Kenji Fujieda

Publications (101)286.2 Total impact

• Article: Four Japanese patients with adrenal hypoplasia congenita and hypogonadotropic hypogonadism caused by DAX-1 gene mutations: mutant DAX-1 failed to repress steroidogenic acute regulatory protein (StAR) and luteinizing hormone beta-subunit gene promoter activity.

  Koji Okuhara, Shuji Abe, Takuma Kondo, Keinosuke Fujita, Noya Koda, Hiroshi Mochizuki, Kenji Fujieda, Toshihiro Tajima
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  ABSTRACT: Mutations of DSS (dosage sensitive sex reversal)-AHC critical region on the X chromosome, gene 1 DAX-1(NROB1)] results in X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HHG). Here we report four Japanese patients with AHC and HHG caused by the mutations of the DAX-1 gene. All patients manifested adrenal crisis at early childhood. Three patients did not show any pubertal sign and were diagnosed as having HHG. One patient manifested spontaneous pubertal development at 17 years of age. Nevertheless, his puberty did not develop further and his gonadotropin and testosterone levels decreased thereafter. Therefore, he was also diagnosed as having HHG. We performed testicular biopsy in another patient with HHG. Histological examination demonstrated Sertoli cell hypoplasia and no sperm formation in the seminiferous tubules. Molecular analysis demonstrated two novel point mutations (V269D and L278R) in two patients. Transient transfection assays showed that all these mutations (V269D, L271X, L278R, and Q395X) abolished the repression activity to both StAR and LHbeta gene promoter activation. In conclusion, we reported patients with AHC and HHG caused by the loss of function mutations of the DAX-1 gene.
  Endocrine Journal 04/2008; 55(1):97-103. · 2.03 Impact Factor
• Article: Matrix metalloproteinases in infants with posthemorrhagic hydrocephalus.

  Toshio Okamoto, Satoru Takahashi, Eiki Nakamura, Ken Nagaya, Tokitsugi Hayashi, Masaru Shirai, Kenji Fujieda
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  ABSTRACT: The cerebrospinal fluid matrix metalloproteinase (MMP) activities were measured in infants with posthemorrhagic hydrocephalus to elucidate the intrinsic mechanism for the resolution of ventricular dilation. Increased MMP-9 activities were observed in the patients who escaped a shunt operation, suggesting its potential contribution to the resolution of ventricular dilation.
  Early Human Development 03/2008; 84(2):137-9. · 2.05 Impact Factor
• Article: Molecular basis of neonatal diabetes in Japanese patients.

  Shigeru Suzuki, Yoshio Makita, Tokuo Mukai, Kumihiro Matsuo, Osamu Ueda, Kenji Fujieda
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  ABSTRACT: Neonatal diabetes mellitus (NDM) is classified clinically into a transient form (TNDM), in which insulin secretion recovers within several months, and a permanent form (PNDM), requiring lifelong medication. However, these conditions are genetically heterogeneous. Our objective was to evaluate the contribution of the responsible gene and delineate their clinical characteristics. The chromosome 6q24 abnormality and KCNJ11 and ABCC8 mutations were analyzed in 31 Japanese patients (16 with TNDM and 15 with PNDM). Moreover, FOXP3 and IPF1 mutations were analyzed in a patient with immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome and with pancreatic agenesis, respectively. A molecular basis for NDM was found in 23 patients: 6q24 in eleven, KCNJ11 in nine, ABCC8 in two, and FOXP3 in one. All the patients with the 6q24 abnormality and two patients with the KCNJ11 mutation proved to be TNDM. Five mutations were novel: two (p.A174G and p.R50G) [corrected] in KCNJ11, two (p.A90V and p.N1122D) in ABCC8, and one (p.P367L) in FOXP3. Comparing the 6q24 abnormality and KCNJ11 mutation, there were some significant clinical differences: the earlier onset of diabetes, the lower frequency of diabetic ketoacidosis at onset, and the higher proportion of the patients with macroglossia at initial presentation in the patients with 6q24 abnormality. In contrast, two patients with the KCNJ11 mutations manifested epilepsy and developmental delay. Both the 6q24 abnormality and KCNJ11 mutation are major causes of NDM in Japanese patients. Clinical differences between them could provide important insight into the decision of which gene to analyze in affected patients first.
  Journal of Clinical Endocrinology &amp Metabolism 11/2007; 92(10):3979-85. · 6.50 Impact Factor
• Article: A novel missense mutation (P366T) of the LHX4 gene causes severe combined pituitary hormone deficiency with pituitary hypoplasia, ectopic posterior lobe and a poorly developed sella turcica.

