The PROP1 2-Base Pair Deletion Is a Common Cause of Combined Pituitary Hormone Deficiency

Combined pituitary hormone deficiency (CPHD) has an incidence of approximately 1 in 8000 births. Although the proportion of familial CPHD cases is unknown, about 10% have an affected first degree relative. We have recently reported three mutations in the PROP1 gene that cause CPHD in human subjects. We report here the frequency of one of these mutations, a 301���302delAG deletion in exon 2 of PROP1, in 10 independently ascertained CPHD kindreds and 21 sporadic cases of CPHD from 8 different countries. Our results show that 55% (11 of 20) of PROP1 alleles have the 301���302delAG deletion in familial CPHD cases. Interestingly, although only 12% (5 of 42) of the PROP1 alleles of our 21 sporadic cases were 301���302delAG, the frequency of this allele (in 20 of 21 of the sporadic subjects given TRH stimulation tests) was 50% (3 of 6) and 0% (0 of 34) in the CPHD cases with pituitary and hypothalamic defects, respectively. Using whole genome radiation hybrid analysis, we localized the PROP1 gene to the distal end of chromosome 5q and identified a tightly linked polymorphic marker, D5S408, which can be used in segregation studies. Analysis of this marker in affected subjects with the 301���302delAG deletion suggests that rather than being inherited from a common founder, the 301���302delAG may be a recurring mutation.

PROP1 Gene Analysis in Portuguese Patients with Combined Pituitary Hormone Deficiency

OBJECTIVE: Mutations of the PROP1 gene lead to combined pituitary hormone deficiency (CPHD), which is characterized by a deficiency of GH, TSH, LH/FSH, PRL and, less frequently, ACTH. This study was undertaken to investigate the molecular defect in a cohort of patients with CPHD. DESIGN, PATIENTS AND MEASUREMENTS: A multicentric study involving 46 cases of CPHD (17 familial cases belonging to seven kindreds and 29 sporadic cases) selected on the basis of clinical and hormonal evidence of GH deficiency, central hypothyroidism and hypogonadotrophic hypogonadism, in the absence of an identified cause of hypopituitarism. Mutations of PROP1 were investigated by DNA sequencing. Clinical, hormonal and neuroradiological data were collected at each centre. RESULTS: PROP1 mutations were identified in all familial cases: five kindreds presented a c. 301-302delAG mutation, one kindred presented a c. 358C --> T (R120C) mutation and one presented a previously unreported initiation codon mutation, c. 2T --> C. Of the 29 sporadic cases, only two (6.9%) presented PROP1 germline mutations (c. 301-302delAG, in both). Phenotypic variability was observed among patients with the same mutations, particularly the presence and age of onset of hypocortisolism, the levels of PRL and the results of pituitary imaging. One patient presented a sellar mass that persisted into adulthood. CONCLUSIONS: This is the first report of a mutation in the initiation codon of the PROP1 gene and this further expands the spectrum of known mutations responsible for CPHD. The low mutation frequency observed in sporadic cases may be due to the involvement of other unidentified acquired or genetic causes.

Mutational Analysis of Portuguese Families with Multiple Endocrine Neoplasia Type 1 Reveals Large Germline Deletions

OBJECTIVE: To determine the spectrum of MEN1 mutations in Portuguese kindreds, and identify mutation-carriers. PATIENTS, DESIGN AND RESULTS: Six unrelated MEN1 families were studied for MEN1 gene mutations by single-strand conformational polymorphism (SSCP) and DNA sequence analysis of the coding region and exon-intron boundaries of the MEN1 gene. These methods identified 4 different heterozygous mutations in four families: two mutations are novel (mt 1539 delG and mt 655 ims 11 bp) and two have been previously observed (mt 735 del 46p and mt 1656 del C) all resulting in a premature stop codon. In the remaining two families, in whom no mutations or abnormal MEN1 transcripts were detected, segregation studies of the 5' intragenic marker D11S4946 and codon 418 polymorphism in exon 9 revealed two large germline deletions of the MEN1 gene. Southern blot and tumour loss of heterozygosity analysis confirmed and refined the limits of these deletions, which spanned the MEN1 gene at least from: exon 7 to the 3' untranslated region, in one family, and the 5' polymorphic site D11S4946 to exon 9 (obliterating the initiation codon), in the other family. Twenty-six mutant-gene carriers were identified, 6 of which were asymptomatic. CONCLUSIONS: These results emphasize the importance of the detection of MEN1 germline deletions in patients who do not have mutations of the coding region. Important clues indicating the presence of such deletions may be obtained by segregation studies using the intragenic polymorphisms D11S4946 and at codon 418. The detection of these mutations will help in the genetic counselling of clinical management of the MEN1 families in Portugal.

