RESUMO
This update, written by authors designated by multiple pediatric endocrinology societies (see List of Participating Societies) from around the globe, concisely addresses topics related to changes in GnRHa usage in children and adolescents over the last decade. Topics related to the use of GnRHa in precocious puberty include diagnostic criteria, globally available formulations, considerations of benefit of treatment, monitoring of therapy, adverse events, and long-term outcome data. Additional sections review use in transgender individuals and other pediatric endocrine related conditions. Although there have been many significant changes in GnRHa usage, there is a definite paucity of evidence-based publications to support them. Therefore, this paper is explicitly not intended to evaluate what is recommended in terms of the best use of GnRHa, based on evidence and expert opinion, but rather to describe how these drugs are used, irrespective of any qualitative evaluation. Thus, this paper should be considered a narrative review on GnRHa utilization in precocious puberty and other clinical situations. These changes are reviewed not only to point out deficiencies in the literature but also to stimulate future studies and publications in this area.
Assuntos
Hormônio Liberador de Gonadotropina/uso terapêutico , Puberdade Precoce , Adolescente , Criança , Feminino , Humanos , Masculino , Puberdade Precoce/diagnóstico , Puberdade Precoce/tratamento farmacológico , Puberdade Precoce/patologia , Puberdade Precoce/fisiopatologiaRESUMO
AIM: To examine the contribution of the FUT2 gene and ABO blood type to the development of Type 1 diabetes in Japanese children. METHODS: We analysed FUT2 variants and ABO genotypes in a total of 531 Japanese children diagnosed with Type 1 diabetes and 448 control subjects. The possible association of FUT2 variants and ABO genotypes with the onset of Type 1 diabetes was statistically examined. RESULTS: The se2 genotype (c.385A>T) of the FUT2 gene was found to confer susceptibility to Type 1A diabetes in a recessive effects model [odds ratio for se2/se2, 1.68 (95% CI 1.20-2.35); corrected P value = 0.0075]. CONCLUSIONS: The FUT2 gene contributed to the development of Type 1 diabetes in the present cohort of Japanese children.
Assuntos
Diabetes Mellitus Tipo 1/genética , Fucosiltransferases/genética , Sistema ABO de Grupos Sanguíneos/genética , Povo Asiático/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Humanos , Japão , Galactosídeo 2-alfa-L-FucosiltransferaseRESUMO
AIMS: The aim of this study was to clarify the significance of previously reported susceptibility variants in the development of autoimmune Type 1 diabetes in non-white children. Tested variants included rs2290400, which has been linked to Type 1 diabetes only in one study on white people. Haplotypes at 17q12-q21 encompassing rs2290400 are known to determine the susceptibility of early-onset asthma by affecting the expression of flanking genes. METHODS: We genotyped 63 variants in 428 Japanese people with childhood-onset autoimmune Type 1 diabetes and 457 individuals without diabetes. Possible association between variants and age at diabetes onset was examined using age-specific quantitative trait locus analysis and ordered-subset regression analysis. RESULTS: Ten variants, including rs2290400 in GSDMB, were more frequent among the people with Type 1 diabetes than those without diabetes. Of these, rs689 in INS and rs231775 in CTLA4 yielded particularly high odds ratios of 5.58 (corrected P value 0.001; 95% CI 2.15-14.47) and 1.64 (corrected P value 5.3 × 10-5 ; 95% CI 1.34-2.01), respectively. Age-specific effects on diabetes susceptibility were suggested for rs2290400; heterozygosity of the risk alleles was associated with relatively early onset of diabetes, and the allele was linked to the phenotype exclusively in the subgroup of age at onset ≤ 5.0 years. CONCLUSIONS: The results indicate that rs2290400 in GSDMB and polymorphisms in INS and CTLA4 are associated with the risk of Type 1 diabetes in Japanese children. Importantly, cis-regulatory haplotypes at 17q12-q21 encompassing rs2290400 probably determine the risk of autoimmune Type 1 diabetes predominantly in early childhood.
