47,XYY and 47,XXX Syndromes and Tetrasomy X

Literature and regulatory information updated: 4 October 2026.

Sex chromosome aneuploidies beyond Turner and Klinefelter: Jacobs syndrome (47,XYY), triple X syndrome (47,XXX), tetrasomy X (48,XXXX) and pentasomy X (49,XXXXX) as a differential diagnosis

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0. Initial Reference Table

Related entities. Turner syndrome (45,X and mosaicism, including 45,X/47,XXX), Klinefelter syndrome (47,XXY) and male polysomies with supernumerary X chromosomes (48,XXYY, 48,XXXY, 49,XXXXY), as well as tetrasomies and pentasomies with supernumerary Y chromosomes (48,XYYY, 49,XYYYY, 49,XXYYY, 49,XXXYY), are part of the differential diagnosis; Bishop and colleagues compared special educational needs in 47,XYY and 47,XXY boys. This article addresses only features specific to the 47,XYY, 47,XXX and 48,XXXX entities, with pentasomy X as a differential diagnosis.

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1. Introduction

Sex chromosome aneuploidies collectively constitute the most frequent chromosomal abnormalities in humans: surveys of consecutive live births show a frequency of around 1 in 400 births, and the frequency at amniocentesis or chorionic villus sampling is even higher, estimated at between 1 in 250 and 1 in 300 [29]. Whereas monosomy X (Turner syndrome) and the 47,XXY karyotype (Klinefelter syndrome) have phenotypes that lead, sooner or later, to medical consultation, 47,XYY and 47,XXX trisomies are characterised by subtle physical phenotypes, without consistent dysmorphism, and largely remain undiagnosed throughout life [4, 7]. In Denmark, which has had a national cytogenetic registry since 1961, only 18% of the expected 47,XYY men and 13% of the expected 47,XXX women ever received a diagnosis [12].

The history of these entities is inseparable from the history of human cytogenetics. In 1959, a few months after the descriptions of trisomies 21 and XXY, Patricia Jacobs and colleagues described in the Lancet a 35-year-old woman of normal intelligence, with secondary amenorrhoea since the age of 19 and a karyotype with three X chromosomes, whom they called, in the terminology of the time, a “super-female” [8, 30]. In 1961, Sandberg and colleagues published the first man with an XYY karyotype [31], and in the same year Carr, Barr and Plunkett described two women with intellectual disability and an XXXX chromosome complement [32]. In 1963, Kesaree and Woolley reported the first child with 49 chromosomes, presumably XXXXX [33]. In 1965, cytogenetic screening of men admitted to a secure psychiatric hospital in Scotland, published in Nature by Jacobs and colleagues, found a high frequency of XYY men and associated the karyotype with aggressive behaviour and intellectual impairment [34]. This association, based on institutionalised populations, gave rise to the myth of the “criminal super-male”, which was corrected only by longitudinal studies of unselected newborns and, later, population registry studies [5, 24, 35].

Current knowledge rests on three sources of data with distinct biases. The first comprises prospective cohorts of newborns identified by neonatal cytogenetic screening in the 1960s and 1970s (Denver, Edinburgh, Toronto, Aarhus, among others), followed into adulthood, which provide the least biased picture of the phenotype [5, 36, 37]. The second comprises contemporary clinical series from specialist centres (such as the eXtraordinarY Kids programme in Colorado), which compare children diagnosed prenatally with children diagnosed after birth because of developmental delay, learning difficulties or behavioural problems [15, 38]. The third comprises national registries and population biobanks (Denmark, UK Biobank, Geisinger MyCode), which have revealed increased mortality, a greater burden of morbidity and socioeconomic disadvantage [13, 39–41]. The spread of non-invasive prenatal testing (NIPT) using circulating cell-free fetal DNA, which frequently includes the sex chromosomes, has made prenatal findings the principal route to these diagnoses and prenatal genetic counselling a core competency of the clinical geneticist [42, 43].

Tetrasomy X and pentasomy X are rare, and knowledge of them derives almost exclusively from reports and small series, generally of patients identified after birth, which makes their natural history uncertain [44]. The general principle, also observed in the male polysomies, is that the severity of the cognitive and malformation phenotype increases with the number of supernumerary sex chromosomes, with an estimated reduction of 10 to 15 intelligence quotient (IQ) points for each additional X [9, 44].

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2. Molecular Genetics and Pathophysiology

2.1 Mechanisms of origin

47,XYY. The supernumerary Y chromosome is always paternal in origin and, in the great majority of cases, results from non-disjunction of Y chromatids in paternal meiosis II following normal chiasmate meiosis I; postzygotic mitotic errors and non-disjunction in meiosis II following achiasmate meiosis I are alternative mechanisms [4]. In Robinson and Jacobs' study of 28 non-mosaic 47,XYY men analysed using polymorphisms at the distal end of the Xp/Yp pseudoautosomal region, 16 of the 19 cases with available parents resulted from non-disjunction in meiosis II following normal chiasmate meiosis I, and the remaining three from a postzygotic error or non-disjunction in meiosis II following achiasmate meiosis I [14]. Unlike trisomies of maternal origin, there is no effect of advanced paternal age [4]. The Brazilian handbook Síndromes Genéticas: Reconhecer para Tratar summarises the chromosome constitutions associated with Jacobs syndrome: 47,XYY resulting from paternal non-disjunction in meiosis II or a postzygotic event; 48,XXYY and 49,XXXYY resulting from non-disjunction in meioses I and II [2].

