45,X/46,XY Mosaicism Presenting With Isolated Unilateral Cryptorchidism and a Normal Blood Karyotype

45,X/46,XY Mosaicism Presenting With Isolated Unilateral Cryptorchidism and a Normal Blood Karyotype Abstract Context 45,X/46,XY mosaicism is a disorder of sex development leading to abnormal gonadal development and to unpredictable genital phenotype, growth, and pubertal development. Case Description A 2-year-old male presented with a right impalpable testis. Blood karyotype was 46,XY. A laparoscopy performed for right orchidopexy revealed a right streak gonad with Mullerian structures, whereas on the left side, a normal descended testis was present. The karyotype of the removed gonad was 45,X/46,XY. The child grew along the second centile, within the midparental height (MPH) range, until the time of puberty, when linear growth worsened due to a lack of a pubertal growth spurt, and growth hormone (GH) therapy was initiated. He developed spontaneous puberty (13 years of age) and showed normal pubertal progression. However, from the age of 15 years, he had low normal testosterone, raised follicle-stimulating hormone, and reduction of inhibin B, possibly suggestive of declining testicular function. His final height was −2.24 standard deviation score (SDS) (−2.4 SDS at GH start; MPH −1.6 SDS). Conclusions Our case describes a mild male phenotype associated with 45,X/46,XY mosaicism characterized by unilateral cryptorchidism, spontaneous onset of puberty, and normal blood karyotype. The case illustrates the difficulties inherent in making a diagnosis of 45,X/46,XY mosaicism when there is no genital ambiguity and makes the point that growth and testicular impairment may occur, mostly manifesting during adolescence. An early diagnosis is crucial to initiate careful monitoring for growth and pubertal disorders, increased tumor risk, and fertility issues commonly seen in these children. The 45,X/46,XY mosaic is a rare (1.7/10,000) sex chromosome disorder of sex development. Heterogeneous phenotypes have been associated with 45,X/46,XY mosaicism encompassing females with and without Turner syndrome stigmata and males with varying degrees of masculinization of external genitalia (1). The conventional karyotype studied in the peripheral lymphocytes has several limitations (2, 3) and does not predict the chromosome constitution of other body tissues (4). Indeed, in some cases, mosaicism can be detected in the gonadal tissue only. We describe the case of a boy presenting with a very mild genital phenotype and a normal peripheral karyotype who was diagnosed with 45,X/46,XY mosaicism on the gonadal karyotype only. Case Report A 2-year-old child, raised as a male, presented with an impalpable testis on the right side. He had normal phallic and scrotal development with a normally descended left gonad. The conventional blood karyotype was 46,XY in 30 cells examined. Right orchidopexy was attempted, but instead of a testis, a streak gonad with a fallopian tube was visualized on the right side. Subsequent examination under anesthesia, with cystoscopy and laparoscopy, revealed a normal left palpable testis in the scrotum and a right streak gonad with surrounding tubular structures, possibly Mullerian remnants. The prostatic urethra and bladder were normal. The histology of the removed right gonad and surrounding structures demonstrated a fallopian tube, a small streak gonad with no identifiable seminiferous tubular or follicular structures, a uterus with normal immature endometrium and myometrium, and some scattered male ductal structures. The gonadal karyotype revealed mosaicism with 45,X in 27 cells and 46,XY in 13 cells analyzed. Given the diagnosis of 45,X/46,XY mosaicism, the child started regular surveillance for growth and pubertal development, tumor risk, infertility, and complications of Turner syndrome. No associated autoimmune, cardiac, and urinary tract phenotypes were detected at diagnosis and during the follow-up. The patient’s growth pattern and pubertal progression are shown in Fig. 1. Up to the age of 8 years, he demonstrated a normal growth velocity along the second centile [−2 standard deviation score (SDS)], appropriate for his midparental height (−1.6 SDS), and a joint decision was made with the family to wait before starting growth hormone (GH) treatment. At 10.25 years, he showed a deceleration in his growth velocity (4.1 cm/y, −1.2 SDS) with an advanced bone age of 11.5 years, giving a predicted adult height of 156 cm (<−2 SDS). GH therapy was initiated (0.03 mg/kg/d and subsequently titrated by insulinlike growth factor 1 concentrations), with substantial improvement of the growth rate after 1 year of treatment (8.2 cm/y, +3.3 SDS). At the age of 13.15 years, he spontaneously entered puberty. During the follow-up period, he progressed normally through puberty, but he