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1.
J Clin Neurosci ; 120: 138-146, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38244528

RESUMO

Craniopharyngiomas are difficult to resect completely, recurrence is frequent, and hypothalamic/pituitary function may be affected after surgery. Therefore, the ideal treatment for craniopharyngiomas is local control with preservation of hypothalamic and pituitary functions. The purpose of this study is to retrospectively evaluate the long-term efficacy and adverse events of stereotactic radiotherapy (SRT) with Novalis for craniopharyngioma. This study included 23 patients with craniopharyngiomas who underwent surgery between 2006 and 2021 and underwent SRT as their first irradiation after surgery. The median post-irradiation observation period was 88 months, with the overall survival rates of 100 % at 10 years and 85.7 % at 20 years. One patient died of adrenal insufficiency 12 years after irradiation. The local control rate of the cystic component was 91.3 % at 5 years, 83.0 % at 15 years, with no increase in the solid component. No delayed impairment of visual or pituitary function due to irradiation was observed. No new hypothalamic dysfunction was observed after radiation therapy. No delayed adverse events such as brain necrosis, cerebral artery stenosis, cerebral infarction, or secondary brain tumors were also observed. SRT was safe and effective over the long term in patients irradiated in childhood as well as adults, with no local recurrence or adverse events. We believe that surgical planning for craniopharyngioma with stereotactic radiotherapy in mind is effective in maintaining a good prognosis and quality of life.


Assuntos
Craniofaringioma , Neoplasias Hipofisárias , Adulto , Humanos , Craniofaringioma/radioterapia , Craniofaringioma/cirurgia , Craniofaringioma/patologia , Estudos Retrospectivos , Qualidade de Vida , Seguimentos , Neoplasias Hipofisárias/radioterapia , Neoplasias Hipofisárias/cirurgia , Neoplasias Hipofisárias/patologia , Resultado do Tratamento , Recidiva Local de Neoplasia/radioterapia , Recidiva Local de Neoplasia/cirurgia
2.
Int J Clin Oncol ; 28(11): 1563-1572, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37646971

RESUMO

BACKGROUND: Hypogonadism is a significant late complication in childhood cancer survivors (CCS). The aim of this study was to elucidate the advantages and limitations of estrogen replacement therapy (ERT) for CCS with hypogonadism. METHODS: Seventeen CCS were divided into two groups: gonadal hypogonadism (GH) group (n = 8) and central hypogonadism (CH) group (n = 9). Pearson correlation coefficients were used to investigate the impact of cancer management on final height, bone density, and uterine development. RESULTS: Seven of GH group had hematologic malignancies, and all of them underwent total body irradiation before bone marrow transplantation. The GH group showed significant positive correlations between the onset age of disease treatment and final height (p < 0.05, R = 0.712) and uterine size following ERT (p < 0.05, R = 0.775). All CCS in the CH group had brain tumors, and seven of them received chemotherapy. There were trends towards positive and negative correlations between the onset age of disease treatment and final height (p = 0.09, R = 0.598) or uterine size (p = 0.07, R = - 0.669), respectively. A negative correlation trend was observed between the age at ERT initiation and final height (p = 0.07, R = - 0.769) or bone density (p = 0.18, R = - 0.626) in six CH patients who received growth hormone therapy. Five CCS in both groups experienced osteoporosis, despite receiving ERT. CONCLUSION: Individualized management strategies beyond ERT are essential to reduce long-term complications in CCS with hypogonadism, considering the type and timing of cancer treatment.


Assuntos
Neoplasias Encefálicas , Sobreviventes de Câncer , Hipogonadismo , Feminino , Humanos , Criança , Terapia de Reposição de Estrogênios/efeitos adversos , Sobreviventes , Neoplasias Encefálicas/terapia , Hipogonadismo/tratamento farmacológico , Hipogonadismo/etiologia
3.
Endocr J ; 70(7): 703-709, 2023 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-37045780

