RESUMO
CONTEXT: Steroid 21-hydroxylase deficiency is the most common enzymatic defect causing congenital adrenal hyperplasia with good genotype/phenotype relationships for common mutations. To determine the severity of rare mutations is essential for genetic counseling and better understanding of the structure-function of the cytochrome P450c21. OBJECTIVE: The p.H62L mutation was the most frequent of 60 new mutations detected in 2900 steroid 21-hydroxylase deficiency patients, either isolated or associated on the same allele with a mild mutation (p.P453S, p.P30L, or partial promoter). Because phenotypes seemed to differ between patients with isolated or associated p.H62L, a detailed phenotype description and functional studies were performed. RESULTS: Regarding phenotype, patients with isolated p.H62L had a nonclassical form, whereas patients with the association p.H62L + mild mutation had a simple virilizing form. Functional studies showed that p.H62L reduced the conversion of the two substrates, progesterone and 17-hydroxyprogesterone, in the same way as the mild p.P453S; the association p.H62L + p.P453S decreased enzymatic activity more strongly while conserving residual activity at a level intermediate between p.P453S and p.I172N. This suggested that p.H62L was a mild mutation, whereas a synergistic effect occurred when it was associated. Analysis of p.H62L in a three-dimensional model structure of the CYP21 protein explained the observed in vitro effects, the H62 being located in a domain implied in membrane anchoring. CONCLUSION: According to phenotype and functional studies, p.H62L is a mild mutation, responsible for a more severe phenotype when associated with another mild mutation. These data are important for patient management and genetic counseling.
Assuntos
Hiperplasia Suprarrenal Congênita/genética , Mutação , Esteroide 21-Hidroxilase/genética , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Dados de Sequência Molecular , Esteroide 21-Hidroxilase/químicaRESUMO
UNLABELLED: Neurofibromatosis 1 (NF1) is a frequent genetic disease. Diagnostic criterias were established in 1988. The patients can exhibit various and unpredictable complications. OBJECTIVES: To check the efficiency of a coordinated follow-up in specialized multidisciplinary centers providing a higher quality of management and to have a better knowledge of the complications including their true frequencies. POPULATION AND METHODS: We report a serie of 100 NF1 children who were followed-up during 4 years in a specialized center at the Tours University Hospital. Three hospital check-up at 2-5, 6-7, 14-15 years of age were performed as well as an annual physical examination. RESULTS: In our serie, the mean age was 7.8 years old with a sex ratio of 1. The mean age at diagnosis was 3.8 years old and the main diagnosis criteria were the café-au-lait spots and the family history for 80% of the patients. The optic nerve glioma has a low frequency of 5%. Learning disabilities clearly represent the most frequent complication (46% of the patients). CONCLUSION: An early detection of these difficulties is a priority for the appropriate management of these children.
Assuntos
Neurofibromatose 1/complicações , Neurofibromatose 1/diagnóstico , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Deficiências da Aprendizagem/etiologia , MasculinoRESUMO
We analyzed the final height of 146 short children with either nonacquired GH deficiency or idiopathic short stature. Our purpose was 1) to assess growth according to the pituitary magnetic resonance imaging findings in the 63 GH-treated children with GH deficiency and 2) to compare the growth of the GH-deficient patients with normal magnetic resonance imaging (n = 48) to that of 32 treated and 51 untreated children with idiopathic short stature (GH peak to provocative tests >10 microg/liter). The mean GH dose was 0.44 IU/kg.wk (0.15 mg/kg.wk), given for a mean duration of 4.6 yr. Among the GH-deficient children, 15 had hypothalamic-pituitary abnormalities (stalk agenesis), all with total GH deficiency (GH peak <5 microg/liter). They were significantly shorter and younger at the time of diagnosis than those with normal magnetic resonance imaging, had better catch-up growth (+2.7 +/- 0.9 vs. +1.3 +/- 0.8 SD score; P < 0.01), and reached greater final height (-1.1 +/- 1.0 vs. -1.7 +/- 1.0 SD score; P < 0.05). Among patients with normal magnetic resonance imaging, there was no difference in catch-up growth and final height between partial and total GH deficiencies. GH-deficient subjects with normal magnetic resonance imaging and treated and untreated patients with idiopathic short stature had comparable auxological characteristics, age at evaluation, and target height. Although they had different catch-up growth (+1.3 +/- 0.8, +0.9 +/- 0.6, and +0.7 +/- 0.9 SD score, respectively; P < 0.01, by ANOVA), these patients reached a similar final height (-1.7 +/- 1.0, -2.1 +/- 0.8, and -2.1 +/- 1.0 SD score, respectively; P = 0.13). Pituitary magnetic resonance imaging findings show the heterogeneity within the group of nonacquired GH deficiency and help to predict the response to GH treatment in these patients. The similarities in growth between the GH-deficient children with normal magnetic resonance imaging and those with idiopathic short stature suggest that the short stature in the former subjects is at least partly due to factors other than GH deficiency.