showed a poor pubertal growth spurt. At the last follow-up (15.98 years), his near-final height was 155.4 cm (−2.24 SDS), and his pubertal staging was genitalia 4 to 5, pubic hair 4, and axillary hair 1, with a left testis volume of 15 to 20 mL. At the last biochemical assessment, testosterone was at the lower end of the normal adult range, and follicle-stimulating hormone was slightly elevated (Table 1). Inhibin B concentrations performed on two occasions (13 and 15 years of age) were normal but showed a considerable decrease over time (Table 1). Figure 1. View largeDownload slide Patient’s growth pattern and pubertal progression. A, axillary hair stage; G, genitalia stage; MPH, midparental height; P, pubic hair stage. Figure 1. View largeDownload slide Patient’s growth pattern and pubertal progression. A, axillary hair stage; G, genitalia stage; MPH, midparental height; P, pubic hair stage. Table 1. Serial Hormonal Profiles Characteristic 2.00 y 11.50 y 13.16 y 15.00 y 15.98 y Reference Ranges Testosterone,a nmol/L <0.69 <0.69 <0.69 1.44 11.00 Prepubertal: <0.5b Adult: 10–30 LH, IU/L < 0.7 <0.2 0.9 2.5 4.6 Prepubertal: <0.5b Tanner stage 2: 1–4 Tanner stage 4: 2–8 FSH, IU/L 0.5 0.8 1.7 10.8 19.3 Tanner stage 1: 0.16–3.5c Tanner stage 2–3: 0.44–6.0 Tanner stage 4: 1.40–11.8 Tanner stage 5: 1.28–14.9 Inhibin B, pg/mL 229.4 47.7 12–17 years: 74–470d AMH, pmol/L 353.5 65.0 Tanner stage 3: 18–587e Tanner stage 4: 12–90 Tanner stage G1, P1, A1 G2, P1, A1 G3, P2, A1 G4, P2, A1 G5, P3, A1 Left testicular volume, mL 2 3 8 12–15 15–20 Characteristic 2.00 y 11.50 y 13.16 y 15.00 y 15.98 y Reference Ranges Testosterone,a nmol/L <0.69 <0.69 <0.69 1.44 11.00 Prepubertal: <0.5b Adult: 10–30 LH, IU/L < 0.7 <0.2 0.9 2.5 4.6 Prepubertal: <0.5b Tanner stage 2: 1–4 Tanner stage 4: 2–8 FSH, IU/L 0.5 0.8 1.7 10.8 19.3 Tanner stage 1: 0.16–3.5c Tanner stage 2–3: 0.44–6.0 Tanner stage 4: 1.40–11.8 Tanner stage 5: 1.28–14.9 Inhibin B, pg/mL 229.4 47.7 12–17 years: 74–470d AMH, pmol/L 353.5 65.0 Tanner stage 3: 18–587e Tanner stage 4: 12–90 Tanner stage G1, P1, A1 G2, P1, A1 G3, P2, A1 G4, P2, A1 G5, P3, A1 Left testicular volume, mL 2 3 8 12–15 15–20 Abbreviations: A, axillary hair stage; AMH, anti-Mullerian hormone; FSH, follicle-stimulating hormone; G, genitalia stage; LH, luteinizing hormone; P, pubic hair stage. a Testosterone levels were taken in the morning. b Brook and Dattani (5). c Siemens (formerly DPC), IMMULITE® and IMMULITE 2000 Reference Range Compendium. d Crofton et al. (6). e Aksglaede et al. (7). View Large Table 1. Serial Hormonal Profiles Characteristic 2.00 y 11.50 y 13.16 y 15.00 y 15.98 y Reference Ranges Testosterone,a nmol/L <0.69 <0.69 <0.69 1.44 11.00 Prepubertal: <0.5b Adult: 10–30 LH, IU/L < 0.7 <0.2 0.9 2.5 4.6 Prepubertal: <0.5b Tanner stage 2: 1–4 Tanner stage 4: 2–8 FSH, IU/L 0.5 0.8 1.7 10.8 19.3 Tanner stage 1: 0.16–3.5c Tanner stage 2–3: 0.44–6.0 Tanner stage 4: 1.40–11.8 Tanner stage 5: 1.28–14.9 Inhibin B, pg/mL 229.4 47.7 12–17 years: 74–470d AMH, pmol/L 353.5 65.0 Tanner stage 3: 18–587e Tanner stage 4: 12–90 Tanner stage G1, P1, A1 G2, P1, A1 G3, P2, A1 G4, P2, A1 G5, P3, A1 Left testicular volume, mL 2 3 8 12–15 15–20 Characteristic 2.00 y 11.50 y 13.16 y 15.00 y 15.98 y Reference Ranges Testosterone,a nmol/L <0.69 <0.69 <0.69 1.44 11.00 Prepubertal: <0.5b Adult: 10–30 LH, IU/L < 0.7 <0.2 0.9 2.5 4.6 Prepubertal: <0.5b Tanner stage 2: 1–4 Tanner stage 4: 2–8 FSH, IU/L 0.5 0.8 1.7 10.8 19.3 Tanner stage 1: 0.16–3.5c Tanner stage 2–3: 0.44–6.0 Tanner stage 4: 1.40–11.8 Tanner stage 5: 1.28–14.9 Inhibin B, pg/mL 229.4 47.7 12–17 years: 74–470d AMH, pmol/L 353.5 65.0 Tanner stage 3: 18–587e Tanner stage 4: 12–90 Tanner stage G1, P1, A1 G2, P1, A1 G3, P2, A1 G4, P2, A1 G5, P3, A1 Left testicular volume, mL 2 3 8 12–15 15–20 Abbreviations: A, axillary hair stage; AMH, anti-Mullerian hormone; FSH, follicle-stimulating hormone; G, genitalia stage; LH, luteinizing hormone; P, pubic hair stage. a Testosterone levels were taken in the morning. b Brook and Dattani (5). c Siemens (formerly DPC), IMMULITE® and IMMULITE 2000 Reference Range Compendium. d Crofton et al. (6). e Aksglaede et al. (7). View Large Discussion 45,X/46,XY mosaicism is a rare genetic finding, leading to complex management issues with respect to sex of rearing and to unpredictability of the genital and gonadal phenotype of the affected children (1, 8). The relative distribution of the 45,X and 46,XY chromosomal cell lines among different tissues probably accounts for this wide phenotypic variation. The blood karyotype has several limitations: the number of cells examined can change the karyotype results, and the percentage of the 45,X cell line can also decrease over time (3, 8). Three cases have been reported so far of discordance between blood (46,XY) and gonadal (45,X/46,XY) karyotype (2, 9, 