RESUMO
The clinical spectrum of Down syndrome (DS) ranges from congenital malformations to premature aging and early-onset senescence. Excessive immunoreactivity and oxidative stress are thought to accelerate the pace of aging in DS patients; however, the immunological profile remains elusive. We investigated whether peripheral blood monocyte-derived dendritic cells (MoDCs) in DS patients respond to lipopolysaccharide (LPS) distinctly from non-DS control MoDCs. Eighteen DS patients (age 2-47 years, 12 males) and 22 controls (age 4-40 years, 15 males) were enrolled. CD14-positive monocytes were immunopurified and cultured for 7 days in the presence of granulocyte-macrophage colony-stimulating factor and IL-4, yielding MoDCs in vitro. After the LPS-stimulation for 48 hours from days 7 to 9, culture supernatant cytokines were measured by multiplex cytokine bead assays, and bulk-prepared RNA from the cells was used for transcriptomic analyses. MoDCs from DS patients produced cytokines/chemokines (IL-6, IL-8, TNF-α, MCP-1, and IP-10) at significantly higher levels than those from controls in response to LPS. RNA sequencing revealed that DS-derived MoDCs differentially expressed 137 genes (74 upregulated and 63 downregulated) compared with controls. A gene enrichment analysis identified 5 genes associated with Toll-like receptor signaling (KEGG: hsa04620, Pâ =â 0.00731) and oxidative phosphorylation (hsa00190, Pâ =â 0.0173) pathways. MoDCs obtained from DS patients showed higher cytokine or chemokine responses to LPS than did control MoDCs. Gene expression profiles suggest that hyperactive Toll-like receptor and mitochondrial oxidative phosphorylation pathways configure the immunoreactive signature of MoDCs in DS patients.
Assuntos
Citocinas , Células Dendríticas , Síndrome de Down , Lipopolissacarídeos , Monócitos , Humanos , Síndrome de Down/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Masculino , Feminino , Adolescente , Adulto , Criança , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Monócitos/imunologia , Monócitos/metabolismo , Pré-Escolar , Pessoa de Meia-Idade , Citocinas/metabolismo , Adulto Jovem , Células CultivadasRESUMO
Gaucher disease (GD) is a lysosomal storage disorder caused by a deficiency in the GBA1-encoded enzyme, ß-glucocerebrosidase. Enzyme replacement therapy is ineffective for neuronopathic Gaucher disease (nGD). High-dose ambroxol has been administered as an alternative treatment for a group of patients with nGD. However, little is known about the clinical indication and the long-term outcome of patients after ambroxol therapy. We herein report a case of a female patient who presented with a progressive disease of GD type 2 from 11 months of age and had the pathogenic variants of p.L483P (formerly defined as p.L444P) and p.R502H (p.R463H) in GBA1. A combined treatment of imiglucerase with ambroxol started improving the patient's motor activity in 1 week, while it kept the long-lasting effect of preventing the deteriorating phenotype for 30 months. A literature review identified 40 patients with nGD, who had received high-dose ambroxol therapy. More than 65% of these patients favorably responded to the molecular chaperone therapy, irrespective of p.L483P homozygous, heterozygous or the other genotypes. These results highlight the long-lasting effect of ambroxol-based chaperone therapy for patients with an expanding spectrum of mutations in GBA1.
