RESUMO
Hypertrophic pulmonary osteoarthropathy (often referred to as Marie-Bamberger syndrome) occurs in 1â-â5â% of all patients with non-small cell lung cancer (NSCLC) as a paraneoplastic syndrome. The complete syndrome is characterised by clubbing of the fingers and toes (often without hypoxia) and pain in the joints and tubular bones. On the basis of four clinical cases, this article shows that this syndrome can precede tumour-specific symptoms and that it is still often overlooked by physicians. An early suspicion of this syndrome is of great clinical value because it can lead to a diagnosis of NSCLC at an earlier tumour stage. In addition to the case reports, the current literature on hypertrophic pulmonary osteoarthropathy is reviewed in this article, with special reference to pathogenetic concepts und to therapeutic options.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Osteoartropatia Hipertrófica Secundária/diagnóstico , Osteoartropatia Hipertrófica Secundária/etiologia , Síndromes Paraneoplásicas/diagnóstico , Síndromes Paraneoplásicas/etiologia , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adulto , Idoso , Broncoscopia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Terapia Combinada , Progressão da Doença , Diagnóstico Precoce , Feminino , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Osteoartropatia Hipertrófica Secundária/terapia , Síndromes Paraneoplásicas/terapia , Prognóstico , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Xenobiotic mediated cellular injury is thought to play a major role in the pathogenesis of pancreatic diseases. Genetic variations that reduce the expression or activity of detoxifying phase II biotransformation enzymes such as the UDP-glucuronosyltransferases might be important in this respect. Recently, a UGT1A7 low detoxification activity allele, UGT1A7*3, has been linked to pancreatic cancer and alcoholic chronic pancreatitis. OBJECTIVE: To investigate whether UGT1A7 polymorphisms contribute to the risk of pancreatitis and pancreatic cancer. METHODS: Genetic polymorphisms in the UGT1A7 gene were assessed in a large cohort of patients with different types of pancreatitis and pancreatic cancer originating from the Czech Republic (n = 93), Germany (n = 638), Netherlands (n = 136), and Switzerland (n = 106), and in healthy (n = 1409) and alcoholic (n = 123) controls from the same populations. Polymorphisms were determined by melting curve analysis using fluorescence resonance energy transfer probes. In addition, 229 Dutch subjects were analysed by restriction fragment length polymorphism. RESULTS: The frequencies of UGT1A7 genotypes did not differ between patients with acute or chronic pancreatitis or pancreatic adenocarcinoma and alcoholic and healthy controls. CONCLUSIONS: The data suggest that, in contrast to earlier studies, UGT1A7 polymorphisms do not predispose patients to the development of pancreatic cancer and pancreatitis.
Assuntos
Predisposição Genética para Doença , Glucuronosiltransferase/genética , Pancreatopatias/enzimologia , Polimorfismo Genético , Adenocarcinoma/metabolismo , Adulto , Estudos de Coortes , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite/enzimologia , XenobióticosRESUMO
BACKGROUND: Vasoactive intestinal peptide (VIP) can be produced by mature neurogenic tumors. Pathologically elevated VIP plasma levels cause secretory diarrhea with excessive loss of water and electrolytes. Despite the clinical severity diagnosis of a VIP-secreting tumor is often delayed and subsequently its extirpation as the mainstay of therapy. PATIENTS: We report on two patients with ganglioneuroblastoma and secretory diarrhea. We contrast the case of a 13-month-old boy with advanced symptoms of secretory diarrhea, high VIP plasma levels, and late diagnosis to the case of a 14-month-old boy with mild secretory diarrhea and normal VIP plasma levels but positive proof of VIP in tumor tissue. Reviewing the literature we found 57 cases of pediatric VIP-secreting tumors. RESULTS: The clinical situation is characterized by the typical symptoms of secretory diarrhea with hypokalemia and metabolic acidosis. Histopathology predominantly reveals ganglioneuroblastoma or ganglioneuroma. The symptoms mostly stop after complete resection of the tumor whereas lack of resection is associated with elevated mortality rates. CONCLUSIONS: In case of prolonged therapy-resistant secretory diarrhea the existence of a VIP-secreting tumor should be considered. Diagnostic work-up should include the assessment of VIP plasma levels, catecholamines in urine, and appropriate imaging techniques in order to rule out or confirm the possibility of a VIP producing tumor.