47,XXX. The supernumerary X is maternal in origin in around 90% of cases. Studies of parental origin show that 58–63% of cases derive from errors in maternal meiosis I, 16–17.4% from errors in maternal meiosis II and 18–19.6% from postzygotic non-disjunction [8, 15]. There is a statistically significant correlation with maternal age, with a risk rising from 1 in 2,500 live births at 33 years to 1 in 450 at 43 years [7, 8]. The Brazilian handbook states that almost all cases result from an error in maternal meiosis I, with a higher risk above 35 years [3]; however, the estimate of around one fifth of cases being postzygotic in molecular series should be considered in counselling. Mosaicism occurs in around 10% of cases and may arise in several combinations (46,XX/47,XXX; 47,XXX/48,XXXX; 45,X/47,XXX; 45,X/46,XX/47,XXX) [7, 8]. Mosaic forms with a 45,X cell line showed no correlation with maternal age, which is consistent with a postzygotic error or trisomy “rescue” [8].

48,XXXX and 49,XXXXX. In eight individuals with sex chromosome tetrasomy or pentasomy studied using X markers, one parent contributed a single sex chromosome and the other three or four, indicating that most, if not all, of these polysomies result from successive non-disjunction events in the same parent [16]. In tetrasomy X, the supernumerary X chromosomes were maternal in origin in the cases studied [17], and a recent Japanese case showed all four X chromosomes to be maternal in origin without any paternal sex chromosome, consistent with the rare coexistence of maternal and paternal non-disjunction or with polysomy “rescue” [45]. In a Brazilian patient with pentasomy X, genotyping identified four maternal X chromosomes and one paternal X, consistent with two maternal meiotic non-disjunction events [18].

2.2 Gene dosage, X inactivation and pseudoautosomal regions

In a 46,XX woman, only one X chromosome is active in each cell; the other is inactivated early in blastogenesis by a process controlled by the X-inactivation centre (XIC), which “counts” the X chromosomes and inactivates all but one per diploid set through XIST expression, DNA methylation and accumulation of histone variants [8]. In trisomy X, two of the three X chromosomes are inactivated; however, genes in the pseudoautosomal regions (PAR1 and PAR2), which have homologues on the Y, and around 5–10% of the remaining X genes escape inactivation and are expressed from all three chromosomes [8, 15]. The prevailing hypothesis is that the phenotype results from overexpression of these escape genes, many of which participate in neurodevelopment; apart from SHOX, the specific genes responsible have not yet been identified [8].

The SHOX (short stature homeobox) gene, located in PAR1 and present on the X and Y chromosomes, escapes inactivation. Its haploinsufficiency explains the short stature in Turner syndrome, and its increased dosage is the proposed determinant of tall stature in aneuploidies with supernumerary sex chromosomes [8, 19]. In Ottesen and colleagues' study of 305 patients, median height standard deviation (SD) was +1.3 in 47,XYY (n = 44), +0.7 in 47,XXX (n = 40), −0.6 in 48,XXXX (n = 13) and −1.0 in 49,XXXXX (n = 3): height increases with the number of extra sex chromosomes, except in women with four or five sex chromosomes (and in men with five), demonstrating a non-linear effect [19]. This non-linear effect is attributed to the increasing contribution of other genes (for overall growth, skeletal development and gonadal action) as dosage becomes more imbalanced.

In pentasomy X, analysis of human–rodent somatic hybrids from a Brazilian patient showed that more than one X was functionally active (12% of X chromosomes with maternal haplotype M1, 43.5% of X chromosomes with haplotype M2 and 100% of the paternal X), with asynchronous late replication patterns, suggesting that disturbed inactivation contributes to the severity of the phenotype [18].

In 47,XYY, Y genes present in double dosage include genes in the pseudoautosomal regions and Y-specific genes, such as those in the Y-linked neuroligin family (NLGN4Y), proposed, together with X-linked neuroligins, as a possible substrate for the communication and autism spectrum disorders observed in sex chromosome trisomies [22]. Neuroimaging shows foci of white matter hyperintensity in all three trisomies, and reduced total brain volumes in trisomy X, with a correlation between smaller brain volume and poorer cognitive performance [8, 46].

2.3 Gonadal physiology

The 47,XYY testis. For decades, testicular function in 47,XYY was assumed to be normal, or even increased: Smith's Recognizable Patterns describes increased testicular volume in 78% and normal testosterone [5], and Bardsley and colleagues' cohort found testicular volume above +2 SD for age in 50% of boys, with testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH) within normal ranges in most [38]. More recent studies show subtle Sertoli cell dysfunction: in 82 47,XYY boys compared with 66 controls, inhibin B was lower (median 84 vs. 109 pg/mL) and anti-Müllerian hormone (AMH) higher (41 vs. 29 ng/mL), with no difference in testosterone, testicular volume or penile length; higher inhibin B and testosterone concentrations were associated with better cognitive and behavioural outcomes and shorter auditory latencies on magnetoencephalography [47]. A systematic review with meta-analysis of 362 patients showed significantly lower testosterone and higher LH and FSH than in 46,XY men, testicular volumes that were frequently normal but reduced in some patients, and an appreciable proportion with oligozoospermia or azoospermia [24]. Most spermatozoa in 47,XYY men are chromosomally normal, which is attributed to loss of XY bivalents and Y univalents during spermatogenesis, or loss of the supernumerary Y in primitive germ cells with a proliferative advantage for XY cells [4].

The 47,XXX and 48,XXXX ovary. Puberty and sexual development are usually normal in trisomy X [7, 20], but there is an increased risk of premature ovarian insufficiency (POI, also termed premature ovarian failure) [7, 8]. In a case–control study, 15 girls with trisomy X (median age 13.4 years) had significantly lower serum AMH than 26 controls (0.7 vs. 2.7 ng/mL), and 67% had AMH below the 2.5th percentile for age (odds ratio 11; 95% CI 2.3–42), suggesting reduced ovarian reserve from adolescence and, potentially, a narrow time window for fertility preservation [25]. In tetrasomy X, menstrual disorders are frequent and fertility is reduced [20], and POI with osteoporosis in adolescence has been described [17, 48]. A considerable proportion of POI cases in trisomy X are associated with autoimmune diseases, particularly autoimmune thyroiditis [8, 26].