Assuntos
Ambroxol , Doença de Gaucher , Doenças por Armazenamento dos Lisossomos , Humanos , Feminino , Doença de Gaucher/tratamento farmacológico , Doença de Gaucher/genética , Doença de Gaucher/patologia , Ambroxol/uso terapêutico , Terapia Combinada , Chaperonas MolecularesRESUMO
BACKGROUND: Infantile-onset Pompe disease (IOPD) is the most severe phenotype of a lysosomal storage disorder caused by acid alpha-glucosidase (GAA) deficiency. An enzymatic newborn screening (NBS) program started regionally in Japan in 2013 for early enzyme replacement therapy (ERT). We report the ERT responses of the first NBS-identified Japanese IOPD case and of another case diagnosed prior to NBS, to discuss the problems of promptly starting ERT in Japan. METHODS: Acid alpha-glucosidase activity was measured by fluorometric assay in both patients. The diagnosis of IOPD was confirmed by next-generation followed by Sanger-method sequencing (patient 1) or direct sequencing of polymerase chain reaction (PCR)-amplified products (patient 2) of the GAA gene. RESULTS: A female infant identified by NBS had a novel out-of-frame (p.F181Dfs*6) variant and a reported pathogenic (p.R600C) variant, along with two pseudodeficiency variants. Enzyme replacement therapy was started at age 58 days when the infant had increased serum levels of creatine kinase and slight myocardial hypertrophy. Clinical and biochemical markers improved promptly. She has been alive and well without delayed development at age 14 months. Patient 2, a Japanese male, received a diagnosis of IOPD at age 5 months before the NBS era. He had a homozygotic variant of GAA (p.R608X), later registered as a cross-reactive immunological material (CRIM)-negative genotype, and developed a high titer of anti-rhGAA antibodies. The patient has survived myocardial hypertrophy with continuous respiratory support for 12 years of ERT. CONCLUSIONS: Enzyme replacement therapy should not be delayed over the age of 2 months for reversible cardiac function, although CRIM-negative cases may hamper turnaround time reduction.
Assuntos
Doença de Depósito de Glicogênio Tipo II , Cardiomegalia , Terapia de Reposição de Enzimas , Feminino , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/genética , Humanos , Japão , Masculino , alfa-Glucosidases/genética , alfa-Glucosidases/uso terapêuticoRESUMO
Background: Juvenile myelomonocytic leukemia (JMML), which is predominantly found in infants, is a clonal abnormality of pluripotent hematopoietic stem cells and presents with the symptoms of both myeloproliferative tumors and myelodysplastic syndromes. Estimates have shown that ~20 cases of JMML occur annually in Japan. Ornithine transcarbamylase deficiency (OTCD), the most common among all urea cycle disorders (UCDs), occurs in 1 of 80,000 people in Japan. Case Presentation: A 10-month-old infant who had fever, vomiting, and diarrhea for 2 days was referred to our hospital for the following abnormalities in blood tests: white blood cell count, 48,200/µL; hemoglobin, 9.0 g/dL; and platelet count, 135,000/µL. Bone marrow examination showed a nucleated cell count of 396,000/mm3 and blast cell count of 5.0%, as well as decreased mature granulocyte count and slightly myeloperoxidase stain-negative blasts but no monoclonal cell proliferation on May-Giemsa staining. Colony assay showed the proliferation of spontaneous colony and high sensitivity to granulocyte-macrophage colony-stimulating factor. Genetic analysis of peripheral blood mononuclear cells showed that the patient was positive for neuroblastoma RAS (NRAS) mutation. The patient was ultimately diagnosed with JMML. Approximately 170 days after his first hematopoietic stem cell transplantation (HSCT), the patient's JMML relapsed. Shortly after the recurrence, nausea, vomiting, hyperventilation, and decreased vitality were observed, followed by a decrease in the level of consciousness. The patient's ammonia level was 472 µmol/L. A test for seven different genetic mutations for the UCD showed the presence of c. 119G>A (amino acid change p. Arg40His). As such, late-onset OTCD was added to his diagnosis. Administration of sodium phenylacetate, l-arginine hydrochloride, and carnitine was continued following the diagnosis of OTCD, after which hyperammonemia was not observed. Regarding JMML relapse, HSCT was performed on day 405 after the first transplantation. Conclusion: Hyperammonemia should be considered a differential diagnosis when unexplained and non-specific symptoms occur during the treatment of hematologic malignancies. Patients should be tested for UCD as a cause of hyperammonemia, and treatment for hyperammonemia should be continued until the cause is identified. The patient shows normal developmental progress, has an intact neurological status, and has not experienced another hyperammonemia attack. His JMML has remained in remission for over 3 years.