Assuntos
Diarreia Infantil/etiologia , Ganglioneuroblastoma/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Peptídeo Intestinal Vasoativo/sangue , Vipoma/diagnóstico , Diagnóstico Diferencial , Diarreia Infantil/diagnóstico , Seguimentos , Ganglioneuroblastoma/sangue , Ganglioneuroblastoma/metabolismo , Ganglioneuroblastoma/patologia , Ganglioneuroblastoma/fisiopatologia , Ganglioneuroblastoma/cirurgia , Humanos , Imuno-Histoquímica , Lactente , Masculino , Pâncreas/patologia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/fisiopatologia , Neoplasias Pancreáticas/cirurgia , Fatores de Tempo , Resultado do Tratamento , Vipoma/sangue , Vipoma/metabolismo , Vipoma/patologia , Vipoma/fisiopatologia , Vipoma/cirurgiaAssuntos
Citosina/metabolismo , Guanina/metabolismo , Histidina/genética , Queratinas/genética , Hepatopatias/genética , Mutação de Sentido Incorreto/genética , Tirosina/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Doença Crônica , Hepatite Autoimune/genética , Hepatite Viral Humana/genética , Humanos , Queratina-8 , Cirrose Hepática/genética , Pessoa de Meia-IdadeAssuntos
Síndrome de Alagille/diagnóstico , Síndrome de Alagille/genética , Diagnóstico Pré-Natal , Aborto Induzido , Adulto , Síndrome de Alagille/embriologia , Proteínas de Ligação ao Cálcio , Evolução Fatal , Feminino , Humanos , Lactente , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Proteínas de Membrana , Mutação , Gravidez , Proteínas , Proteínas Serrate-JaggedRESUMO
As case report we describe a rare cause of intractable "gastroenteritis" detected by ultrasonography. The 14 months-old boy was admitted to hospital because of intensive dehydration due to massive vomiting and diarrhoea. A salmonella enteritis with intractable hyponatraemia and hypokalaemia was thought to be the cause. After a dramatic relapse during oral treatment measures, further extensive laboratory tests finally disclosed an elevated serum level of vasoactive intestinal polypeptide ("VIP"). The VIP secreting tumor ("VIPoma") was detected ultrasonographically in a retroperitoneal localization mediocaudally of the right kidney. Diffuse distinct calcifications and an increased perfusion could be demonstrated. Intraspinal tumour spread was excluded by magnetic resonance imaging. After complete surgical removal of the tumour the clinical symptomatology normalized promptly and permanently. A VIP-excreting ganglioneuroblastoma with low grade growth fraction ("VIPoma") was diagnosed histologically. Common gastroenteritis in childhood represents no indication for ultrasound. In cases of unclear and therapy-resistant symptomatology, however, diagnostic work-up should include ultrasonography to search for retroperitoneal or pancreatic VIP-excreting tumours.
Assuntos
Gastroenterite/etiologia , Neoplasias Pancreáticas/diagnóstico por imagem , Vipoma/diagnóstico por imagem , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/cirurgia , Ultrassonografia , Peptídeo Intestinal Vasoativo/análise , Vipoma/diagnóstico , Vipoma/metabolismo , Vipoma/cirurgiaRESUMO
BACKGROUND: An association between alpha1-antitrypsin deficiency and chronic pancreatitis (CP) has been reported in several case reports and two systematic studies. However, conflicting results have been shown in other studies of patients with CP. All previous studies were performed by phenotyping or by measurement of serum concentrations of alpha1-antitrypsin. The aim of this study was to investigate the relationship between alpha1-antitrypsin deficiency and CP by genetic analysis. METHODS: Ninety-six unrelated children and adolescents with idiopathic or hereditary CP and 185 healthy controls were enrolled. DNA was extracted from peripheral blood leukocytes and the exons 5 and 7 of the alpha1-antitrypsin gene were amplified by polymerase chain reaction using mutagenic forward primers introducing a Taq I restriction site. Genotyping of the S allele and the Z allele was performed by restriction fragment length polymorphism analysis using Taq I. RESULTS: Seven out of 96 patients (7.3%) with CP were heterozygous for an alpha1-antitrypsin deficiency allele (4 for the S allele and 3 for the Z allele). No patient was homozygous or compound heterozygous for these alleles. Twenty out of 185 control individuals (10.8%) were heterozygous for the S or Z allele (PiS: 12 controls; PiZ: 8 controls). No significant differences were found between the allele frequency in patients and the control individuals (P > 0.1). CONCLUSIONS: Alpha1-antitrypsin deficiency is not related to the pathogenesis of idiopathic or hereditary CP.