Assuntos
Estatura , Hormônio do Crescimento/uso terapêutico , Crescimento , Hormônio do Crescimento Humano/deficiência , Hipófise/anatomia & histologia , Adolescente , Criança , Feminino , Hormônio do Crescimento Humano/metabolismo , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
The hereditary syndrome of unresponsiveness to ACTH is a rare autosomal recessive disorder characterized by low levels of serum cortisol and high levels of plasma ACTH. There is no cortisol response to exogenous ACTH. Recent cloning of the human ACTH receptor gene has enabled us to study this gene in patients with glucocorticoid deficiency. By using the PCR to amplify the coding sequence of the ACTH receptor gene, we identified three mutations in two unrelated patients. One mutation present in homozygous form converted the negatively charged Asp107, located in the third transmembrane domain, to an uncharged Asn residue. The second patient was a compound heterozygote: the paternal allele contained a one-nucleotide insertion leading to a stop codon within the third extracellular loop, and the maternal allele contained a point mutation converting Cys251 to Phe, also in the third extracellular loop. Normal and mutant ACTH receptor genes were expressed in the M3 cell line, and intracellular cAMP production in response to ACTH was measured. For the mutant receptors, no response to physiological ACTH concentrations was detected, suggesting an impaired binding of ACTH to the receptors and/or an altered coupling to the adenylate cyclase effector.
Assuntos
Glucocorticoides/deficiência , Mutação Puntual , Receptores da Corticotropina/biossíntese , Receptores da Corticotropina/genética , Hormônio Adrenocorticotrópico/sangue , Sequência de Aminoácidos , Animais , Ácido Aspártico , Sequência de Bases , Células CHO , Linhagem Celular , Pré-Escolar , Cricetinae , DNA/sangue , Primers do DNA , Feminino , Genes Recessivos , Homozigoto , Humanos , Hidrocortisona/sangue , Linfócitos , Masculino , Melanoma Experimental , Camundongos , Dados de Sequência Molecular , Linhagem , Reação em Cadeia da Polimerase , Estrutura Secundária de Proteína , Receptores da Corticotropina/fisiologia , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/metabolismo , Síndrome , TransfecçãoRESUMO
The aim of this study was to analyse the outcome of membranous ventricular septal defects (VSD) with respect to the echocardiographic data obtained during the first year of life. This retrospective series included patients born between January 1st 1986 and December 31st 1995, in the Indre et Loire department, with membranous ventricular septal defects alone or associated with minor abnormalities. The initial echocardiography, an echocardiography performed 2 to 6 months later, one a year later and the final echocardiography were compared. Three groups of VSD were constituted according to their diameter: group I (< or = 3 mm), group II (3-6 mm), and group III (> 6 mm). Depending on the outcome, the patients were classified as spontaneous closure (group A), surgical closure (group B) or persistent VSD (group C). The population comprised 84 children. There were 6 spontaneous deaths, three of which were unexplained, and 7 children were lost to follow-up. After the initial echocardiography, the VSD were classified as group I (38%), group II (26.2%) and group III (35.7%). After the second echocardiogram, 24 VSD changed group (31.5%), by increase (N = 10) or decrease (N = 14) in diameter. Aneurysms of the membranous septum were observed during the first two echocardiographies in 31.2% and 79.3% of VSDs of group I, 31.8% and 70% of VSDs of group II and 6.6% and 3.3% of VSDs of group III (p < 0.01). The average follow-up was 3.1 years (range 1 month-10 years). In group A (N = 22), the mean age of closure of the VSD was 26 months (3 months-7 years). In group B (N = 28), surgery was undertaken at an average age of 10 months (range 3 months-5 years). In group C (N = 21), the VSDs were classified as group I (N = 19) or group II (N = 2) at the last echocardiography. The frequency of aneurysms of the membranous septum in groups A, B and C were respectively 100%, 7.1% and 66.6% (p < 0.01). At the second echocardiographic examination, a significant relationship (p < 0.001) was observed between the diameter of the VSDs and their outcome. The VSDs of group A were associated with aneurysms of the membranous septum more often than those of group C (p < 0.005). The authors conclude that surgery is required in about one third of membranous VSD. At medium term, the others either close spontaneously or become smaller in comparable numbers. The outcome is directly related to the diameter of the VSD and the development of an aneurysm of the membranous septum. During the first 6 months, the dimensions of membranous VSDs change in about 30% of cases with an increase in frequency of aneurysms of the membranous septum.
