RESUMO
Noonan syndrome is a heterogeneous congenital disorder. The main features are typical facial features, short stature and cardiac defects. The diagnosis is clinical: in 80% of patients with Noonan syndrome a genetic defect can be shown. Inheritance is predominantly autosomal dominant and seldom autosomal recessive. In 2001, PTPN11 was the first gene connected to Noonan syndrome, and until now, at least 20 other genes have been discovered. All genes code for proteins involved in the RAS-MAP-kinase pathway, and therefore, Noonan syndrome is one of the known RASopathies. Other RASopathies include neurofibromatosis and CFC syndrome. Short stature is one of the defining features of Noonan syndrome. The cause is not fully understood but is multifactorial. Other endocrinological features are confined to delayed puberty and hypogonadism in boys and males. To increase adult height, children with Noonan syndrome have been treated with human growth hormone since the 1990s. This seems to be beneficial in most of the children treated. In this narrative review, we describe the current knowledge on growth, endocrinological features and growth hormone treatment in patients with Noonan syndrome.
RESUMO
Children with Noonan syndrome show rapid decline of growth in the first year of life and feeding problems are present in over 50%. The aim of this study was to explore whether growth decelerates because of feeding problems or other Noonan syndrome-related factors. We performed a retrospective, longitudinal cohort study of clinically and genetically diagnosed subjects with Noonan syndrome (n = 143). Questionnaires about the phenotypic-genotypic profile and reported feeding problems were sent to eligible subjects. Data on first-year growth was obtained from growth charts. Ninety-one participants were excluded because of different criteria. A total of 52 subjects with Noonan syndrome were included. The largest decline in weight and length standard deviation score (SDS) occurred in the first 2.5 months after birth (-1.93 and -1.15, respectively), with feeding problems causing a decline of 0.57 SDS in the remaining months. At 1 year, children with feeding problems were on average 290 g lighter and 0.8 cm shorter than children without feeding problems. Weight gain was also negatively influenced by having a PTPN11 mutation (n = 39) and a higher gestational age, whereas children of parents with Noonan syndrome and with a higher birth weight gained more weight. Growth in length was reduced by having cardiac surgery and a higher gestational age, but positively influenced by birth length and maternal height. Growth in children with Noonan syndrome is impaired right after birth and only partially associated with feeding problems. In addition, several specific Noonan syndrome-related factors seem to influence growth in the first year.
Assuntos
Síndrome de Noonan/genética , Alelos , Criança , Pré-Escolar , Comportamento Alimentar , Feminino , Genótipo , Gráficos de Crescimento , Humanos , Lactente , Estudos Longitudinais , Masculino , Mutação , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/epidemiologia , Razão de Chances , Fenótipo , Estudos Retrospectivos , Inquéritos e Questionários , Fatores de TempoRESUMO
CONTEXT: GH treatment is effective in improving height in short children born small for gestational age (SGA). GH is thought to have limited effect when started during adolescence. OBJECTIVE: The aim of this study was to investigate GH treatment efficacy in short SGA children when treatment was started during adolescence; to assess whether GH 2 mg/m(2) · d during puberty improves adult height (AH) compared with 1 mg/m(2) · d; and to assess whether an additional 2-yr postponement of puberty by GnRH analog (GnRHa) improves AH in children who are short at the start of puberty (<140 cm), with a poor AH expectation. PATIENTS AND DESIGN: In this longitudinal, randomized, dose-response GH trial, we included 121 short SGA children (60 boys) at least 8 yr of age. We performed intention-to-treat analyses on all children and uncensored case analyses on 84 children who reached AH. Besides, we evaluated growth during 2 yr of combined GH/GnRHa and subsequent GH treatment until AH in a subgroup of 40 pubertal children with a height of less than 140 cm at the start. RESULTS: Short SGA children started treatment at a median age of 11.2 yr, when 46% had already started puberty. Median height increased from -2.9 at start to -1.7 sd score (SDS) at AH (P < 0.001). Treatment with GH 2 vs. 1 mg/m(2) · d during puberty resulted in significantly better AH (P = 0.001), also after correction for gender, age at start, height SDS at start, treatment years before puberty, and target height SDS. AH was similar in children who started puberty at less than 140 cm and received GH/GnRHa, compared with children who started puberty greater than 140 cm and received GH only (P = 0.795). CONCLUSION: When started in adolescence, GH treatment significantly improves AH in short SGA children, particularly with GH 2 mg/m(2) · d during puberty. When SGA children are short at the start of puberty, they can benefit from combined GH/GnRHa treatment.
