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.
Retrospective longitudinal study of 40 patients followed between 1982 and 2017 in France.
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).
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.
The 45,X/46,XY mosaic is a rare condition, with an incidence between 1 in 6000 and 1 in 15000 live births (1, 2). 45,X/46,XY patients present a large spectrum of phenotypes, ranging from normal female phenotype, ambiguous genitalia (3) to male phenotype with normal external genitalia. Antenatal karyotype studies with systematic examination of the genitals at birth have assessed that more than 90% of these patients have normal external genitalia (1, 3). However, cohorts of 45,X/46,XY patients diagnosed in the postnatal period are mainly patients with severe genital anomalies in the literature, 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 genital ambiguity frequently have impaired testicular function, infertility and reduced adult height (4, 6, 7, 8, 9, 10). However, little is known about boys with a normal male phenotype or mild genital anomaly. These patients develop two testes, with secretion of AMH and testosterone during fetal development, allowing Mullerian ducts regression and virilization of genital organs. Thus, the diagnosis is rather difficult as they have few associated signs (6). Moreover, upon diagnosis, notably when it is incidentally found on an antenatal karyotype, these patients are rarely investigated or followed after birth. Currently, most of the diagnosed patients are identified in adulthood because of infertility (11, 12, 13). However, despite the absence of genital anomaly at birth, sporadic case reports have suggested that these patients may have dysgenetic testes, responsible for early decline of testicular function with pubertal delay and infertility (6, 14). Furthermore, they may also have short stature and other Turner syndrome-like features that need to be considered for proper management (15, 16, 17).
This study evaluates the clinical outcome of 45,X/46,XY male patients with normal or minor abnormalities of external genitalia (unilateral cryptorchidism or glanular hypospadias), in terms of growth, pubertal development and other phenotypic characteristics. It underlines the importance of an early diagnosis, of the necessity of long-term follow-up and should lead to a better management of these patients.
Inclusion criteria were phenotypically male patient (fetus, neonate, child or adult) with a 45,X/46,XY karyotype, followed between 1982 and 2017 by endocrinology or urology services in France. External genitalia had to be normal or only present a minor abnormality such as unilateral cryptorchidism or glanular hypospadias, with an External Masculinization Score (EMS) >10. Patients with an EMS ≤10 were excluded. Consent was obtained from each patient after full explanation of the purpose and nature of all procedures used. This observational study was approved by the Local and National Ethics Review Committee for Biomedical Research Project (N°2017/347_2, N°28164) and the French data protection authority (CNIL, DR-2018-049, N°918051), in accordance with the Declaration of Helsinki.
The following data were collected by retrospective investigation of medical records, growth charts and biological data:
Clinical data: term of pregnancy, birth parameters, obstetrical and neonatal medical history including intra-uterine growth retardation (IUGR), parental target height (defined by mean of height of the two parents +6.5 cm), age at diagnosis (defined as age of karyotype sampling), height and pubertal Tanner stage at diagnosis and at the end of puberty and reason for performing the karyotype. Phenotypic features due to 45,X monosomy were reported, such as facial particularities, pterygium colli, pectus carinatum, multiple naevi, high-arched palate, low posterior hairline, multiple otitis media or deafness and orthopedic defects such as scoliosis or leg length discrepancy. For each patient, weight and height data were collected at several ages throughout infancy and adolescence. Height measures are expressed as values both in centimeters and in standard deviation to the mean, corrected for target height (height SDS − target height SDS). Age at onset of pubertal development (G2 defined as a testicular size ≥4 mL or 25 mm), whether testosterone therapy was needed to induce puberty or thereafter and development of a testicular tumor were noted. Information on growth hormone therapy was gathered: duration, dose and stature gain after the first 2 years of treatment.
Chromosomal analyses were performed on peripheral blood lymphocytes. At least 30 mitoses were examined to determine the degree of mosaicism and Y chromosome rearrangements. All patients with an antenatal diagnosis had a postnatal karyotype in order to confirm the chromosome abnormality, apart from one patient due to parental refusal. In patients with a structural anomaly of the Y chromosome, breakpoints, TSPY gene, SHOX gene and Azoospermia Factor (AZF) loci analyses were noted when specified by geneticists. If not, we deduced from the Y chromosome structural anomaly, the number of copies of the SHOX and the TSPY gene present as well as possible alteration of the AZF loci in patients, in order to analyze phenotype/genotype correlations.