RESUMO
Citrin deficiency is an autosomal recessive disorder caused by mutations in the SLC25A13 gene. The disease can present with age-dependent clinical manifestations: neonatal intrahepatic cholestasis by citrin deficiency (NICCD), failure to thrive, and dyslipidemia by citrin deficiency (FTTDCD), and adult-onset type II citrullinemia (CTLN2). As a nationwide study to investigate the clinical manifestations, medical therapy, and long-term outcome in Japanese patients with citrin deficiency, we collected clinical data of 222 patients diagnosed and/or treated at various different institutions between January 2000 and December 2019. In the entire cohort, 218 patients were alive while 4 patients (1 FTTDCD and 3 CTLN2) had died. All patients <20 years were alive. Patients with citrin deficiency had an increased risk for low weight and length at birth, and CTLN2 patients had an increased risk for growth impairment during adolescence. Liver transplantation has been performed in only 4 patients (1 NICCD, 3 CTLN2) with a good response thereafter. This study reports the diagnosis and clinical course in a large cohort of patients with citrin deficiency and suggests that early intervention including a low carbohydrate diet and MCT supplementation can be associated with improved clinical course and long-term outcome.
Assuntos
Colestase Intra-Hepática , Citrulinemia , Dislipidemias , Transportadores de Ânions Orgânicos , Adolescente , Adulto , Colestase Intra-Hepática/etiologia , Colestase Intra-Hepática/terapia , Citrulinemia/diagnóstico , Citrulinemia/genética , Citrulinemia/terapia , Insuficiência de Crescimento , Humanos , Recém-Nascido , Japão , Proteínas de Transporte da Membrana Mitocondrial/genética , MutaçãoRESUMO
BACKGROUND: Pompe disease is an autosomal recessive inherited metabolic disorder caused by a deficiency of the acid α-glucosidase (GAA). Pompe disease manifests as an accumulation of lysosomal glycogen in the skeletal and heart muscle. We conducted newborn screening (NBS) for Pompe disease in Japan from April 2013 to October 2020 to determine the feasibility and utility of NBS for Pompe disease. RESULTS: From the 296,759 newborns whose enzyme activity was measured, 107 of which underwent GAA analysis, we found one patient with infantile-onset Pompe disease (IOPD) and seven with potential late-onset Pompe disease (LOPD). We identified 34 pseudodeficient individuals and 65 carriers or potential carriers. The frequency of patients with IOPD was similar to that in the United States, but significantly lower than that in Taiwan. One patient with IOPD underwent early enzyme replacement therapy within a month after birth before presenting exacerbated manifestations, whereas those with potential LOPD showed no manifestations during the follow-up period of six years. CONCLUSIONS: The frequency of IOPD in Japan was similar to that in the United States, where NBS for Pompe disease is recommended. This indicates that NBS for Pompe disease may also be useful in Japan. Therefore, it should be used over a wider region in Japan.
Assuntos
Doença de Depósito de Glicogênio Tipo II , Terapia de Reposição de Enzimas , Humanos , Recém-Nascido , Japão , Triagem Neonatal , alfa-Glucosidases/genética , alfa-Glucosidases/metabolismoRESUMO
Urea cycle disorders (UCDs) are inherited metabolic diseases that lead to hyperammonemia. Severe hyperammonemia adversely affects the brain. Therefore, we conducted a nationwide study between January 2000 and March 2018 to understand the present status of UCD patients in Japan regarding diagnosis, treatments, and outcomes. A total of 229 patients with UCDs (126 patients: ornithine transcarbamylase deficiency [OTCD]; 33: carbamoyl phosphate synthetase 1 deficiency [CPS1D]; 48: argininosuccinate synthetase deficiency [ASSD]; 14: argininosuccinate lyase deficiency [ASLD]; and 8: arginase 1 deficiency [ARG1D]) were enrolled in the present study. Although growth impairment is common in patients with UCDs, we discovered that Japanese patients with UCDs were only slightly shorter than the mean height of the general adult population in Japan. Patients with neonatal-onset UCDs are more likely to experience difficulty finding employment and a spouse; however, some patients with late-onset UCDs were employed and married. Additionally, intellectual and developmental disabilities, such as attention deficit hyperactivity disorder (ADHD) and autism, hinder patients with UCDs from achieving a healthy social life. Moreover, we identified that it is vital for patients with UCDs presenting with mild to moderate intellectual disabilities to receive social support. Therefore, we believe the more robust social support system for patients with UCDs may enable them to actively participate in society.