10). Two patients presented with ambiguous genitalia at the age of 1 year (2) and with a left undescended testis and penoscrotal hypospadias at the age of 16 years (9), respectively. The third case was a neonate with ambiguous genitalia in whom chromosome Y–derived sequences were detected in the dysgenetic gonad and skin fibroblasts (10). To our knowledge, our patient is the phenotypically mildest reported case of 45,X/46,XY mosaicism (isolated unilateral impalpable testis with normal male genitalia and spontaneous puberty) diagnosed only on the gonadal karyotype. Nonetheless, in keeping with previously reported cases (11), from the age of 15 years, our patient showed biochemical features of possible declining testicular function. It is well known that most 45,X/46,XY patients born with ambiguous genitalia are infertile. However, even in patients with mild phenotypes in childhood, spermatogenesis may be impaired in adulthood (11). Therefore, at diagnosis, possibilities of fertility preservation should be discussed with the patient and his family (1). 45,X/46,XY patients exhibit an increased tumor risk, not only when abdominal undifferentiated gonads are present but also in dysgenetic or “apparently normal” intrascrotal testes (1, 11, 12). In dysgenetic gonads, the formation of in situ gonadoblastoma or of an invasive germ cell tumor occurs in 15% to 52% of cases (12). However, the risk of germ cell malignancies is mainly defined by histological markers that do not distinguish “maturation-delayed” from “malignant” germ cells, probably leading to an overdiagnosis of cancer and also to overtreatment by gonadectomy (12, 13). Although in the past gonadectomy was recommended, a more conservative approach is now preferred to allow endogenous hormone production and therefore spontaneous puberty and to delay irreversible surgery until adulthood. Individualized management has recently been suggested in 45,X/46,XY patients, taking into consideration genetic factors, the localization of the gonad, the age and cooperation of the patient, and the histological and immunohistochemical findings (12–14). However, it must be pointed out that the risk of progression from histologically malignant lesions to clinical disease with actual morbidity and risk of metastases in these patients is unknown. An international Disorders of Sex Development registry that currently exists will hopefully offer greater insights on the long-term morbidity and mortality associated with malignancies in these patients (14). The evidence available on 45,X/46,XY patients suggests that no correlation exists between the clinical phenotype and the degree of mosaicism (4, 8, 11). The pubertal course, the fertility outcome, and the tumor risk seem to be predicted more by degree of genital ambiguity and gonadal differentiation than by the blood/gonadal karyotype (4, 8, 11). However, most patients, including mild cases without genital ambiguity and those starting puberty spontaneously, will develop some testicular impairment in adolescence or young adulthood (11). In our case, the preserved gonad maintained sufficient Leydig cell function to induce puberty, but the current hormonal profile possibly suggests declining testicular function, raising concerns for future fertility. Growth seems to be consistently impaired in these patients (11). Variable outcomes have been reported on GH treatment, with a recent review concluding that although there may be some short-term to midterm improvement in growth, long-term data on adult height are disappointing (15). However, supraphysiological GH doses and earlier commencement might result in better outcomes, as could have possibly been the case in our patient. Because fibroblasts have the same mesenchymal origin as chondrocytes and osteoblasts, karyotype from skin fibroblasts could be more useful than the blood karyotype to predict the growth phenotype of these patients (15). Furthermore, periodic screening for cardiac and autoimmune complications should be considered in 45,X/46,XY patients (16, 17). Our case report highlights that 45,X/46,XY mosaicism may present with a very mild phenotype and a normal blood karyotype. Cases without genital ambiguity can be easily missed. However, short stature and decline in testicular function over time are common features, even in mild cases, and these patients also exhibit a considerable risk of tumors and infertility. An early diagnosis of gonadal dysgenesis is therefore important in all cases to optimize growth, puberty, and fertility outcomes and to monitor for the increased tumor risk. Abbreviations: Abbreviations: GH growth hormone SDS standard deviation score Acknowledgments Financial Support: No funding was secured for this study. M.T.D. receives funding from the Great Ormond Street Hospital Children’s Charity. This research was supported by the National Institute of Health Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the National Health Service (NHS), the National Institute of Health Research (NIHR), or the Department of Health. Disclosure Summary: The authors have nothing to disclose. References 1. Wu Q , Wang C , Shi H , Kong X , Ren S , Jiang M . The clinical manifestation and genetic evaluation in patients with 45,X/46,XY mosaicism . Sex Dev . 