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Should 45,X/46,XY Boys with No Or Mild Anomaly of External Genitalia 3 179 L Dumeige and others 45,X/46,XY phenotypic boys, 179:3 181–190 Clinical Study not so benign? Should 45,X/46,XY boys with no or mild anomaly of external genitalia be investigated and followed up? Laurence Dumeige1,2, Livie Chatelais3, Claire Bouvattier4, Marc De Kerdanet5, Capucine Hyon6, Blandine Esteva7, Dinane Samara-Boustani8, Delphine Zenaty1, Marc Nicolino9, Sabine Baron10, Chantal Metz-Blond11, Catherine Naud-Saudreau12, Clémentine Dupuis13, Juliane Léger1, Jean-Pierre Siffroi6, Bruno Donadille14, Sophie Christin-Maitre14, Jean-Claude Carel1, Regis Coutant3 and Laetitia Martinerie1,2 1Pediatric Endocrinology Department, CHU Robert Debré, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Assistance-Publique Hôpitaux de Paris and Université Paris Diderot, Sorbonne Paris Cité, Paris, France, 2INSERM UMR-S1185, Le Kremlin Bicêtre, France, 3Pediatric Department, CHU Angers, Angers, France, 4Pediatric Endocrinology Department, CHU Bicêtre, Centre de Référence des Anomalies du Développement Génital, Assistance-Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France, 5Pediatric Department, CHU Rennes, Rennes, France, 6Genetic Department, 7Pediatric Endocrinology Department, CHU Armand Trousseau, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Assistance-Publique Hôpitaux de Paris, Paris, France, 8Pediatric Endocrinology Department, CHU Necker-Enfants Malades, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Assistance-Publique Hôpitaux de Paris, Paris, France, 9Pediatric Endocrinology Department, CHU Lyon, Centre de Référence des Anomalies du Développement Génital, Lyon, France, Pediatric Correspondence Department 10CHU Nantes, Nantes, France, 11CHRU Brest, Brest, France, 12Centre Hospitalier de Bretagne Sud, should be addressed Lorient, France, 13CHU Grenoble, La Tronche, France, and 14Endocrinology Department, CHU St-Antoine, Centre de to L Martinerie Référence des Maladies Endocriniennes Rares de la Croissance, Assistance-Publique Hôpitaux de Paris, Paris, France Email [email protected] Abstract Objective: Few studies of patients with a 45,X/46,XY mosaicism have considered those with normal male phenotype. The purpose of this study was to evaluate the clinical outcome of 45,X/46,XY boys born with normal or minor abnormalities of external genitalia, notably in terms of growth and pubertal development. European Journal European of Endocrinology Methods: Retrospective longitudinal study of 40 patients followed between 1982 and 2017 in France. Results: Twenty patients had a prenatal diagnosis, whereas 20 patients had a postnatal diagnosis, mainly for short stature. Most patients had stunted growth, with abnormal growth spurt during puberty and a mean adult height of 158 ± 7.6 cm, i.e. −2.3 DS with correction for target height. Seventy percent of patients presented Turner-like syndrome features including cardiac (6/23 patients investigated) and renal malformations (3/19 patients investigated). Twenty- two patients had minor abnormalities of external genitalia. One patient developed a testicular embryonic carcinoma, suggesting evidence of partial gonadal dysgenesis. Moreover, puberty occurred spontaneously in 93% of patients but 71% (n = 5) of those evaluated at the end of puberty presented signs of declined Sertoli cell function (low inhibin B levels and increased FSH levels). Conclusion: This study emphasizes the need to identify and follow-up 45,X/46,XY patients born with normal male phenotype until adulthood, as they present similar prognosis than those born with severe genital anomalies. Currently, most patients are diagnosed in adulthood with azoospermia, consistent with our observations of decreased testicular function at the end of puberty. Early management of these patients may lead to fertility preservation strategies. European Journal of Endocrinology (2018) 179, 181–190 www.eje-online.org © 2018 European Society of Endocrinology Published by Bioscientifica Ltd. https://doi.org/10.1530/EJE-18-0309 Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 10:51:05PM via free access -18-0309 Clinical Study L Dumeige and others 45,X/46,XY phenotypic boys, 179:3 182 not so benign? Introduction followed between 1982 and 2017 by endocrinology or urology services in France. External genitalia had to be The 45,X/46,XY mosaic is a rare condition, with an normal or only present a minor abnormality such as incidence between 1 in 6000 and 1 in 15000 live births unilateral cryptorchidism or glanular hypospadias, with (1, 2). 