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3. Clinical Spectrum and Manifestations by System

3.1 47,XYY syndrome (Jacobs syndrome)

3.1.1 Physical phenotype

Clinical features are absent in the perinatal period: birth weight, length and head circumference do not differ from controls [2, 4]. From 2 years, growth velocity increases until puberty, and boys enter puberty 7–8 cm taller than controls; the pubertal growth spurt is prolonged and mean final height is 188 cm (91st to 98th percentiles) [4]. The tendency towards tall stature usually becomes apparent between 5 and 6 years, although some boys are already long at birth [2, 5]. Despite their size, these boys are generally neither strong nor well coordinated, and have poor muscular development of the shoulder girdle and pectoral region [5]. The Oxford Desk Reference emphasises that there are no consistent dysmorphic features [4], whereas Smith's and the Brazilian handbook describe a variable pattern of minor findings that may raise clinical suspicion [2, 5]. Figure 1 in the Smith's chapter (p. 63) shows an 8-year-old boy assessed for behavioural problems and poor school performance, with a relatively long face and large ears [5], and Figure 1.6.1 in the Brazilian handbook shows a prominent forehead, a dysmorphic ear, long fingers and bilateral cryptorchidism [2].

In the cross-sectional cohort of 90 47,XYY boys and young men (mean age 9.6 years) assessed at two academic centres, the incidences of asthma, seizures, tremor and autism spectrum disorder (ASD) were higher than in the general population, and no differences in physical phenotype were observed between those diagnosed prenatally and after birth [38]. The Orphanet definition adds mild hypertelorism, low-set ears and a slightly flat malar region as facial features [1]. The Brazilian handbook includes a case published in the Portuguese-language literature of a premature 47,XYY newborn with total anomalous pulmonary venous return and short stature, whose association the authors considered probably coincidental [2, 49]: the Oxford Desk Reference points out that if a 47,XYY boy has dysmorphism or malformations, these should not be attributed to the karyotype without further investigation [4].

3.1.2 Neurodevelopment and behaviour

Overall IQ lies within normal limits (range 80–140 in Smith's), but on average 10–15 points below that of siblings; verbal IQ is more affected than performance IQ [4, 5]. Leggett and colleagues' systematic review, focusing on samples not biased by clinical referral, confirmed IQ in the normal range in 47,XYY men, but marked difficulties with speech and language, motor skills and school performance, common to all three sex chromosome trisomies [36]. Speech and language delay is frequent and around 70% receive speech and language therapy; more than 50% have special educational needs (SEN), and only 10% of Bishop and colleagues' cohort had neither SEN nor any diagnosis [4]. In Ratcliffe's series of 19 boys, 54% had reading difficulties (18% in controls) and 47% had been referred to psychiatry (9% in controls) [4, 37]. Severe intellectual disability is rare [4]. Data are available on SEN, speech and language therapy and diagnoses in 47,XYY boys comparing prenatal diagnosis and patient association groups.

Attention deficit hyperactivity disorder (ADHD). In a study of 167 participants aged 6 to 20 years with four sex chromosome aneuploidies, 76% of 47,XYY boys met DSM-IV criteria for ADHD on parent questionnaires (36% in 47,XXY, 52% in 47,XXX and 72% in 48,XXYY), with a higher frequency of hyperactivity/impulsivity symptoms in 47,XYY and 48,XXYY; treatment with psychostimulants was effective in 78.6% (66/84) of treated patients [21]. The Oxford Desk Reference states that stimulants helped in 80% [4]. Behavioural problems — distractibility, hyperactivity and tantrums — are present in childhood and early adolescence; aggression is not usually a problem and these children learn to control anger with age [5]. Compared with 47,XXY boys, 47,XYY boys had higher scores on the behavioural problems, externalising, withdrawal, thought problems and attention problems subscales of the Child Behavior Checklist and a higher frequency of hyperactivity/impulsivity symptoms [50].

Autism spectrum disorder. In Bishop and colleagues' study, 11 of 58 47,XYY boys (19%) had a diagnosis of ASD, a 10- to 20-fold increase even over the most liberal estimates of population prevalence; after excluding cases with ASD, communication profiles with mild autistic traits were frequent [4, 22]. On screening with the Social Communication Questionnaire, 50% of 47,XYY boys scored above 15 (12% in 47,XXY boys) [50]. Smith's reports ASD in 11% of those diagnosed prenatally and 40% of those diagnosed after birth [5], and Bardsley's cohort showed that boys diagnosed prenatally had better cognitive outcomes and a lower likelihood of an ASD diagnosis [38]. General cognitive ability, language, verbal memory and some aspects of attention, executive function and motor function are reduced [5]. In an in-depth comparison of 167 individuals aged 5 to 25 years (102 with 47,XXY and 65 with 47,XYY) assessed using a battery of 15 standardised neurocognitive scales, the 47,XYY group showed greater impairment overall than the 47,XXY group, with a similar relationship between cognition and adaptive functioning in both karyotypes; this was a research sample recruited through referral rather than a population cohort [51].

Adolescence and adulthood. A recent narrative review, accompanied by an adolescent series, describes increased psychiatric vulnerability in adolescence and adulthood, with higher rates of mood, psychotic and substance use disorders, and a trajectory marked by early developmental delays, progressive behavioural dysregulation in adolescence and a limited or inconsistent response to several classes of psychotropic medication in a subgroup of patients [52]. Sexual orientation is as in the general population and heterosexual activity is normal [4, 5].