Assuntos
Cromossomos Humanos Par 17/genética , Diabetes Mellitus Tipo 1/genética , Haplótipos/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Idade de Início , Idoso , Alelos , Criança , Pré-Escolar , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Humanos , Lactente , Japão/etnologia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
INTRODUCTION: We report a 34-year-old Japanese female with a Silver-Russell syndrome (SRS)-like phenotype and a mosaic Turner syndrome karyotype (45,X/46,XX). METHODS/RESULTS: Molecular studies including methylation analysis of 17 differentially methylated regions (DMRs) on the autosomes and the XIST-DMR on the X chromosome and genome-wide microsatellite analysis for 96 autosomal loci and 30 X chromosomal loci revealed that the 46,XX cell lineage was accompanied by maternal uniparental isodisomy for all chromosomes (upid(AC)mat), whereas the 45,X cell lineage was associated with biparentally derived autosomes and a maternally derived X chromosome. The frequency of the 46,XX upid(AC)mat cells was calculated as 84% in leukocytes, 56% in salivary cells, and 18% in buccal epithelial cells. DISCUSSION: The results imply that a parthenogenetic activation took place around the time of fertilisation of a sperm missing a sex chromosome, resulting in the generation of the upid(AC)mat 46,XX cell lineage by endoreplication of one blastomere containing a female pronucleus and the 45,X cell lineage by union of male and female pronuclei. It is likely that the extent of overall (epi)genetic aberrations exceeded the threshold level for the development of SRS phenotype, but not for the occurrence of other imprinting disorders or recessive Mendelian disorders.
Assuntos
Cromossomos Humanos X/genética , Aberrações dos Cromossomos Sexuais , Dissomia Uniparental/genética , Adulto , Quimerismo , Feminino , Humanos , Cariotipagem , Mosaicismo , Fenótipo , Síndrome de Silver-Russell/genética , Síndrome de Turner/genéticaRESUMO
Application of liver transplantation to methylmalonic acidemia (MMAemia) is controversial because MMAemia is caused by a systemic defect of methylmalonyl-CoA mutase. The clinical courses of seven pediatric patients with MMAemia undergoing living donor liver transplantation (LDLT) were reviewed. Serum and urinary methylmalonic acid (MMA) levels were found to be significantly decreased after LDLT, whereas serum and urinary MMA levels did not return to normal in any patient. One patient died of sepsis 44 days after LDLT. The other six patients are currently doing well. All patients had preoperative history of acute metabolic decompensation and/or metabolic stroke. However, no episode of acute metabolic decompensation or metabolic stroke was observed postoperatively in any surviving patients. In the preoperative period, all patients showed lethargy and cognitive deficit, both of which were eradicated after LDLT in all surviving patients. Preoperatively, all patients were subjected to dietary protein intake restriction and tube feeding, and were administered several metabolism-correcting medications. The metabolism-correcting medications being administered remained mostly unchanged after LDLT, whereas protein restriction was liberalized and tube feeding became unnecessary in all surviving patients. In addition, physical and neurodevelopmental growth delay remained in all surviving patients during the observation period, which ranged from 4 to 21 months with a median of 10.5 months.
Assuntos
Transplante de Fígado/métodos , Doadores Vivos , Erros Inatos do Metabolismo/cirurgia , Ácido Metilmalônico/sangue , Criança , Pré-Escolar , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/fisiopatologia , Feminino , Seguimentos , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/fisiopatologia , Humanos , Lactente , Transplante de Fígado/fisiologia , Masculino , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/metabolismo , Ácido Metilmalônico/efeitos adversos , Ácido Metilmalônico/urina , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