2017 ; 11 ( 2 ): 64 – 69 . Google Scholar CrossRef Search ADS PubMed 2. Nishina-Uchida N , Fukuzawa R , Hasegawa Y , Morison IM . Identification of X monosomy cells from a gonad of mixed gonadal dysgenesis with a 46,XY karyotype: case report . Medicine (Baltimore) . 2015 ; 94 ( 14 ): e720 . Google Scholar CrossRef Search ADS PubMed 3. Takahashi I , Miyamoto J , Hasegawa Y . Limitations of G-banding karyotype analysis with peripheral lymphocytes in diagnosing mixed gonadal dysgenesis . Clin Pediatr Endocrinol . 2006 ; 15 ( 3 ): 109 – 115 . Google Scholar CrossRef Search ADS PubMed 4. Tosson H , Rose SR , Gartner LA . Description of children with 45,X/46,XY karyotype . Eur J Pediatr . 2011 ; 171 ( 3 ): 521 – 529 . Google Scholar CrossRef Search ADS PubMed 5. Brook CGD , Dattani MT . Handbook of Clinical Pediatric Endocrinology . 2nd ed . Oxford, United Kingdom : Wiley-Blackwell ; 2012 . Google Scholar CrossRef Search ADS 6. Crofton PM , Evans AE , Groome NP , Taylor MR , Holland CV , Kelnar CJ . Inhibin B in boys from birth to adulthood: relationship wih age, pubertal stage, FSH and testosterone . Clin Endocrinol (Oxf) . 2002 ; 56 ( 2 ): 215 – 221 . Google Scholar CrossRef Search ADS PubMed 7. Aksglaede et al. . J Clin Endocrinol Metab . 2010 ; 95 ( 12 ): 5357 – 5364 . 8. Rosa RF , D’Ecclesiis WF , Dibbi RP , Rosa RC , Trevisan P , Graziadio C , Paskulin GA , Zen PR . 45,X/46,XY mosaicism: report on 14 patients from a Brazilian hospital. A retrospective study . Sao Paulo Med J . 2014 ; 132 ( 6 ): 332 – 338 . Google Scholar CrossRef Search ADS PubMed 9. Anand A , Gupta NP , Singh MK , Mathur SR , Nayyar R . Mixed gonadal dysgenesis with normal karyotype: a rare case report . Indian J Pathol Microbiol . 2010 ; 53 ( 2 ): 313 – 315 . Google Scholar CrossRef Search ADS PubMed 10. Karatza A , Chrysis D , Stefanou EG , Mantagos S , Salakos C . Mixed gonadal dysgenesis in a 45,X neonate with chromosome Y material in the dysgenetic gonad . J Pediatr Endocrinol Metab . 2009 ; 22 ( 11 ): 1083 – 1086 . Google Scholar CrossRef Search ADS PubMed 11. Martinerie L , Morel Y , Gay CL , Pienkowski C , de Kerdanet M , Cabrol S , Lecointre C , Coutant R , Baron S , Colle M , Brauner R , Thibaud E , Leger J , Nihoul-Fekete C , Bouvattier C . Impaired puberty, fertility, and final stature in 45,X/46,XY mixed gonadal dysgenetic patients raised as boys . Eur J Endocrinol . 2012 ; 166 ( 4 ): 687 – 694 . Google Scholar CrossRef Search ADS PubMed 12. Cools M , Pleskacova J , Stoop H , Hoebeke P , Van Laecke E , Drop SLS , Lebl J , Oosterhuis JW , Looijenga LHJ , Wolffenbuttel KP ; Mosaicism Collaborative Group . Gonadal pathology and tumor risk in relation to clinical characteristics in patients with 45,X/46,XY mosaicism . J Clin Endocrinol Metab . 2011 ; 96 ( 7 ): E1171 – E1180 . Google Scholar CrossRef Search ADS PubMed 13. Cools M , Stoop H , Kersemaekers A-MF , Drop SLS , Wolffenbuttel KP , Bourguignon J-P , Slowikowska-Hilczer J , Kula K , Faradz SMH , Oosterhuis JW , Looijenga LHJ . Gonadoblastoma arising in undifferentiated gonadal tissue within dysgenetic gonads . J Clin Endocrinol Metab . 2006 ; 91 ( 6 ): 2404 – 2413 . Google Scholar CrossRef Search ADS PubMed 14. Spoor JA , Oosterhuis JW , Hersmus R , Biermann K , Wolffenbuttel KP , Cools M , Kazmi Z , Ahmed SF , Looijenga LHJ . Histological assessment of gonads in DSD: relevance for clinical management . Sex Dev . 2018 ; 12 ( 1-3 ): 106 – 122 . Google Scholar CrossRef Search ADS PubMed 15. Bertelloni S , Baroncelli GI , Massart F , Toschi B . Growth in boys with 45,X/46,XY mosaicism: effect of growth hormone treatment on statural growth . Sex Dev . 2015 ; 9 ( 4 ): 183 – 189 . Google Scholar CrossRef Search ADS PubMed 16. Bertelloni S , Dati E , Valetto A , Bertini V , Danti A , Baroncelli GI . Long-term growth hormone treatment in a boy with 45,X/46,X,idic(Yp) mixed gonadal dysgenesis: comparison with growth pattern of an untreated patient . Hormones (Athens) . 2015 ; 14 ( 1 ): 142 – 147 . Google Scholar PubMed 17. De Groote K , Cools M , De Schepper J , Craen M , François I , Devos D , Carbonez K , Eyskens B , De Wolf D . Cardiovascular pathology in males and females with 45,X/46,XY mosaicism . PLoS One . 2013 ; 8 ( 2 ): e54977 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

45,X/46,XY Mosaicism Presenting With Isolated Unilateral Cryptorchidism and a Normal Blood Karyotype

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Endocrine Society
