RESUMO
OBJECTIVE: To evaluate ovarian function, especially ovulation rate, in adolescents with McCune-Albright syndrome (MAS) and a history of peripheral precocious puberty. DESIGN: Prospective cross-sectional study. SETTING: Academic center. PATIENT(S): A total of eight adolescents with MAS were compared with 15 healthy adolescents matched by age, Tanner stage and body mass index. INTERVENTION(S): We determined basal gonadotropins, sex steroids, sex hormone binding globulin, anti-Müllerian hormone, glucose and insulin. A leuprolide acetate test was performed to measure luteinizing hormone (LH) and follicle stimulating hormone (FSH) (at 0 and 3 h), and 17B-estradiol, testosterone and 17-OH-progesterone (at 0 and 24 h). Salivary progesterone levels were used to assess ovulation during the 13th, 18th, 23rd and 28th days of each menstrual cycle for three to five consecutive cycles, and one pelvic ultrasound was performed during the follicular phase. MAIN OUTCOME MEASURE(S): Ovulation rate in adolescents with MAS. RESULT(S): The proportion of ovulatory cycles was 52.6% in controls compared with 35.7% in patients with MAS. CONCLUSION(S): The adolescent girls with MAS appear to have a lower ovulatory rate compared with controls.
Assuntos
Displasia Fibrosa Poliostótica/fisiopatologia , Ovário/fisiopatologia , Ovulação , Adolescente , Adulto , Estudos Transversais , Feminino , Displasia Fibrosa Poliostótica/sangue , Displasia Fibrosa Poliostótica/patologia , Hormônio Foliculoestimulante Humano/sangue , Fase Folicular , Hormônio Liberador de Gonadotropina/agonistas , Humanos , Hiperandrogenismo/etiologia , Leuprolida , Hormônio Luteinizante/sangue , Ovário/diagnóstico por imagem , Ovário/patologia , Ovulação/efeitos dos fármacos , Estudos Prospectivos , Puberdade Precoce/etiologia , Ultrassonografia , Adulto JovemRESUMO
McCune-Albright syndrome (MAS), usually presenting with polyostotic bone dysplasia, café-au-lait skin lesions and sexual precocity, results from a somatic activating mutation of the GNAS1 gene, which encodes the Gs-alpha protein involved in signalling of several G-protein-coupled receptors. The clinical spectrum depends on tissue distribution of mutant-bearing cells. Sexual precocity has been ascribed to the occurrence of a mutant GNAS1 allele in the gonadal anlage, from which all somatic cells of the differentiated gonads arise. In boys, precocious activation of Leydig cell androgen secretion results in pubertal spermatogenesis, leading to testicular enlargement, and in the development of secondary sex characteristics. However, sexual precocity is rare in MAS males while isolated testicular enlargement is frequently observed. We recently reported the case of a boy with macro-orchidism and signs of Sertoli cell hyperactivity but no signs of hyperandrogenism, which was unexpected since Gs-alpha is functional in both Sertoli and Leydig cells. To understand its pathophysiology, we microdissected an available testicular biopsy to separate Sertoli from Leydig cells. The R201H-GNAS1 allele was present only in Sertoli cells, resulting in isolated Sertoli cell hyperfunction, evidenced by increased AMH expression and cell hyperplasia leading to prepubertal macro-orchidism, with no signs of Leydig cell activation. The different early embryologic origin of precursors contributing to Sertoli and Leydig cell lineages may underlie the differential existence of the mutated GNAS1 gene. Lack of occurrence of the mutation in Leydig cells may explain why sexual precocity is rarely observed in boys with MAS.