Although clinical features of Turner syndrome have primarily been explained by the dosage effects of SHOX (short stature homeobox-containing gene) and the putative lymphogenic gene together with chromosomal effects leading to nonspecific features, several matters remain to be determined, including modifying factors for the effects of SHOX haploinsufficiency, chromosomal location of the lymphogenic gene, and genetic factors for miscellaneous features such as multiple pigmented nevi. To clarify such unresolved issues, we examined clinical findings in 47 patients with molecularly defined Xp deletion chromosomes accompanied by the breakpoints on Xp21-22 (group 1; n = 19), those accompanied by the breakpoints on Xp11 (group 2; n = 16), i(Xq) or idic(X)(p11) chromosomes (group 3; n = 8), and interstitial Xp deletion chromosomes (group 4; n = 4). The deletion size of each patient was determined by fluorescence in situ hybridization and microsatellite analyses for 38 Xp loci including SHOX, which was deleted in groups 1-3 and preserved in group 4. The mean GH-untreated adult height was -2.2 SD in group 1 and -2.7 SD in group 2 (GH-untreated adult heights were scanty in group 3). The prevalence of spontaneous breast development in patients aged 12.8 yr or more (mean +/- 2 SD for B2 stage) was 11 of 11 in group 1, 7 of 12 in group 2, and 1 of 7 in group 3. The prevalence of wrist abnormality suggestive of Madelung deformity was 8 of 18 in group 1 and 2 of 23 in groups 2 and 3, and 9 of 18 in patients with spontaneous puberty and 1 of 23 in those without spontaneous puberty. The prevalence of short neck was 1 of 19 in group 1 and 7 of 24 in groups 2 and 3. Soft tissue and visceral anomalies were absent in group 1 preserving the region proximal to Duchenne muscular dystrophy and were often present in groups 2 and 3 missing the region distal to monoamine oxidase A (MAOA). Multiple pigmented nevi were observed in groups 1-3, with the prevalence of 0 of 7 in patients less than 10 yr of age and 15 of 36 in those 10 yr or older regardless of the presence or absence of spontaneous puberty. Turner phenotype was absent in group 4, including a fetus aborted at 21 wk gestation who preserved the region distal to MAOA. The results provide further support for the idea that clinical features in X chromosome aberrations are primarily explained by haploinsufficiency of SHOX and the lymphogenic gene and by the extent of chromosome imbalance in mitotic cells and pairing failure in meiotic cells. Furthermore, it is suggested that 1) expressivity of SHOX haploinsufficiency in the limb and faciocervical regions is primarily influenced by gonadal function status and the presence or absence of the lymphogenic gene, respectively; 2) the lymphogenic gene for soft tissue and visceral stigmata is located between Duchenne muscular dystrophy and MAOA; and 3) multiple pigmented nevi may primarily be ascribed to cooperation between a hitherto unknown genetic factor and an age-dependent factor other than gonadal E.
Assuntos
Deleção de Genes , Síndrome de Turner/genética , Cromossomo X/genética , Adulto , Aberrações Cromossômicas , Feminino , Crescimento/fisiologia , Mãos/crescimento & desenvolvimento , Deformidades da Mão/genética , Proteínas de Homeodomínio/genética , Humanos , Cariotipagem , Ovário/fisiopatologia , Transtornos da Pigmentação/genética , Radiografia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína de Homoeobox de Baixa Estatura , Síndrome de Turner/diagnóstico por imagem , Síndrome de Turner/fisiopatologiaRESUMO
To provide information about species differences in GH-releasing hormone (GHRH) receptors useful for studies of receptor-ligand binding properties and receptor function, we have cloned the ovine and bovine pituitary GHRH receptors (GHRHRs). The ovine receptor (oGHRHR) was cloned from a pituitary complementary DNA library and encodes a protein that is similar to that of porcine, human, rat, and mouse with, respectively, 84.3, 80.7, 75.9, and 74.0% amino acid identity. Surprisingly, oGHRHR has a 16 amino acid truncation at its carboxyl-terminal end when compared with GHRHRs from other known mammals. RT-PCR using pooled pituitary RNA from a different population of sheep could detect only truncated receptor. Bovine GHRHR (bGHRHR) was cloned by RT-PCR and shows 92.5% amino acid sequence identity with oGHRHR, but has no truncation. Genomic sequencing of the appropriate region of goat receptor intron 13 showed that the caprine receptor shares the same truncation seen in sheep. Photoaffinity cross-linking of GHRH to ovine and bovine pituitary membranes confirms that the native ovine pituitary GHRHR protein is smaller by the amount predicted by the cloned sequences. The truncation did not affect GHRH binding as oGHRHR, bGHRHR, human GHRHR, and human GHRHR, which was truncated by site-directed mutagenesis to match the oGHRHR, all showed comparable GHRH binding affinity when expressed in transfected cell lines. In contrast, the ovine and truncated human receptors demonstrated enhanced sensitivity for GHRH stimulation of cAMP (lowered ED(50)) relative to hGHRHR and bGHRHR. This suggests that this C-terminal domain acts to inhibit cAMP signaling possibly through a role in receptor down regulation.