Assuntos
Mutação , Pancreatite/genética , Deficiência de alfa 1-Antitripsina/genética , alfa 1-Antitripsina/genética , Adolescente , Adulto , Sequência de Bases , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Doença Crônica , Feminino , Genótipo , Humanos , Masculino , Dados de Sequência Molecular , Pancreatite/diagnóstico , Reação em Cadeia da Polimerase , Probabilidade , Prognóstico , Estudos Prospectivos , Valores de Referência , Sensibilidade e Especificidade , alfa 1-Antitripsina/análise , Deficiência de alfa 1-Antitripsina/diagnósticoRESUMO
Chronic pancreatitis (CP) is a continuing or relapsing inflammatory disease of the pancreas. In approximately one-third of all cases, no aetiological factor can be found, and these patients are classified as having idiopathic disease. Pathophysiologically, autodigestion and inflammation may be caused by either increased proteolytic activity or decreased protease inhibition. Several studies have demonstrated mutations in the cationic trypsinogen gene (PRSS1) in patients with hereditary or idiopathic CP. It is thought that these mutations result in increased trypsin activity within the pancreatic parenchyma. Most patients with idiopathic or hereditary CP, however, do not have mutations in PRSS1 (ref. 4). Here we analysed 96 unrelated children and adolescents with CP for mutations in the gene encoding the serine protease inhibitor, Kazal type 1 (SPINK1), a pancreatic trypsin inhibitor. We found mutations in 23% of the patients. In 18 patients, 6 of whom were homozygous, we detected a missense mutation of codon 34 (N34S). We also found four other sequence variants. Our results indicate that mutations in SPINK1 are associated with chronic pancreatitis.
Assuntos
Mutação/genética , Pancreatite/genética , Inibidor da Tripsina Pancreática de Kazal/genética , Adolescente , Criança , Cromossomos Humanos Par 5/genética , Doença Crônica , Análise Mutacional de DNA , Éxons/genética , Feminino , Genótipo , Haplótipos/genética , Humanos , Íntrons/genética , Desequilíbrio de Ligação/genética , Escore Lod , Masculino , Modelos Biológicos , Mutação de Sentido Incorreto/genética , Polimorfismo Genético/genéticaRESUMO
PURPOSE: To present the predominantly ultrasonographic (initial and follow-up) imaging in a disease that is rare among the Central European paediatric population--and to evaluate the role of ultrasound for initial staging and follow-up under antihelmintic therapy. METHOD: The imaging documents as well as the clinical record of a 10-year old Armenian girl with systemic hydatid disease (cystic echinococcosis) were analysed retrospectively. RESULTS: By means of ultrasound, the complete initial systemic spread of the disease with at least 11 cysts within the liver, 1 cyst in the left kidney, 1 peri-/2 intracardiac cysts, and 1 cyst in the dorsal musculature was detected. Repeated sonographic examinations allowed the estimation of successful medical treatment by the following criteria: size reduction of all cysts with changing internal structures from an initially echo-free to an increasingly homogeneous echodense character; no developing new cysts. In addition, CT and MRI enabled a more complete demonstration of especially the intra- and pericardiac lesions (preoperatively) and the exclusion of further intracranial cysts. CONCLUSION: In paediatric hydatid disease, ultrasonography yields important information not only with regard to the initial staging, but also to the antihelmintic therapeutic effects and thus helps to determine when to discontinue medical treatment.