RESUMO
Phosphaturic mesenchymal tumor, mixed connective tissue variant (PMT-MCT) causes tumor-induced osteomalacia (TIO). Most cases follow a benign clinical course, with rare occurrences of malignant transformation. We report a case of malignant PMT-MCT and review previous malignant cases to identify predictive factors for transformation. A 13-yr-old female, who presented with hypophosphatemic rickets, elevated serum intact fibroblast growth factor 23 (FGF23) levels, and a nodule in the back, received a diagnosis of TIO because of the benign PMT histopathology. After resection of the primary tumor, regular imaging analyses did not indicate any relapse. At 17 years of age, a tumor developed in the left leg and increased in size. The resected tumor showed a histopathology of pleomorphic sarcoma positive for the TP53 mutation. Despite amputation of the affected leg, the patient died due to multiple metastases at 18 years of age. A literature review revealed that 14 out of 15 reported malignant PMT-MCT tumors occurred in adults, and found no predictive factors for malignant transformation and treatment outcome. Changes in size or number of the tumors along with intact FGF23 levels have been considered as the only sign of malignant transformation. This pediatric case report and literature review indicate the need for prolonged regular monitoring for PMT-MCT.
RESUMO
Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD), failure to thrive and dyslipidemia (FTTDCD), and adult-onset type II citrullinemia (CTLN2). Owing to a defect in the NADH-shuttle, citrin deficiency impairs hepatic glycolysis and de novo lipogenesis leading to hepatic energy deficit. To investigate the physiological role of citrin, we studied the growth of 111 NICCD-affected subjects (51 males and 60 females) and 12 NICCD-unaffected subjects (five males and seven females), including the body weight, height, and genotype. We constructed growth charts using the lambda-mu-sigma (LMS) method. The NICCD-affected subjects showed statistically significant growth impairment, including low birth weight and length, low body weight until 6 to 9 months of age, low height until 11 to 13 years of age, and low body weight in 7 to 12-year-old males and 8-year-old females. NICCD-unaffected subjects showed similar growth impairment, including low birth weight and height, and growth impairment during adolescence. In the third trimester, de novo lipogenesis is required for deposition of body fat and myelination of the developing central nervous system, and its impairment likely causes low birth weight and length. The growth rate is the highest during the first 6 months of life and slows down after 6 months of age, which is probably associated with the onset and recovery of NICCD. Adolescence is the second catch-up growth period, and the proportion and distribution of body fat change depending on age and sex. Characteristic growth impairment in citrin deficiency suggests a significant role of citrin in the catch-up growth via lipogenesis.
Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Citrulinemia/complicações , Insuficiência de Crescimento/etiologia , Transtornos do Crescimento/etiologia , Transportadores de Ânions Orgânicos/metabolismo , Adolescente , Criança , Pré-Escolar , Colestase Intra-Hepática/etiologia , Citrulinemia/diagnóstico , Dislipidemias/etiologia , Feminino , Humanos , Lactente , Recém-Nascido , Japão , MasculinoRESUMO
Children born small for gestational age (SGA) are at a higher risk for metabolic disorders later in life. In this study, we aimed to characterize young SGA children without catch-up growth and evaluate the effects of GH treatment on endocrinological, metabolic, and immunological parameters. Study design is a one-year single hospital-based study included prospective observation of SGA patients during 12 months of GH treatment. Clinical and laboratory profiles of SGA children at baseline were compared with controls born appropriate size for age. Twenty-six SGA children (median age, 3.4 years) and 26 control children (median age, 3.8 years) were enrolled. Anthropometric, hematologic, biochemical, immunological, and endocrinological parameters were assessed at baseline and 1, 3, 6, 9, and 12 months after the start of GH treatment. As a result, median height SD score (SDS) of SGA children increased by +0.42 with 12-month GH treatment. Body mass index SDS was lower in SGA children than in controls. Serum apolipoprotein A1 increased, whereas apolipoprotein B decreased during GH treatment. Serum leptin and resistin levels, which were lower in SGA children than in controls at baseline, did not change remarkably with GH treatment. Monocyte counts, which were lower in SGA patients at baseline, increased after GH treatment. Neutrophil counts significantly increased after GH treatment. Natural killer cell ratios, which were higher in SGA patients, decreased after GH treatment. In conclusion, there was no evidence suggesting metabolic abnormalities in SGA children. Serum apolipoprotein changes might predict the beneficial role of GH treatment in lowering cardiometabolic risk.
