on day 62. LT4 replacement therapy was administered from day 65 to 3 years of age. Genetic analysis showed a heterozygous variant of DUOX2. Exposure to ICM can result in hypothyroidism, requiring LT4 replacement therapy. The severity of hypothyroidism may depend on risk factors, such as genetic predisposition, preterm birth, thyroid hypoplasia, or early exposure to ICM.

Intracranial germinoma in the lateral ventricle with polydipsia and polyuria: a case report and literature review.

Central nervous system germ cell tumors (CNSGCTs) are rare neoplasms which usually develop in the midline structures. They are occasionally involved in off-midline structures of the brain. Here, we report an extremely rare case of an intracranial germinoma in the lateral ventricle. The patient was a 10-year-old boy with a 1-year history of polydipsia and polyuria. Brain magnetic resonance imaging (MRI) showed a relatively homogeneously enhancing lesion in the lateral ventricle, and the posterior pituitary gland was not hyperintense on T1-weighted imaging. Subependymoma was suspected, and tumor removal operation was performed; however, because the intraoperative pathological investigation revealed germinoma, we could only perform partial removal of the tumor. Postoperative histology also confirmed germinoma. Then, the patient received chemotherapy, followed by radiation therapy. MRI showed no recurrence for 6 years after treatment. Intracranial germinoma in the lateral ventricle is extremely rare. The diagnosis is occasionally challenging, especially when the tumors are located in atypical locations. This paper presents a literature review of previously described CNSGCTs of the lateral ventricle to improve awareness of CNSGCTs in atypical locations. We also consider the relationship between imaging findings and clinical manifestations.

An elderly patient with 17α-hydroxylase deficiency misdiagnosed as primary aldosteronism: a case report.

BACKGROUND: 17α-hydroxylase deficiency (17OHD) is a rare autosomal recessive disorder. Aldosterone levels are usually low in patients with 17OHD. However, among the approximately 150 cases of 17OHD reported to date, aldosterone levels were not low in all cases. Therefore, some 17OHD cases may have been misdiagnosed as primary aldosteronism (PA) cases. Often before puberty, 17OHD is diagnosed because of abnormal genital morphology and menstrual irregularities. However, we report a very rare case of 17OHD in an elderly patient with a high aldosterone/renin ratio (ARR) similar to that in PA. CASE PRESENTATION: A 63-year-old Japanese woman was transferred to our medical facility for the evaluation of bilateral adrenal hypertrophy, which was incidentally discovered during an abdominal examination after cholecystectomy. The patient had hypokalemia and a high aldosterone/renin ratio. Her medical history included hypertension and right intracerebral capsular hemorrhage at the age of 30 years. Additional testing revealed low cortisol, high adrenocorticotropic hormone, and low testosterone and dehydroepiandrosterone sulfate, indicating congenital adrenal hyperplasia. Genetic analysis revealed a mutation in the CYP17A1 gene and a karyotype of 46, XY; hence, she was diagnosed with 17OHD. CONCLUSION: 17OHD can resemble PA. The combination of a high ARR and low cortisol level should trigger the consideration of 17OHD.

Genetic and functional analyses of TBX4 reveal novel mechanisms underlying pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a fatal disease, with approximately 10% of cases associated with genetic variants. Recent genetic studies have reported pathogenic variants in the TBX4 gene in patients with PAH, especially in patients with childhood-onset of the disease, but the pathogenesis of PAH caused by TBX4 variant has not been fully uncovered. METHODS: We analysed the TBX4 gene in 75 Japanese patients with sporadic or familial PAH using a PCR-based bidirectional sequencing method. Detected variants were evaluated using in silico analyses as well as in vitro analyses including luciferase assay, immunocytochemistry and chromatin immunoprecipitation (ChIP) whether they have altered function. We also analysed the function of TBX4 using mouse embryonic lung explants with inhibition of Tbx4 expression. RESULTS: Putative pathogenic variants were detected in three cases (4.0%). Our in vitro functional analyses revealed that TBX4 directly regulates the transcriptional activity of fibroblast growth factor 10 (FGF10), whereas the identified TBX4 variant proteins failed to activate the FGF10 gene because of disruption of nuclear localisation signal or poor DNA-binding affinity. Furthermore, ex vivo inhibition of Tbx4 resulted in insufficiency of lung morphogenesis along with specific downregulation of Tie2 and Kruppel-like factor 4 expression. CONCLUSION: Our results implicate variants in TBX4 as a genetic cause of PAH in a subset of the Japanese population. Variants in TBX4 may lead to PAH through insufficient lung morphogenesis by disrupting the TBX4-mediated direct regulation of FGF10 signalling and pulmonary vascular endothelial dysfunction involving PAH-related molecules.