Antisocial behaviour: the current state of the evidence. In a large Danish study of 161 47,XYY men, the overall risk of conviction (excluding traffic offences) was moderately increased, but became similar to that of controls after adjustment for socioeconomic parameters; mean IQ values were lower in those convicted, and intellectual impairment appears to be the main risk factor for antisocial and unlawful behaviour [4, 35]. Smith's reports increased convictions for sexual abuse, robbery and arson [5]; these data should be interpreted in the light of the socioeconomic adjustment mentioned and never used to characterise an individual. 47,XYY men change jobs more frequently than controls, but the range of jobs is broad and most should have normal employment prospects [4].

3.1.3 Puberty, gonadal function and fertility

Secondary sexual development is normal, although onset may be delayed by around 6 months compared with controls; in some cases early pubertal development occurs [4, 5]. Most 47,XYY men are fertile and have chromosomally normal offspring [2, 4, 5]. However, recent data point to reduced fertility: in the Danish registry, 47,XYY men were less likely to be fathers than the general population (although more likely than men with Klinefelter syndrome) [53], and the 2025 meta-analysis identified oligozoospermia or azoospermia in a relevant proportion of patients [24]. Smith's also mentions that an increased risk of offspring with chromosomal abnormalities, miscarriage and perinatal death has been suggested [5]. Based on normal testicular biopsies from seven 47,XYY men, it was concluded that there is no increased risk of gonadal tumours [5]. In UK Biobank, 47,XYY men aged 40 to 70 years appeared to have normal reproductive function, unlike 47,XXY men [13].

3.1.4 Morbidity and mortality in adulthood

In the Danish registry of 208 47,XYY men, life expectancy was 67.5 years, compared with 77.9 years in controls, with an all-cause mortality hazard ratio (HR) of 3.6 (95% CI 2.6–5.1) and a significant increase in mortality from cancer, pulmonary and neurological diseases, trauma and unspecified causes [5, 39]. Adjustment for marital status and education reduced the HR to 2.7, indicating that socioeconomic disadvantage (fewer marital relationships, lower income and educational attainment, earlier retirement) explains part of the excess mortality [53]. The Brazilian handbook includes leukaemias and lymphomas among causes of morbidity [2]. In UK Biobank, only 1 of 143 47,XYY men (0.7%) had a recorded diagnosis; the karyotype was associated with increased risks of type 2 diabetes (relative risk 2.6), venous thrombosis (7.4), pulmonary embolism (3.7) and chronic obstructive pulmonary disease (4.6), explained only partly by body mass index, socioeconomic deprivation and smoking [13]. In a joint analysis of two biobanks (Geisinger MyCode and UK Biobank), adults with aneuploidies involving supernumerary sex chromosomes had a 4- to 5-fold higher risk of venous thromboembolism than 46,XX or 46,XY individuals (HR 5.4 and 4.1, respectively) [41].

3.2 Triple X syndrome (47,XXX)

3.2.1 Physical phenotype

The appearance is usually that of a girl or woman without marked dysmorphism, and features are virtually absent in the perinatal period [3, 7]. There is no malformation pattern associated with this karyotype [20]. At birth, 47,XXX girls have, on average, lower weight and smaller head circumference [46]. Height increases in early childhood and, in adolescence, most are at or above the 75th percentile; tall stature (> 80th percentile) is a consistent finding, with body proportions of long lower limbs and short sitting height, without a difference in bone age [7, 8]. Mean adult height is 172 cm in Smith's and 171 cm (range 157–179 cm) in Wigby and colleagues' series [15, 20]. Mean head circumference is around the 10th to 20th percentile; microcephaly (< 5th percentile) is rare in the series, although the Brazilian handbook includes it in the clinical picture [3, 7, 8, 20]. Figure 1.7.1 in the Brazilian handbook shows a 47,XXX girl (face and whole body) [3], and Figure 1 in Tartaglia and colleagues (open access) illustrates facial variability, from epicanthic folds and hypertelorism at 2 years to the absence of dysmorphism at 19 years [8].

Other minor findings include upslanting palpebral fissures, overlapping digits, flat feet, pectus excavatum and joint hyperextensibility [3, 8]. Congenital heart defects have been described — atrial and ventricular septal defects, atrioventricular septal defect, pulmonary stenosis and coarctation of the aorta [3, 8]. In Wigby and colleagues' series of 74 girls, 23% had some congenital abnormality (cleft lip or palate or velopharyngeal insufficiency, heart defect, renal or genitourinary abnormality, clubfoot), 34% had early feeding difficulties, and kyphoscoliosis and tremor tended to increase with age [15]. Scoliosis is probably more frequent in adolescence [46]. Seizures include absence, partial and generalised seizures, with a good response to conventional antiepileptic drugs [8], and there is a small excess of epilepsy and EEG abnormalities [7]. The Oxford Desk Reference indicates that the frequency of structural urogenital abnormalities may be slightly increased [7]. The Brazilian handbook also includes diarrhoea and constipation among gastrointestinal manifestations [3].

3.2.2 Neurodevelopment, language and mental health

Children with trisomy X have an increased risk of motor and language delays. Mean age at independent walking is 16.2 months (range 11–22) and at first words 18.5 months (range 12–40) in prospective cohorts [8]; in Wigby's series, these were 15.3 and 12.9 months, respectively [15]. Expressive language is frequently more affected than receptive language, sometimes with a pattern of developmental verbal dyspraxia, and difficulties persist into school age and adulthood as deficits in language processing, verbal fluency, comprehension and pragmatics [8]. Overall IQ ranges from 55 to 115 across the different series, with a mean of 85–90 and intellectual disability in around 5–10%; verbal deficits predominate over performance deficits, although many patients have difficulties in both domains [8, 20]. Otter and colleagues estimate an IQ around 20 points below that of controls, with lower verbal IQ [46], and the Oxford Desk Reference a mean 10–15 points below that of siblings [7]. Of the three sex chromosome trisomies, 47,XXX has the highest rate of SEN and the poorest cognitive outcomes [7, 36]. Delayed motor milestones, poor coordination and lack of dexterity are common, with motor planning difficulties, gait abnormalities and poor joint stability [8, 20]. Auditory processing disorders are not rare and EEG abnormalities appear frequent [46].