Assuntos
Bovinos/genética , Clonagem Molecular , Receptores de Neuropeptídeos/química , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/química , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética , Ovinos/genética , Sequência de Aminoácidos , Animais , Reagentes de Ligações Cruzadas , AMP Cíclico/metabolismo , DNA Complementar/química , DNA Complementar/isolamento & purificação , Hormônio Liberador de Hormônio do Crescimento/metabolismo , Hormônio Liberador de Hormônio do Crescimento/farmacologia , Humanos , Dados de Sequência Molecular , Marcadores de Fotoafinidade , Receptores de Neuropeptídeos/metabolismo , Receptores de Hormônios Reguladores de Hormônio Hipofisário/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Alinhamento de Sequência , Análise de Sequência de DNA , Transdução de Sinais , Especificidade da EspécieRESUMO
Human GH receptor (hGHR) was recently expressed on a Ba/F3 cell line, which is a mouse pro-B cell lymphoma that has been induced to become a cloned cell line (Ba/F3-hGHR). Using a Ba/F3-hGHR cell line, we have established a bioassay for serum hGH. hGH stimulated cell proliferation in a dose-dependent manner in concentrations ranging from 1 ng to 100 ng/mL. Cell proliferation was not influenced by other hormones or growth factors in the bioassay, with the exception of insulin-like growth factor I (IGF-I) and GH binding protein. Free IGF-I significantly stimulated the proliferation of Ba/F3-hGHR cells at concentrations over 25.85 ng/mL in this bioassay system, but serum IGF-I did not stimulate cell proliferation because the sensitivity of cell proliferation was insufficient for free IGF-I in serum. GH binding protein, however, did suppress cell proliferation at the highest concentration (100 ng/mL), but did not at the average concentration (20 ng/mL). Human serum stimulated cell proliferation, which was completely suppressed by anti-GH antibody. The GH bioactivity of serum samples from normal children and patients with non-GH deficient short stature correlated strongly with the serum hGH concentration determined by immunoradiometric assay (IRMA) (r = 0.967, r = 0.924, P < 0.0001, respectively). The ratio of bioactivity/IRMA was 1.01+/-0.26 in sera from normal children and 1.18+/-0.24 and 1.00+/-0.29 at basal values and peak values in GH stimulation tests, respectively, in sera from patients with non-GH deficient short stature. The bioactivity/IRMA ratio for the serum GH bioactivity of a patient who had biologically inactive GH caused by an amino acid substitution was 0.333+/-0.056 (mean +/- SD). In conclusion, we established a new sensitive bioassay for hGH that is specific for hGH somatogenic action and is useful for screening of patients with short stature caused by biologically inactive hGH.
Assuntos
Hormônio do Crescimento Humano/sangue , Anticorpos/farmacologia , Bioensaio/métodos , Divisão Celular/efeitos dos fármacos , Criança , Células Clonais , Transtornos do Crescimento/sangue , Hormônio do Crescimento Humano/imunologia , Hormônio do Crescimento Humano/farmacologia , Humanos , Valores de Referência , Análise de Regressão , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Células Tumorais CultivadasRESUMO
The somatogenic action of the 20 kilodalton human growth hormone (20 K) was studied using the spontaneous dwarf rat (SDR), which has an isolated GH deficiency. Saline or 2.5 microg, 10 microg, or 100 microg/rat/day of recombinant 20 K or 22 K was administered to prepubertal male and female SDRs for 10 days. Their body weights, serum IGF-I, glucose and insulin were measured, and their body composition was determined. Body weights and serum IGF-I increased dose-dependently in both the 20 K- and 22 K-treated groups. There was no significant difference in body weights and serum IGF-I between the 20 K- and 22 K-treated groups except at the dose of 100 microg/rat, in which the IGF-I concentrations were higher in the 22 K-treated male SDRs (P< 0.05: 20 K vs 22 K). Blood glucose was not significantly different between the Spague-Dawley (SD) normal rats and the SDR control groups; however, serum insulin levels of the SDR were higher than those of the SD control group (P< 0.05). Additionally, there was a tendency for serum insulin and glucose levels to increase following 22 K treatment, but the differences were not significant. The percentage of body fat decreased with hGH treatment in both groups (P< 0.01: GH 10, 100 microg/rat group vs SDR control group), however, no significant differences were observed in body composition between the 20 K and 22 K treatment groups. In summary, the 20 K-hGH showed almost the same somatogenic activity as the 22 K-hGH in prepubertal male and female SDRs.