An infant with congenital nephrogenic diabetes insipidus presenting with hypercalcemia and hyperphosphatemia.

SUMMARY: We report a male infant with congenital nephrogenic diabetes insipidus (NDI) who presented with hypercalcemia and hyperphosphatemia since birth. Serum sodium started to increase at 39 days. Although there was no polyuria, urine osmolality was 71 mOsm/kg, when serum osmolality was 296 mOsm/kg with plasma arginine vasopressin 22.5 pg/mL. He was thus diagnosed as NDI. An undetectable level of urine calcium and unsuppressed intact parathyroid hormone suggested hyperparathyroidism including calcium-sensing receptor mutations that could cause hypercalcemia-induced NDI. Polyuria became apparent after the initiation of i.v. infusion for the treatment of hypernatremia. Low calcium and low sodium formula with hypotonic fluid infusion did not correct hypernatremia, hypercalcemia, or hyperphosphatemia. Hydrochlorothiazide and subsequently added celecoxib effectively decreased urine output and corrected electrolytes abnormalities. Normal serum electrolytes were maintained after the discontinuation of low calcium formula. The genetic analysis revealed a large deletion of the arginine vasopressin receptor-2 (AVPR2) gene but no pathogenic variant in the calcium-sensing receptor (CASR) gene. Whether hypercalcemia and hyperphosphatemia were caused by dehydration alone or in combination with other mechanisms remains to be clarified. LEARNING POINTS: Congenital NDI can present with neonatal hypercalcemia and hyperphosphatemia. Hypercalcemia and hyperphosphatemia can be treated with low calcium and low sodium formula, hydration, hydrochlorothiazide, and celecoxib. Genetic testing is sometimes necessary in the differentiating diagnosis of hypercalcemia associated with NDI.

A novel mutation in the ACAN gene in a family with autosomal dominant short stature and intervertebral disc disease.

Heterozygous mutations in the ACAN gene have been reported in individuals with short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans. We report a family with a phenotypic constellation carrying a novel mutation in the ACAN gene. The proband was a 7-year-old Japanese girl with short stature. Her mother and maternal grandmother also had short stature and intervertebral disc disease. We analyzed the ACAN gene in the family and identified a novel heterozygous mutation: c.4634delT, Leu1545Profs*11.

A novel SOX10 variant in a Japanese girl with Waardenburg syndrome type 4C and Kallmann syndrome.

We report the first case of Waardenburg syndrome type 4C and Kallmann syndrome in the same person. The patient, a Japanese girl, presented with bilateral iris depigmentation, bilateral sensorineural hearing loss, Hirschsprung disease, hypogonadotropic hypogonadism, and anosmia. We identified a novel SOX10 variant, c.124delC, p.Leu42Cysfs*67.

Relapsing 6q24-related transient neonatal diabetes mellitus with insulin resistance: A case report.