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10.1210/jc.2017-02671
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Abstract

Abstract Context 45,X/46,XY mosaicism is a disorder of sex development leading to abnormal gonadal development and to unpredictable genital phenotype, growth, and pubertal development. Case Description A 2-year-old male presented with a right impalpable testis. Blood karyotype was 46,XY. A laparoscopy performed for right orchidopexy revealed a right streak gonad with Mullerian structures, whereas on the left side, a normal descended testis was present. The karyotype of the removed gonad was 45,X/46,XY. The child grew along the second centile, within the midparental height (MPH) range, until the time of puberty, when linear growth worsened due to a lack of a pubertal growth spurt, and growth hormone (GH) therapy was initiated. He developed spontaneous puberty (13 years of age) and showed normal pubertal progression. However, from the age of 15 years, he had low normal testosterone, raised follicle-stimulating hormone, and reduction of inhibin B, possibly suggestive of declining testicular function. His final height was −2.24 standard deviation score (SDS) (−2.4 SDS at GH start; MPH −1.6 SDS). Conclusions Our case describes a mild male phenotype associated with 45,X/46,XY mosaicism characterized by unilateral cryptorchidism, spontaneous onset of puberty, and normal blood karyotype. The case illustrates the difficulties inherent in making a diagnosis of 45,X/46,XY mosaicism when there is no genital ambiguity and makes the point that growth and testicular impairment may occur, mostly manifesting during adolescence. An early diagnosis is crucial to initiate careful monitoring for growth and pubertal disorders, increased tumor risk, and fertility issues commonly seen in these children. The 45,X/46,XY mosaic is a rare (1.7/10,000) sex chromosome disorder of sex development. Heterogeneous phenotypes have been associated with 45,X/46,XY mosaicism encompassing females with and without Turner syndrome stigmata and males with varying degrees of masculinization of external genitalia (1). The conventional karyotype studied in the peripheral lymphocytes has several limitations (2, 3) and does not predict the chromosome constitution of other body tissues (4). Indeed, in some cases, mosaicism can be detected in the gonadal tissue only. We describe the case of a boy presenting with a very mild genital phenotype and a normal peripheral karyotype who was diagnosed with 45,X/46,XY mosaicism on the gonadal karyotype only. Case Report A 2-year-old child, raised as a male, presented with an impalpable testis on the right side. He had normal phallic and scrotal development with a normally descended left gonad. The conventional blood karyotype was 46,XY in 30 cells examined. Right orchidopexy was attempted, but instead of a testis, a streak gonad with a fallopian tube was visualized on the right side. Subsequent examination under anesthesia, with cystoscopy and laparoscopy, revealed a normal left palpable testis in the scrotum and a right streak gonad with surrounding tubular structures, possibly Mullerian remnants. The prostatic urethra and bladder were normal. The histology of the removed right gonad and surrounding structures demonstrated a fallopian tube, a small streak gonad with no identifiable seminiferous tubular or follicular structures, a uterus with normal immature endometrium and myometrium, and some scattered male ductal structures. The gonadal karyotype revealed mosaicism with 45,X in 27 cells and 46,XY in 13 cells analyzed. Given the diagnosis of 45,X/46,XY mosaicism, the child started regular surveillance for growth and pubertal development, tumor risk, infertility, and complications of Turner syndrome. No associated autoimmune, cardiac, and urinary tract phenotypes were detected at diagnosis and during the follow-up. The patient’s growth pattern and pubertal progression are shown in Fig. 1. Up to the age of 8 years, he demonstrated a normal growth velocity along the second centile [−2 standard deviation score (SDS)], appropriate for his midparental height (−1.6 SDS), and a joint decision was made with the family to wait before starting growth hormone (GH) treatment. At 10.25 years, he showed a deceleration in his growth velocity (4.1 cm/y, −1.2 SDS) with an advanced bone age of 11.5 years, giving a predicted adult height of 156 cm (<−2 SDS). GH therapy was initiated (0.03 mg/kg/d and subsequently titrated by insulinlike growth factor 1 concentrations), with substantial improvement of the growth rate after 1 year of treatment (8.2 cm/y, +3.3 SDS). At the age of 13.15 years, he spontaneously entered puberty. During the follow-up period, he progressed normally through puberty, but he showed a poor pubertal growth spurt. At the