Assuntos
Crescimento/efeitos dos fármacos , Hormônio do Crescimento Humano/farmacologia , Animais , Glicemia/metabolismo , Composição Corporal/efeitos dos fármacos , Feminino , Hormônio do Crescimento/deficiência , Hormônio do Crescimento Humano/química , Humanos , Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Rim/anatomia & histologia , Rim/efeitos dos fármacos , Masculino , Peso Molecular , Tamanho do Órgão/efeitos dos fármacos , Ovário/anatomia & histologia , Ovário/efeitos dos fármacos , Ratos , Ratos Mutantes , Ratos Sprague-Dawley , Testículo/anatomia & histologia , Testículo/efeitos dos fármacos , Aumento de Peso/efeitos dos fármacosRESUMO
Growth hormone-secretagogue receptor (GHSR) RNA is known to be expressed in the hypothalamus and pituitary. Since endogenous GH secretagogue (GHS) is still unknown, the physiological role of GHS and GHSR in growth is not well understood. In this study, we have determined the effects of growth hormone in GH-releasing hormone receptor (GHRHR) and GHSR RNA expression in spontaneous Dwarf rats (SDRs) which are deficient in GH secretion, with or without GH replacement. Twenty-five-day-old SDRs received daily s.c. injection of human GH (40 microg/kg BW x 2/day) or control solution for two weeks. On day 40, the rats were sacrificed by decapitation and the pituitaries were immediately removed and quickly frozen. Total RNA was extracted from the pituitary, and mRNA coding GHSR was detected and semi-quantitated by competitive RT-PCR. Pituitaries from control SDRs showed strong GHSR RNA expression and the expression level was 5 to 10 times higher in females than in males. When GH was replaced, GHSR RNA expression greatly decreased. Pituitary GHRHR RNA expression, determined by RNase Protection Assay, was similar in male and female control animals; and was also greatly reduced in rats treated with GH when compared to the control. These results suggest that the expression of both GHSR and GHRHR is regulated by growth hormone, presumably via changes in hypothalamic GHRH and/or endogenous GHS. The apparent sexual dimorphism in GHSR indicates different regulatory effects of sex steroid in young growing SDRs.
Assuntos
Nanismo/metabolismo , Hipófise/metabolismo , RNA Mensageiro/metabolismo , Receptores de Superfície Celular/genética , Receptores Acoplados a Proteínas G , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética , Animais , Animais Recém-Nascidos , Feminino , Hormônio do Crescimento Humano/farmacologia , Humanos , Injeções Subcutâneas , Masculino , RNA Mensageiro/antagonistas & inibidores , Ratos , Ratos Mutantes , Receptores de Grelina , Caracteres SexuaisRESUMO
Almost all of the serum IGFs are found in a ternary complex composed of IGF, IGFBP-3 and acid-labile subunit (ALS). It was reported that ALS levels were age- and sex-dependent. In the present study we measured serum ALS levels in 264 normal children (145 boys and 119 girls) aged from 5 days to 16 years, and 15 patients with growth hormone deficiency (GHD) aged from 11 months to 13 years. Serum ALS levels increased during childhood, and reached peak values in mid to late puberty. ALS levels reached their highest levels 2 years earlier in girls than in boys. Serum ALS levels were significantly correlated with serum IGF-I levels and IGFBP-3 levels. Serum ALS levels were below -2SD in 6 out of 7 children with complete GHD (CGHD), while serum ALS levels were below -2SD in 1 out of 8 patients with partial GHD (PGHD). These results indicate that serum ALS levels are regulated by GH, and that the measurement of ALS is useful for the diagnosis of CGHD in children.
Assuntos
Proteínas de Transporte/sangue , Glicoproteínas/sangue , Adolescente , Envelhecimento/sangue , Criança , Pré-Escolar , Feminino , Hormônio do Crescimento Humano/deficiência , Humanos , Lactente , Recém-Nascido , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/análise , Masculino , Puberdade/sangue , Valores de Referência , Caracteres SexuaisRESUMO
The bone mineral density (BMD) of the second metacarpal bone of the left hand was measured in 57 patients with Turner syndrome by the digital image processing (DIP) method to study the relations between the treatment regimen and their bone mineral density. BMD SD score in the patients who had started the GH treatment before 10 years old was within +/-2SD of the standard before 14 years, but the score decreased to below -2SD after 14 years. In the patients who had started GH treatment after 10 years old, BMD score were significantly lower than -2SD, although there was tendency to increased. In the patients who had estrogen after 15 years old, BMD did not increase with GH alone and slowly increased after estrogen replacement. In the other two patients who had started sex steroid hormone replacement treatment before 15 years old, BMD maintained +/-2SD. In patients who received combined GH and LH-RH analog treatment, their BMD score did not increase during LH-RH analog treatment. It slowly increased but was still below -3SD after stop of LH-RH analog and start of estrogen treatment. In Turner syndrome, GH may play a role in maintaining prepubertal BMD levels [4], and estrogen plays an important role in pubertal BMD increment. It is recommended that estrogen treatment is started before 15 years of age for maintenance of normal BMD level.