Assuntos
Estatura/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio do Crescimento/uso terapêutico , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento , Adolescente , Adulto , Estatura/fisiologia , Criança , Relação Dose-Resposta a Droga , Feminino , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , Resultado do TratamentoRESUMO
OBJECTIVE: To describe the clinical features and relevant genetic mutations in 22 children with congenital hyperinsulinism in the north-east Netherlands. DESIGN: Retrospective, descriptive study. METHOD: Children born between June 1988 and June 2009, who were presented at the academic medical centres of Nijmegen and Groningen were included. They were clinically suspected of having congenital hyperinsulinism and DNA diagnostics were carried out. Clinical course, laboratory results, genetic data, interventions, follow-up data and patient demographics were documented. RESULTS: A total of 22 children from 20 families were included. Of these 22 children, 5 were born macrosomic. In 16 children the disorder was picked up within the first 4 days of life either through glucose screening of premature children or because they had symptoms. All children were treated with diazoxide; 12 (55%) did not respond to this treatment. Ultimately, 9 children underwent pancreatectomy. Five children had focal type congenital hyperinsulinism. In 15 children 13 different mutations were identified in relevant genes. We found 9 different mutations in the ABCC8-gene, including 2 novel mutations (c.2117-2A>T and c.4076C>G), 1 in the KCNJ11 gene, 1 in the GCK gene, and 2 in the GLUD1 gene. In the villages of Aalten and Silvolde a high prevalence of congenital hyperinsulinism was observed (1 in 6930), probably due to a common ancestor. CONCLUSION: The clinical characteristics of Dutch children with congenital hyperinsulinism were comparable with those reported in other study populations. We found two novel mutations in the ABCC8 gene. The mutations in the north-east Netherlands were diverse; no one mutation occurred more frequently than any other.
Assuntos
Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/patologia , Análise Mutacional de DNA , Linhagem , Transportadores de Cassetes de Ligação de ATP/genética , Hiperinsulinismo Congênito/tratamento farmacológico , Hiperinsulinismo Congênito/cirurgia , Diazóxido/uso terapêutico , Feminino , Humanos , Recém-Nascido , Masculino , Mutação , Pancreatectomia , Canais de Potássio Corretores do Fluxo de Internalização/genética , Estudos RetrospectivosRESUMO
Various syndromes of the Ras-mitogen-activated protein kinase (MAPK) pathway, including the Noonan, Cardio-Facio-Cutaneous, LEOPARD and Costello syndromes, share the common features of craniofacial dysmorphisms, heart defect and short stature. In a subgroup of patients, severe muscle hypotonia, central nervous system involvement and failure to thrive occur as well. In this study we report on five children diagnosed initially with classic metabolic and clinical symptoms of an oxidative phosphorylation disorder. Later in the course of the disease, the children presented with characteristic features of Ras-MAPK pathway-related syndromes, leading to the reevaluation of the initial diagnosis. In the five patients, in addition to the oxidative phosphorylation disorder, disease-causing mutations were detected in the Ras-MAPK pathway. Three of the patients also carried a second, mitochondrial genetic alteration, which was asymptomatically present in their healthy relatives. Did we miss the correct diagnosis in the first place or is mitochondrial dysfunction directly related to Ras-MAPK pathway defects? The Ras-MAPK pathway is known to have various targets, including proteins in the mitochondrial membrane influencing mitochondrial morphology and dynamics. Prospective screening of 18 patients with various Ras-MAPK pathway defects detected biochemical signs of disturbed oxidative phosphorylation in three additional children. We concluded that only a specific, metabolically vulnerable sub-population of patients with Ras-MAPK pathway mutations presents with mitochondrial dysfunction and a more severe, early-onset disease. We postulate that patients with Ras-MAPK mutations have an increased susceptibility, but a second metabolic hit is needed to cause the clinical manifestation of mitochondrial dysfunction.