Assuntos
Apolipoproteína A-I/sangue , Apolipoproteínas B/sangue , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Estatura/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , Transtornos do Crescimento/sangue , Hormônio do Crescimento Humano/farmacologia , Humanos , Recém-Nascido Pequeno para a Idade Gestacional , Leptina/sangue , Masculino , Estudos Prospectivos , Resistina/sangue , Resultado do TratamentoRESUMO
Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome that is occasionally associated with hyperinsulinemic hypoglycemia (HH) in the neonatal period. Sotos syndrome (SS) and Kabuki syndrome (KS) are other malformation syndromes that may be complicated with HH, however, the detailed clinical characteristics of HH accompanied with these syndromes remain unclear. We herein conducted a nationwide questionnaire survey in Japan. We sent a primary questionnaire concerning the clinical experience for these syndromes to 347 perinatal care institutions. As a result, 222 departments or hospitals returned the questionnaires and the total numbers of BWS, SS, and KS patients were 113, 88, and 51, respectively. We sent a secondary questionnaire to 31 institutions where patients with these syndromes presented with HH during infancy. The secondary questionnaires were returned from the institutions and the numbers of patients were 16 for BWS, 9 for SS, and 3 for KS, respectively. Then, we compared the clinical characteristics of infants suffering from transient HH with and without these dysmorphic syndromes. As a result, BWS, SS, and KS patients showed significantly larger body size, lower Apgar scores, higher insulin levels at HH, and shorter durations of HH than non-dysmorphic infants with transient HH. We propose that a careful observation for the signs of HH, even if not specific to the syndromes, is important for the diagnosis of patients with BWS, SS, and KS in the postnatal period. © 2016 Wiley Periodicals, Inc.
Assuntos
Anormalidades Múltiplas/sangue , Síndrome de Beckwith-Wiedemann/sangue , Face/anormalidades , Doenças Hematológicas/sangue , Hiperinsulinismo/sangue , Hipoglicemia/sangue , Síndrome de Sotos/sangue , Doenças Vestibulares/sangue , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/epidemiologia , Índice de Apgar , Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/epidemiologia , Feminino , Testes Genéticos , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/epidemiologia , Testes Hematológicos , Humanos , Recém-Nascido , Japão/epidemiologia , Masculino , Fenótipo , Vigilância da População , Gravidez , Complicações na Gravidez/epidemiologia , Síndrome de Sotos/diagnóstico , Síndrome de Sotos/epidemiologia , Inquéritos e Questionários , Doenças Vestibulares/diagnóstico , Doenças Vestibulares/epidemiologiaRESUMO
Three recessive mutations in the sodium leak channel, nonselective (NALCN) have been reported to cause intellectual disability and hypotonia. In addition, 14 de novo heterozygous mutations have been identified in 15 patients with arthrogryposis and neurodevelopmental impairment. Here, we report three patients with neurodevelopmental disease and hypotonia, harboring one recurrent (p.R1181Q) and two novel mutations (p.L312V and p.V1020F) occurring de novo in NALCN. Mutation p.L312 is located in the pore forming S6 region of domain I and p.V1020F in the S5 region of domain III. Mutation p.R1181Q is in a linker region. Mapping these three mutations to a model of NALCN showed p.Leu312 and p.Val1020 positioned in the hydrophobic core of the pore modules, indicating these two mutations may affect the gating function of NALCN. Although p.R1181Q is unlikely to affect the ion channel structure, previous studies have shown that an analogous mutation in Caenorhabditis elegans produced a phenotype with a coiling locomotion, suggesting that p.R1181Q could also affect NALCN function. Our three patients showed profound intellectual disability and growth delay, facial dysmorphologies and hypotonia. The present data support previous work suggesting heterozygous NALCN mutations lead to syndromic neurodevelopmental impairment.