The overexpression of imprinted genes on chromosome 6q24 causes 6q24-related transient neonatal diabetes mellitus (6q24-TNDM). Most cases of 6q24-TNDM show transient diabetes mellitus (DM) during the neonatal period, followed by relapse after puberty. These two courses of DM are both characterized by insulin insufficiency. However, there has been no previously reported case of 6q24-TNDM with insulin resistance at relapse. We report the case of a 10-yr-old Japanese girl with relapsing 6q24-TNDM. In the neonatal period, she had hyperglycemia and was treated with insulin injection until 2 mo of age. After several years of remission of DM, her HbA1c level increased to 7.4% at 10 yr of age. Homeostasis model assessment of insulin resistance (HOMA-IR) score was high at 6.2. After starting metformin therapy, her glycemic control improved along with normalization of HOMA-IR score. Using microsatellite marker analysis on the 6q24 region and array comparative genome hybridization, we diagnosed her with 6q24-TNDM due to paternally inherited duplication of 6q24. These data indicate that patients with 6q24-TNDM can develop relapsing DM with insulin resistance.

Acquired partial lipodystrophy with metabolic disease in children following hematopoietic stem cell transplantation: a report of two cases and a review of the literature.

Hematopoietic stem cell transplantation (HSCT) has been newly identified as an etiology underlying acquired lipodystrophy (ALD). We report about two children with leukemia who underwent HSCT and later manifested aberrant fat distributions consistent with acquired partial lipodystrophy (APL). Both patients manifested graft-versus-host disease (GVHD), suggesting that GVHD may trigger lipodystrophy. The patients exhibited diabetic blood glucose patterns in the oral glucose tolerance test (OGTT) with high homeostasis model assessment ratios (HOMA-Rs), hypertriglyceridemia, fatty liver, and decreased serum leptin and adiponectin levels. Both patients were diagnosed with APL with metabolic disease. A review of the data of patients with ALD after HSCT revealed common clinical features, including aberrant fat distribution, impaired glucose tolerance (IGT) or diabetes and dyslipidemia. Based on previous reports and our two cases, we speculate that GVHD in the adipose tissue supports the development of ALD after HSCT. In conclusion, children may develop APL after HSCT. Therefore, evaluations of fat distribution and metabolic disease may be important during the long-term follow-up of these patients.

Rapid Growth and Early Metastasis of Papillary Thyroid Carcinoma in an Adolescent Girl with Graves' Disease.

BACKGROUND: The risk factors for rapid growth and early metastasis of papillary thyroid carcinoma (PTC) and the role of coexisting Graves' disease in the clinical course of PTC remain uncertain in children. CASE DESCRIPTION: We report on a Japanese girl, whose PTC rapidly grew and metastasized within 4 years. Graves' disease was diagnosed by the presence of serum TSH receptor antibodies at 8 years of age when thyroid ultrasonography detected no nodules. After 4 years of effective treatment with thiamazole, multifocal nodules - up to 47 mm in diameter - were detected on thyroid ultrasonography. Chest CT scan revealed multiple metastatic lesions in the lung. After total thyroidectomy, PTC was pathologically diagnosed. The patient underwent two courses of radioactive iodine (RAI) treatment, but the pulmonary metastatic lesions did not take up the RAI. Molecular analyses of the PTC tissue identified a TFG/NTRK1 chimeric gene and disclosed the preserved expression of TSHR and the reduced expression of SLC5A5 compared with non-tumor thyroid tissue. CONCLUSIONS: Rapid growth and early metastasis of PTC with coexisting Graves' disease in this patient can be related to a combination of multiple factors including preserved TSHR expression, reduced SLC5A5 expression, and TFG/NTRK1 rearrangement.

Histological Changes in Autoimmune Hepatitis with Graves' Disease: A Child Case Report.

We herein report a child case of autoimmune hepatitis (AIH) accompanied with Graves' disease. Elevated aminotransferase levels were found in a 12-year-old Japanese girl with Graves' disease. In her first liver biopsy, necrosis and inflammation was limited to the centrilobular area, while the second biopsy showed different findings. Namely, portal injury newly appeared, including interface hepatitis, which represents the histological characteristics of AIH. As the histological findings at the onset of AIH do not always show typical findings, a re-biopsy is considered to be important in individuals suspected to have AIH. AIH should be included in the differential diagnosis of liver dysfunction in Graves' disease, even in children.