The following table, adapted from the Oxford Desk Reference using Bishop and colleagues' study, shows the proportion of 47,XXX girls with special schooling, SEN, speech and language therapy or specific diagnoses. Group I comprises prenatal referrals from regional centres (including ten prenatally diagnosed cases whose parents joined the Unique association before the first birthday); group II comprises prenatally or postnatally diagnosed cases whose parents joined Unique after the first birthday [7, 22].

*Diagnoses coded as mutually exclusive. OR, odds ratio relative to the comparison group; national data: Special Educational Needs in England 2008 [7].

ADHD and executive function. ADHD is present in 25–35% of cases in older clinical series, with inattention, distractibility and poor organisation predominating over hyperactivity [8], and reached 52% in a parent survey [21] and 45–52% in Wigby's series, without a difference between prenatal and postnatal diagnosis [15]. Learning disorders (dyslexia, language-based and mathematics learning disorders) occurred in 36–39%, and 64.4% of participants aged 5 years or older received special education support [15]. In Smith's, 60% require special education classes at secondary school [20].

Autism. Bishop and colleagues found no increase in the risk of autism in 47,XXX [7, 22]; however, Smith's reports ASD in 10% and sensory integration disorder in 13% [20], and in Wigby's series ASD was diagnosed in 4.5% of prenatally diagnosed girls and 20% of postnatally diagnosed girls [15]. The discrepancy reflects differences in recruitment and the overrepresentation of cases with developmental problems in postnatal series.

Mental health. Increased rates of anxiety (social, generalised and separation anxiety), depression/dysthymia and adjustment disorders have been described [8]. In Smith's, behavioural problems, including mild depression, conduct disorder or under-socialisation, occur in 30%, and any psychiatric mood disorder in 38%; low self-esteem, requiring psychological, behavioural and educational support, is common, and cyclothymic and labile personality traits are frequent [20]. In Wigby's series, 38% met DSM-IV criteria for a psychiatric disorder — anxiety (19.5%), depression or dysthymia (17.8%), bipolar or psychotic disorder (13.3%) [15]. Psychotic illness appears more prevalent in adult 47,XXX women than in controls and responds well to psychotropic medication [46]. Social immaturity and language difficulties make some girls vulnerable to peer pressure and victimisation [8]. In an American survey of 11 47,XXX women, they were less well adjusted and experienced more stress and employment and relationship problems in adolescence and early adulthood than their 46,XX sisters, but were, overall, self-sufficient and functioning reasonably well [7]. Most adapt as young adults without major problems, and 47,XXX women feel better after leaving school, often finding jobs that reflect their performance skills [20, 46]. Better outcomes occur in stable families [46]. In a German study of 44 adult 47,XXX women (mean age 30.5 years) compared with 50 controls matched for age and education, there was no difference in depression, trait anxiety, verbal IQ or personality traits, but social anxiety and elevated autistic traits were more frequent and empathy lower, suggesting a potential benefit from social skills training [54].

3.2.3 Puberty, fertility and premature ovarian insufficiency

Pubertal development is normal, with a mean age at menarche of 12 years [20]; in Wigby's series, the median was 12 years (range 9–14), similar to national data, and no participant had POI, although the maximum age was 24 years [15]. Precocious puberty has been described but is not typical [8]. Most 47,XXX women are fertile and have chromosomally normal children [3, 7]; fertility is probably normal unless complicated by genitourinary malformation or POI [8]. POI is more prevalent than in controls [20, 46]. Published cases of POI with hypergonadotrophic hypogonadism occurred between 19 and 40 years [8]. Among 52 consecutive women with secondary amenorrhoea due to POI and no stigmata of Turner syndrome, 3.8% had trisomy X, both with autoimmune thyroiditis [26]. In a Brazilian series of 141 patients with amenorrhoea, patients with a phenotype of isolated ovarian failure had only Xq deletions or trisomy X, leading the authors to recommend cytogenetic analysis in all women with ovarian failure of unknown cause, even without dysmorphism [55]. The finding of low AMH in 47,XXX girls (section 2.3) suggests that ovarian reserve may be compromised before menstrual abnormalities arise [25]. Cases of ovarian or uterine dysgenesis have also been described in children and young adults [3, 8]. The Brazilian handbook summarises the course throughout life: microcephaly in the newborn, learning and coordination impairment in the child, menstrual irregularity in the adolescent, and difficulty conceiving and premature ovarian failure in the adult [3].

3.2.4 Morbidity and mortality in adulthood

In the Danish registry of 136 women with 47,XXX or a compatible karyotype, the incidence of diagnosis was 10.7 per 100,000 female live births, with a diagnostic delay of 18.2 years or more in half the cases. All-cause mortality was increased (HR 2.5; 95% CI 1.6–3.9), corresponding to a difference of 7.7 years in median survival, with excess mortality from cardiovascular diseases, chromosomal and congenital abnormalities and unspecified causes [20, 40]. Swerdlow and colleagues' British cohort suggested a modest increase in cardiovascular risk [7, 56]. The association with autoimmune diseases (thyroiditis and cases of systemic lupus erythematosus) and the risk of venous thromboembolism described in biobanks for supernumerary aneuploidies as a group warrant clinical attention [26, 41, 57]. In a federated clinical records database (TriNetX, 2010–2024), the recorded prevalence of systemic lupus erythematosus and Sjögren disease in women coded as having trisomy X was 1.3% and 0.8%, respectively, compared with 0.381% and 0.388% in women in the general population; these values measure coded diagnoses in a population in which trisomy X is largely underdiagnosed (coded prevalence of 0.0010%), rather than population frequencies [58].