Assuntos
Equinococose Hepática/diagnóstico por imagem , Equinococose/diagnóstico por imagem , Equinococose/fisiopatologia , Rim/diagnóstico por imagem , Fígado/diagnóstico por imagem , Músculo Esquelético/diagnóstico por imagem , Anti-Helmínticos/uso terapêutico , Armênia/etnologia , Criança , Equinococose/tratamento farmacológico , Ecocardiografia , Feminino , Alemanha , Humanos , Rim/parasitologia , Fígado/parasitologia , Imageamento por Ressonância Magnética , Músculo Esquelético/parasitologia , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND & AIMS: In pancreatitis, a key role has been attributed to the inappropriate conversion of trypsinogen to trypsin. Recently, two mutations of the cationic trypsinogen gene were found in families with hereditary pancreatitis. This study was conducted to determine the spectrum and frequency of cationic trypsinogen mutations in unrelated patients with idiopathic or hereditary chronic pancreatitis (CP). METHODS: DNA samples from 44 unrelated children and adolescents with CP (30 patients with idiopathic CP and 14 with hereditary CP) and from 56 family members were investigated. The cationic trypsinogen gene was screened for mutations by single-strand conformation polymorphism analysis and DNA sequencing. RESULTS: A mutation in the cationic trypsinogen gene was detected in 5 patients: in 2 patients with a family history of CP and in 3 patients with idiopathic CP. In 1 patient the formerly described R122H mutation was detected. In 4 patients a hitherto unknown mutation was found at the signal peptide cleavage site leading to an alanine to valine exchange in codon 16. The mutations were inherited in all cases. In 95 unrelated control individuals the A16V mutation was not found. CONCLUSIONS: Heterozygosity for the A16V mutation is strongly associated with CP. These results indicate that a significant percentage of patients with idiopathic CP may have a genetic basis for their disorder; therefore, genetic testing should be included in the diagnostic evaluation of these patients.
Assuntos
Mutação/fisiologia , Pancreatite/genética , Sinais Direcionadores de Proteínas/genética , Tripsinogênio/genética , Adolescente , Sequência de Aminoácidos/genética , Cátions , Criança , Pré-Escolar , Doença Crônica , Feminino , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita SimplesRESUMO
BACKGROUND: The study aimed to assess the effect of pre- and postnatal tobacco smoke exposure on specific sensitization to food allergens and inhalant allergens during the first 3 years of life. METHODS: A total of 342 children of a prospective and observational birth cohort study on atopy (MAS) were included on the basis of a complete follow-up of specific IgE measurements at the ages of 1, 2, and 3 years with available questionnaire information about the parental smoking habit at birth, 18 months, and 3 years of age. Study children were grouped into four exposure categories representing in utero and postnatal environmental tobacco smoke (ETS) exposure, and according to the number of cigarettes smoked by the parents. The effect on the development of allergic sensitization to food, outdoor, and indoor allergens by 3 years of age was determined by multiple logistic regression analyses. RESULTS: At the age of 3, children who were pre- and postnatally exposed to tobacco smoke had a significantly higher risk of sensitization to food allergens (odds ratio: 2.3, 95% C.I.: 1.1-4.6) than unexposed children. Children who were only postnatally exposed by a smoking mother also had a 2.2 times higher risk (95% C.I.: 0.9-5.9) of sensitization than unexposed children. These two categories (pre- and/or postnatal exposure) contribute to the significant overall effect of the tobacco smoke exposure (P< or =0.02). No significant association between tobacco smoke exposure and specific sensitization to inhalant allergens was observed. The determining risk factors for this type of sensitization were atopic family history and mite- and cat-allergen exposure levels. CONCLUSIONS: During the first 3 years of life, both prenatal and postnatal tobacco smoke exposure has an adjuvant effect on allergic sensitization which seems to be restricted to allergens to which children are mainly exposed, in combination with the peak of the ETS exposure around the first birthday.