  Toshihiro Tajima, Tsukasa Hattori, Takeo Nakajima, Koji Okuhara, Junko Tsubaki, Kenji Fujieda
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  ABSTRACT: LIM homeodomain transcription factors regulate many aspects of development in multicellular organisms. LHX4/Lhx4 is a protein that is essential for pituitary development and motor neuron specification in mammals. In human, a heterozygous splicing mutation of the LHX4 gene was reported in a family with combined pituitary hormone deficiencies (CPHD). In addition to CPHD, these patients were characterized by small sella turcica and chiari malformation. Here we report a Japanese patient with CPHD (GH, PRL, TSH, LH, FSH, and ACTH deficiency) due to a novel missense mutation (P366T) of the LHX 4 gene. She showed severe respiratory disease and hypoglycemia soon after birth. Brain MRI demonstrated hypoplastic anterior pituitary, ectopic posterior lobe, a poorly developed sella turcica, and chiari malformation. Sequence analysis of the LHX 4 gene identified a heterozygous missense mutation (P366T) in exon 6, which was present in LIM4 specific domain. Neither of the patient's parents harbored this mutation, indicating de novo mutation.
  Endocrine Journal 09/2007; 54(4):637-41. · 2.03 Impact Factor
• Article: Leukemia in Cardio-facio-cutaneous (CFC) syndrome: a patient with a germline mutation in BRAF proto-oncogene.

  Yoshio Makita, Yoko Narumi, Makoto Yoshida, Tetsuya Niihori, Shigeo Kure, Kenji Fujieda, Yoichi Matsubara, Yoko Aoki
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  ABSTRACT: Cardio-facio-cutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by a distinctive facial appearance, ectodermal abnormalities, and heart defects. Clinically, it overlaps with both Noonan syndrome and Costello syndrome, which are caused by mutations in 2 genes that encode molecules of the RAS/MAPK (mitogen activated protein kinase) pathway (PTPN11 and HRAS, respectively). Recently, mutations in KRAS, BRAF, and MEK1/2 have been identified in patients with CFC syndrome. Somatic mutations in KRAS and BRAF have been identified in various tumors. In contrast, the association with malignancy has not been noticed in CFC syndrome. Here we report a 9-year-old boy diagnosed with CFC syndrome and acute lymphoblastic leukemia. Sequencing analysis of the entire coding region of KRAS and BRAF showed a de novo germline BRAF E501G (1502A-->G) mutation. Molecular diagnosis and careful observations should be considered in children with CFC syndrome because they have germline mutations in proto-oncogenes and might develop malignancy.
  Journal of Pediatric Hematology/Oncology 06/2007; 29(5):287-90. · 1.16 Impact Factor
• Article: Etiology of severe sensorineural hearing loss in children: independent impact of congenital cytomegalovirus infection and GJB2 mutations.

  Hiroshi Ogawa, Tatsuo Suzutani, Yohko Baba, Shin Koyano, Naoki Nozawa, Kei Ishibashi, Kenji Fujieda, Naoki Inoue, Koichi Omori
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  ABSTRACT: Sensorineural hearing loss (SNHL) is the most common congenital disease. Longitudinal studies of infants with congenital cytomegalovirus (CMV) infection have demonstrated an association between CMV and SNHL. However, because of the lack of suitable neonatally collected specimens, the proportion of CMV-associated SNHL has not been defined, nor has the relationship between CMV and the major genetic causes of SNHL, such as mutations in the GJB2 gene. Sixty-seven children with severe SNHL were analyzed for CMV and human herpesvirus 6 (HHV-6) infections and for GJB2 mutations. DNA specimens were prepared from dried umbilical cords, which are available for everyone born in Japan. Four children with typical symptomatic infection at birth served as positive control subjects. Congenital CMV infection and GJB2 mutations were identified in 15% and 24% of the patients, respectively. HHV-6 was not detected. All children with CMV-associated cases developed SNHL before they were 2 years old. Most children with CMV-associated SNHL had no obvious clinical abnormality at birth, and their viral loads were lower than those of symptomatic children. Congenital CMV infection is an important cause of severe SNHL, and it has an incidence comparable to that of GJB2-associated SNHL.
  The Journal of Infectious Diseases 04/2007; 195(6):782-8. · 6.41 Impact Factor
• Article: Multiple endocrine neoplasia syndromes.

  Kenji Fujieda
  Hormone Research 02/2007; 68 Suppl 5:100. · 2.48 Impact Factor
• Article: Novel SLC12A1 (NKCC2) mutations in two families with Bartter syndrome type 1.