Assuntos
Síndrome de Barth/genética , Sistema de Sinalização das MAP Quinases/genética , Encefalomiopatias Mitocondriais/genética , Deficiência Múltipla de Acil Coenzima A Desidrogenase/genética , Mutação , Proteínas ras/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Adolescente , Pré-Escolar , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , DNA Mitocondrial/genética , Feminino , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Humanos , Lactente , Síndrome LEOPARD/genética , Síndrome LEOPARD/patologia , Pessoa de Meia-Idade , Encefalomiopatias Mitocondriais/patologia , Deficiência Múltipla de Acil Coenzima A Desidrogenase/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Anormalidades da Pele/genética , Anormalidades da Pele/patologia , Proteínas ras/metabolismoRESUMO
UNLABELLED: Abstract Background and scope: Similar biological medicinal products, also called 'biosimilars', are copies of biopharmaceutical products whose patent has expired. Whether biosimilars are truly comparable and interchangeable with their reference biopharmaceutical products in terms of quality, efficacy and tolerability, is still a matter of debate. This review discusses the controversies related to the criteria for regulatory approval of biosimilars. These concerns are illustrated using recombinant human growth hormone (rhGH) biosimilars as an example. METHODS: Publications on the regulatory approval of biosimilars in general and rhGH biosimilars in particular were searched in MEDLINE by exploding and combining the medical subject heading terms 'human growth hormone', 'efficacy' or 'safety' and the free-text words 'biosimilar', 'biopharmaceutical', 'similar biological medicinal product', 'follow-up biologic' or 'biogeneric'. Searches were limited to full-text English-language articles. The websites from the European Medicines Agency (EMA) and from the American Food and Drug Administration were also consulted. Regulatory status: To obtain regulatory approval of a biosimilar product by EMA, demonstration of comparability with an approved reference biopharmaceutical product in terms of quality, efficacy and tolerability is needed. Thus, comparative quality studies, non-clinical and clinical efficacy and tolerability studies are required. However, in contrast to the reference product, comparative non-clinical pharmacokinetics, safety pharmacology, reproduction toxicology, mutagenicity and carcinogenicity studies are not mandatory to obtain approval of a biosimilar. In addition, comparable efficacy and tolerability only needs to be established by one study in a single population during a limited time interval (12 months) and often allows extrapolation to all other approved indications of the reference product. Consequently, for the currently approved rhGH biosimilars, long-term efficacy and tolerability in all indications has not been proven to the same degree as for the reference products. CONCLUSIONS: The validity of the current criteria for comparability and interchangeability of biosimilars and their reference products remains controversial. The authors conclude that long-term clinical investigations and systematic monitoring of the efficacy and tolerability of rhGH biosimilars in all indications are needed. In addition, the medico-economical environment should allow physicians to take a free and informed decision about the type of rhGH to be prescribed.
Assuntos
Produtos Biológicos/uso terapêutico , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Proteínas Recombinantes/uso terapêuticoRESUMO
Dehydroepiandrosterone (DHEA) sulfotransferase, known as SULT2A1, converts the androgen precursor DHEA to its inactive sulfate ester, DHEAS [corrected], thereby preventing the conversion of DHEA to an active androgen. SULT2A1 requires 3'-phosphoadenosine-5'-phosphosulfate (PAPS) for catalytic activity. We have identified compound heterozygous mutations in the gene encoding human PAPS synthase 2 (PAPSS2) in a girl with premature pubarche, hyperandrogenic anovulation, very low DHEAS levels, and increased androgen levels. In vitro coincubation of human SULT2A1 and wild-type or mutant PAPSS2 proteins confirmed the inactivating nature of the mutations. These observations indicate that PAPSS2 deficiency is a monogenic adrenocortical cause of androgen excess.
Assuntos
Complexos Multienzimáticos/genética , Mutação , Puberdade Precoce/genética , Sulfato Adenililtransferase/genética , Androgênios/sangue , Androstenodiona/sangue , Criança , Desidroepiandrosterona/sangue , Desidroepiandrosterona/metabolismo , Diagnóstico Diferencial , Feminino , Heterozigoto , Humanos , Complexos Multienzimáticos/deficiência , Complexos Multienzimáticos/metabolismo , Síndrome do Ovário Policístico/diagnóstico , Puberdade Precoce/sangue , RNA Mensageiro/metabolismo , Análise de Sequência de DNA , Sulfato Adenililtransferase/deficiência , Sulfato Adenililtransferase/metabolismo , Sulfotransferases/sangue , Sulfotransferases/metabolismo , Testosterona/sangueRESUMO
CONTEXT: Several studies showed a decrease in height velocity during GnRH analogue (GnRHa) treatment. No information is available on GH levels during GnRHa treatment in short SGA girls. OBJECTIVE: To study overnight GH profiles and IGF-I and IGFBP-3 levels in girls with Tanner stage 2 and stage 3, before and after 3 months of GnRHa treatment, and to compare levels with those found in prepubertal short SGA girls. PATIENTS: Twenty-four pubertal and 16 prepubertal short SGA girls. INTERVENTION: After baseline overnight GH profiles, pubertal girls received leuprorelide acetate depots of 3.75 mg subcutaneously every 4 weeks. OUTCOME MEASURES: GH, IGF-I and IGFBP-3 levels. RESULTS: At baseline, GH levels were comparable to levels found in prepubertal short SGA girls and IGF-I and IGFBP-3 SDS were significantly below the population mean. After 3 months of GnRHa treatment, AUC(0) (P = 0.02), mean (P = 0.02) and maximum GH levels (P = 0.008) had significantly decreased. Mean GH levels were significantly lower than in prepubertal short SGA girls (P = 0.03). Eight girls with more than 40% decrease in mean GH levels also had a significantly greater decrease in IGF-I and IGFBP-3 levels. Mean and maximum GH levels at baseline correlated significantly with those after 3 months of GnRHa treatment. CONCLUSION: Short SGA girls lack the normal increase in GH levels seen in puberty and have reduced IGF-I and IGFBP-3 levels, which might explain their reduced pubertal growth spurt. GnRHa treatment led to a significant reduction in GH levels. Therefore, combining GnRHa treatment with GH treatment might improve adult height of short SGA girls.