Hormone plasma levels were collected at several time points during follow-up: IGF1, FSH, LH, Inhibin B, AMH and testosterone concentrations. Sertoli cell dysfunction was defined by increased FSH level >10 IU/L and/or decreased inhibin B level <60 pg/mL from the onset of puberty. Results of sperm count were noted, when performed. Azoospermia was defined as the total absence of sperm in the semen.
Imaging investigations were reviewed, particularly with regards to the gonads (ultrasound or MRI), kidney and cardiovascular system.
Results are expressed as mean ± s.d. For hormone levels, results are expressed as median and interquartile. Statistical analyses were performed using a non-parametric Mann–Whitney U test for comparison between two groups, a Kruskal–Wallis test for comparison between more than two groups and a Fisher’s test for qualitative variables (Graph prism, Graphpad Software Inc.). Significant threshold was set at 0.05.
Forty patients were included in the study, originating from 12 centers.
Twenty patients had a prenatal diagnosis, whereas 20 patients had a postnatal diagnosis. Signs leading to amniocentesis were generally unrelated with the karyotype abnormality such as an increase of trisomy 21 markers or maternal age (9 patients). However, in some cases, features found by ultrasound imaging were similar to those observed in Turner syndrome: nuchal fold thickness (4 patients), short thighbone (2 patients), severe IUGR (3 patients) and renal malformation (2 patients). Ten patients were diagnosed during childhood mainly for short stature, associated with psychomotor delay in one patient and minor abnormalities of external genitalia in two patients. Among these ten patients, three were diagnosed because Mullerian ducts derivatives were incidentally found during testicular surgery (orchidopexy). Finally, six patients were diagnosed during puberty for isolated short stature, and four patients during adulthood for infertility.
All patients had a 45,X/46,XY karyotype. The mean plasma percentage of the 45,X lineage was 26.1% (range: 4–80%). Twenty patients (50%) had a structural defect of the Y chromosome: 13 patients with an isochromosome Y (11 Yp and 2 isodicentric Yq), 5 patients with a ring Y chromosome, 1 patient with a translocation between short arms of chromosomes Y and 18 and 1 patient with a Yq deletion. Thus, 12 patients had a defect concerning Yq, potentially leading to part or complete loss of the AZF region, compromising their fertility. Similarly, we deduced that 13 patients (those with an isochromosome Y) had two copies of the TSPY gene, implicated in testicular tumorigenesis.
Characteristics of external and internal genitalia
Normal external genitalia were observed in 18 patients while the 22 remaining patients had minor abnormalities of genital development (Table 1). There was no significant difference between patients with a prenatal diagnosis and patients with a postnatal diagnosis (Table 2). Internal genitalia were investigated by imaging or surgery in 12 patients, and Mullerian ducts derivatives were reported for 5 (42%) of these patients (all were patients with a postnatal diagnosis).
Phenotypic characteristics of patients external genitalia.
|Normal external genitalia||18||45|
|Unilateral cryptorchidism or asymmetry of testicular volume||11||27.5|
|Association of cryptorchidism/asymmetry of testicular volume and glanular hypospadias/penile curvature||6||15|
|Bilateral testicular hypotrophy||2||5|
Clinical characteristics of patients according to the timing of the diagnosis. For clinical and biological characteristics, results are expressed as the number of patients presenting with the anomaly, among the number of patients for whom screening of this anomaly was performed and the relative percentage.