Assuntos
Cardiopatias Congênitas/diagnóstico por imagem , Comunicação Interventricular/diagnóstico por imagem , Feminino , Cardiopatias Congênitas/mortalidade , Cardiopatias Congênitas/cirurgia , Comunicação Interventricular/mortalidade , Comunicação Interventricular/cirurgia , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Resultado do Tratamento , UltrassonografiaRESUMO
The case of a girl who presented with gastrointestinal upsets with nausea, vomiting and occasional hypoglycaemic attacks during childhood is reported. At about 5 years of age generalised muscular weakness with severe amyotrophy, cardiomegaly with a cardiothoracic ratio of 0,63, left ventricular hypertrophy on electrocardiography and left ventricular dilatation with hypokinesis on echocardiography were observed. A few weeks later she developed severe cardiac failure. Muscle biopsy showed muscular dystrophy with lipid infiltration due to carnitine deficiency )serum carnitine 9 nmoles/ml, normal values: 46 +/- 6,9 nmoles/ml; muscle carnitine 0,27 nmoles/mg, normal values: 3,0 +/- 0,79 nmoles/mg fresh frozen weight). She improved rapidly with carnitine chlorhydrate and a diet low in lipids and high in medium chain triglycerides. Regression of muscular symptoms and cardiac failure was observed. After 13 months follow-up with no tonicardiac therapy she is much improved; the signs of heart failure have disappeared, the cardiothoracic ratio is now 0,55 and the electrocardiogramme and echocardiogramme are normal.
Assuntos
Cardiomiopatias/etiologia , Carnitina/deficiência , Lipidoses/etiologia , Doenças Musculares/etiologia , Biópsia , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/metabolismo , Carnitina/uso terapêutico , Criança , Feminino , Seguimentos , Humanos , Metabolismo dos Lipídeos , Lipidoses/tratamento farmacológico , Lipidoses/metabolismo , Músculos/análise , Músculos/patologia , Doenças Musculares/tratamento farmacológico , Doenças Musculares/metabolismoRESUMO
BACKGROUND: Testicular tumors have been reported in boys and adolescents with congenital adrenal hyperplasia (CAH) inadequately controlled by hormonal therapy. CASE REPORTS: Two adolescents were treated for CAH due to 21-hydroxylase deficiency. They developed hyperplastic nodular testes at the age of 16 and 17 years, respectively. CAH in both was inadequately controlled as confirmed by hormonal studies. The tumors regressed after adequate steroid therapy in the first patient but persisted in the second patient despite normalization of 17-OH progesterone and plasma renin activity. CONCLUSION: Testicular ultrasonography should be systematic in all male patients with CAH since radiological findings are earlier than clinical manifestations. The ACTH-dependent tumors require intensification of hormonal therapy in order to obtain tumoral regression and to prevent infertility.
Assuntos
Hiperplasia Suprarrenal Congênita/complicações , Neoplasias Testiculares/complicações , Adolescente , Hiperplasia Suprarrenal Congênita/enzimologia , Anti-Inflamatórios/uso terapêutico , Humanos , Masculino , Esteroides , Neoplasias Testiculares/tratamento farmacológico , Testículo/diagnóstico por imagem , UltrassonografiaRESUMO
BACKGROUND: The number of children of foreign origin adopted in France has increased in the past 15 years. The aim of this study was to analyse distinctive features and medical problems associated with international adoption. PATIENTS AND METHODS: The files of 68 foreign-origin adopted children who attended or were admitted to the Medical and Nutrition Unit of the Pediatric Hospital in Tours between January 1st 1986 and December 31st 1997, were studied retrospectively. Various parameters were analysed: age at first consultation, age at adoption, country of origin and health problems, especially nutritional status, infectious diseases, growth and development. RESULTS: In the majority of cases, children were adopted before 12 months of age (61.2%), particularly before six months of age (49.3%). The children came mainly from Africa and countries in the Indian Ocean (48.5%), and from Southeastern Asia (33.9%). Malnutrition was frequent in children from Africa. Twenty-one children (30.9%) presented with severe malnutrition characterized by weight less than the mean-2SD for height and required hospitalization. No children had congenital hypothyroidism, hyperphenylalaninemia, nor were HIV positive. Some patients had infectious diseases: 11 Hepatitis B, four congenital syphilis and six tuberculosis, with favorable outcomes after treatment. The other most frequent diseases were acute diarrhea, chronic diarrhea, intestinal parasites, and scabies, varying according to countries. Three girls adopted from southern Asia developed precocious puberty. Growth and psychomotor development were satisfactory overall, but abnormalities were observed in 15 children (22.1%), which is higher than in the general population. CONCLUSION: The expansion of international adoption with distinctive diseases proves the importance of a checkup as soon as possible after the arrival of these children in France. This checkup has to include nutritional and general evaluation and supplementary tests, especially for specific serology and vaccination status. Following this, it would be possible to propose a suitable follow-up to the adoptive parents.
