Proposal of an obesity classification based on weight history: an official document by the Brazilian Society of Endocrinology and Metabolism (SBEM) and the Brazilian Society for the Study of Obesity and Metabolic Syndrome (ABESO)

ABSTRACT Obesity is a chronic disease associated with impaired physical and mental health. A widespread view in the treatment of obesity is that the goal is to normalize the individual's body mass index (BMI). However, a modest weight loss (usually above 5%) is already associated with clinical improvement, while weight losses of 10%-15% bring even further benefits, independent from the final BMI. The percentage of weight reduction is accepted as a treatment goal since a greater decrease in weight is frequently difficult to achieve due to metabolic adaptation along with environmental and lifestyle factors. In this document, the Brazilian Society of Endocrinology and Metabolism (SBEM) and the Brazilian Society for the Study of Obesity and Metabolic Syndrome (ABESO) propose a new obesity classification based on the maximum weight attained in life (MWAL). In this classification, individuals losing a specific proportion of weight are classified as having "reduced" or "controlled" obesity. This simple classification - which is not intended to replace others but to serve as an adjuvant tool - could help disseminate the concept of clinical benefits derived from modest weight loss, allowing individuals with obesity and their health care professionals to focus on strategies for weight maintenance instead of further weight reduction. In future studies, this proposed classification can also be an important tool to evaluate possible differences in therapeutic outcomes between individuals with similar BMIs but different weight trajectories.

Lack of mutations in the leptin receptor gene in severely obese children.

OBJECTIVE: To analyze the LEPR gene in obese children and to investigate the associations between molecular findings and anthropometric and metabolic features. SUBJECTS AND METHODS: Thirty-two patients were evaluated regarding anthropometric characteristics, blood pressure, heart rate, serum glucose, insulin, leptin levels, and lipid profile. The molecular study consisted of the amplification and automatic sequencing of the coding region of LEPR in order to investigate new mutations. RESULTS: We identified a high prevalence of metabolic disorders: impaired fasting glucose in 12.5% of the patients, elevated HOMA-IR in 85.7%, low HDL-cholesterol levels in 46.9%, high triglyceride levels in 40.6%, and hypertension in 58.6% of the patients. The molecular study identified 6 already described allelic variants: rs1137100 (exon-2), rs1137101 (exon-4), rs1805134 (exon-7), rs8179183 (exon-12), rs1805096 (exon-18), and the deletion/insertion of the pentanucleotide CTTTA at 3'untranslated region. CONCLUSIONS: The frequency of alleles observed in this cohort is similar to that described in the literature, and was not correlated with any clinical feature. The molecular findings in the analysis of the LEPR did not seem to be implicated in the etiology of obesity in these patients.

Lack of mutations in the leptin receptor gene in severely obese children / Ausência de mutação no gene receptor de leptina em crianças gravemente obesas

OBJECTIVE: To analyze the LEPR gene in obese children and to investigate the associations between molecular findings and anthropometric and metabolic features. SUBJECTS AND METHODS: Thirty-two patients were evaluated regarding anthropometric characteristics, blood pressure, heart rate, serum glucose, insulin, leptin levels, and lipid profile. The molecular study consisted of the amplification and automatic sequencing of the coding region of LEPR in order to investigate new mutations. RESULTS: We identified a high prevalence of metabolic disorders: impaired fasting glucose in 12.5% of the patients, elevated HOMA-IR in 85.7%, low HDL-cholesterol levels in 46.9%, high triglyceride levels in 40.6%, and hypertension in 58.6% of the patients. The molecular study identified 6 already described allelic variants: rs1137100 (exon-2), rs1137101 (exon-4), rs1805134 (exon-7), rs8179183 (exon-12), rs1805096 (exon-18), and the deletion/insertion of the pentanucleotide CTTTA at 3'untranslated region. CONCLUSIONS: The frequency of alleles observed in this cohort is similar to that described in the literature, and was not correlated with any clinical feature. The molecular findings in the analysis of the LEPR did not seem to be implicated in the etiology of obesity in these patients.