The PROP1 2-Base Pair Deletion Is a Common Cause of Combined Pituitary Hormone Deficiency

Combined pituitary hormone deficiency (CPHD) has an incidence of approximately 1 in 8000 births. Although the proportion of familial CPHD cases is unknown, about 10% have an affected first degree relative. We have recently reported three mutations in the PROP1 gene that cause CPHD in human subjects. We report here the frequency of one of these mutations, a 301-302delAG deletion in exon 2 of PROP1, in 10 independently ascertained CPHD kindreds and 21 sporadic cases of CPHD from 8 different countries. Our results show that 55% (11 of 20) of PROP1 alleles have the 301-302delAG deletion in familial CPHD cases. Interestingly, although only 12% (5 of 42) of the PROP1 alleles of our 21 sporadic cases were 301-302delAG, the frequency of this allele (in 20 of 21 of the sporadic subjects given TRH stimulation tests) was 50% (3 of 6) and 0% (0 of 34) in the CPHD cases with pituitary and hypothalamic defects, respectively. Using whole genome radiation hybrid analysis, we localized the PROP1 gene to the distal end of chromosome 5q and identified a tightly linked polymorphic marker, D5S408, which can be used in segregation studies. Analysis of this marker in affected subjects with the 301-302delAG deletion suggests that rather than being inherited from a common founder, the 301-302delAG may be a recurring mutation.

S��ndrome de Cushing e Gravidez

Descreve-se um caso de gravidez em doente com S��ndrome de Cushing por adenoma da supra-renal, tratado cirurgicamente ap��s o parto e com recupera����o total do eixo hipot��lamo-hip��fise-supra-renal. A gravidez teve evolu����o favor��vel, com parto pr��-termo e rec��m-nascido normal.

Obesidade. Experi��ncia de Dois Anos de Consulta

Os autores procederam ao estudo retrospectivo de 681 obesos, consultados num per��odo de dois anos. Vinte por cento eram crian��as e, dos adultos, 87% eram do sexo feminino. Vinte e quatro por cento dos adultos eram obesos desde a inf��ncia e 1/3 das mulheres relacionava o in��cio da obesidade com a gravidez. Foi encontrada uma elevada preval��ncia de Obesidade e Diabetes Mellitus nos antecedentes familiares. Sessenta e dois por cento dos adultos inclu��a-se no grupo de m��dio risco e, em 300 doentes, havia complica����es manifestas da obesidade. Na avalia����o final foi significativa a redu����o do grupo de alto risco.

Barnacle Allergy: Allergen Characterization and Cross-Reactivity with Mites

Background: Barnacles are a type of seafood with worldwide distribution and abundant along the shores of temperate seas. They are particularly appreciated and regularly consumed in Portugal as well as in Spain, France and South America, but barnacle allergy is a rare condition of which there is only one reference in the indexed literature. The molecular allergens and possible cross-reactivity phenomena implicated (namely with mites) have not been established. Objective: To demonstrate the IgE-mediated allergy to barnacle and to identify the proteins implicated as well as possible cross-reactivity phenomena with mites. Methods: We report the clinical and laboratory data of five patients with documented IgE-mediated allergy to barnacle. The diagnosis was based on a suggestive clinical history combined with positive skin prick tests (SPT) to barnacle ��� prick to prick method. Two barnacle extracts were prepared (raw and cooked barnacle) and sodium dodecylsulphate polyacrylamide gel electrophoresis (SDS-PAGE) and IgE-immunoblotting were performed. An immunoblotting inhibition assay with Dermatophagoides pteronyssinus was also done in order to evaluate cross-reactivity. Results: All patients had mite-related asthma and the allergic rhinoconjunctivitis; they all experienced mucocutaneous symptoms. All of them had positive SPT to barnacle, and the immunoblotting showed several allergenic fractions with a wide molecular weight range (19 ��� 94 kDa). The D. pteronyssinus extract inhibited several IgE-binding protein fractions in the barnacle extract. Conclusions: We describe five patients with IgE-mediated barnacle allergy. We also describe a group of IgEbinding+ proteins between 30 and 75 kDa as the allergenic fractions of this type of Crustacea. Cross-reactivity with D. pteronyssinus was demonstrated in two cases.