Assuntos
Densidade Óssea , Terapia de Reposição de Estrogênios , Hormônio do Crescimento/uso terapêutico , Síndrome de Turner/tratamento farmacológico , Síndrome de Turner/metabolismo , Adolescente , Adulto , Densidade Óssea/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , Humanos , Estudos Longitudinais , Metacarpo/efeitos dos fármacos , Metacarpo/metabolismoRESUMO
It has been reported that mutations in the FGFR3 gene cause autosomal dominant forms of dwarfism, achondroplasia (ACH) and hypochondroplasia (HCH). In the present study, we analyzed the FGFR3 gene in 26 Japanese patients with ACH and 14 with HCH. Genomic DNAs of the patients were isolated from whole blood. For the ACH patients, a 164-bp fragment of the FGFR3 gene that spans the entire transmembrane domain was amplified by polymerase chain reaction (PCR), and the PCR products were analyzed by direct sequencing of the PCR products and by digestion of the PCR products with restriction enzymes. For the HCH patients, a 206-bp fragment of the FGFR3 gene which encodes a part of the TK1 domain was amplified, and the PCR products were directly sequenced. The heterozygous G380R mutations were identified in all of the 26 ACH patients, whereas the heterozygous N540K mutations were identified in 8 out of 14 HCH patients. These results were consistent with previous reports from abroad.
Assuntos
Acondroplasia/genética , Proteínas Tirosina Quinases , Receptores de Fatores de Crescimento de Fibroblastos/genética , Sequência de Aminoácidos/genética , Substituição de Aminoácidos , Sequência de Bases/genética , Humanos , Japão , Dados de Sequência Molecular , Mutação/genética , Receptor Tipo 3 de Fator de Crescimento de FibroblastosRESUMO
Hypercalciuria is a common side effect during total parenteral nutrition (TPN). We report a patient with long-term TPN, who demonstrated hypercalciuria, hypercalcemia and growth retardation. The patient is a six-year-old Japanese girl with Hirschsprung disease (jejunal agangliosis). Jejunostomy was performed at one-month old and since then her nutrition has depended mostly on TPN. When she was 3 years old, continuous TPN was switched to cyclic TPN (on TPN for 11 hrs and off TPN for 13 hrs). The urinary calcium level has been elevated (Ca/Cre ratio, 1.0) since 3 months of age, whereas serum calcium levels stayed within normal range for a while. The serum calcium levels started to elevate to 12 to approximately 13 mg/dl when she was 3 years and 8 months old. She showed growth retardation (height SD score was -4.2SD when she was 5 years and 8 months old) and deteriorated renal tubular function with renal glycosuria, elevated beta 2-microglobulin (beta2-MG) and N-acetyl-beta-D-glucosaminidase. She was referred to our division for the investigation and treatment of growth disturbance and Ca metabolism. Her bone age was delayed (BA/CA 0.62) and serum IGF-I level was decreased but her GH response to provocation test was normal. Bilateral nephrocalcinosis was revealed by renal echogram and CT scan. By reducing calcium content in TPN solution, the serum and urinary calcium levels could be maintained within normal range and her renal function and growth velocity was improved.
Assuntos
Cálcio/urina , Transtornos do Crescimento/etiologia , Hipercalcemia/etiologia , Hipercalcemia/urina , Doenças Metabólicas/etiologia , Nutrição Parenteral Total/efeitos adversos , Cálcio/administração & dosagem , Pré-Escolar , Feminino , Doença de Hirschsprung/terapia , Humanos , Nefrocalcinose/sangue , Nefrocalcinose/etiologia , Nefrocalcinose/terapia , Nefrocalcinose/urina , Soluções/administração & dosagem , Soluções/química , Resultado do TratamentoRESUMO
Familial male-limited precocious puberty (FMPP) is a rare disease caused by constitutively activating mutations in the luteinizing hormone receptor (LH-R) gene. In the present study, we analyzed the LH-R gene in members of a Japanese FMPP family. Two males of the family were affected and had a heterozygous M398T mutation; one patient developed pubertal signs as early as 2 years of age, and the other at 6 years of age. Both patients had elevated serum testosterone levels and prepubertal gonadotropin secretions. The father of the latter patient carried the M398T mutation, but lacked history of precocious puberty. Thus, phenotypic differences were observed in the three males with the same LH-R mutation belonging to the same family. In summary, we have described a Japanese family with FMPP.