RESUMO

Lymphocytic hypophysitis (LYH) is a rare chronic inflammatory disease characterized by lymphocytic infiltration of the anterior or posterior pituitary gland and hypothalamus. LYH is subdivided into lymphocytic adenohypophysitis (LAH), lymphocytic infundibulo-neurohypophysitis (LINH), and lymphocytic panhypophysitis (LPH) depending on the primary site. Most cases occur in adults, with few cases reported in children, and it is especially important to distinguish LYH from suprasellar malignancies, such as germ cell tumors and other neoplastic diseases. Although a biopsy is necessary for definitive diagnosis, it is desirable to be able to diagnose the disease without biopsy if possible, especially in children, because of the surgical invasiveness of the procedure. Recently, serum anti-rabphilin-3A antibodies have attracted attention as diagnostic markers for LYH, especially in LINH, but there are only a few reports on pediatric patients. In the present study, we experienced two children with LPH and LAH, respectively, who tested positive for anti-rabphilin-3A antibodies. This is the first report of children with LYH other than LINH positive for anti-rabphilin-3A antibodies, and anti-rabphilin-3A antibodies may be a useful non-invasive diagnostic marker not only for LINH but also for LYH in general. We also discuss the sensitivity and specificity of anti-rabphilin-3A antibody testing in cases where histological diagnosis has been made.


Assuntos
Hipofisite Autoimune , Hipopituitarismo , Doenças da Hipófise , Neuro-Hipófise , Adulto , Humanos , Criança , Hipofisite Autoimune/complicações , Hipopituitarismo/complicações , Doenças da Hipófise/diagnóstico
4.
J Hum Genet ; 61(7): 585-91, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26984564

RESUMO

The etiology of idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD) in European patients is known to include SHOX mutations and copy-number variations (CNVs) involving SHOX and/or the highly evolutionarily conserved non-coding DNA elements (CNEs) flanking the gene. However, the frequency and types of SHOX abnormalities in non-European patients and the clinical importance of mutations in the CNEs remains to be clarified. Here, we performed systematic molecular analyses of SHOX for 328 Japanese patients with ISS or LWD. SHOX abnormalities accounted for 3.8% of ISS and 50% of LWD cases. CNVs around SHOX were identified in 16 cases, although the ~47 kb deletion frequently reported in European patients was absent in our cases. Probably damaging mutations and benign/silent substitutions were detected in four cases, respectively. Although CNE-linked substitutions were detected in 15 cases, most of them affected poorly conserved nucleotides and were shared by unaffected individuals. These results suggest that the frequency and mutation spectrum of SHOX abnormalities are comparable between Asian and European patients, with the exception of a European-specific downstream deletion. Furthermore, this study highlights the clinical importance and genetic heterogeneity of the SHOX-flanking CNVs, and indicates a limited clinical significance of point mutations in the CNEs.


Assuntos
Nanismo/diagnóstico , Nanismo/genética , Estudos de Associação Genética , Variação Genética , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Proteínas de Homeodomínio/genética , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Variações do Número de Cópias de DNA , Feminino , Heterogeneidade Genética , Humanos , Lactente , Japão , Masculino , Mutação , Fenótipo , Análise de Sequência de DNA , Proteína de Homoeobox de Baixa Estatura , Síndrome
5.
Am J Med Genet A ; 161A(9): 2234-43, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23913813

RESUMO

Kabuki syndrome is a congenital anomaly syndrome characterized by developmental delay, intellectual disability, specific facial features including long palpebral fissures and ectropion of the lateral third of the lower eyelids, prominent digit pads, and skeletal and visceral abnormalities. Mutations in MLL2 and KDM6A cause Kabuki syndrome. We screened 81 individuals with Kabuki syndrome for mutations in these genes by conventional methods (n = 58) and/or targeted resequencing (n = 45) or whole exome sequencing (n = 5). We identified a mutation in MLL2 or KDM6A in 50 (61.7%) and 5 (6.2%) cases, respectively. Thirty-five MLL2 mutations and two KDM6A mutations were novel. Non-protein truncating-type MLL2 mutations were mainly located around functional domains, while truncating-type mutations were scattered through the entire coding region. The facial features of patients in the MLL2 truncating-type mutation group were typical based on those of the 10 originally reported patients with Kabuki syndrome; those of the other groups were less typical. High arched eyebrows, short fifth finger, and hypotonia in infancy were more frequent in the MLL2 mutation group than in the KDM6A mutation group. Short stature and postnatal growth retardation were observed in all individuals with KDM6A mutations, but in only half of the group with MLL2 mutations.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Doenças Hematológicas/genética , Histona Desmetilases/genética , Mutação , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Doenças Vestibulares/genética , Anormalidades Múltiplas/diagnóstico , Adolescente , Adulto , Substituição de Aminoácidos , Criança , Pré-Escolar , Exoma , Fácies , Feminino , Estudos de Associação Genética , Doenças Hematológicas/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Taxa de Mutação , Fenótipo , Doenças Vestibulares/diagnóstico , Inativação do Cromossomo X , Adulto Jovem
6.
J Hum Genet ; 56(10): 707-15, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21850009