3.3 Tetrasomy X (48,XXXX)

Tetrasomy X was described in 1961 in two women with intellectual disability [32]. Around 100 cases have been reported worldwide, around 60 described in the scientific literature, one third in adolescents or adults [9]. With the exception of intellectual disability, all other findings are variable [20]. Patients have normal to tall stature [20]; Rooman and colleagues' review, prompted by a girl with a height of 181.8 cm and primary ovarian failure, concluded that neither tall stature nor ovarian failure is an essential feature of the phenotype [48], and median height SD in 13 patients was −0.6 [19].

In the neurodevelopmental study of three 48,XXXX girls (6.4 to 11 years), non-verbal IQs were 56, 80 and 91; all three had childhood apraxia of speech of variable severity and similar executive dysfunction, externalising problems and social difficulties, and the patient with IQ 91 was the second described with normal intellect [23]. In a 4.5-year-old Serbian girl, multidisciplinary assessment revealed borderline intellectual functioning and mild global delay, significant motor delay (independent walking at 2.5 years), marked receptive–expressive discrepancy and global sensory hyporeactivity [9]. The patient originally described by Carr and colleagues, reassessed at 56 years, was in good physical health, without intellectual deterioration (overall IQ 56) [20]. The Brazilian handbook places tetrasomy X as a variant of triple X syndrome, emphasising that the more X chromosomes there are, the greater the delay in physical and mental development, and describes microcephaly in the newborn, mental and speech disorders in the child, behavioural disorders in the adolescent and reduced fertility in the adult [3]. Cases with combined pituitary hormone deficiency and a Rathke's cleft cyst [60] and with hypersomnia (section 10) [59] have also been published. Despite menstrual disorders and reduced fertility, the offspring of these women tend to be normal [20].

3.4 Pentasomy X (49,XXXXX) — differential diagnosis

Pentasomy X is the most severe form of female X polysomy. In a review of 26 postnatal cases, intellectual disability and developmental delay were the only findings common to all [10]. The Orphanet definition describes global developmental delay, intellectual disability, musculoskeletal abnormalities (particularly small hands and feet, camptodactyly, clinodactyly, radioulnar synostosis) and craniofacial abnormalities (microcephaly, plagiocephaly, upslanting palpebral fissures, hypertelorism, flat nasal bridge, external ear malformations, micrognathia); congenital heart defects, immunoglobulin abnormalities with increased susceptibility to infections, and gonadal dysfunction with usually normal external genitalia may occur [1, 10]. Unlike trisomy X, stature is typically short (median SD −1.0) [8, 19]. Coexistence of pentasomy X with hyper-IgE syndrome has been described as two distinct genetic diseases [61], and a 47,XXX/48,XXXX/49,XXXXX mosaic case presented with primary amenorrhoea, ovarian failure and osteoporosis at 16 years [27]. Prenatal detection is difficult because there is no typical ultrasound sign: in the fifth case diagnosed prenatally, only early symmetrical fetal growth restriction and a slightly increased nuchal fold were observed, without major malformations at autopsy [10]; in 2022, the first case detected by non-invasive prenatal screening and confirmed by QF-PCR and fetal karyotyping was published [11].

3.5 Comparative table of the dosage gradient in female X polysomies

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4. Clinical Recognition and Warning Signs

A common feature of these conditions is the paucity of physical signs that allow clinical suspicion: more than 85% of 47,XYY men are never diagnosed prenatally or postnatally [4], and only around 10% of 47,XXX women receive a diagnosis [8]. Referrals come from two main sources: an incidental prenatal finding (fetal karyotyping performed because of maternal age or suspected fetal abnormality, or, increasingly, an NIPT result) and investigation of children with learning and behavioural difficulties, a setting in which the finding may have clinical significance [4]. In Denmark, median age at diagnosis of 47,XYY was 17.1 years [39], and in Wigby's series mean age at postnatal diagnosis of trisomy X was 5.9 years, with developmental delay the most frequent indication (63%) [15].

4.1 When to request karyotyping in a boy (suspected 47,XYY)

The clinical differential diagnosis should include other causes of tall stature in childhood, speech delay and concentration difficulties [2].

4.2 When to request karyotyping in a girl or woman (suspected 47,XXX or 48,XXXX)

Tartaglia and colleagues recommend considering karyotyping in girls and women with: developmental delays (speech and/or motor); hypotonia; hypertelorism, epicanthic folds or clinodactyly; tall stature; POI; learning disorder or intellectual disability; attention deficit or ADHD; anxiety, mood disorders or other psychiatric symptoms [8]. Assessment of tall stature in a girl should include karyotyping to exclude 47,XXX [8]. Some girls are identified in the neonatal period because of suspected trisomy 21 or trisomy 21 mosaicism, due to hypotonia, hypertelorism and epicanthic folds [8]. In girls diagnosed before 1 year of age without a prenatal diagnosis, the reasons were more significant medical problems and dysmorphism (cleft palate or Pierre Robin sequence, congenital heart defect, hemihypertrophy) or marked early motor delays [15].

Tetrasomy X should be suspected when a presentation similar to trisomy X is accompanied by intellectual disability, apraxia of speech and facial dysmorphism (midface hypoplasia, upslanting palpebral fissures, hypertelorism), radioulnar synostosis or dental abnormalities; pentasomy X when there is severe intellectual disability with short stature, microcephaly, limb abnormalities and a heart defect [1, 8, 20].

In adult women, POI — with hypergonadotrophic hypogonadism, frequently associated with autoimmune thyroid disease — is the principal late presentation of trisomy X and, in some women, its only manifestation [3, 26].