Assuntos
Adoção , Criança Abandonada , Fatores Etários , Pré-Escolar , Feminino , França , Nível de Saúde , Hospitalização , Humanos , Lactente , Recém-Nascido , Masculino , Estado Nutricional , Desempenho Psicomotor , Fatores SexuaisRESUMO
Growth hormone (GH) deficiency is not an unusual cause of short stature which, in absence of treatment, may lead to dwarfism. The diagnosis of growth hormone deficiency must be suspected very early, sometime at birth, by careful evaluation of growth curve which shows marked growth deceleration. Two stimulation tests of GH secretion<20 mUI/l are necessary to confirm the diagnosis of GH deficiency in order to start treating the patients. MRI of the pituitary gland should be realized to diagnose defects in the hypophyseal and hypothalamic structures. Bio-engineered exogenous GH have very limited side effects and are currently prescribed. Administered early in life at adequate dosage, GH replacement therapy may significantly increase ultimate adult growth in children with GH deficiency.
Assuntos
Hormônio do Crescimento Humano/deficiência , Diagnóstico , Hormônio do Crescimento Humano/metabolismo , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Hipotálamo/patologia , Lactente , Imageamento por Ressonância Magnética , Masculino , Hipófise/patologia , Hipófise/fisiopatologiaRESUMO
Familial isolated glucocorticoid deficiency syndrome is characterized by low cortisol plasma levels despite high ACTH levels without any stimulation of steroid production after ACTH administration. However, the mineralocorticoid function is well-preserved in this syndrome which indicates a specific resistance to ACTH. Recent cloning of the ACTH receptor allowed to study this receptor in this particular syndrome. After studying sixteen affected families, we have found three mutations in two patients from non-related families. One of these patients was a double heterozygote compound (C251F, G217fs) while the other one was homozygote for another mutation D107N. The mutant receptors were expressed in vitro in transfected M3 cells (S91 Cloudman cells) which represents a working expression system to express the ACTH receptor. Production of intracellular cyclic AMP was calculated in the presence of increasing concentrations of ACTH. The EC50 values were estimated (C251F: 3.5 +/- 0.9 x 10(-9) M, D107N: 3.0 +/- 0.9 x 10(-9) M, G217fs: 4.8 +/- 0.9 x 10(-9) M) and comparison with the value obtained for the wild type ACTH receptor (5.1 +/- 0.9 x 10(-10) M) indicates a clear 6 to 9 shift to the right due to an impaired function of these mutant receptors. Such results were expected for the G217fs mutation, and could be explained by a decrease in ligand affinity or an impaired coupling to adenylate cyclase in the case of amino acid substitutions. A total of twelve mutations has been described in the literature although eight of them have not been tested in vitro until now.
Assuntos
Glucocorticoides/deficiência , Glucocorticoides/genética , Mutação , Receptores da Corticotropina/genética , Expressão Gênica , Humanos , Técnicas In Vitro , Lactente , Recém-Nascido , Receptores da Corticotropina/metabolismo , SíndromeRESUMO
Cushing's disease in children is rare and not familar to pediatricians. We report here 7 cases concerning children between 8 and 16 years of age, treated by pituitary surgery with 1 to 9 year follow-up. A remission of hypercorticism was obtained in all cases. However, a pituitary deficiency requiring replacement opotherapy and/or a recurrence was observed in 5 out of 7 patients. From our experience and the review of literature (around 130 cases), Cushing's disease is more serious in children than in adult. We suggest therapeutic management with transsphenoidal surgery as the treatment of choice. Given the frequency of recurrence (13 à 54%) often late (9-12 years), we stress the need of regular and extended postoperative follow-up.