last follow-up (15.98 years), his near-final height was 155.4 cm (−2.24 SDS), and his pubertal staging was genitalia 4 to 5, pubic hair 4, and axillary hair 1, with a left testis volume of 15 to 20 mL. At the last biochemical assessment, testosterone was at the lower end of the normal adult range, and follicle-stimulating hormone was slightly elevated (Table 1). Inhibin B concentrations performed on two occasions (13 and 15 years of age) were normal but showed a considerable decrease over time (Table 1). Figure 1. View largeDownload slide Patient’s growth pattern and pubertal progression. A, axillary hair stage; G, genitalia stage; MPH, midparental height; P, pubic hair stage. Figure 1. View largeDownload slide Patient’s growth pattern and pubertal progression. A, axillary hair stage; G, genitalia stage; MPH, midparental height; P, pubic hair stage. Table 1. Serial Hormonal Profiles Characteristic 2.00 y 11.50 y 13.16 y 15.00 y 15.98 y Reference Ranges Testosterone,a nmol/L <0.69 <0.69 <0.69 1.44 11.00 Prepubertal: <0.5b Adult: 10–30 LH, IU/L < 0.7 <0.2 0.9 2.5 4.6 Prepubertal: <0.5b Tanner stage 2: 1–4 Tanner stage 4: 2–8 FSH, IU/L 0.5 0.8 1.7 10.8 19.3 Tanner stage 1: 0.16–3.5c Tanner stage 2–3: 0.44–6.0 Tanner stage 4: 1.40–11.8 Tanner stage 5: 1.28–14.9 Inhibin B, pg/mL 229.4 47.7 12–17 years: 74–470d AMH, pmol/L 353.5 65.0 Tanner stage 3: 18–587e Tanner stage 4: 12–90 Tanner stage G1, P1, A1 G2, P1, A1 G3, P2, A1 G4, P2, A1 G5, P3, A1 Left testicular volume, mL 2 3 8 12–15 15–20 Characteristic 2.00 y 11.50 y 13.16 y 15.00 y 15.98 y Reference Ranges Testosterone,a nmol/L <0.69 <0.69 <0.69 1.44 11.00 Prepubertal: <0.5b Adult: 10–30 LH, IU/L < 0.7 <0.2 0.9 2.5 4.6 Prepubertal: <0.5b Tanner stage 2: 1–4 Tanner stage 4: 2–8 FSH, IU/L 0.5 0.8 1.7 10.8 19.3 Tanner stage 1: 0.16–3.5c Tanner stage 2–3: 0.44–6.0 Tanner stage 4: 1.40–11.8 Tanner stage 5: 1.28–14.9 Inhibin B, pg/mL 229.4 47.7 12–17 years: 74–470d AMH, pmol/L 353.5 65.0 Tanner stage 3: 18–587e Tanner stage 4: 12–90 Tanner stage G1, P1, A1 G2, P1, A1 G3, P2, A1 G4, P2, A1 G5, P3, A1 Left testicular volume, mL 2 3 8 12–15 15–20 Abbreviations: A, axillary hair stage; AMH, anti-Mullerian hormone; FSH, follicle-stimulating hormone; G, genitalia stage; LH, luteinizing hormone; P, pubic hair stage. a Testosterone levels were taken in the morning. b Brook and Dattani (5). c Siemens (formerly DPC), IMMULITE® and IMMULITE 2000 Reference Range Compendium. d Crofton et al. (6). e Aksglaede et al. (7). View Large Table 1. Serial Hormonal Profiles Characteristic 2.00 y 11.50 y 13.16 y 15.00 y 15.98 y Reference Ranges Testosterone,a nmol/L <0.69 <0.69 <0.69 1.44 11.00 Prepubertal: <0.5b Adult: 10–30 LH, IU/L < 0.7 <0.2 0.9 2.5 4.6 Prepubertal: <0.5b Tanner stage 2: 1–4 Tanner stage 4: 2–8 FSH, IU/L 0.5 0.8 1.7 10.8 19.3 Tanner stage 1: 0.16–3.5c Tanner stage 2–3: 0.44–6.0 Tanner stage 4: 1.40–11.8 Tanner stage 5: 1.28–14.9 Inhibin B, pg/mL 229.4 47.7 12–17 years: 74–470d AMH, pmol/L 353.5 65.0 Tanner stage 3: 18–587e Tanner stage 4: 12–90 Tanner stage G1, P1, A1 G2, P1, A1 G3, P2, A1 G4, P2, A1 G5, P3, A1 Left testicular volume, mL 2 3 8 12–15 15–20 Characteristic 2.00 y 11.50 y 13.16 y 15.00 y 15.98 y Reference Ranges Testosterone,a nmol/L <0.69 <0.69 <0.69 1.44 11.00 Prepubertal: <0.5b Adult: 10–30 LH, IU/L < 0.7 <0.2 0.9 2.5 4.6 Prepubertal: <0.5b Tanner stage 2: 1–4 Tanner stage 4: 2–8 FSH, IU/L 0.5 0.8 1.7 10.8 19.3 Tanner stage 1: 0.16–3.5c Tanner stage 2–3: 0.44–6.0 Tanner stage 4: 1.40–11.8 Tanner stage 5: 1.28–14.9 Inhibin B, pg/mL 229.4 47.7 12–17 years: 74–470d AMH, pmol/L 353.5 65.0 Tanner stage 3: 18–587e Tanner stage 4: 12–90 Tanner stage G1, P1, A1 G2, P1, A1 G3, P2, A1 G4, P2, A1 G5, P3, A1 Left testicular volume, mL 2 3 8 12–15 15–20 Abbreviations: A, axillary hair stage; AMH, anti-Mullerian hormone; FSH, follicle-stimulating hormone; G, genitalia stage; LH, luteinizing hormone; P, pubic hair stage. a Testosterone levels were taken in the morning. b Brook and Dattani (5). c Siemens (formerly DPC), IMMULITE® and IMMULITE 2000 Reference Range Compendium. d Crofton et al. (6). e Aksglaede et al. (7). View Large Discussion 45,X/46,XY mosaicism is a rare genetic finding, leading to complex management issues with respect to sex of rearing and to unpredictability of the genital and gonadal phenotype of the affected children (1, 8). The relative distribution of the 45,X and 46,XY chromosomal cell lines among different tissues probably accounts for this wide phenotypic variation. The blood karyotype has several limitations: the number of cells examined can change the karyotype results, and the percentage of the 45,X cell line can also decrease over time (3, 8). Three cases have been reported so far of discordance between blood (46,XY) and gonadal (45,X/46,XY) karyotype (2, 9, 10). Two patients presented with ambiguous