45,X/46,XY patients present a large spectrum of an External Masculinization Score (EMS) >10. Patients phenotypes, ranging from normal female phenotype, with an EMS ≤10 were excluded. Consent was obtained ambiguous genitalia (3) to male phenotype with normal from each patient after full explanation of the purpose external genitalia. Antenatal karyotype studies with and nature of all procedures used. This observational systematic examination of the genitals at birth have study was approved by the Local and National Ethics assessed that more than 90% of these patients have normal Review Committee for Biomedical Research Project external genitalia (1, 3). However, cohorts of 45,X/46,XY (N°2017/347_2, N°28164) and the French data protection patients diagnosed in the postnatal period are mainly authority (CNIL, DR-2018-049, N°918051), in accordance patients with severe genital anomalies in the literature, with the Declaration of Helsinki. while patients with a normal male phenotype or minor anomalies of genital development account for only 10% of the patients described (4, 5). 45,X/46,XY patients with Data collection genital ambiguity frequently have impaired testicular function, infertility and reduced adult height (4, 6, 7, 8, 9, The following data were collected by retrospective 10). However, little is known about boys with a normal male investigation of medical records, growth charts and phenotype or mild genital anomaly. These patients develop biological data: two testes, with secretion of AMH and testosterone during – Clinical data: term of pregnancy, birth parameters, fetal development, allowing Mullerian ducts regression and obstetrical and neonatal medical history including virilization of genital organs. Thus, the diagnosis is rather intra-uterine growth retardation (IUGR), parental difficult as they have few associated signs (6). Moreover, target height (defined by mean of height of the two upon diagnosis, notably when it is incidentally found on an parents +6.5 cm), age at diagnosis (defined as age of antenatal karyotype, these patients are rarely investigated karyotype sampling), height and pubertal Tanner or followed after birth. Currently, most of the diagnosed stage at diagnosis and at the end of puberty and patients are identified in adulthood because of infertility reason for performing the karyotype. Phenotypic (11, 12, 13). However, despite the absence of genital features due to 45,X monosomy were reported, European Journal European of Endocrinology anomaly at birth, sporadic case reports have suggested that such as facial particularities, pterygium colli, pectus these patients may have dysgenetic testes, responsible for carinatum, multiple naevi, high-arched palate, low early decline of testicular function with pubertal delay and posterior hairline, multiple otitis media or deafness infertility (6, 14). Furthermore, they may also have short and orthopedic defects such as scoliosis or leg length stature and other Turner syndrome-like features that need discrepancy. For each patient, weight and height data to be considered for proper management (15, 16, 17). were collected at several ages throughout infancy and This study evaluates the clinical outcome of adolescence. Height measures are expressed as values 45,X/46,XY male patients with normal or minor both in centimeters and in standard deviation to the abnormalities of external genitalia (unilateral mean, corrected for target height (height SDS − target cryptorchidism or glanular hypospadias), in terms of height SDS). Age at onset of pubertal development (G2 growth, pubertal development and other phenotypic defined as a testicular size ≥4 mL or 25 mm), whether characteristics. It underlines the importance of an early testosterone therapy was needed to induce puberty or diagnosis, of the necessity of long-term follow-up and thereafter and development of a testicular tumor were should lead to a better management of these patients. noted. Information on growth hormone therapy was gathered: duration, dose and stature gain after the first 2 years of treatment. Methods – Chromosomal analyses were performed on peripheral blood lymphocytes. At least 30 mitoses were Patients examined to determine the degree of mosaicism and Inclusion criteria were phenotypically male patient (fetus, Y chromosome rearrangements. All patients with an neonate, child or adult) with a 45,X/46,XY karyotype, antenatal diagnosis had a postnatal karyotype in order www.eje-online.org Downloaded from Bioscientifica.com at 09/27/2021 10:51:05PM via free access Clinical Study L Dumeige and others 45,X/46,XY phenotypic boys, 179:3 183 not so benign? to confirm the chromosome abnormality, apart from (2 patients). Ten patients were diagnosed during childhood one patient due to parental refusal. In patients with a mainly for short stature, associated with psychomotor structural anomaly of the Y chromosome, breakpoints, delay in one patient and minor abnormalities of external TSPY gene,
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