Assuntos
Mutação de Sentido Incorreto , Puberdade Precoce/genética , Receptores do LH/genética , Pré-Escolar , Enzimas de Restrição do DNA , Feminino , Hormônio Foliculoestimulante/sangue , Hormônio Liberador de Gonadotropina , Heterozigoto , Humanos , Japão , Hormônio Luteinizante/sangue , Masculino , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Testosterona/sangueRESUMO
Congenital lipoid adrenal hyperplasia (CLAH) is an autosomal recessive disorder characterized by impaired synthesis of adrenal and gonadal steroids. It was demonstrated that loss-of-function mutations in the steroidogenic acute regulatory protein (StAR) gene cause CLAH and that 46,XX patients with CLAH develop spontaneous puberty. We had reported that three 46,XX patients with CLAH had presented spontaneous puberty and one of the patients had developed life-threatening ovarian cysts, before the etiology of CLAH had been clarified. In the present study, we analyzed their StAR gene and demonstrated mutations. Endocrinological examinations of the patients revealed that serum LH and FSH levels and their responses to the LHRH stimulation were not exaggerated before the onset of puberty. Serum LH levels and its response to LHRH were increased during puberty, whereas serum FSH levels remained within the normal range. Serum estradiol increased after the administration of human menopausal gonadotropins in the pubertal patient, suggesting that the ovary might have another system than StAR to facilitate cholesterol transport into the mitochondria. Although the patients had menstrual cycles, they remained anovulatory, and the resultant increased secretion of LH was speculated to be responsible for the development of ovarian cysts.
Assuntos
Hiperplasia Suprarrenal Congênita/sangue , Hiperplasia Suprarrenal Congênita/genética , Fosfoproteínas/genética , Puberdade Precoce/sangue , Cromossomo X , Adulto , Criança , Códon sem Sentido , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Mutação da Fase de Leitura , Humanos , Metabolismo dos Lipídeos , Hormônio Luteinizante/sangue , RadioimunoensaioRESUMO
Congenital lipoid adrenal hyperplasia (CLAH) is an autosomal recessive disorder characterized by impaired synthesis of all adrenal and gonadal steroid hormones. Recently, it was reported that mutations in the steroidogenic acute regulatory protein (StAR) gene cause CLAH. In the present study, we have analyzed the StAR gene of a Japanese patient with CLAH. PCR amplification and subsequent nucleotide sequencing of the StAR gene and those of her parents revealed that the patient has a compound heterozygous mutation of this gene. In one allele, an undescribed G to C transversion in codon 217, which occurred at the last base of exon 5 and thus altered the splice donor site sequence, apparently resulted in a substitution of Arg to Thr (AGG to ACG: R217T), and in the other allele, a C to T transition in codon 218 caused a substitution of Ala to Val (GCG to GTG: A218V), which has been previously shown to abolish StAR activity. In vitro expression analysis of an allelic minigene that consists of exons 4-6 of the R217T mutant StAR gene showed that the G to C transversion in the splice donor site of exon 5 caused by the R217T mutation disrupts normal splicing, resulting in the complete skipping of exon 5, which alters the translation reading frame of exon 6, introduces a stop codon at amino acid position 174, and thus impairs the activity. A functional expression study of the R217T replacement mutant revealed that the mutant has no steroidogenesis-enhancing activity if the transcript of the R217T mutant allele is ever spliced normally and translated into the protein. From the genetic analysis of 50 healthy subjects, the novel R217T mutation was unlikely to be due to polymorphism. Together, these results indicate that this patient is a compound heterozygote for the mutation in the StAR gene (T217R and A218V) and that these mutations inactivate the StAR function and give rise to clinically manifest CLAH.
Assuntos
Hiperplasia Suprarrenal Congênita/genética , Mutação , Fosfoproteínas/genética , Alelos , Sequência de Bases , Códon , Éxons , Feminino , Expressão Gênica , Heterozigoto , Humanos , Recém-Nascido , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Splicing de RNA , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , TransfecçãoRESUMO
A 68-year-old woman was admitted to our hospital with congestive heart failure. She had been diagnosed with hypertrophic cardiomyopathy 12 years ago in another hospital. She had received irradiation therapy for left breast cancer 33 years ago after resection of her left breast. Echocardiography revealed left ventricular hypertrophy and wall motion hypokinesis, and multiple cavities in the myocardium of the left ventricle, interventricular septum, and anterior wall. Some cavities were observed to connect to the left ventricular cavity and Doppler echocardiography showed slow velocity flows in them different from that of the coronary artery. The pathologic diagnosis was severe sclerosis of the left coronary artery, especially the left descending artery and its branch, which was the area with irradiation. Histopathology revealed sclerotic changes of the coronary artery causing acute and chronic myocardial infarction, and incomplete regeneration and hypertrophy of cardiac cells. There was no sign of hypertrophic cardiomyopathy. Myocardial degeneration and deciduation were present next to the cavities connected to left ventricle-like fistulas.