Assuntos
Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Hipotonia Muscular/genética , Mutação de Sentido Incorreto , Canais de Sódio/genética , Alelos , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Feminino , Genótipo , Heterozigoto , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Canais Iônicos , Masculino , Proteínas de Membrana , Modelos Moleculares , Hipotonia Muscular/diagnóstico , Fenótipo , Conformação Proteica , Análise de Sequência de DNA , Canais de Sódio/química , SíndromeRESUMO
Here we present the case of a 14-yr-old girl who developed thyroid follicular carcinoma accompanied by Graves' disease. She was diagnosed with Graves' disease at 10 yr of age and soon achieved a euthyroid state after starting treatment. When she was 13 yr of age, her hyperthyroidism and goiter worsened despite medical therapy. Multiple nodules were found in her enlarged thyroid gland by ultrasonography. Her serum Tg level seemed within the normal range. She underwent near-total thyroidectomy for control of thyroid function. Histopathological study demonstrated that multiple oxyphilic follicular neoplasms were surrounded by the thyroid tissue compatible with Graves' disease. Capsular invasion was identified in one of the nodules, and thus the histological diagnosis was minimally invasive follicular carcinoma. She did not have signs suggesting metastasis, and has had no relapse for 18 mo after the operation. Although some previous studies showed a high prevalence of thyroid cancer with an aggressive nature in adult patients with Graves' disease, few reports about thyroid cancer accompanied by Graves' disease are available in children. The present case, however, suggests that careful investigation is needed when we detect thyroid nodules or progressive thyroid enlargement, especially in children with Graves' disease.
RESUMO
Sotos syndrome (OMIM #117550) is a congenital syndrome characterized by overgrowth with advanced bone age, macrocephaly, and learning difficulties. Endocrine complications of this syndrome have not yet been fully described in previous reports. We here investigated the clinical manifestations of Sotos syndrome in Japanese patients who presented with hyperinsulinemic hypoglycemia of infancy. We recruited patients diagnosed as having Sotos syndrome who presented with the complication of hyperinsulinemia during the neonatal period using a survey of the abstracts of Pediatric Meetings in domestic areas of Japan from 2007 to 2011. As a result, five patients (four females and one male) were recruited to evaluate the clinical presentation of Sotos syndrome by reference to the clinical record of each patient. A 5q35 deletion including the NSD1 gene was detected in all patients. Major anomalies in the central nervous, cardiovascular, and genito-urinary systems were frequently found. Hypoglycemia occurred between 0.5 and 3 hr after birth and high levels of insulin were initially found within 3 days of birth. The patients were treated with intravenous glucose infusion at a maximum rate of 4.6-11.0 mg/kg/min for 12-49 days. Three of the five patients required nasal tube feeding. One patient received medical treatment with diazoxide. This study shows that patients with Sotos syndrome may present with transient hyperinsulinemic hypoglycemia in the neonatal period.
Assuntos
Hiperinsulinismo Congênito/genética , Síndrome de Cri-du-Chat/genética , Síndrome de Sotos/genética , Trissomia/genética , Povo Asiático/genética , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Hiperinsulinismo Congênito/fisiopatologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Seguimentos , Histona Metiltransferases , Histona-Lisina N-Metiltransferase , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Japão , Cariótipo , Deficiências da Aprendizagem/genética , Deficiências da Aprendizagem/fisiopatologia , Masculino , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fenótipo , Síndrome de Sotos/fisiopatologiaRESUMO
The late-onset type of ornithine transcarbamylase (OTC) deficiency is almost asymptomatic before an abrupt onset of metabolic crisis in adolescence. This study focused on coagulopathy in OTC deficiency. We collected laboratory data regarding coagulation from OTC-deficient patients in Kyushu University Hospital in Japan or from cases reported from previous articles. Five patients with late-onset OTC deficiency, admitted to Kyushu University Hospital at the first metabolic attack or who presented at the outpatient clinic in the hospital, were analyzed, and 3 additional cases of OTC deficiency with coagulopathy in previous articles were included. As a result, the blood ammonia levels in these patients were remarkably high at the time of the metabolic attack, and prothrombin times were far below the normal level. The prothrombin times remained significantly abnormal on remission, despite almost normal levels of blood ammonia, serum aspartate aminotransferase, and alanine aminotransferase. Coagulation abnormality is a previously unidentified complication of OTC deficiency in remission state. This information will aid in the identification of patients with OTC deficiency before a lethal metabolic crisis occurs during adolescence.