genitalia at the age of 1 year (2) and with a left undescended testis and penoscrotal hypospadias at the age of 16 years (9), respectively. The third case was a neonate with ambiguous genitalia in whom chromosome Y–derived sequences were detected in the dysgenetic gonad and skin fibroblasts (10). To our knowledge, our patient is the phenotypically mildest reported case of 45,X/46,XY mosaicism (isolated unilateral impalpable testis with normal male genitalia and spontaneous puberty) diagnosed only on the gonadal karyotype. Nonetheless, in keeping with previously reported cases (11), from the age of 15 years, our patient showed biochemical features of possible declining testicular function. It is well known that most 45,X/46,XY patients born with ambiguous genitalia are infertile. However, even in patients with mild phenotypes in childhood, spermatogenesis may be impaired in adulthood (11). Therefore, at diagnosis, possibilities of fertility preservation should be discussed with the patient and his family (1). 45,X/46,XY patients exhibit an increased tumor risk, not only when abdominal undifferentiated gonads are present but also in dysgenetic or “apparently normal” intrascrotal testes (1, 11, 12). In dysgenetic gonads, the formation of in situ gonadoblastoma or of an invasive germ cell tumor occurs in 15% to 52% of cases (12). However, the risk of germ cell malignancies is mainly defined by histological markers that do not distinguish “maturation-delayed” from “malignant” germ cells, probably leading to an overdiagnosis of cancer and also to overtreatment by gonadectomy (12, 13). Although in the past gonadectomy was recommended, a more conservative approach is now preferred to allow endogenous hormone production and therefore spontaneous puberty and to delay irreversible surgery until adulthood. Individualized management has recently been suggested in 45,X/46,XY patients, taking into consideration genetic factors, the localization of the gonad, the age and cooperation of the patient, and the histological and immunohistochemical findings (12–14). However, it must be pointed out that the risk of progression from histologically malignant lesions to clinical disease with actual morbidity and risk of metastases in these patients is unknown. An international Disorders of Sex Development registry that currently exists will hopefully offer greater insights on the long-term morbidity and mortality associated with malignancies in these patients (14). The evidence available on 45,X/46,XY patients suggests that no correlation exists between the clinical phenotype and the degree of mosaicism (4, 8, 11). The pubertal course, the fertility outcome, and the tumor risk seem to be predicted more by degree of genital ambiguity and gonadal differentiation than by the blood/gonadal karyotype (4, 8, 11). However, most patients, including mild cases without genital ambiguity and those starting puberty spontaneously, will develop some testicular impairment in adolescence or young adulthood (11). In our case, the preserved gonad maintained sufficient Leydig cell function to induce puberty, but the current hormonal profile possibly suggests declining testicular function, raising concerns for future fertility. Growth seems to be consistently impaired in these patients (11). Variable outcomes have been reported on GH treatment, with a recent review concluding that although there may be some short-term to midterm improvement in growth, long-term data on adult height are disappointing (15). However, supraphysiological GH doses and earlier commencement might result in better outcomes, as could have possibly been the case in our patient. Because fibroblasts have the same mesenchymal origin as chondrocytes and osteoblasts, karyotype from skin fibroblasts could be more useful than the blood karyotype to predict the growth phenotype of these patients (15). Furthermore, periodic screening for cardiac and autoimmune complications should be considered in 45,X/46,XY patients (16, 17). Our case report highlights that 45,X/46,XY mosaicism may present with a very mild phenotype and a normal blood karyotype. Cases without genital ambiguity can be easily missed. However, short stature and decline in testicular function over time are common features, even in mild cases, and these patients also exhibit a considerable risk of tumors and infertility. An early diagnosis of gonadal dysgenesis is therefore important in all cases to optimize growth, puberty, and fertility outcomes and to monitor for the increased tumor risk. Abbreviations: Abbreviations: GH growth hormone SDS standard deviation score Acknowledgments Financial Support: No funding was secured for this study. M.T.D. receives funding from the Great Ormond Street Hospital Children’s Charity. This research was supported by the National Institute of Health Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the National Health Service (NHS), the National Institute of Health Research (NIHR), or the Department of Health. Disclosure Summary: The authors have nothing to disclose. References 1. Wu Q , Wang C , Shi H , Kong X , Ren S , Jiang M . The clinical manifestation and genetic evaluation in patients with 45,X/46,XY mosaicism . Sex Dev . 