OBJETIVO: Analisar o LEPR em crianças obesas e investigar associações entre achados moleculares e características antropométricas e metabólicas. SUJEITOS E MÉTODOS: Foram avaliados 32 pacientes quanto às características antropométricas, à pressão arterial, à frequência cardíaca, às dosagens séricas de glicemia, à insulina, à leptina e ao perfil lipídico. O estudo molecular consistiu na amplificação e no sequenciamento automático da região codificadora do LEPR para pesquisar mutações. RESULTADOS: Identificou-se uma alta prevalência de distúrbios metabólicos: glicemia de jejum alterada em 12,5%, HOMA-IR elevado em 85,7%, níveis de HDL-colesterol baixos em 46,9%, níveis de triglicérides elevados em 40,6% e hipertensão arterial em 58,6%. O estudo molecular identificou 6 variações alélicas já descritas na literatura: rs1137100 (éxon-2), rs1137101 (éxon-4), rs1805134 (éxon-7), rs8179183 (éxon-12), rs1805096 (éxon-18) e deleção/inserção do pentanucleotídeo CTTTA na região 3' não traduzida. CONCLUSÕES: A frequência das variações alélicas observada é semelhante à descrita na literatura e não se correlacionou com nenhuma característica clínica. Os resultados da análise molecular do LEPR não parecem estar implicados na etiologia da obesidade desses pacientes.

[Recent progress and novel perspectives on obesity pharmacotherapy]. / Progressos recentes e novas perspectivas em farmacoterapia da obesidade.

Obesity prevalence has risen dramatically over the past decades, which poses a great number of patients at risk of metabolic and cardiovascular complications. Long-term efficacy of lifestyle modification isolated has shown to be modest which, therefore, urges the need of more aggressive interventions such as adjuvant pharmacotherapy or the more radical surgical approach. Bariatric surgery has proven to date to be the most effective treatment, although it may be associated with nutritional and metabolic complications not yet completely recognized. By contrast, there is limited availability of antiobesity agents currently in the market, as well as historical facts involving the suspension of previously existing medications due to safety concerns. This article aims to present recent data on clinical trials of novel weight-loss drugs with short perspective to enter the market, if approved by the regulatory agencies. This review will discuss the efficacy and safety of these compounds, which include lorcaserin (selective serotonin 5-HT2c agonist), tesofensine (triple monoamine reuptake inhibitor), liraglutide (GLP-1 analogue) and cetilistat (gastrointestinal lipase inhibitor), as well as the combination therapies of bupropion/naltrexone, bupropion/zonisamide, phentermine/topiramate and pramlintide/metreleptin.

[Characterization of metabolic resting rate and proposal of a new equation for a female Brazilian population]. / Padronização do gasto metabólico de repouso e proposta de nova equação para uma população feminina brasileira.

OBJECTIVES: The goals of this study were to standardize resting metabolic rate (RMR) in the Brazilian female population and evaluate the suitability of the HB equation. SUBJECTS AND METHODS: In order to do so, 760 indirect calorimetry (CI) measurements performed in Brazilian female patients between 18 and 65 years old, were used. The results were tabulated, the population distributed according to the quintiles of weight, and the statistical analyses applied. RESULTS: The average RMR varied from 1,226 to 1,775 calories/day. The HB equation overestimated the RMR by about 7%. From the correlation between the variables, we conclude that weight has a positive correlation with RMR and age a negative correlation. CONCLUSION: The RMR and respiratory quotient (QR) can be used as obesity predictors. Two new equations were proposed in our study, one for the population with body mass index (BMI) > 35 kg/m(2) and another for the population with BMI < 35 kg/m(2).

Progressos recentes e novas perspectivas em farmacoterapia da obesidade / Recent progress and novel perspectives on obesity pharmacotherapy

O aumento da prevalência da obesidade, nas últimas décadas, é alarmante, o que implica um grande número de pacientes sob risco de complicações metabólicas e cardiovasculares associadas. A eficácia modesta a longo prazo das modificações de estilo de vida isoladamente exige a necessidade de intervenções mais agressivas, seja por meio do uso adjuvante de medicamentos ou da abordagem mais radical cirúrgica. A cirurgia bariátrica, embora até hoje tenha se mostrado o método mais efetivo de tratamento dessa enfermidade, pode estar associada a complicações nutricionais e metabólicas ainda não totalmente esclarecidas. Contrasta com esse fato a disponibilidade limitada de agentes antiobesidade atualmente no mercado, além de fatos históricos que envolveram a suspensão de alguns fármacos previamente existentes, por questões de segurança. Este artigo tem como objetivo apresentar dados recentes de estudos clínicos de novas drogas propostas para o tratamento da obesidade com perspectivas breves de serem lançadas no mercado, caso passem pela aprovação das agências regulatórias. Nesta revisão serão discutidas a eficácia e a segurança desses fármacos, que incluem a lorcaserina (agonista serotoninérgico seletivo 5-HT2c), tesofensina (inibidor triplo de recaptação de monoaminas), liraglutide (análogo do GLP-1) e cetilistate (inibidor de lipases gastrointestinais), além das combinações de bupropiona/naltrexona, bupropiona/zonisamida, fentermina/topiramato e pramlintide/metreleptina.