4.3 Prenatal presentation

A prenatal finding (section 8.1) is now the most frequent presentation. In Wigby's series, 59.5% of 47,XXX girls had a prenatal diagnosis, 81.8% of them because of advanced maternal age; three had been tested because of ultrasound abnormalities (ventricular septal defect and clubfoot, prominent nuchal fold, single umbilical artery) [15]. Introduction of cell-free DNA screening was associated with an immediate and sustained increase in the rate of sex chromosome aneuploidy diagnosis in infants under 2 years (from 3.55 to 6.56 cases per 100,000), without a change in older children [43].

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5. Diagnosis: Criteria, Tests and Algorithms

5.1 Cytogenetic and molecular tests

Diagnosis is confirmed by demonstrating the 47,XYY, 47,XXX, 48,XXXX or 49,XXXXX karyotype [2, 3, 5]. Peripheral blood karyotyping (G-banding) is the standard test; fluorescence in situ hybridisation (FISH) and chromosomal microarray analysis (CMA) also identify Y duplication or supernumerary X chromosomes [2, 3, 8]. Each method has its own advantages:

Following prenatal amniocentesis or chorionic villus sampling, postnatal confirmation with FISH in 50 or more cells is recommended to assess mosaicism, given its frequency (around 10%) and its impact on follow-up [8, 15]. It is particularly important to identify a 45,X cell line, because it changes medical surveillance (cardiovascular, renal, auditory, endocrine), which then follows the recommendations for Turner syndrome [8]. A 47,XXX cell line is present in 5–15% of women with Turner syndrome, and in patients with a Turner phenotype and a non-mosaic 47,XXX karyotype in lymphocytes, analysis of another tissue (skin or buccal mucosa) revealed 45,X mosaicism; therefore, a woman with trisomy X and a Turner phenotype should have a second tissue analysed by karyotyping or FISH [8]. In tetrasomy X, a case with 48,XXXX/47,XXX mosaicism in blood showed a pure 48,XXXX constitution in fibroblasts [17].

Incidental detection has specific implications: in UK Biobank, analysis of genotyping or exome data from 207,067 men identified 143 47,XYY men, of whom only one had a recorded diagnosis [13].

5.2 Non-invasive prenatal screening and sex chromosomes

The American College of Medical Genetics and Genomics (ACMG) strongly recommends that NIPT screening be offered to all pregnant women to detect fetal sex chromosome aneuploidies [42]. In a 2017 meta-analysis, the pooled detection rate for sex chromosome aneuploidies other than monosomy X was 100% (95% CI 83.6–100%), with a false-positive rate of 0.004%, but with only 17 affected cases, which the authors considered insufficient for a precise assessment of performance [62]. The positive predictive value (PPV) in clinical settings is modest and varies by type of aneuploidy: in a Chinese series of 67,099 pregnant women, the overall PPV for sex chromosome aneuploidies was 38.26% (101/264), with 22 confirmed cases of trisomy X and 23 of 47,XYY [63]; in an American series with confirmation in 36 cases, PPV was 50% for trisomy X and 100% for Jacobs syndrome, albeit with small numbers [64].

Discordant results arise from confined placental mosaicism, true fetal mosaicism or, with appreciable frequency, maternal aneuploidy: in a prospective study, 16 of 181 (8.6%) positive results for sex chromosome aneuploidy were due to an abnormal maternal X karyotype (frequently maternal X mosaicism) [65]. False positives have been described in which the aneuploidy was maternal and the newborn had a normal karyotype [66]. Therefore, when NIPT suggests fetal sex chromosome aneuploidy, maternal aneuploidy should be considered [29, 66], and an NIPT result suggestive of trisomy X may in fact be the route to diagnosis of a 47,XXX woman or one with 45,X/46,XX/47,XXX mosaicism [65].

5.3 Summary diagnostic algorithm

1. NIPT suggestive of 47,XXX, 47,XYY or another sex chromosome aneuploidy → genetic counselling consultation; detailed fetal anomaly ultrasound; offer invasive diagnosis (amniocentesis preferable to chorionic villus sampling when the aim is to exclude confined placental mosaicism); consider maternal karyotyping, particularly for trisomy X or monosomy X results and when the fetal fraction or dosage pattern suggests maternal origin [29, 65, 66].
2. Confirmed invasive diagnosis → prenatal counselling (section 8.1); plan postnatal confirmation with karyotyping and FISH in ≥ 50 cells [8, 15].
3. Postnatal suspicion (developmental delay, ADHD, ASD, tall stature, POI) → karyotyping; if the laboratory performs CMA as the first-line test, confirm the aneuploidy by karyotyping or FISH to assess mosaicism and exclude structural rearrangements [8].
4. 47,XXX karyotype with a Turner phenotype → second tissue (buccal mucosa or skin) by FISH or karyotyping [8].
5. Phenotype more severe than expected (moderate to severe intellectual disability, major malformations, significant dysmorphism) → additional genetic investigation (CMA, exome), because another disease may coexist given the 1:1,000 frequency of these aneuploidies [4, 8]. Coexistence of trisomy X and a 16p11.2 deletion in an atypical phenotype has, for example, been described [67].
6. Girl with suspected fragile X syndrome and a negative test → karyotyping to exclude trisomy X [8].

5.4 Test limitations and report content

In these entities, the “genetic test” is cytogenetic or genomic copy number testing, and the limitations to consider are chiefly those relating to mosaicism and the tissues analysed. The usual count of 20 metaphases in a karyotype excludes, with 95% confidence, only mosaicism at or above around 14%; to exclude proportions of around 10% or 6%, around 30 or 50 cells are required, respectively, supporting the recommendation for FISH in ≥50 nuclei [8, 68]. A cell line confined to another tissue (skin, buccal mucosa, gonad) is not detected in blood: in a 2-month-old Brazilian child with atypical genitalia, the initial karyotype 47,XYY[30] was followed by 45,X[2]/47,XYY[98] on an expanded count, FISH in buccal mucosa with 36% of nuclei lacking Y, and a final diagnosis of mixed gonadal dysgenesis; in the review of 4403 published cases accompanying the report, a female or atypical phenotype in a 47,XYY karyotype was chiefly associated with a 45,X cell line or another cause of a difference of sex development [69]. Chromosomal microarray detects the aneuploidy and coexisting copy number variants, but may not detect low-level mosaicism and does not identify balanced rearrangements; NIPT and exome or genome sequencing detect sex chromosome imbalances through read depth, but do not reliably distinguish fetal, maternal or placental origin or quantify mosaicism, and therefore require cytogenetic confirmation [8, 13, 65]. A normal blood result does not exclude mosaicism in another tissue when the phenotype is suggestive (for example, a Turner phenotype with a 47,XXX karyotype) [8].