2017 ; 11 ( 2 ): 64 – 69 . Google Scholar CrossRef Search ADS PubMed 2. Nishina-Uchida N , Fukuzawa R , Hasegawa Y , Morison IM . Identification of X monosomy cells from a gonad of mixed gonadal dysgenesis with a 46,XY karyotype: case report . Medicine (Baltimore) . 2015 ; 94 ( 14 ): e720 . Google Scholar CrossRef Search ADS PubMed 3. Takahashi I , Miyamoto J , Hasegawa Y . Limitations of G-banding karyotype analysis with peripheral lymphocytes in diagnosing mixed gonadal dysgenesis . Clin Pediatr Endocrinol . 2006 ; 15 ( 3 ): 109 – 115 . Google Scholar CrossRef Search ADS PubMed 4. Tosson H , Rose SR , Gartner LA . Description of children with 45,X/46,XY karyotype . Eur J Pediatr . 2011 ; 171 ( 3 ): 521 – 529 . Google Scholar CrossRef Search ADS PubMed 5. Brook CGD , Dattani MT . Handbook of Clinical Pediatric Endocrinology . 2nd ed . Oxford, United Kingdom : Wiley-Blackwell ; 2012 . Google Scholar CrossRef Search ADS 6. Crofton PM , Evans AE , Groome NP , Taylor MR , Holland CV , Kelnar CJ . Inhibin B in boys from birth to adulthood: relationship wih age, pubertal stage, FSH and testosterone . Clin Endocrinol (Oxf) . 2002 ; 56 ( 2 ): 215 – 221 . Google Scholar CrossRef Search ADS PubMed 7. Aksglaede et al. . J Clin Endocrinol Metab . 2010 ; 95 ( 12 ): 5357 – 5364 . 8. Rosa RF , D’Ecclesiis WF , Dibbi RP , Rosa RC , Trevisan P , Graziadio C , Paskulin GA , Zen PR . 45,X/46,XY mosaicism: report on 14 patients from a Brazilian hospital. A retrospective study . Sao Paulo Med J . 2014 ; 132 ( 6 ): 332 – 338 . Google Scholar CrossRef Search ADS PubMed 9. Anand A , Gupta NP , Singh MK , Mathur SR , Nayyar R . Mixed gonadal dysgenesis with normal karyotype: a rare case report . Indian J Pathol Microbiol . 2010 ; 53 ( 2 ): 313 – 315 . Google Scholar CrossRef Search ADS PubMed 10. Karatza A , Chrysis D , Stefanou EG , Mantagos S , Salakos C . Mixed gonadal dysgenesis in a 45,X neonate with chromosome Y material in the dysgenetic gonad . J Pediatr Endocrinol Metab . 2009 ; 22 ( 11 ): 1083 – 1086 . Google Scholar CrossRef Search ADS PubMed 11. Martinerie L , Morel Y , Gay CL , Pienkowski C , de Kerdanet M , Cabrol S , Lecointre C , Coutant R , Baron S , Colle M , Brauner R , Thibaud E , Leger J , Nihoul-Fekete C , Bouvattier C . Impaired puberty, fertility, and final stature in 45,X/46,XY mixed gonadal dysgenetic patients raised as boys . Eur J Endocrinol . 2012 ; 166 ( 4 ): 687 – 694 . Google Scholar CrossRef Search ADS PubMed 12. Cools M , Pleskacova J , Stoop H , Hoebeke P , Van Laecke E , Drop SLS , Lebl J , Oosterhuis JW , Looijenga LHJ , Wolffenbuttel KP ; Mosaicism Collaborative Group . Gonadal pathology and tumor risk in relation to clinical characteristics in patients with 45,X/46,XY mosaicism . J Clin Endocrinol Metab . 2011 ; 96 ( 7 ): E1171 – E1180 . Google Scholar CrossRef Search ADS PubMed 13. Cools M , Stoop H , Kersemaekers A-MF , Drop SLS , Wolffenbuttel KP , Bourguignon J-P , Slowikowska-Hilczer J , Kula K , Faradz SMH , Oosterhuis JW , Looijenga LHJ . Gonadoblastoma arising in undifferentiated gonadal tissue within dysgenetic gonads . J Clin Endocrinol Metab . 2006 ; 91 ( 6 ): 2404 – 2413 . Google Scholar CrossRef Search ADS PubMed 14. Spoor JA , Oosterhuis JW , Hersmus R , Biermann K , Wolffenbuttel KP , Cools M , Kazmi Z , Ahmed SF , Looijenga LHJ . Histological assessment of gonads in DSD: relevance for clinical management . Sex Dev . 2018 ; 12 ( 1-3 ): 106 – 122 . Google Scholar CrossRef Search ADS PubMed 15. Bertelloni S , Baroncelli GI , Massart F , Toschi B . Growth in boys with 45,X/46,XY mosaicism: effect of growth hormone treatment on statural growth . Sex Dev . 2015 ; 9 ( 4 ): 183 – 189 . Google Scholar CrossRef Search ADS PubMed 16. Bertelloni S , Dati E , Valetto A , Bertini V , Danti A , Baroncelli GI . Long-term growth hormone treatment in a boy with 45,X/46,X,idic(Yp) mixed gonadal dysgenesis: comparison with growth pattern of an untreated patient . Hormones (Athens) . 2015 ; 14 ( 1 ): 142 – 147 . Google Scholar PubMed 17. De Groote K , Cools M , De Schepper J , Craen M , François I , Devos D , Carbonez K , Eyskens B , De Wolf D . Cardiovascular pathology in males and females with 45,X/46,XY mosaicism . PLoS One . 2013 ; 8 ( 2 ): e54977 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 Endocrine Society

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Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Mar 30, 2018

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