A case of mature teratoma with a falsely high serum estradiol value measured with an immunoassay.

BACKGROUND: Immunoassays (IAs) are widely used to measure concentration of serum estradiol (E2) despite some limitations including cross-reactivity. Liquid chromatography-tandem mass spectrometory (LC-MS/MS) for E2 measurement has a theoretically greater specificity and sensitivity than IAs. We report a case with unexpected discrepancy in E2 values measured by IA and LC-MS/MS. CASE PRESENTATION: A 7-year-old girl was referred because of an ovarian tumor. Physical examinations revealed prepubertal statuses. Serum E2 with ECLIA was 69 pg/mL. GnRH stimulation test revealed a prepubertal response. On imaging studies, the diagnosis was mature teratoma of the right ovary. After tumor enucleation, the diagnosis was pathologically confirmed. E2 with ECLIA decreased to 11 pg/mL. Preoperative E2 with LC-MS/MS was 1.15 pg/mL. CONCLUSIONS: We conclude the preoperative E2 with ECLIA was falsely high. We speculate the antibody used in ECLIA had cross-reactivity to endogenous compounds. LC-MS/MS should be considered when high serum E2 measured with IA is inconsistent with physical and/or endocrinological data.

Human Chorionic Gonadotropin Stimulation Test in Prepubertal Children with Micropenis Can Accurately Predict Leydig Cell Function in Pubertal or Postpubertal Adolescents.

BACKGROUND/AIM: To evaluate the accuracy of the human chorionic gonadotropin (hCG) stimulation test in children with micropenis in predicting later Leydig cell function. METHODS: We conducted a retrospective investigation of testosterone response to a 3-day hCG test (3,000 IU/m2/day) in prepuberty to indicate the need for hormone replacement therapy (HRT) in adolescence. RESULTS: Fifty Japanese boys (range, 0.8-15.4 years of age; median, 8.9) with micropenis were enrolled. Thirty-four spontaneously developed puberty and preserved the ability of testosterone production (group 1), while 16 did not develop any pubertal signs without HRT (group 2). Serum testosterone levels after the hCG test (post-hCG T) in group 2 (range, <0.05-1.1 ng/ml; median, 0.24) were significantly lower than in group 1 (range, 0.5-8.7 ng/ml; median, 2.4; p < 0.0001). Based on true positives who required continuous HRT, the area under the receiver-operating characteristics curve for post-hCG T was 0.983 [95% confidence interval (CI), 0.90-1.00]. The post-hCG T cut-off level corresponding to the Youden index was 1.1 ng/ml (95% CI, 1.0-1.1), with a sensitivity of 100.0% (95% CI, 79.4-100.0) and a specificity of 94.1% (95% CI, 80.3-99.3). CONCLUSIONS: The hCG test in prepubertal children with micropenis can be useful for predicting Leydig cell function in pubertal or postpubertal adolescents. The post-hCG T cut-off level of 1.1 ng/ml is recommended to screen for those who will likely require HRT for pubertal development.

Meningitis and septicemia caused by nontypeable Haemophilus influenzae in a previously healthy 2-year-old girl.

Nontypeable Haemophilus influenzae (NTHi) commonly colonizes the upper respiratory tract of children and causes otitis media, sinusitis, and bronchitis. Invasive NTHi diseases such as meningitis and septicemia have rarely been reported, especially in children with underlying predisposing conditions such as head trauma and immune compromise. However, we report a previously healthy 2-year-old girl who developed meningitis and septicemia caused by NTHi biotype ΙΙΙ. She was treated with dexamethasone, meropenem, and ceftriaxone, and recovered uneventfully. We wish to emphasize that NTHi should be borne in mind as a potential pathogen that can cause meningitis and septicemia, even in previously healthy children.