Chiropractic Manipulation: Reasons for Concern?

Chiropractic's popularity is rising among the general population. Moreover, few studies have been conducted to properly evaluate its safety. We report three cases of serious neurological adverse events in patients treated with chiropractic manipulation. The first case is a 41 years old woman who developed a vertebro-basilar stroke 48 h after cervical manipulation. The second case represents a 68 years old woman who presented a neuropraxic injury of both radial nerves after three sessions of spinal manipulation. The last case is a 34 years old man who developed a cervical epidural haematoma after a chiropractic treatment for neck pain. In all three cases there were criteria to consider a causality relation between the neurological adverse events and the chiropractic manipulation. The described serious adverse events promptly recommend the implementation of a risk alert system.

A Seguran��a dos Doentes - Indicador de Qualidade em Sa��de

Rev��-se a hist��ria dos erros e acidentes na presta����o dos Cuidados de Sa��de, nomeadamente as conclus��es do Harvard Medical Practice Study e da publica����o ���To Err is Human���, onde se conclu��a que s�� nos EUA morriam por ano entre 44.000 e 98.000 doentes por erros evit��veis no Sistema de Sa��de. Estes erros seriam dominantemente o resultado de erros de profissionais honestos e cumpridores operando em sistemas de desenho faltoso. Em termos gerais, estima-se que, em cada 100 internamentos hospitalares, 10 sejam eivados de um qualquer erro, erros que em 2/3 dos casos n��o provocam acidentes, em 1/3 causam danos ligeiros ou moderados e em cerca de 5% provocam danos irrevers��veis. Mais de metade seria, contudo, evit��vel e ocorrem em todas as ��reas da actividade, nomeadamente a prescri����o de medicamentos e os ambientes de alta tecnologia como os blocos operat��rios e as unidades intensivas. Rev��-se a taxonomia dos erros e dos acidentes e analisam-se as suas causas determinantes, normalmente multifactoriais. Os mecanismos dos acidentes em Sa��de englobam factores humanos e de equipa, factores organizacionais, factores de ambiente e o acaso. A complexidade das tarefas condiciona, igualmente a performance. Como conseguir um sistema de sa��de mais seguro? Certamente, colocando ��nfase mais nos sistemas do que nas pessoas e redesenhando sistemas, de forma a torn��-los ���error proof���, e investindo simultaneamente nos prestadores, nos processos de trabalho e nas organiza����es, mas tamb��m nos doentes e na sociedade. Em resumo, promovendo uma Cultura Organizacional de Seguran��a, centrada em equipas, ou seja, uma cultura ���just��� em que as pessoas n��o s��o punidas por cometer erros, s�� as viola����es de processo ser��o exemplarmente punidas, ainda uma cultura de reporte de eventos e uma cultura de aprendizagem em torno dos erros. As quest��es de seguran��a dizem respeito a todos ��� prestadores, sistema, doentes e sociedade e est��o intimamente ligadas �� Qualidade na presta����o de Cuidados de Sa��de.

Avalia����o e Tratamento do Doente com Acne - Parte I: Epidemiologia, Etiopatogenia, Cl��nica, Classifica����o, Impacto Psicossocial, Mitos e Realidades, Diagn��stico Diferencial e Estudos Complementares

O Portuguese Acne Advisory Board (PAAB), grupo de dermatologistas portugueses que, �� semelhan��a de grupos cong��neres internacionais, tem dedicado particular aten����o �� defini����o de linhas de orienta����o para o tratamento da acne, pretende que o presente documento constitua uma ferramenta ��til na abordagem dos doentes com esta patologia. Elaborou-se um dossier, para educa����o m��dica cont��nua, subdividido em 2 partes: Parte I ��� etiopatogenia e cl��nica; Parte II ��� abordagem terap��utica. Nesta Parte I, rev��em-se os principais aspectos da cl��nica e da fisiopatogenia da acne �� luz dos conhecimentos actuais. Discute-se a import��ncia do impacto psicol��gico e social desta entidade e analisam-se os principais mitos e realidades com ela relacionados. Descrevem-se, sucintamente, as patologias mais relevantes no diagn��stico diferencial das les��es de acne. Enumeram-se as indica����es para estudo hormonal, bem como os exames a efectuar nos doentes com esta patologia.