Assuntos
Hipersensibilidade Alimentar/imunologia , Efeitos Tardios da Exposição Pré-Natal , Hipersensibilidade Respiratória/imunologia , Poluição por Fumaça de Tabaco/efeitos adversos , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Imunoglobulina E/sangue , Lactente , Recém-Nascido , Masculino , Razão de Chances , Gravidez , Estudos Prospectivos , Fatores de RiscoRESUMO
AIM: of our study was to investigate the effect of pre- and postnatal passive tobacco smoke exposure on the incidence of allergic sensitization. PATIENTS AND METHODS: Specific sensitization to food, outdoor and indoor allergens was determined in 342 children at the age of 1, 2 and 3 years. Parents were asked about their smoking habit at the birth of their children, at 18 months and 3 years of age. RESULTS: Multivariate regression analysis indicated, that during the first 3 years of life, pre- and postnatally exposed children had a significantly higher risk for sensitization to food allergens compared to children never exposed to tobacco smoke (OR 2.2, 95% CI 1.1-4.2; P = 0.02). With respect to inhalant allergens no significant influence of tobacco smoke exposure on specific sensitization could be demonstrated. CONCLUSION: During early childhood both pre- and postnatal tobacco smoke exposure has an adjuvant effect on allergic sensitization to food allergens.
Assuntos
Feto/efeitos dos fármacos , Hipersensibilidade/etiologia , Troca Materno-Fetal , Poluição por Fumaça de Tabaco/efeitos adversos , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Gravidez , Análise de RegressãoRESUMO
The aim of our study was to investigate the effect of platelet-activating factor on human bronchial ciliary beat frequency (CBF) ex vivo. Brush biopsies were obtained from eight children (mean age 6.6 years) who underwent bronchoscopy for clinical reasons (i.e., foreign body aspiration, chronic cough, stridor). Immediate measurement of CBF by phase-contrast microscopy and photoelectric technique was performed before further treatment, and then on three subsamples: after adding platelet-activating factor (PAF) (10(-5) M); after adding the inhibitor WEB 2086 (10(-4) M); and after adding both PAF and WEB 2086. Addition of 10(-5) M PAF reduced mean CBF by 2.1 Hz to 9.2 Hz (p < 0.05). The inhibitory effect of PAF was completely reversed by the addition of the PAF-inhibitor WEB 2086, whereas WEB 2086 alone did not significantly influence CBF. Optimum PAF concentration had been determined in previous dose-response experiments. Our data indicates that PAF involved in airway inflammation contributes to a decrease in mucociliary clearance in humans.
Assuntos
Brônquios/citologia , Cílios/fisiologia , Células Epiteliais/fisiologia , Fator de Ativação de Plaquetas/farmacologia , Adolescente , Criança , Pré-Escolar , Cílios/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Lactente , Fatores de TempoAssuntos
Sobrevivência de Enxerto , Rim/fisiopatologia , Hepatopatias/cirurgia , Transplante de Fígado/fisiologia , Doenças Metabólicas/cirurgia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Testes de Função Renal , Testes de Função Hepática , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de SobrevidaAssuntos
Hormônio Adrenocorticotrópico/deficiência , Cor de Cabelo/genética , Obesidade/genética , Polimorfismo Genético , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/fisiologia , Pré-Escolar , Códon/genética , Éxons , Feminino , Humanos , Masculino , Fenótipo , Pró-Opiomelanocortina/deficiência , Deleção de SequênciaRESUMO
The main indication for orthotopic liver transplantation (OLTx) in Wilson's disease (WD) is severe hepatic decompensation. Our 15-year-old patient is the second case to date in whom OLTx was performed because of neurologic manifestations resulting from WD. His initial condition involving recurrent headaches, tremor, and athetoid hand movements progressively deteriorated during therapy with D-penicillamine, zinc sulfate, and trientine until he was severely dysarthric, unable to walk, and bedridden. After OLTx, his neurologic condition became almost normal.