Obesity prevalence has risen dramatically over the past decades, which poses a great number of patients at risk of metabolic and cardiovascular complications. Long-term efficacy of lifestyle modification isolated has shown to be modest which, therefore, urges the need of more aggressive interventions such as adjuvant pharmacotherapy or the more radical surgical approach. Bariatric surgery has proven to date to be the most effective treatment, although it may be associated with nutritional and metabolic complications not yet completely recognized. By contrast, there is limited availability of antiobesity agents currently in the market, as well as historical facts involving the suspension of previously existing medications due to safety concerns. This article aims to present recent data on clinical trials of novel weight-loss drugs with short perspective to enter the market, if approved by the regulatory agencies. This review will discuss the efficacy and safety of these compounds, which include lorcaserin (selective serotonin 5-HT2c agonist), tesofensine (triple monoamine reuptake inhibitor), liraglutide (GLP-1 analogue) and cetilistat (gastrointestinal lipase inhibitor), as well as the combination therapies of bupropion/naltrexone, bupropion/zonisamide, phentermine/topiramate and pramlintide/metreleptin.

Is a diagnosis of metabolic syndrome applicable to children?

OBJECTIVE: To present the components of the metabolic syndrome in children and adolescents and to discuss how they are assessed in the pediatric population in addition to presenting the major metabolic syndrome classifications for the age group. SOURCES: A review of literature published from 1986 to 2008 and found on MEDLINE databases. SUMMARY OF THE FINDINGS: The prevalence of childhood obesity has been increasing globally over recent decades and as a result its complications, such as diabetes mellitus, arterial hypertension and dyslipidemia, have also increased. The concept of metabolic syndrome, already common with adults, is now beginning to be applied to children through classifications using the criteria for adults modified for the younger age group. Notwithstanding, these classifications differ in terms of the cutoff points used and whether they employ body mass index or waist circumference to define obesity. The review presents these classifications, highlighting the points on which they differ and the debate about them. CONCLUSIONS: If childhood obesity goes untreated, it will have severe consequences in the future. A number of models for classifying metabolic syndrome in children have been published, but there is considerable diversions between them. The criteria for classifying metabolic syndrome in children therefore need to be standardized in order to identify those people at greatest risk of future complications.

O diagnóstico de síndrome metabólica é aplicável às crianças? / Is a diagnosis of metabolic syndrome applicable to children?

OBJETIVO: Abordar os componentes da síndrome metabólica (SM) na criança e no adolescente discutindo como eles são avaliados na população infantil e apresentando as principais classificações de SM nessa faixa etária. FONTES DOS DADOS: Revisão da literatura utilizando as bases de dados MEDLINE no período de 1986 a 2008. SÍNTESE DOS DADOS: A prevalência de obesidade infantil nas últimas décadas tem aumentado no mundo todo e, consequentemente, suas complicações, como diabetes melito, hipertensão arterial e dislipidemia. O conceito de SM, já usado em adultos, começa a ser aplicado em crianças por meio de classificações que utilizam os critérios para adultos modificados para faixas etárias menores. No entanto, essas classificações apresentam divergências quanto ao valor de pontos de corte usados nos critérios e quanto à utilização do índice de massa corporal ou da medida da circunferência abdominal para definir a obesidade. Esta revisão apresenta essas classificações mostrando os pontos discordantes e a discussão em torno delas. CONCLUSÕES: Se não for tratada, a obesidade infantil terá consequências graves no futuro. Alguns modelos de classificação de SM em crianças já foram apresentados, e observam-se consideráveis divergências entre eles. Assim, torna-se necessária a padronização desses critérios para a identificação dos indivíduos com maior risco de complicações futuras.