Assuntos
Síndrome de Cushing/cirurgia , Hipófise/cirurgia , Adolescente , Criança , Síndrome de Cushing/tratamento farmacológico , Feminino , Terapia de Reposição Hormonal , Humanos , Masculino , RecidivaRESUMO
Nine patients with polycystic ovary syndrome revealed by primary amenorrhea were studied clinically, biochemically and ultrasonographically. One of them had excess weight, four had hirsutism and five acne. Testosterone and delta 4-androstenedione levels were high in all patients. Luteinizing hormone (LH) basal levels were increased in five patients. Basal values of follicle-stimulating hormone (FSH) remained within normal range. The LH to FSH ratio was elevated (over 2) in six patients. The LSH response to gonadotropin-releasing hormone (GnRH) was explosive in all patients. Ultrasonography showed that three out of five patients had enlarged ovaries with multiple follicles not exceeding 8 mm. Following treatment, two patients had children after ovulation was induced with clomiphene citrate, one patient became pregnant spontaneously but thereafter opted for voluntary interruption; two patients are still on ovulation-inducing therapy; four patients still have contraception. These results indicate the clinical heterogeneity and the diagnostic problems that surround this uncommon form of a frequently observed disease.
Assuntos
Amenorreia/etiologia , Síndrome do Ovário Policístico/complicações , Adolescente , Adulto , Androstenodiona/análise , Clomifeno/uso terapêutico , Congêneres do Estradiol/uso terapêutico , Feminino , Hormônio Foliculoestimulante/análise , Seguimentos , Humanos , Hormônio Luteinizante/análise , Indução da Ovulação , Síndrome do Ovário Policístico/diagnóstico por imagem , Síndrome do Ovário Policístico/tratamento farmacológico , Gravidez , Congêneres da Progesterona/uso terapêutico , Testosterona/análise , UltrassonografiaRESUMO
The first patient suffered from a very severe atopic dermatitis with intense pruritus and thickened skin. He had also recurrent infections, particularly related to Staphylococcus coagulase +, and axillary and inguinal lymphodermopathy. The use of tetracosactide given intramuscularly allowed controlling the evolution of his atopic dermatitis. After several months of treatment, the skin became less infiltrated, lymphodermopathy disappeared and no severe infection had happened. The second patient had a less severe atopic dermatitis and recurrent infections without any particular severity. Topical corticosteroids allowed to control the atopic dermatitis. These two patients had high levels of circulating IgE and an important deficiency of polymorphonuclear chemotaxis which was evaluated by migration through boyden room. Study of the family showed atopic manifestations in several members, but with lower levels of IgE. The most characteristic abnormality of this syndrome is the according to considerable increase of IgE. The deficit in polymorphonuclear chemotaxis may vary according to time and even become normal. The prognosis over long periods remains to be determined.
Assuntos
Dermatite Atópica/genética , Hipergamaglobulinemia/genética , Imunoglobulina E/análise , Dermatopatias Infecciosas/genética , Infecções Estafilocócicas/genética , Quimiotaxia de Leucócito , Pré-Escolar , Dermatite Atópica/imunologia , Humanos , Lactente , Masculino , Neutrófilos/fisiologia , Prognóstico , Recidiva , Síndrome , Linfócitos T Reguladores/fisiologiaRESUMO
Pseudohypoparathyroidism (PHP) covers a heterogeneous group of disorders, which have in common resistance to parathyroid hormone (PTH). However, they differ in many aspects such as site of the defect in signal transduction, clinical picture (with or without Albright's hereditary osteodystrophy (AHO)), extension of hormone resistance, and the tissue activity of protein Gs. PHP type Ic, a rare subtype, is characterized by resistance to several hormones, the presence of AHO, and normal activity of protein Gs. We present the case of a patient with PHP type Ic. Although resistance to TSH was suggested at the age of 12 months, diagnosis was made when she presented with hypocalcemia and resistance to PTH. Resistance to GH was also detected, and partial resistance to gonadotropins became clear after puberty. We demonstrated a defective lipolytic response to epinephrine, suggesting a role of this resistance in the pathogenesis of her morbid obesity. In view of the difficulties in the management of overweight in this disorder, treatment with a cannabinoid receptor type 1 (CB1) antagonist was started, and it proved to be highly effective, lowering the patient's body mass index from 40.5 to 33.5, which was quite impressive. We propose that an underactive melanocortin-4 receptor, which is found in certain patients with PHP, leads to upregulation of the CB1 receptor and consequently to a good response to treatment with CB1 antagonists. Another interesting finding was the GNAS mutation that was identified in this patient. A nonsense mutation resulted in a truncated Gsa that was able to stimulate adenylyl cyclase efficiently, but could not bind to receptors in a normal way.