Assuntos
Encefalopatias/terapia , Degeneração Hepatolenticular/terapia , Transplante de Fígado , Adolescente , Encefalopatias/complicações , Cobre/metabolismo , Degeneração Hepatolenticular/complicações , Degeneração Hepatolenticular/metabolismo , Humanos , MasculinoRESUMO
Hepatic associated metabolic disorders represent 5% of the indications for orthotopic liver transplantation (OLTX) according to the European Liver Transplant Registry. We studied the outcome of this group at our institution after OLTX and combined liver/kidney transplantation. Between September 1988 and January 1997, 837 OLTXs were performed in 735 patients. Patient survival and graft function at 1 yr were 91.3 and 86%, respectively. Thirty-nine OLTXs were performed in 38 patients (15 female/23 male, median age +/- SD: 35 +/- 14 yr, range 4-60 yr) due to liver associated metabolic disorders (4.7%). Indications included Wilson's disease (n = 14), alpha-1-anti-trypsin-deficiency (n = 7), hemochromatosis (n = 4), erythropoetic protoporphyria (n = 4), cystic fibrosis (n = 2), Crigler-Najjar syndrome type I (n = 1), glycogenosis type I (n = 1), ornithine-transcarbomylase-deficiency (n = 1). In addition 4 patients suffering from primary hyperoxaluria type I received combined liver/kidney grafts. Survival rate the 1 yr after OLTX and combined OLTX/NTX was 91.8%. Twenty patients received cyclosporin A (55%) and 17 patients tacrolimus (45%) as primary immunosuppression. The mean follow-up was 28.6 months (range 4-73 months). Two patients with hemochromatosis died 1 and 3 months after OLTX, respectively, from Aspergillus sepsis followed by multiorgan-failure. One patient died of malignant lymphoma 5 months after transplantation. One patient required retransplantation 2 months after OLTX following arterial thrombosis and ischemic type biliary lesion. One year after OLTX, all patients demonstrated good graft function, liver grafts (ALT 17.9 +/- 13.6 IU/L, bilirubin 0.8 +/- 0.3.mg/dl, thromboplastin time 94 +/- 15%), and combined liver/kidney grafts (creatinine 2.4 +/- 1.4 mg/dl). OLTX, respectively combined OLTX/NTX, represent a successful therapy for hepatic associated metabolic disorders. Survival rates and graft function are similar to those in liver graft recipients for established indications at our institution. OLTX seems to be an excellent treatment for hepatic based therapy resistant neurological disorders.
Assuntos
Cirrose Hepática/cirurgia , Falência Hepática Aguda/cirurgia , Transplante de Fígado , Doenças Metabólicas/cirurgia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Cirrose Hepática/etiologia , Falência Hepática Aguda/etiologia , Masculino , Doenças Metabólicas/complicações , Doenças Metabólicas/diagnóstico , Pessoa de Meia-Idade , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Sequential cleavage of the precursor protein pre-pro-opiomelanocortin (POMC) generates the melanocortin peptides adrenocorticotrophin (ACTH), melanocyte-stimulating hormones (MSH) alpha, beta and gamma as well as the opioid-receptor ligand beta-endorphin. While a few cases of isolated ACTH deficiency have been reported (OMIM 201400), an inherited POMC defect has not been described so far. Recent studies in animal models elucidated a central role of alpha-MSH in the regulation of food intake by activation of the brain melanocortin-4-receptor (MC4-R; refs 3-5) and the linkage of human obesity to chromosome 2 in close proximity to the POMC locus, led to the proposal of an association of POMC with human obesity. The dual role of alpha-MSH in regulating food intake and influencing hair pigmentation predicts that the phenotype associated with a defect in POMC function would include obesity, alteration in pigmentation and ACTH deficiency. The observation of these symptoms in two probands prompted us to search for mutations within their POMC genes. Patient 1 was found to be a compound heterozygote for two mutations in exon 3 (G7013T, C7133delta) which interfere with appropriate synthesis of ACTH and alpha-MSH. Patient 2 was homozygous for a mutation in exon 2 (C3804A) which abolishes POMC translation. These findings represent the first examples of a genetic defect within the POMC gene and define a new monogenic endocrine disorder resulting in early-onset obesity, adrenal insufficiency and red hair pigmentation.