OBJECTIVE: To present the components of the metabolic syndrome in children and adolescents and to discuss how they are assessed in the pediatric population in addition to presenting the major metabolic syndrome classifications for the age group. SOURCES: A review of literature published from 1986 to 2008 and found on MEDLINE databases. SUMMARY OF THE FINDINGS: The prevalence of childhood obesity has been increasing globally over recent decades and as a result its complications, such as diabetes mellitus, arterial hypertension and dyslipidemia, have also increased. The concept of metabolic syndrome, already common with adults, is now beginning to be applied to children through classifications using the criteria for adults modified for the younger age group. Notwithstanding, these classifications differ in terms of the cutoff points used and whether they employ body mass index or waist circumference to define obesity. The review presents these classifications, highlighting the points on which they differ and the debate about them. CONCLUSIONS: If childhood obesity goes untreated, it will have severe consequences in the future. A number of models for classifying metabolic syndrome in children have been published, but there is considerable diversions between them. The criteria for classifying metabolic syndrome in children therefore need to be standardized in order to identify those people at greatest risk of future complications.

Combinations of drugs in the Treatment of Obesity.

Obesity is a chronic disease associated with excess morbidity and mortality. Clinical treatment, however, currently offers disappointing results, with very high rates of weight loss failure or weight regain cycles, and only two drugs (orlistat and sibutramine) approved for long-term use. Drugs combinations can be an option for its treatment but, although widely used in clinical practice, very few data are available in literature for its validation. Our review focuses on the rationale for their use, with advantages and disadvantages; on combinations often used, with or without studies; and on new perspectives of combinations being studied mainly by the pharmaceutical industry.

Padronização do gasto metabólico de repouso e proposta de nova equação para uma população feminina brasileira / Characterization of metabolic resting rate and proposal of a new equation for a female Brazilian population

OBJETIVOS: Os objetivos do estudo foram normatizar o gasto metabólico de repouso (GMR) de mulheres brasileiras, avaliar a adequação da fórmula de Harris Benedict (HB), a relação entre suas variáveis e propor novas equações para estimativa do GMR. SUJEITOS E MÉTODOS: Para tanto, foram utilizados 760 exames de calorimetria indireta (CI) de mulheres com idade entre 18 e 65 anos. Os resultados foram tabulados, a população foi dividida de acordo com quintis de peso e, então, realizaram-se as análises estatísticas. RESULTADOS: A média de GMR variou entre 1.226 calorias/dia a 1.775 calorias/dia. A fórmula de HB superestimou o GMR em torno de 7 por cento.Concluímos, a partir da correlação entre as variáveis, que o peso possui correlação positiva com o GMR, e a idade, uma correlação negativa. CONCLUSÃO: GMR assim como coeficiente respiratório (QR) podem ser utilizados como preditores de obesidade. Nosso estudo trouxe duas novas propostas de equações, uma para a população com índice de massa corpórea (IMC) > 35 kg/m² e outra para a população com IMC < 35 kg/m².

OBJETIVES: The goals of this study were to standardize resting metabolic rate (RMR) in the Brazilian female population and evaluate the suitability of the HB equation. SUBJECTS AND METHODS: In order to do so, 760 indirect calorimetry (CI) measurements performed in Brazilian female patients between 18 and 65 years old, were used. The results were tabulated, the population distributed according to the quintiles of weight, and the statistical analyses applied. RESULTS: The average RMR varied from 1,226 to 1,775 calories/day. The HB equation overestimated the RMR by about 7 percent. From the correlation between the variables, we conclude that weight has a positive correlation with RMR and age a negative correlation. CONCLUSION: The RMR and respiratory quotient (QR) can be used as obesity predictors. Two new equations were proposed in our study, one for the population with body mass index (BMI) > 35 kg/m² and another for the population with BMI < 35 kg/m².

Obesidade / Obesity

Obesidade é uma doença de prevalência crescente nas últimas décadas e que vem adquirindo proporções epidêmicas, sendo um dos principais problemas de saúde pública da sociedade moderna. A obesidade está implicada como fator desencadeante ou agravante de doenças em praticamente todos os sistemas orgânicos, sendo já bem conhecida sua associação com diabetes mellitus tipo 2, dislipidemia, doenças cardio e cerebrovascular, alterações da coagulação, doenças articulares degenerativas, neoplasias, esteatose hepática, apneia do sono etc. Em pacientes com obesidade mórbida tais doenças têm maior risco, com aumento significativo da mortalidade (250% em relação a pacientes não obesos). Esses dados, evidenciados em vários estudos ao longo dos últimos anos, levaram a uma modificação na atitude médica em relação ao indivíduo obeso, sendo os cuidados com a prevenção e o tratamento da obesidade mandatórios na boa prática médica moderna.