|Prenatal diagnosis||Postnatal diagnosis|
|n (%)||20 (50)||20 (50)|
|Mild anomaly of external genitalia||7/20 (35%)||14/20 (70%)|
|IUGR||13/20 (65%)||9/13 (69%)|
|Height after correction for target height (DS ± s.d., n)|
|−0.79 ± 1.13 (n = 15)|
−0.88 ± 1.53 (n = 10)
−1.5 ± 0.07 (n = 2)
|−1.7 ± 0.97 (n = 5)|
−1.93 ± 1.07 (n = 13)
−2.65 ± 0.76 (n = 5)
|Mean pubertal growth spurt (cm ± s.d., n)||18.8 ± 0.28 (n = 2)||11.8 ± 1.95 (n = 4)|
|Mean final height (cm ± s.d., n)||163 ± 0.07 (n = 3)||160 ± 0.07 (n = 7)|
|Growth hormone treatment (n, %)||6/20 (30%)||10/20 (50%)|
|Turner syndrome features (n, %)||7/20 (35%)||14/20 (70%)a|
|Declined Sertoli cell function at puberty (defined by FSH ≥10 IU/L and/or inhibin B <60 pg/mL), n (%)||1/4 (25%)||7/20 (35%)|
|Mean age at last evaluation (years ± s.d.)||6.5 ± 6.5||12.69 ± 5.17b|
Twenty-one patients presented features suggestive of 45,X monosomy, aside from genital abnormality or growth deficiency (Fig. 1). In most cases, they concerned dysmorphic features consistent with Turner-like syndrome. Orthopedic defects were noted in eight patients as cubitus valgus, scoliosis or leg length asymmetry. Multiple otitis media was reported for five patients, including two suffering from conductive deafness. A mild psychomotor delay was noted for four patients. Autoimmunity was noted for three patients (Pernicious anemia and Hashimoto thyroiditis in one patient, isolated Hashimoto thyroiditis in one patient and positive anti adrenal and anti-GAD auto-antibodies in one patient). Twenty-six percent of patients investigated (6/23) had cardiac malformations (bicuspid aortic valve, mild aortic dilatation, ventricular septal defect with aortic insufficiency, atrial septum defect or aortic insufficiency) and 16% (3/19) had renal abnormalities (horseshoe kidneys or unilateral renal agenesis). There were significantly more Turner syndrome features in patients with a postnatal diagnosis than in patients with a prenatal diagnosis, particularly concerning orthopedic defects (P = 0.04) and dysmorphic features (P = 0.03) (Table 2). No difference was observed between patients with normal male phenotype and patients with minor abnormalities of external genitalia.
Prenatal and postnatal growth
Birth parameters were available for 33 patients investigated during childhood. Mean birth height was less than the 10th percentile for 22/33 patients (IUGR). No significant difference was observed between children with a prenatal or a postnatal diagnosis. Mean height standard deviation score (SDS) corrected for target height decreased progressively from the neonatal period to adolescence and adulthood (Fig. 2A). This growth pattern was confirmed for the five patients followed longitudinally until end of puberty (Fig. 2B). Adult height, evaluated in seven patients followed from childhood was 158 ± 7.6 cm (−2.30 DS ± 1.23 DS) with a poor pubertal growth spurt of 14.1 ± 4 cm. There was no significant difference in final height or pubertal growth spurt between patients with a prenatal and postnatal diagnosis (Table 2). In contrast, the mean height of patients diagnosed in adulthood was 166 ± 1.5 cm. A minor abnormality of external genitalia was significantly associated with a shorter adult height (P = 0.032). Conversely, Y chromosome structural defects were not associated with height variation; most notably, there was no correlation between the number of SHOX gene copies and final height (P = 0.25). Sixteen patients were treated with GH, including six patients with a prenatal diagnosis and ten patients with a postnatal diagnosis (Table 2). Mean age at onset of treatment was 7.4 ± 3.4 years, with an average dose of 49.7 ± 15 µg/kg/day. Mean duration of treatment was 4.5 ± 2.6 years, and GH therapy is still ongoing for six patients. The average height gain after 2 years of treatment evaluated in 11 patients was 0.92 ± 0.44 s.d. However, at final height assessment, there was no statistical difference between patients treated with GH and others (P = 0.87), and GH treatment did not seem to modify pubertal stunting in patients free of testosterone treatment (Fig. 2B).
Mini-puberty, evaluated in seven patients with a prenatal diagnosis at a mean age of 1.3 ± 0.6 months, showed adequate increase of testosterone and inhibin B levels, rising above 1.5 ng/mL and 150 pg/mL respectively, except for two patients evaluated prior to 1 month of life. hCG test, performed in six patients at various ages (6 months to 11 years), demonstrated an increase in testosterone level above 1.5 ng/mL. Among patients diagnosed during infancy, 15 have currently reached pubertal age. Puberty occurred spontaneously at a mean age of 12.7 ± 1.1 years, except for one patient who required testosterone therapy. Gonadal function was studied in ten patients during puberty (Fig. 3) and longitudinal follow-up was available for five patients (Fig. 4A). Clinical characteristics of these five patients are reported in Fig. 4B. Most of these patients, including one patient with a prenatal diagnosis, presented signs of declined Sertoli cell function at the end of puberty characterized by an abnormal rise in FSH levels and concomitant decrease of inhibin B levels. In particular, three patients had an inhibin B level of less than 60 pg/mL (N = 125–330) at the end of puberty. Conversely, Leydig cell function seems to be less affected with testosterone levels remaining in the normal range for age, but with half of the patients having testosterone levels at the lower limit and two patients having increased LH levels. Among patients diagnosed because of infertility, 50% had signs of Sertoli cell dysfunction and all had azoospermia, while Leydig cell function was preserved with testosterone levels between 4.5 and 7 ng/mL, although associated with increased LH levels in one patient. One adult patient had a testicular biopsy performed that showed Leydig cell hyperplasia and spermatocytic arrest, without carcinoma in situ component, as previously described in 45,X/46,XY men (9).