Avalia����o e Tratamento do Doente com Acne - Parte II: Tratamento T��pico, Sist��mico e Cir��rgico, Tratamento da Acne na Gr��vida, Algoritmo Terap��utico

O Portuguese Acne Advisory Board (PAAB), grupo de dermatologistas portugueses que, �� semelhan��a de grupos cong��neres internacionais, tem dedicado particular aten����o �� defini����o de linhas de orienta����o para o tratamento da acne, pretende que o presente documento constitua uma ferramenta ��til na abordagem dos doentes com esta patologia. Elaborou-se um dossier, para educa����o m��dica cont��nua, subdividido em 2 partes: Parte I ��� etiopatogenia e cl��nica; Parte II ��� abordagem terap��utica. Nesta Parte II discute-se a abordagem terap��utica ��� t��pica e sist��mica ��� em cada forma cl��nica de acne, dando particular ��nfase aos retin��ides e aos antimicrobianos, e salientam-se as estrat��gias a adoptar para limitar a crescente resist��ncia bacteriana aos antibi��ticos. Referem-se as indica����es espec��ficas para terap��utica hormonal e analisam-se as particularidades do tratamento da acne na gr��vida e lactante. Descrevem-se algumas t��cnicas para correc����o das cicatrizes da acne. Por ��ltimo, publica-se um algoritmo que pretende ilustrar a classifica����o da acne e definir, para cada tipo cl��nico, a abordagem terap��utica consensualmente recomendada.

Hemoperitoneu Como Forma de Apresenta����o de Carcinoma Hepatocelular. Contributo da Tomografia Computorizada Para o Diagn��stico

Nos pa��ses europeus, o hemoperitoneu por ruptura de carcinoma hepatocelular (HCC) �� muito raro. Apresentam-se dois casos cl��nicos de hemoperitoneu secund��rio a ruptura espont��nea de carcinoma hepatocelular, em que a Tomografia Computorizada (TC) abdominal foi de primordial import��ncia para o diagn��stico. A prop��sito faz-se revis��o da literatura sobre os aspectos mais relevantes desta patologia.

As Perturba����es Emocionais: Ansiedade e Depress��o na Crian��a e no Adolescente.

A Perturba����o da Ansiedade e a Perturba����o Depressiva constituem entidades cl��nicas de elevada preval��ncia na inf��ncia e na adolesc��ncia, e podem ser precursoras de psicopatologia na idade adulta. Por ambos os motivos, o seu diagn��stico precoce e interven����o atempada tornam-se essenciais, assim como a detec����o de eventuais factores de risco que as possam promover. Os Cuidados de Sa��de Prim��rios assumem, neste contexto, uma fun����o primordial na triagem de casos, assim como na interven����o e eventual referencia����o para os servi��os de Pedopsiquiatria. Neste artigo, abordamos, abreviadamente, aspectos referentes aos factores de risco, preval��ncia, diagn��stico, interven����o cl��nica e progn��stico para as Perturba����es da Ansiedade e Depressiva.

Desvios Axiais dos Membros Inferiores

As deformidades axiais dos membros inferiores constituem um dos principais motivos de consulta na ��rea de Ortopedia Infantil. Esta situa����o deve-se, por um lado, ao facto de haver uma grande percentagem de crian��as (cerca de 20%) que apresentam uma deformidade fisiol��gica durante o desenvolvimento e, por outro, �� ��tradi����o�� existente, segundo a qual estes desvios necessitam de um tratamento, usualmente por cal��ado ortop��dico. Torna-se, por isso, imperioso destrin��ar o fisiol��gico do patol��gico, diferenciar as diferentes etiologias e corrigi-las precocemente medicamente e, ainda, determinar quando uma deformidade �� pass��vel de correc����o espont��nea ou quando exige uma terap��utica cir��rgica.