RESUMO

Costello syndrome (CS) is a congenital disease that is characterized by a distinctive facial appearance, failure to thrive, mental retardation and cardiomyopathy. In 2005, we discovered that heterozygous germline mutations in HRAS caused CS. Several studies have shown that CS-associated HRAS mutations are clustered in codons 12 and 13, and mutations in other codons have also been identified. However, a comprehensive comparison of the substitutions identified in patients with CS has not been conducted. In the current study, we identified four mutations (p.G12S, p.G12A, p.G12C and p.G12D) in 21 patients and analyzed the associated clinical manifestations of CS in these individuals. To examine functional differences among the identified mutations, we characterized a total of nine HRAS mutants, including seven distinct substitutions in codons 12 and 13, p.K117R and p.A146T. The p.A146T mutant demonstrated the weakest Raf-binding activity, and the p.K117R and p.A146T mutants had weaker effects on downstream c-Jun N-terminal kinase signaling than did codon 12 or 13 mutants. We demonstrated that these mutant HRAS proteins induced senescence when overexpressed in human fibroblasts. Oncogene-induced senescence is a cellular reaction that controls cell proliferation in response to oncogenic mutation and it has been considered one of the tumor suppression mechanisms in vivo. Our findings suggest that the HRAS mutations identified in CS are sufficient to cause oncogene-induced senescence and that cellular senescence might therefore contribute to the pathogenesis of CS.


Assuntos
Senescência Celular/genética , Síndrome de Costello/genética , Síndrome de Costello/fisiopatologia , Fibroblastos/metabolismo , Mutação/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adolescente , Adulto , Animais , Linhagem Celular , Criança , Pré-Escolar , Códon/genética , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Lactente , Masculino , Camundongos , Células NIH 3T3 , Fenótipo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais/genética , Regulação para Cima
7.
Brain Dev ; 26(7): 442-7, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15351079

RESUMO

For the last 15 years, we have tried to understand the pathophysiology of childhood chronic fatigue syndrome (CCFS) in Japan. In this condition, two major symptoms are important: easy fatigability and disturbed learning and memorization. In CCFS patients we clinically evaluated autonomic nervous system function, circadian rhythm of hormonal secretion (melatonin, cortisol and 3-endorphin), core body temperature, and sleep-wake pattern. Most patients showed autonomic nervous system dysfunction and circadian rhythm disturbances, similar to those observed in jet lag. Radiological imaging studies (SPECT, Xe-CT, and MRS) revealed decreased blood flow in the frontal and thalamic areas, and accumulation of choline in the frontal lobe. We analyzed the relationship between the laboratory data and clinical symptoms in CCFS.


Assuntos
Síndrome de Fadiga Crônica/fisiopatologia , Síndrome de Fadiga Crônica/psicologia , Deficiências da Aprendizagem/etiologia , Transtornos da Memória/etiologia , Transtornos Fóbicos/etiologia , Adolescente , Adulto , Doenças do Sistema Nervoso Autônomo/etiologia , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Circulação Cerebrovascular/fisiologia , Criança , Transtornos Cronobiológicos/etiologia , Transtornos Cronobiológicos/fisiopatologia , Síndrome de Fadiga Crônica/diagnóstico por imagem , Feminino , Humanos , Japão , Deficiências da Aprendizagem/diagnóstico por imagem , Deficiências da Aprendizagem/fisiopatologia , Masculino , Transtornos da Memória/diagnóstico por imagem , Transtornos da Memória/fisiopatologia , Transtornos Fóbicos/diagnóstico por imagem , Transtornos Fóbicos/fisiopatologia , Cintilografia
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