One patient developed a testicular embryonal carcinoma (Fig. 4, patient 4). This boy had surgery at 4 months of life for inguinal hernia on the left side and surgery for penile curvature correction during infancy. At the age of 12 years, he was referred to the pediatric endocrinology department for short stature. Upon diagnosis of the 45,X/46,XY mosaicism, growth hormone therapy was initiated. At age 17 years, testicular cancer was diagnosed on an increase of the right testis size at 6 cm. Pathology examination revealed an embryonal carcinoma with a yolk sac tumor component, adjacent to a dysgenetic tissue comprising a carcinoma in situ component. Orchidectomy was performed. There was neither locoregional nor systemic metastatic extension, and no chemotherapy or radiotherapy was necessary. Despite preservation of the left testis, the patient developed testicular failure, with a high increase in FSH and LH levels (42.1 (N = 1.5–12.5) and 30.6 (N = 1.7–8.6) IU/L, respectively). Testosterone levels were low (2.15 ng/mL) and sperm count showed azoospermia. Treatment by intra-muscular testosterone therapy was initiated. Considering the risk of tumor recurrence, it was decided to perform a left orchidectomy after germ cell preservation.
This study describes to our knowledge, the largest cohort of 45,X/46,XY boys with normal or mild genital anomaly (EMS >10). We demonstrate that these patients may have Turner-like syndrome features and a certain degree of gonadal dysgenesis, in mirror to 45,X/46,XY patients with genital ambiguity, highlighting the need of an early diagnosis and long-term follow-up as proposed in Table 3.
Suggestion of follow-up guidelines for 45,X/46,XY male patients with no or mild genital anomaly (EMS >10).
|Initial screening at diagnosis||Annual follow-up|
|• Clinical examination including external genitalia, identification of Turner syndrome dysmorphic features or skeletal defects and psychomotor evaluation|
• Identification on the karyotype of potential structural abnormality of the Y chromosome, and deletion of the AZF loci
• Pelvic ultrasound for detection of potential Mullerian ducts
• Cardiac and renal ultrasound for detection of potential malformations
• ENT evaluation
• Auto-immune evaluation (thyroid, coeliac disease) and metabolic evaluation after puberty (fasting glucose concentrations, blood pressure, standard lipid evaluation)
|• Clinical examination including assessment of pubertal progression|
• Growth monitoring
• Testicular function, starting from onset of puberty or age 12
• Testicular tumor screening: palpation and annual ultrasound
• Testicular biopsy should be discussed during infancy (in combination with orchidopexy if required) and at the end of puberty, or in case of ultrasound anomaly
• Auto-immune evaluation (thyroid, coeliac disease) and metabolic evaluation after puberty (fasting glucose concentrations, blood pressure, standard lipid evaluation) every two years
• ENT, cardiac, renal or orthopedic follow-up depending on the initial evaluation
• Proposition of fertility preservation at the end of puberty
45,X/46,XY mosaicism is due to a post-zygotic mitotic error during embryogenesis, causing loss of the Y chromosome in a cell line. The timing of this loss, and therefore, the number and distribution of 45,X cells within the organism, differs among patients, producing a broad phenotypic spectrum (18). Nevertheless clinical phenotype is not correlated with the percentage of 45,X cells on lymphocytic karyotype (6, 7, 8). Factors determining the distribution of 45,X cells are unknown (19). In the gonads, it has been suggested that gonadal differentiation depends on the percentage of 45,X cells colonizing the urogenital ridge during embryogenesis (4, 20). Indeed, several case reports have shown a predominance of 45,X cells in streak gonads in patients with a female phenotype, and a predominance of 46,XY cells in patients with testes and a male phenotype (21, 22). Interestingly, our results suggest that even 45,X/46,XY patients with normal male differentiation may present a certain degree of testicular dysgenesis. Indeed, 55% of our patients had minor abnormalities of external genitalia, such as unilateral cryptorchidism or glanular hypospadias, which appears more frequent than in the general population (23). It should be noted that five