Assuntos
Neoplasias da Mama/radioterapia , Ventrículos do Coração/patologia , Ventrículos do Coração/efeitos da radiação , Idoso , Cardiomiopatia Hipertrófica/diagnóstico , Doença da Artéria Coronariana/patologia , Vasos Coronários/patologia , Vasos Coronários/efeitos da radiação , Diagnóstico Diferencial , Ecocardiografia Doppler , Feminino , Humanos , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/etiologia , Radioterapia/efeitos adversosRESUMO
The effect of combined treatment with growth hormone (GH) and a luteinizing hormone-releasing hormone (LHRH) analogue, or GH alone, on pubertal height gain was assessed in an uncontrolled study in 15 boys and 10 girls with GH deficiency (GHD). Seven boys and six girls were treated with GH alone (group 1), and eight boys and four girls were treated with a combination of GH and an LHRH analogue during puberty (group 2). Mean ages (+/- SD) at the start of GH treatment and at the onset of puberty were significantly lower in group 2 (8.0 +/- 3.3 years and 11.2 +/- 0.8 years, respectively, in boys, and 6.3 +/- 1.6 years and 10.8 +/- 0.7 years in girls) than in group 1 (12.8 +/- 1.9 years and 13.7 +/- 1.4 years in boys, and 11.2 +/- 1.0 years and 12.5 +/- 1.2 years in girls). Height at the onset of puberty was less in group 2 than in group 1, but the difference was significant only for the boys. Combination treatment was started at a mean age of 11.7 +/- 1.2 years in boys and 11.5 +/- 1.0 years in girls. The duration of the combination treatment was 5.1 +/- 1.5 years in boys and 2.3 +/- 0.7 years in girls. The duration of the period between the onset of puberty and the end of GH treatment was significantly longer in group 2 (6.8 +/- 1.2 years in boys and 5.5 +/- 1.0 years in girls) than in group 1 (4.3 +/- 1.6 years in boys and 3.6 +/- 1.4 years in girls). The pubertal height gain was also significantly greater in group 2 (36.7 +/- 6.5 cm in boys and 29.0 +/- 8.3 cm in girls) than in group 1 (21.9 +/- 4.1 cm in boys and 18.6 +/- 4.1 cm in girls). Final height was significantly greater in group 2 than in group 1 in boys. Although there was no significant difference in final height between groups in the girls, the change in height SDS from the start of GH treatment until final height was significantly greater in group 2 (2.7 +/- 1.6 in boys and 4.5 +/- 0.5 SD in girls) than in group 1 (1.0 +/- 0.8 in boys and 1.8 +/- 0.9 SD in girls), in both boys and girls. In conclusion, it appears that combination of an LHRH analogue and GH may increase the pubertal height gain and the final height of children with GHD. The improvement is attributed to the prolongation of the treatment period, permitting slow bone maturation, and to the maintenance of height velocity. This combination treatment appears to be more effective in boys than girls. To fully assess this therapeutic approach, prospective controlled studies are needed.
Assuntos
Estatura/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/administração & dosagem , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/administração & dosagem , Adolescente , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Seguimentos , Transtornos do Crescimento/etiologia , Hormônio do Crescimento Humano/deficiência , Humanos , Japão , Masculino , Valores de Referência , Fatores Sexuais , Resultado do TratamentoRESUMO
To study the acute and long-term effect of GH on its down-stream axis, we measured serum GH-binding protein (GHBP) by ligand-mediated immunofunctional assay. Diurnal changes in serum GHBP were determined by every 20-min sampling for 24 h in four normal short children. There were small or negligible fluctuations in serum GHBP levels, and no correlation with GH pulses was observed. The short-term effect of GH on GHBP levels was assessed in eight GH-deficient children by daily administration of GH (0.1 U/kg) for 10 days. Serum GHBP levels did not significantly change, but IGF-I levels increased significantly. We also studied the long-term effect of GH administration on GHBP levels in seventeen patients with GH deficiency over six months. In twelve out of 17 patients, serum GHBP levels showed an increase when compared to the levels before treatment. In these patients, BMI was not largely changed during treatment, while it tended to decrease in patients whose GHBP levels did not increase. In conclusion, endogenous pulsatile GH secretion and short-term exogenous GH administration had no effect on serum GHBP levels. On the other hand, long-term GH administration increased GHBP levels in 70% of patients with GH deficiency. Changes in BMI may partly be attributed to this change. The direct long-term regulatory effect of GH on GHBP should be further studied.