Autosomal dominant familial neurohypophyseal diabetes insipidus caused by a novel mutation in arginine-vasopressin gene in a Brazilian family / Diabetes insípido neuro-hipofisário familial causado por uma nova mutação no gene da arginina-vasopressina em uma família brasileira

Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is a rare autosomal dominant disorder characterized by polyuria and polydipsia due to deficiency of arginine vasopressin (AVP). More than 50 mutations causing adFNDI have been already reported in the AVP gene. The aim of the present study is to analyze the AVP gene in four generations of one Brazilian kindred with adFNDI. The proband was a 31-year old female with huge hypotonic polyuria (10 L/day) dated from childhood. Molecular analysis included amplification of all exons and exon-intron regions of the AVP gene by PCR and direct sequencing. Sequencing analysis showed a novel point mutation in heterozygous: G88V (GGC>GTC). All affected patients presented the same mutation also in heterozygous, while it was absent in four normal members. We expand the repertoire of mutations in AVP describing the novel G88V mutation in one Brazilian kindred with adFNDI.

Diabetes insípido neuro-hipofisário com herança autossômica dominante (adFNDI) é uma doença autossômica dominante rara, caracterizada por poliúria e polidipsia devido à deficiência de arginina-vasopressina (AVP). Mais de 50 mutações causando adFNDI foram descritas no gene AVP. O objetivo deste estudo foi analisar o gene AVP em quatro gerações de uma família brasileira com DINF. O caso-índice é de uma paciente de 31 anos, com volumosa poliúria hipotônica desde a infância (10 L/dia). A análise molecular incluiu amplificação por PCR e seqüenciamento automático dos éxons e regiões éxon-íntron do gene AVP. A análise do seqüenciamento mostrou uma nova mutação de ponto em heterozigose: G88V (GGC>GTC). Todos os pacientes afetados apresentaram a mesma mutação, que não foi encontrada em quatro indivíduos normais da família. Expandimos a lista de mutações no gene AVP, descrevendo a nova mutação G88V em uma família brasileira com adFNDI.

[Analysis of resting metabolic rate evaluated by indirect calorimetry in obese women with low and high caloric intake]. / Análise da taxa metabólica de repouso avaliada por calorimetria indireta em mulheres obesas com baixa e alta ingestão calórica.

The aim of this study was to evaluate if obese women with the lowest values of caloric intake (CI) determined by food questionnaire also present the lowest values of resting metabolic rate (RMR), which could lead to excessive weight gain, caused by changes in energy balance. With this purpose, 77 obese women, with IMC>30 kg/m2, aged 20 to 45 years, had their physical activity level and CI evaluated. According to the values of CI obtained from food intake reports, the participants were divided in 3 groups: low (G1), medium (G2), high (G3) CI and were submitted to indirect calorimetry. Height, weight, body surface area (BSA), fat free mass and fat mass measured by bioimpedance were evaluated. The highest values of weight, BSA an fat mass were obtained in G1, as well as values above 1.2 for the CI:RMR ratio, which indicates a probable underestimation of CI. The highest values of physical activity and RMR were observed in the G3 (with high caloric intake). In conclusion, this paper shows that a tendency towards underestimation of self-reported caloric intake exists among obese women and that the maintenance of weight in some patients can be due to their low level of physical activity.

Análise da taxa metabólica de repouso avaliada por calorimetria indireta em mulheres obesas com baixa e alta ingestão calórica / Analysis of resting metabolic rate evaluated by indirect calorimetry in obese women with low and high caloric intake