patients had a glanular hypospadias and/or penile curvature, which may have hidden a more severe hypospadias. The EMS score may thus underestimate the degree of under masculinization of some of these patients. Nevertheless, this suggests that androgen production may have been inadequate at a critical time of genital development. However, dysfunction appears to be transient as patients have testicular function within normal limits during mini-puberty and most patients had spontaneous pubertal onset. However, patients followed longitudinally demonstrated signs of declined Sertoli cell function at the end of puberty, characterized by low inhibin B levels and increased FSH levels while Leydig cell function seemed to be preserved with increase of testosterone levels during puberty, as described in 45,X/46,XY patients with genital ambiguity (7, 9) and patients with Klinefelter syndrome (24). It remains to be determined whether this phenotype is linked to a moderately altered gonadal function starting from the fetal period, which is unmasked for most patients during puberty or whether it is in relation to a progressive alteration of testicular phenotype toward dysgenesis, due to accelerated loss of the Y chromosome and emergence of the 45,X cell line in gonads.
Another determinant of the phenotype relies on structural defects of the Y chromosome found in 50% of our patients, corroborating results from 45,X/46,XY patients with major genital anomalies (7). These chromosomal rearrangements induce instability and result in loss of part of the chromosome and/or duplication of other fragments (25, 26). In our cohort, Y chromosome structural defects were predominantly isochromosome Y(p), compromising fertility by inducing deletion of the AZF region (27), required for normal spermatogenesis (28). Indeed, the five patients evaluated for fertility in our cohort had azoospermia. Among these patients, four patients had a structural defect of the Y chromosome including one patient with a deletion of the AZF loci. In the literature, 45,X/46,XY karyotype has a prevalence of 0.3–1% among patients referred for non-obstructive azoospermia (11, 13) related to testicular dysgenesis and defects of the AZF loci (29). Thus, fertility evaluation in these patients should be an early concern in order to propose assisted reproductive techniques such as testicular sperm extraction, as it has readily been proposed for patients with 45,X/46,XY mosaicism or AZF microdeletions (13, 30). The ethical dilemma raised by potential transmission of an unstable Y chromosome remains to be evaluated (31, 32) and may suggest a need for pre-implantation genetic screening.
One patient of our cohort (2.5%) developed testicular embryonal carcinoma. This is less than the estimated prevalence of 15% (33) reaching 50% in the third decade according to Donahoe et al. (34). However, only 27.5% of our patients have reached adult age and very few patients have had testicular biopsies; thus, this prevalence could be underestimated in our cohort. This risk is related to the persistence of germ cells blocked in their maturation, which express embryonal markers such as OCT3/4 and TSPY gene, regulators of apoptosis and proliferation, promoting transformation of embryonal germ cells into precursor lesions (35, 36). According to Cools et al., gonadal tumor risk is more pronounced in the case of poorly differentiated gonads (37). Tumor risk is considered intermediate for 45,X/46,XY patients with intra-scrotal testes, although some observations report early-stage gonadoblastoma already present in fetuses or infants (1, 14). Regardless of these observations, it has never been properly evaluated because these patients are often inadequately monitored (35). It is therefore legitimate to propose that these patients should benefit from similar management than patients with signs of undervirilization, i.e. a conservative approach with systematic orchidopexy and annual ultrasonography monitoring. Testicular biopsy should be discussed during infancy (in combination with orchidopexy if required) and at the end of puberty or in case of ultrasound anomaly (3, 33, 37). As a result, despite a reassuring presentation, it seems essential to follow 45,X/46,XY patients with normal male phenotype, especially regarding testicular function, fertility and tumor risk.