  Masanori Adachi, Yumi Asakura, Yoshiaki Sato, Toshihiro Tajima, Takeo Nakajima, Toshiyuki Yamamoto, Kenji Fujieda
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  ABSTRACT: Bartter syndrome (BS) type 1, also referred to antenatal BS, is a genetic tubulopathy with hypokalemic metabolic alkalosis and prenatal onset of polyuria leading to polyhydramnios. It has been shown that BS type 1 is caused by mutations in the SLC12A1 gene encoding bumetanide-sensitive Na-K-2Cl (-) cotransporter (NKCC2). We had the opportunity to care for two unrelated Japanese patients of BS type 1 with typical manifestations including polyhydramnios, prematurity, hypokalemia, alkalosis, and infantile-onset nephrocalcinosis. Analysis of the SLC12A1 gene demonstrated four novel mutations: N117X, G257S, D792fs and N984fs. N117X mutation is expected to abolish most of the NKCC2 protein, whereas G257, which is evolutionary conserved, resides in the third transmembrane domain. The latter two frameshift mutations reside in the intra-cytoplasmic C-terminal domain, which illustrates the importance of this domain for the NKCC2 function. In conclusion, we found four novel SLC12A1 mutations in two BS type 1 patients. Development of effective therapy for hypercalciuria is mandatory to prevent nephrocalcinosis and resultant renal failure.
  Endocrine Journal 02/2007; 54(6):1003-7. · 2.03 Impact Factor
• Article: A Japanese patient of congenital hypothyroidism with cerebellar atrophy.

  Toshihiro Tajima, Fumie Fujiwara, Akira Sudo, Shinji Saito, Kenji Fujieda
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  ABSTRACT: We encountered a Japanese patient of congenital hypothyroidism with severe cerebellum atrophy. The boy was born after 40 weeks of gestation by normal vaginal delivery from nonconsanguineous parents. There were no abnormal physical findings; however neonatal mass screening for congenital hypothyroidism at 5 days of age demonstrated elevated thyrotropin (TSH) level (15.5 microU/ml, normal range 0.54-10.0 microU/ml). He was suspected to have subclinical or mild congenital hypothyroidism (CH). Thus he was treated with L-thyroxine using a regimen that rendered his serum TSH concentration within normal range from 27 days of age. Despite early and adequate treatment, he showed signs of global developmental delay and became gradually hypotonic and exhibited a staggering gait at 3 years of age. Brain magnetic resonance imaging (MRI) demonstrated marked cerebellar atrophy with an intact brainstem. Thyroidal uptake of radioiodide and thyroid gland size were normal, indicating a functional defect only. The relation between congenital hypothyroidism and severe cerebellar atrophy in our patient is not clear. As only a few cases of the combination of CH and cerebellar anomalies have been described previously, cerebellar symptoms in CH should be examined carefully.
  Endocrine Journal 02/2007; 54(6):941-4. · 2.03 Impact Factor
• Article: Postnatal development of brainstem serotonin-containing neurons projecting to lumbar spinal cord in rats.

  Hajime Tanaka, Satoshi Amamiya, Nao Miura, Akiko Araki, Junko Ohinata, Kenji Fujieda
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  ABSTRACT: We quantified postnatal changes in brainstem serotonin (5-hydroxytryptamine, 5-HT)-containing neurons projecting to lumbar spinal cord. The medulla-spinal cord descending neurons were identified by a retrograde neurotracer, choleratoxin B subunit (CTb), and 5-HT neurons were stained by immunohistochemistry. Double-labeled neurons were assumed to be 5-HT neurons projecting to the lumbar spinal cord, and were quantitatively analyzed in each raphe nucleus in the medulla. The following results were obtained: (1) At PND 3, numerous CTb-labeled neurons (CTLN) were already present in the raphe pallidus (B1), while few CTLN were seen in raphe obscurus (B2) and raphe magnus (B3). CTLN then rapidly increased in number and were separately distributed after PND 7 in B3 and after PND 14 in B2. (2) At PND 3, numerous 5-HT-containing neurons were already present in B1-B3, with 23.4% and 14.0% of them labeled with CTb in B1 and B2, respectively, while there were few double-labeled neurons in B3. From PND 3 to 28, although the proportion of double-labeled to 5-HT neurons remained unchanged in B1 and B2, that in B3 rapidly increased from 5.8% at PND 7 to 28.8% at PND 14. Previous studies have shown that the 5-HT neurons in B3 send fibers mainly to the dorsal horn, while those in B1 and B2 send fibers mainly to the ventral horn at all spinal cord levels. Taken together, the present findings suggest that the brainstem 5-HT systems influence the ventral horn of the spinal cord, where spinal motoneurons exist earlier than in the dorsal horn. The functional significance of these early 5-HT systems in motor development and/or disabilities is discussed.
  Brain and Development 11/2006; 28(9):586-91. · 2.12 Impact Factor
• Article: Molecular analysis of the CLCNKB gene in Japanese patients with classic Bartter syndrome.