Assuntos
Displasia Fibrosa Poliostótica/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Mosaicismo , Mutação , Puberdade Precoce/genética , Testículo/metabolismo , Sequência de Bases , Linhagem Celular , Criança , Pré-Escolar , Cromograninas , Displasia Fibrosa Poliostótica/fisiopatologia , Subunidades alfa Gs de Proteínas de Ligação ao GTP/fisiologia , Humanos , Células Intersticiais do Testículo/metabolismo , Células Intersticiais do Testículo/patologia , Luciferases/genética , Luciferases/metabolismo , Masculino , Modelos Biológicos , Regiões Promotoras Genéticas , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Células de Sertoli/metabolismo , Células de Sertoli/patologia , Transdução de Sinais , Testículo/patologia , TransfecçãoAssuntos
Displasia Fibrosa Poliostótica/diagnóstico , Displasia Fibrosa Poliostótica/fisiopatologia , Puberdade Precoce/diagnóstico , Anti-Inflamatórios/uso terapêutico , Neoplasias do Sistema Nervoso Central/epidemiologia , Criança , Pré-Escolar , Difosfonatos/uso terapêutico , Antagonistas de Estrogênios/uso terapêutico , Feminino , Displasia Fibrosa Óssea/tratamento farmacológico , Displasia Fibrosa Poliostótica/genética , Proteínas Heterotriméricas de Ligação ao GTP/genética , Humanos , Masculino , Menarca/fisiologia , Pamidronato , Puberdade Precoce/tratamento farmacológico , Puberdade Precoce/genética , Tamoxifeno/uso terapêuticoRESUMO
A síndrome de McCune-Albright (SMA) é uma doença genética esporádica determinada por mutaçäo esporádica pós-zigótica e caracterizada por hiperfunçäo glandular, displasia fibrosa poliostótica e hiperpigmentaçäo cutânea café-com-leite. É causada por mutaçäo do gene que codifica a subunidade a da proteína G estimuladora, locus gênico 20q13.2, especificamente nos codons 201 ou 227. A mutaçäo altera a capacidade GTPase intrínseca da subunidade a, determinando a ativaçäo constitutiva persistente do sistema adenilil-ciclase com consequente acúmulo do AMPc intracelular. O quadro clínico é variável, desde a apresentaçäo isolada de cada componente do síndrome, até um quadro sistêmico e grave onde várias glândulas endócrinas e tecidos näo endócrinos säo afetados. O comprometimento hepático e/ou cardiovascular confere maior gravidade, aumentando o risco de episódios fatais. As anormalidades decorrem da hiperativaçäo primária dos tecidos afetados e devem ser tratadas com fármacos que atuem primariamente no tecido alvo, como o cetoconazol para as gônadas e adrenais, os análogos da somatostatina na hiperfunçäo hipofìsária e os bisfosfonatos na displasia óssea. O emprego de agentes que atuem no sistema adenilil-ciclase poderäo futuramente propiciar um controle mais adequado e específico das anormalidades presentes na SMA.
Assuntos
Humanos , Displasia Fibrosa Poliostótica/diagnóstico , Displasia Fibrosa Poliostótica/história , Acromegalia , Antifúngicos/uso terapêutico , Displasia Fibrosa Poliostótica/fisiopatologia , Hiperpigmentação/diagnóstico , Cetoconazol , Puberdade PrecoceRESUMO
OBJECTIVES: An open trial of pamidronate treatment was undertaken in 5 children and 4 young adults with polyostotic fibrous dysplasia associated with McCune Albright syndrome to assess clinical response, bone turnover, and cardiovascular status over a 2-year period. STUDY DESIGN: Pamidronate was administered by intravenous infusion 1 mg/kg/d for 3 days every 6 months for 2 years. Bone turnover was measured at 0, 6, 12, 18, and 24 months with bone mineral density, and cardiac output was assessed by echocardiography at 0, 12, and 24 months. RESULTS: All subjects reported marked reduction in bone pain and sustained increased mobility. The fracture rate decreased in most. Orthopedic insertion of intramedullary rods was successful with maintenance of rod position. Mean osteocalcin levels fell from 35.5 +/- 5.6 microg/L to 28.4 +/- 4.1 microg/L (P <.03). Other bone turnover marker changes were not significant. The mean bone mineral density at lumbar spine increased from 0.5 +/- 0.08 to 0.67 +/- 0.03 g/cm(2) (P <.002) in children and 1.16 +/- 0.6 to 1.33 +/- 0.08 g/cm(2) in adults (P <.005). Other changes in bone mineral density were not significant. Cardiac output did not change significantly. CONCLUSIONS: Pamidronate treatment is an effective therapeutic modality for children with polyostotic fibrous dysplasia, with a good short-term safety profile. Failure to demonstrate major biochemical or bone densitometry improvements is due to the nature of the fibrous dysplasia and intercurrent microfracture.
Assuntos
Difosfonatos/administração & dosagem , Displasia Fibrosa Poliostótica/tratamento farmacológico , Adolescente , Adulto , Densidade Óssea/fisiologia , Osso e Ossos/metabolismo , Débito Cardíaco/fisiologia , Criança , Pré-Escolar , Feminino , Displasia Fibrosa Poliostótica/complicações , Displasia Fibrosa Poliostótica/fisiopatologia , Fraturas Ósseas/etiologia , Fraturas Ósseas/prevenção & controle , Humanos , Infusões Intravenosas , Masculino , Osteocalcina/sangue , PamidronatoRESUMO
OBJECTIVE: The aim of this study was to evaluate the possibility of persistence of autonomous ovarian activity in girls with McCune-Albright syndrome (MAS) after withdrawal of medroxyprogesterone therapy administered for precocious puberty. DESIGN, SETTING, AND PARTICIPANTS: Five girls with MAS were followed-up 1.2 to 8.5 years after the end of treatment. The girls underwent luteinizing hormone-releasing hormone (LH-RH) tests, estradiol (E2) basal measurement, and pelvic ultrasound two times in the follow-up period. RESULTS: Menses resumed in four of five girls, 1.4 +/- 0.9 years after the end of treatment, at chronologic age of 11.3 +/- 1.3 years. Cycles for all girls were irregular. Three patients presented inadequate E2 levels (from 56 to 320 pg/mL) associated with low or absent gonadotropin response to LH-RH tests. The pelvic ultrasound showed ovarian cysts at the time of the study. CONCLUSION: These hormonal and ultrasonographic findings provide evidence of persistence of autonomous ovarian activity in some young women with MAS.