In addition, 70% of our patients had features seen in Turner syndrome, most predominantly short stature, observed in half of the patients. Growth is altered starting from the antenatal period and worsens at puberty in relation to a poor pubertal growth spurt. Furthermore, mean final stature for patients assessed at the end of puberty was 158 ± 7.6 cm, similar to 45,X/46,XY patients with genital ambiguity raised as boys (7). Thus, our study suggests that patients with a 45,X/46,XY mosaicism with or without genital anomaly could display similar growth pattern (4, 6, 7, 9). By analogy with Turner syndrome, some authors propose that this altered growth is related to the 45,X cellular contingent, by SHOX haploinsufficiency (38). However, many studies have failed to find a correlation between patient’s phenotype, including final height, and the proportion of 45,X cells in lymphocyte’s karyotype (14). Growth failure could also be linked to an additive deletion of the SHOX gene from the Y chromosome PAR1 region in the 46,XY cells. However, we found no significant height difference between patients with Y structural abnormality and those with normal Y chromosome. The most frequent cytogenetic abnormality in our patients was isodicentric Y(p), which may result in two copies of the SHOX gene. Anyhow, no correlation was found between the number of SHOX gene estimated copies and adult height. Yet, stature is probably mainly determined by the relative expression of 45,X cells and defective 46,XY cells, in the testes, bone and growth plate. Therefore, considering the importance of growth failure among 45,X/46,XY boys, it could be relevant to perform a systematic karyotype (or guided by associated signs of testicular impairment) in boys referred for short stature, as it is already done in girls to detect Turner syndrome. This screening remains to be evaluated by a prospective study but could lead to earlier diagnosis of these patients.
In our cohort, 16 patients were treated with GH, with results similar to 45,X/46,XY patients with genital ambiguity (15) and 45,X/46,XY Turner patients (39) in terms of initial two-year height gain. However, despite the initial GH response, there was no statistical difference at last evaluation between the treated and untreated group, as already described (40). This may be related to the fact that GH treatment was offered to the shortest patients and that treatment resulted in a similar height. Thus, prospective studies are still required to assess whether GH treatment could be of benefit in improving adult height in this population. Finally, 22.5% of the cohort presented cardiac or kidney malformations, as it has already been sporadically described in some case studies. However, it should be noted that only about 50% of the cohort had a cardiac and/or renal exploration, which may lead to an underestimation of the frequency of these malformations in our patients, as already suggested by Klàskovà et al., underlying the crucial importance of detailed cardiovascular screening, regardless of the initial clinical presentation of these patients (41). Even if the risk of malformation is much lower than that of patients with an homogeneous 45,X karyotype (39), it should not be ignored and 45,X/46,XY patients should be investigated.
Results must obviously be nuanced because of the observational nature of retrospective data collection and missing data. Several studies have suggested that patients diagnosed prior birth have a less severe phenotype (42). We also found a higher prevalence of Turner-like features in patients with a postnatal diagnosis. However, this is likely due to the significantly longer follow-up period of these patients compared to those with a prenatal diagnosis. Indeed, dysmorphic features or orthopedic abnormalities may appear only during late childhood or at puberty (43). As a result, our findings also emphasize that all patients, including those diagnosed prenatally, should be followed on the long term. Indeed, these patients are not exempt from complications related to the 45,X monosomy such as short stature, malformations or impaired gonadal function. Nevertheless, in order to accurately assess their phenotype, it would be essential to conduct a longitudinal prospective study of 45,X/46,XY children diagnosed prior birth.
Our results have important clinical implications. We have shown that these patients may exhibit signs of Turner syndrome including stunted growth and have mild gonadal dysgenesis with exhaustion of Sertoli cell function at puberty, raising concerns for fertility and risk of developing a testicular tumor. However, the current prevalence of these findings is difficult to specify given the absence of prospective follow-up studies. Therefore, it seems essential to identify these patients by considering the systematic evaluation of karyotype in patients referred for growth failure especially among those who have associated gonadal malfunction or Turner syndrome features. Finally these patients, upon diagnosis, must be followed throughout their life, with particular attention paid to growth, testicular function and testicular tumor screening and fertility preservation should eventually be considered.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study.
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Author contribution statement
L Dumeige and L Martinerie conceptualized and designed the study, drafted the initial manuscript, coordinated data collection and reviewed and revised the manuscript. L Chatelais, collected data, carried out the initial analyses and reviewed the manuscript. C Bouvattier, M De Kerdanet, C Hyon, B Esteva, D Samara-Boustani, D Zenaty, M Nicolino, S Baron, C Metz-Blond, C Naud-Sandreau, C Dupuis , J Léger , J P Siffroi, S Christin-Maitre, B Donadille, J-C Carel collected data and critically reviewed and revised the manuscript. R Coutant coordinated data collection and critically reviewed the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
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