RESUMEN

OBJECTIVE: Acid-labile subunit deficiency (ACLSD), caused by inactivating mutations in both IGFALS gene alleles, is characterized by marked reduction in IGF-I and IGFBP-3 levels associated with mild growth retardation. The aim of this study was to expand the known phenotype and genetic characteristics of ACLSD by reporting data from four index cases and their families. DESIGN: Auxological data, biochemical and genetic studies were performed in four children diagnosed with ACLSD and all available relatives. METHODS: Serum levels of IGF-I, IGFBP-3, acid-labile subunit (ALS), and in vitro ternary complex formation (ivTCF) were determined. After sequencing the IGFALS gene, pathogenicity of novel identified variants was evaluated by in vitro expression in transfected Chinese hamster ovarian (CHO) cells. ALS protein was detected in patients' sera and CHO cells conditioned media and lysates by Western immunoblot (WIB). RESULTS: Four index cases and four relatives were diagnosed with ACLSD. The following variants were found: p.Glu35Glyfs*17, p.Glu35Lysfs*87, p.Leu213Phe, p.Asn276Ser, p.Leu409Phe, p.Ala475Val and p.Ser490Trp. ACLSD patients presented low IGF-I and low or undetectable levels of IGFBP-3 and ALS. Seven out of 8 patients did not form ivTCF. CONCLUSIONS: This study confirms previous findings in ACLSD, such as the low IGF-I and a more severe reduction in IGFBP-3 levels, and a gene dosage effect observed in heterozygous carriers (HC). In addition, father-to-son transmission (father compound heterozygous and mother HC), preservation of male fertility, and marginal ALS expression with potential involvement in preserved responsiveness to rhGH treatment, are all novel aspects, not previously reported in this condition.

Asunto(s)

Glicoproteínas/deficiencia , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Adolescente , Adulto , Anciano , Animales , Proteínas Portadoras/genética , Niño , Preescolar , Cricetulus , Familia , Femenino , Fertilidad , Variación Genética , Glicoproteínas/genética , Trastornos del Crecimiento/genética , Heterocigoto , Humanos , Lactante , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/deficiencia , Factor I del Crecimiento Similar a la Insulina/deficiencia , América Latina , Masculino , Persona de Mediana Edad , Mutación , Transfección , Adulto Joven

RESUMEN

PURPOSE: Testotoxicosis is an autosomal dominant form of gonadotropin-independent precocious puberty caused by heterozygous constitutively activating mutations of the luteinizing hormone/choriogonadotropin receptor (LHCGR) gene. The aim of this study was to describe two Brazilian siblings with testotoxicosis, to confirm the molecular diagnosis, and to perform an in silico analysis of a novel mutation in the hot spot of the LHCGR gene. MATERIALS AND METHODS: Molecular analysis of the mutation on the LHCGR gene was performed by direct Sanger sequencing, followed by an in silico analysis using HOPE bioinformatics tool to predict a functional defect of the mutant. RESULTS: Both patients presented with gonadotropin-independent precocious puberty before the age of four years. Genetic analysis revealed a novel non-maternally inherited p.Asp578Val mutation of the LHCGR gene. An in silico analysis showed that the p.Asp578Val mutation disturbed amino acid physicochemical features regarding its size, charge, and hydrophobicity value. CONCLUSIONS: Clinical and hormonal profile of the siblings here evaluated was not different while compared to those patients previously described. An in silico mutation analysis reinforced the causative role of recurrent activating mutations in the intracellular loop and transmembrane helices of the LHCGR. The segregation of this mutation with the offsprings' phenotype indicated that it is causative.