Este trabalho analisou se mulheres obesas com baixa ingestão calórica (IC), aferidas por questionário alimentar, apresentam valores diminuídos de taxa metabólica de repouso (TMR), o que favoreceria um desequilíbrio no balanço energético (BE) e conseqüente ganho de peso. Foram avaliados o índice de atividade física (AF) e sua relação com a IC em 77 mulheres obesas, com índice de massa corporal (IMC) acima de 30 kg/m², entre 20 e 45 anos. A partir dos valores da IC, as mulheres foram divididas em três grupos: baixa (G1), média (G2) e alta (G3) IC e submetidas a exame de calorimetria indireta de repouso. Foram avaliados: peso, altura, superfície de área corpórea (SAC), composição corporal por bioimpedância. O G1 apresentou maior valor de peso, SAC, peso de gordura corpórea e também valores abaixo de 1,2 na razão IC:TMR, o que indica provável subestimação da IC. Os maiores valores de AF e de TMR (por quilo de massa magra) foram verificados no G3. O G1 apresentou o BE mais negativo. O G3 apresentou valores positivos. Em suma, este estudo mostrou que existe tendência à subestimação da IC de algumas mulheres obesas e que a manutenção do peso corporal em algumas pacientes se deve ao baixo nível de AF.

The aim of this study was to evaluate if obese women with the lowest values of caloric intake (CI) determined by food questionnaire also present the lowest values of resting metabolic rate (RMR), which could lead to excessive weight gain, caused by changes in energy balance. With this porpouse, 77 obese women, with IMC > 30kg/m², aged 20 to 45 years, had their physical activity level and CI evaluated. According to the values of CI obtained from food intake reports, the participants were divided in 3 groups: low (G1), medium (G2), high (G3) CI and were submitted to indirect calorimetry. Height, weight, body surface area (BSA), fat free mass and fat mass measured by bioimpedance were evaluated. The highest values of weight, BSA an fat mass were obtained in G1, as well as values above 1.2 for the CI:RMR ratio, which indicates a probable underestimation of CI. The highest values of physical activity and RMR were observed in the G3 (with high caloric intake). In conclusion, this paper shows that a tendency towards underestimation of self-reported caloric intake exists among obese women and that the maintenance of weight in some patients can be due to their low level of physical activity.

Autosomal dominant familial neurohypophyseal diabetes insipidus caused by a novel mutation in arginine-vasopressin gene in a Brazilian family.

Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is a rare autosomal dominant disorder characterized by polyuria and polydipsia due to deficiency of arginine vasopressin (AVP). More than 50 mutations causing adFNDI have been already reported in the AVP gene. The aim of the present study is to analyze the AVP gene in four generations of one Brazilian kindred with adFNDI. The proband was a 31-year old female with huge hypotonic polyuria (10 L/day) dated from childhood. Molecular analysis included amplification of all exons and exon-intron regions of the AVP gene by PCR and direct sequencing. Sequencing analysis showed a novel point mutation in heterozygous: G88V (GGC>GTC). All affected patients presented the same mutation also in heterozygous, while it was absent in four normal members. We expand the repertoire of mutations in AVP describing the novel G88V mutation in one Brazilian kindred with adFNDI.

Estudo do gene LHX4 em pacientes com hipopituitarismo associado a neuro-hipófise ectópica / Molecular analysis of the LHX4 gene in hypopituitary patients with ectopic posterior pituitary lobe

O fenótipo dos pacientes com mutação do LHX4 em humanos é caracterizado por hipopituitarismo associado a neuro-hipófise ectópica. O objetivo do estudo é verificar a presença de mutações no LHX4 em 63 pacientes com o citado fenótipo. Os pacientes foram submetidos à avaliação hormonal e por imagem através de ressonância magnética. A análise molecular incluiu amplificação do gene por PCR, sequenciamento automático direto e uso de enzima de restrição. Encontramos deficiência hipofisária múltipla em 81 por cento dos pacientes. A neuro-hipófise foi localizada na eminência média em 35 por cento dos pacientes com haste visualizada e em 33 por cento dos pacientes sem haste visualizada. Identificamos 5 novas variações alélicas e três delas caracterizamos como polimorfismos. Concluímos que mutações no LHX4 são causas raras de hipopituitarismo / LHX4 gene mutation phenotype is characterized by hypopituitarism associated to ectopic posterior pituitary lobe (EPL). To investigate clinical characteristics and LHX4 mutations in 63 patients with this phenotype, evaluation of pituitary function, imaging and molecular analysis of LHX4 using PCR, automatic sequencing and restriction enzyme were performed. Combined pituitary hormone deficiency was found in 81 per cent of patients. The EPL was located at median eminence in 35 per cent of patients with visualized pituitary stalk and in 33 per cent of patients without visualized pituitary stalk. We found five new allelic variations, three of them characterized as new polymorphisms without clear relationship to the phenotype. LHX4 gene mutations remain rare causes of hypopituitarism associated to EPL...