Assuntos
Transtornos da Coagulação Sanguínea/complicações , Transtornos da Coagulação Sanguínea/diagnóstico , Doença da Deficiência de Ornitina Carbomoiltransferase/complicações , Doença da Deficiência de Ornitina Carbomoiltransferase/diagnóstico , Transtornos da Coagulação Sanguínea/enzimologia , Criança , Humanos , Lactente , Masculino , Doença da Deficiência de Ornitina Carbomoiltransferase/sangue , Indução de Remissão , Adulto JovemRESUMO
BACKGROUND AND AIMS: GH plays a significant role in the lipid metabolism. In this study, we focused on the JAK2 - signal transducer and activator of the transcription 5 (STAT5) pathway, which transmit the signals from the GH receptor, and selected the STAT5A/B gene as a candidate for the regulation of lipid metabolism in GH deficiency (GHD). DESIGN AND PARTICIPANTS: The study population comprised 83 children with idiopathic GHD. The serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and the non-HDL cholesterol (non-HDL-C) levels were monitored before and at 3, 6, 9 and 12 months after starting GH treatment. The height, weight, body mass index, and serum insulin-like growth factor-I (IGF-I) level were also measured before and 12 months after starting the GH treatment. For the genetic analysis of the STAT5A/B gene, five tag SNPs were selected using the tag SNP picker programme on the homepage of the HapMap project. The evaluation of promoter activity of the -44816A/G SNP in the STAT5B gene was performed by a luciferase assay in vitro. RESULTS: The TC and non-HDL-C levels were gradually decreased during the GH treatment. Five tag SNPs (rs4029774, rs6503691, rs9900213, rs16967637 and rs2272087) were picked up for the STAT5A/B gene, and the genetic study demonstrated that the paediatric GHD patients who were heterozygotes or homozygotes of minor alleles of the analysed SNPs in the same block of the STAT5B gene showed significantly higher serum TC or non-HDL-C levels both before and after GH treatment for 12 months. Most of the SNPs also demonstrated significant differences among genotypes in the decreases in serum TC or non-HDL-C levels during the 12 months of GH treatment. A luciferase assay showed that the -44816A/G SNP (rs4029774) in the STAT5B gene functionally affected the expression level in vitro. CONCLUSION: These results indicate that STAT5B may therefore play a role in regulating the cholesterol metabolism in children with GHD.
Assuntos
Colesterol/metabolismo , Nanismo Hipofisário/genética , Metabolismo dos Lipídeos/genética , Polimorfismo Genético/fisiologia , Fator de Transcrição STAT5/genética , Povo Asiático , Criança , Colesterol/sangue , Nanismo Hipofisário/metabolismo , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Receptores da Somatotropina/metabolismoRESUMO
Glycogen storage disease type I is an autosomal recessive disorder caused by the defect in the glucose-6-phosphate enzyme system. Frequent intake of glucose-containing glycogen storage disease formula, uncooked cornstarch, or both, are usually needed to maintain normal blood glucose level. We report a glycogen storage disease type 1b girl with biotin deficiency caused by an exclusive glucose-containing glycogen storage disease formula for years, presenting with the appearance of severe skin lesions, and diagnosed by urinary organic acid analysis by gas chromato-spectrometry, and blood acylcarnitine analysis by tandem mass-spectrometry.
Assuntos
Biotina/administração & dosagem , Biotina/deficiência , Doença de Depósito de Glicogênio Tipo I/dietoterapia , Fórmulas Infantis/administração & dosagem , Deficiência de Vitaminas do Complexo B/etiologia , Pré-Escolar , Feminino , Humanos , Lactente , Transtornos da Nutrição do Lactente/dietoterapia , Transtornos da Nutrição do Lactente/etiologia , Deficiência de Vitaminas do Complexo B/dietoterapiaRESUMO
A 17-day-old Japanese boy was transferred to the hospital because of vomiting and impaired consciousness. His external genitalia was pigmented associated with small penis and penoscrotal hypospadias. He was diagnosed as suffering from adrenal deficiency according to severe electrolyte abnormality, moderate hypoglycemia, metabolic acidosis and extremely elevated 17-OHP and testosterone levels. He turned out to be a compound heterozygote of CYP21A2 mutations by genetic analysis. Through endocrinological evaluation, he seemed to have normal hypophyseal function, intact testosterone production and appropriate 5-alpha-reductase-2 activity. Partial androgen insensitivity could not be ruled out by slight decrease of SHBG in hCG loading test, although mutation was not detected on androgen receptor gene. This is a rare case of a male patient with 21-hydroxylase deficiency accompanied by hypospadias. As the cause of hypospadias in this case has yet to be elucidated, further investigation and careful follow-up are required.