Asunto(s)

Pubertad Precoz/genética , Receptores de HL/genética , Adolescente , Brasil , Niño , Humanos , Masculino , Mutación , Hermanos

RESUMEN

Morning glory syndrome (MGS) is a congenital optic disc dysplasia often associated with craniofacial anomalies, especially basal encephalocele and hypopituitarism. Clinical signs are varied and often occult. The PAX6 gene is involved in ocular morphogenesis and is expressed in numerous ocular tissues during development especially in the developing central nervous system. The aim of the present study is to evaluate PAX6 in MGS associated with isolated growth hormone deficiency. Three pre-pubertal males (A, B and C) with MGS and short stature due to growth hormone deficiency, treated with recombinant human growth hormone with limited response, were reported. Two of them had basal encephalocele. Coding and non-coding sequences corresponding of PAX6 different transcripts were analyzed by direct sequencing. Nucleotide variations causing putative aminoacid change were not observed. Patient A presented the new IVS2+9G>A transition, whereas patients A and C were heterozygous for known single nucleotide polymorphisms (SNP) within the intron 4. In addition, two SNP heterozygoses were observed for patient C in both intron 9 and 13. Sequencing also revealed several nucleotide variations in patient B. Two heterozygoses for known polymorphisms were identified along with a novel C>A nucleotide change in intron 4. This patient also presented a low number on the TG repeat in intron 9 and a new IVS11+33A>T transversion. Gene regulation and transcription of PAX6 are complex processes; there are two major protein isoforms, PAX6(-5a) and PAX6(+5a), and nine transcripts described. Furthermore, extra transcription regulatory elements have been postulated within PAX6 introns. Considering that neither population distributions on PAX6 polymorphism nor their linkeages with diseases have been reported, a functional effect due to alterations described here cannot be discarded.

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A síndrome de Morning Glory (SMG) é uma displasia óptica congênita associada a anomalias craniofaciais, principalmente encefalocele basal e hipopituitarismo. Os sinais clínicos são variados e muitas vezes ocultos. O gene PAX6 está envolvido na morfogênese ocular e se expressa em vários tecidos oculares durante o desenvolvimento do sistema nervoso central. O objetivo deste estudo foi avaliar o gene PAX6 na SMG associada com deficiência isolada de hormônio de crescimento. Foram relatados três pacientes pré-púberes (A, B e C) com SMG e baixa estatura por deficiência de hormônio de crescimento tratados com hormônio de crescimento recombinante humano. As seqüências codificadoras e não-codificadoras correspondentes ao PAX6 em diferentes transcritos foram analisadas por seqüenciamento direto. Variações nucleotídeas com trocas pontuais de aminoácidos não foram encontradas. O paciente A apresentou uma transição nova IVS2+9G>A, enquanto os pacientes A e C foram heterozigotos para um polimorfismo (SNP) no íntron 4. Ainda, dois SNPs em heterozigose nos íntrons 9 e 13 foram observados no paciente C. O seqüenciamento também mostrou várias variações nucleotídeas no paciente B. Dois SNPs conhecidos com a alteração nucleotídea nova C>A no íntron 4 foram observados em heterozigose. Este paciente também apresentou um baixo número de repetições TG no íntron 9 e uma nova transversão IVS11+33A>T. A regulação e a transcrição do gene PAX6 são um processo complexo; existem 2 isoformas principais da proteína, PAX6(-5a) e PAX6(+5a) e 9 transcritos descritos. Considerando que nem a distribuição de SNPs no PAX6 e nem as suas ligações com as doenças foram relatadas, um defeito funcional devido às alterações descritas não pode ser descartado.

Asunto(s)

Niño , Humanos , Proteínas del Ojo/genética , Proteínas de Homeodominio/genética , Hormona de Crecimiento Humana/deficiencia , Mutación , Disco Óptico/anomalías , Enfermedades del Nervio Óptico/genética , Factores de Transcripción Paired Box/genética , Proteínas Represoras/genética , Secuencia de Bases , Encefalocele/diagnóstico , Heterocigoto , Hormona de Crecimiento Humana/uso terapéutico , Intrones/genética , Enfermedades del Nervio Óptico/congénito , Polimorfismo Genético , Análisis de Secuencia de ADN , Síndrome

RESUMEN

Growth failure is frequent and a clinically important issue in children with chronic kidney disease (CKD). Many factors contribute to impaired growth in these children, including abnormalities in the growth hormone (GH)--insulin-like growth factor 1 (IGF-1) axis, malnutrition, acidosis, renal bone disease and glucocorticoid associated treatment. The management of growth failure in children with CKD is complicated by the presence of other-disease related complications requiring medical intervention. Despite evidence of GH efficacy and safety in this population, this therapy is still underutilized. This review shows the impact, the causes and the treatment of growth failure in children with CKD.