  Toshihiro Tajima, Mitsuru Nawate, Yutaka Takahashi, Yumiko Mizoguchi, Shigetaka Sugihara, Masaaki Yoshimoto, Mutsumi Murakami, Masanori Adachi, Katsuhiko Tachibana, Hiroshi Mochizuki, Kenji Fujieda
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  ABSTRACT: Deletions or mutations in the gene encoding the basolateral chloride channel CLC-Kb (CLCNKB) cause classic Bartter syndrome (MIM 602023), which is characterized by hypokalemic metabolic alkalosis, hyperreninemic hyperaldosteronism and hypercalciura. These patients are usually diagnosed during infancy or childhood due to failure to thrive and growth retardation. The purpose of this study was to investigate the underlying mutations in Japanese patients with classic Bartter syndrome. Seven Japanese patients from seven different families diagnosed as having classic Bartter syndrome were studied. Analysis of CLCNKB demonstrated a large deletion in two patients, a partial deletion in one patient and two mutations (DeltaL130 in exon 4 and W610X in exon 16) in the remaining four patients. DeltaL130 is a novel mutation, but W610X was previously reported in three unrelated Japanese patients. Six out of the seven patients were diagnosed due to typical characteristics of classic Bartter syndrome such as failure to thrive and poor weight gain however, one patient was asymptomatic with mild hypokalemia. In conclusion, we identified a novel mutation of the CLCNKB gene, DeltaL130. We did not determine whether the W610X mutation in our patients was from a common ancestor or if this mutation is frequent in Japan.
  Endocrine Journal 11/2006; 53(5):647-52. · 2.03 Impact Factor
• Article: Low-dose growth hormone treatment (0.175 mg/kg/week) for short stature in patients with Turner Syndrome: data from KIGS Japan.

  Yoshiya Ito, Kenji Fujieda, Toshiaki Tanaka, Kazue Takano, Kazuo Chihara, Yoshiki Seino, Minoru Irie
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  ABSTRACT: Turner syndrome is a common sex chromosome anomaly. Human growth hormone (hGH) is effective for treating short stature, which is a major characteristic of the disease. In this report, we analyzed the results of low-dose GH treatment for short stature in 212 Turner syndrome patients with growth hormone deficiency. These patients were enrolled in KIGS Japan. After 5 years of treatment, change in height was more than the mean growth curve in many patients, and the standard deviation (SD) for stature improved by +1.22 SDS. As the treatment progressed, the weight-for-height index (WHI) decreased in patients aged 8.1 years or older but not more than 14.8 years at the commencement of the treatment.
  Endocrine Journal 11/2006; 53(5):699-703. · 2.03 Impact Factor
• Article: [Down syndrome].

  Osamu Ueda, Kenji Fujieda
  Nippon rinsho. Japanese journal of clinical medicine 10/2006; Suppl 3:119-21.
• Article: [Leprechaunism (Donohue syndrome)].

  Kenji Fujieda
  Nippon rinsho. Japanese journal of clinical medicine 10/2006; Suppl 3:94-9.
• Article: [Steroid sulphatase deficiency].

  Shigeru Suzuki, Kenji Fujieda
  Nippon rinsho. Japanese journal of clinical medicine 10/2006; Suppl 3:494-6.
• Article: [Prader-Willi syndrome].

  Kenji Fujieda
  Nippon rinsho. Japanese journal of clinical medicine 07/2006; Suppl 2:229-33.
• Article: [Klinefelter syndrome].

  Kenji Fujieda
  Nippon rinsho. Japanese journal of clinical medicine 07/2006; Suppl 2:487-90.
• Article: [Adrenogenital syndrome].

  Kenji Fujieda
  Nippon rinsho. Japanese journal of clinical medicine 07/2006; Suppl 2:643-6.
• Article: [20,22 Desmolase deficiency].

  Kenji Fujieda
  Nippon rinsho. Japanese journal of clinical medicine 06/2006; Suppl 1:696-8.
• Article: [Congenital adrenal hyperplasia].

  Kenji Fujieda
  Nippon rinsho. Japanese journal of clinical medicine 06/2006; Suppl 1:673-6.