Asunto(s)

Trastornos del Crecimiento/tratamiento farmacológico , Hormona de Crecimiento Humana/uso terapéutico , Fallo Renal Crónico/complicaciones , Corticoesteroides/efectos adversos , Estatura/efectos de los fármacos , Trastornos del Crecimiento/fisiopatología , Hormona de Crecimiento Humana/metabolismo , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo

RESUMEN

Acquired Immunodeficiency Syndrome (Aids) was initially related to HIV-associated wasting syndrome, and its metabolic disturbances to altered body composition. After Highly Active Antiretroviral Therapy (HAART) was started, malnutrition has declined and HIV-associated lipodystrophy syndrome has emerged as an important metabolic disorder. Aids is also characterized by hormonal disturbances, principally in growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis. The use of recombinant human GH (hrGH) was formerly indicated to treat wasting syndrome, in order to increase lean body mass. Even though the use of hrGH in lipodystrophy syndrome has been considered, the decrease in insulin sensitivity is a limitation for its use, which has not been officially approved yet. Diversity in therapeutic regimen is another limitation to its use in Aids patients. The present study has reviewed the main HIV-related endocrine-metabolic disorders as well as the use of hrGH in such conditions.

Asunto(s)

Síndrome de Inmunodeficiencia Adquirida/complicaciones , Síndrome de Emaciación por VIH/tratamiento farmacológico , Síndrome de Lipodistrofia Asociada a VIH/tratamiento farmacológico , Hormona de Crecimiento Humana/uso terapéutico , Factor I del Crecimiento Similar a la Insulina/metabolismo , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Adolescente , Adulto , Terapia Antirretroviral Altamente Activa/efectos adversos , Niño , Síndrome de Emaciación por VIH/complicaciones , Síndrome de Lipodistrofia Asociada a VIH/complicaciones , Hormona de Crecimiento Humana/efectos adversos , Hormona de Crecimiento Humana/metabolismo , Humanos , Proteínas Recombinantes/uso terapéutico

RESUMEN

O atraso no crescimento é freqüente e grave em crianças com doença renal crônica (DRC). Vários fatores contribuem para o comprometimento do crescimento nestas crianças, incluindo as alterações no eixo hormônio de crescimento (GH) - insulin-like growth factor 1 (IGF-1), desnutrição, acidose, doença renal óssea e uso de corticóides. Em crianças com DRC, o tratamento do atraso no crescimento é difícil em virtude da presença de doenças associadas que necessitem de adequado tratamento médico. Apesar de as evidências a respeito da segurança e de a eficácia do GH nesta população, este tratamento ainda é pouco utilizado. Esta revisão mostra o impacto, as causas e o tratamento do atraso no crescimento em crianças com DRC.

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Growth failure is frequent and a clinically important issue in children with chronic kidney disease (CKD). Many factors contribute to impaired growth in these children, including abnormalities in the growth hormone (GH) - insulin-like growth factor 1 (IGF-1) axis, malnutrition, acidosis, renal bone disease and glucocorticoid associated treatment. The management of growth failure in children with CKD is complicated by the presence of other-disease related complications requiring medical intervention. Despite evidence of GH efficacy and safety in this population, this therapy is still underutilized. This review shows the impact, the causes and the treatment of growth failure in children with CKD.

Asunto(s)

Humanos , Trastornos del Crecimiento/tratamiento farmacológico , Hormona de Crecimiento Humana/uso terapéutico , Fallo Renal Crónico/complicaciones , Corticoesteroides/efectos adversos , Estatura/efectos de los fármacos , Trastornos del Crecimiento/fisiopatología , Hormona de Crecimiento Humana/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo

RESUMEN

As primeiras descrições da síndrome da imunodeficiência adquirida (Aids) associavam-se à síndrome de emaciamento, e os distúrbios metabólicos às alterações na composição corporal. Após a introdução da terapia anti-retroviral altamente ativa (HAART), houve declínio na desnutrição, e surge a lipodistrofia como importante distúrbio metabólico. A Aids também se caracteriza por distúrbios hormonais, principalmente no eixo hormônio de crescimento/fator de crescimento insulina-like tipo 1 (GH/IGF-1). O uso do GH recombinante humano (hrGH) foi inicialmente indicado na síndrome de emaciamento, a fim de aumentar a massa muscular. Embora também não existam dúvidas quanto aos efeitos do hrGH na lipodistrofia, a diminuição na sensibilidade à insulina limita o seu uso, o qual ainda não está oficialmente aprovado. A diversidade nos esquemas de tratamento é outro limitante do uso dessa medicação em pacientes com Aids. Esta revisão apresenta os principais distúrbios endócrino-metabólicos associados à Aids e ao uso do hrGH nessas condições.

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Acquired Immunodeficiency Syndrome (Aids) was initially related to HIV-associated wasting syndrome, and its metabolic disturbances to altered body composition. After Highly Active Antiretroviral Therapy (HAART) was started, malnutrition has declined and HIV-associated lipodystrophy syndrome has emerged as an important metabolic disorder. Aids is also characterized by hormonal disturbances, principally in growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis. The use of recombinant human GH (hrGH) was formerly indicated to treat wasting syndrome, in order to increase lean body mass. Even though the use of hrGH in lipodystrophy syndrome has been considered, the decrease in insulin sensitivity is a limitation for its use, which has not been officially approved yet. Diversity in therapeutic regimen is another limitation to its use in Aids patients. The present study has reviewed the main HIV-related endocrine-metabolic disorders as well as the use of hrGH in such conditions.

Asunto(s)

Adolescente , Adulto , Niño , Humanos , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Síndrome de Emaciación por VIH/tratamiento farmacológico , Síndrome de Lipodistrofia Asociada a VIH/tratamiento farmacológico , Hormona de Crecimiento Humana/uso terapéutico , Factor I del Crecimiento Similar a la Insulina/metabolismo , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Terapia Antirretroviral Altamente Activa/efectos adversos , Síndrome de Emaciación por VIH/complicaciones , Síndrome de Lipodistrofia Asociada a VIH/complicaciones , Hormona de Crecimiento Humana/efectos adversos , Hormona de Crecimiento Humana/metabolismo , Proteínas Recombinantes/uso terapéutico

RESUMEN

Morning glory syndrome (MGS) is a congenital optic disc dysplasia often associated with craniofacial anomalies, especially basal encephalocele and hypopituitarism. Clinical signs are varied and often occult. The PAX6 gene is involved in ocular morphogenesis and is expressed in numerous ocular tissues during development especially in the developing central nervous system. The aim of the present study is to evaluate PAX6 in MGS associated with isolated growth hormone deficiency. Three pre-pubertal males (A, B and C) with MGS and short stature due to growth hormone deficiency, treated with recombinant human growth hormone with limited response, were reported. Two of them had basal encephalocele. Coding and non-coding sequences corresponding of PAX6 different transcripts were analyzed by direct sequencing. Nucleotide variations causing putative aminoacid change were not observed. Patient A presented the new IVS2+9G>A transition, whereas patients A and C were heterozygous for known single nucleotide polymorphisms (SNP) within the intron 4. In addition, two SNP heterozygoses were observed for patient C in both intron 9 and 13. Sequencing also revealed several nucleotide variations in patient B. Two heterozygoses for known polymorphisms were identified along with a novel C>A nucleotide change in intron 4. This patient also presented a low number on the TG repeat in intron 9 and a new IVS11+33A>T transversion. Gene regulation and transcription of PAX6 are complex processes; there are two major protein isoforms, PAX6(-5a) and PAX6(+5a), and nine transcripts described. Furthermore, extra transcription regulatory elements have been postulated within PAX6 introns. Considering that neither population distributions on PAX6 polymorphism nor their linkeages with diseases have been reported, a functional effect due to alterations described here cannot be discarded.

Asunto(s)

Proteínas del Ojo/genética , Proteínas de Homeodominio/genética , Hormona de Crecimiento Humana/deficiencia , Mutación , Disco Óptico/anomalías , Enfermedades del Nervio Óptico/genética , Factores de Transcripción Paired Box/genética , Proteínas Represoras/genética , Secuencia de Bases , Niño , Encefalocele/diagnóstico , Heterocigoto , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Intrones/genética , Enfermedades del Nervio Óptico/congénito , Factor de Transcripción PAX6 , Polimorfismo Genético , Análisis de Secuencia de ADN , Síndrome