The report should use International System for Human Cytogenomic Nomenclature (ISCN 2024) nomenclature, indicating the number of cells analysed and counted, each cell line with its respective number in square brackets (for example, mos 47,XXX[n]/46,XX[n]), tissue, resolution and limitations; for microarray, the ISCN notation for gains (for example, arr(X)x3 or arr(X)x1,(Y)x2) and the reference genome version [70]. The concept of a MANE transcript and HGVS sequence nomenclature do not apply to whole-chromosome aneuploidy, but do apply to any coexisting monogenic finding, which should be reported with the gene, versioned transcript, HGVS, zygosity and ACMG/AMP classification: in the Brazilian patient with trisomy X and 21-hydroxylase deficiency, for example, the MANE Select transcript for CYP21A2 is NM_000500.9 [71, 72]. Coexisting copy number variants, such as the 16p11.2 deletion described in an atypical trisomy X phenotype, are classified according to the joint ACMG/ClinGen technical standards for constitutional copy number variants [67, 73]. A coexisting variant of uncertain significance does not become pathogenic because the phenotype is more severe than expected for the aneuploidy, or because of partial segregation in the family; family studies in these situations constitute investigation of the variant [73].

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6. Differential Diagnosis

Once karyotyping confirms trisomy X, the differential diagnosis is closed unless there is moderate or severe intellectual disability, congenital malformations or medical problems incompatible with the phenotype, in which case further assessment is warranted [8]. The same principle applies to 47,XYY: dysmorphism or malformations should not be attributed to the karyotype [4].

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7. Treatments and Risk Management Strategies

There is no treatment targeting the chromosomal mechanism in any of these conditions, nor any drug approved specifically for them. Management is symptomatic, with educational support and assessment and therapy by a multidisciplinary team [2, 3]. The guiding principle is early intervention: if developmental or educational problems arise, they should be addressed actively rather than adopting a wait-and-see approach, because they are unlikely to “catch up” without targeted intervention and delayed treatment leads to poorer outcomes [4, 8]. Parents should have a low threshold for seeking professional help for developmental, behavioural or learning difficulties [4, 7].

7.1 Neurodevelopmental intervention

Wigby and colleagues' recommendations were formulated for trisomy X, but apply, with adaptations, to 47,XYY and tetrasomy X; for 47,XYY, Ross and colleagues recommend comprehensive psychoeducational assessment and screening for learning disorders, ADHD and ASD in all boys [50]. In tetrasomy X, individualised multidisciplinary assessment with early intervention targeting apraxia of speech, motor skills and sensory processing is essential [9, 23].

7.2 Pharmacological treatment of neuropsychiatric comorbidities

Pharmacological treatments for ADHD, anxiety and other mental disorders are the same as in the general population, but starting with low doses is recommended given the neurodevelopmental complexity [8]. In Tartaglia and colleagues' series, psychostimulants were effective in 78.6% of patients with sex chromosome aneuploidies treated for ADHD [21]. Behavioural symptoms related to learning disorder, ADHD, deficits in language comprehension and anxiety overlap, and the treatment plan should consider all comorbidities [8]. A limited or inconsistent response to several classes of psychotropic medication has been described in a subgroup of 47,XYY adolescents, requiring prolonged specialist follow-up [52]. Psychotic disorders in trisomy X respond well to psychotropic medication [46]. Epileptic seizures respond to the usual antiepileptic drugs [8]. There are no dosing regimens specific to these conditions, so doses are those of the label for the general indication, applied by extension: for immediate-release methylphenidate (Ritalin®; Rubifen® in Portugal), from 6 years of age, starting at 5 mg once or twice daily with weekly increments of 5 to 10 mg, up to a maximum of 60 mg/day; for extended-release methylphenidate (Concerta®), starting at 18 mg once daily with 18 mg increments at intervals of about one week, up to 54 mg/day from 6 to 12 years and 72 mg/day in adolescents aged 13 to 17 years (US label) and in adults (Portuguese SmPC, which sets 54 mg/day as the maximum in children) [74–77]. The low starting doses recommended by clinical sources correspond to the lower end of these ranges [8].

7.3 Endocrine and reproductive management

47,XYY. Puberty is usually spontaneous and routine hormone therapy is not indicated. The 2025 meta-analysis recommends regular surveillance for hypogonadism and counselling about infertility, with assisted reproduction techniques when indicated [24].

47,XXX and 48,XXXX — premature ovarian insufficiency. Adolescents and women with delayed menarche, menstrual irregularities or fertility problems should be assessed by an endocrinologist or gynaecologist to exclude POI, also considering other autoimmune diseases, particularly of the thyroid [3, 8]. In tetrasomy X, screening for ovarian insufficiency in early adolescence is recommended, because hormone replacement therapy may be necessary to prevent osteoporosis [17]. The 2024 guideline from the European Society of Human Reproduction and Embryology (ESHRE), together with ASRM, CRE-WHiRL and the International Menopause Society, states that a single FSH determination above 25 IU/L in the appropriate clinical context is sufficient to diagnose POI, allowing AMH and repeat FSH testing when there is uncertainty; it includes updated recommendations on genetic tests, oestrogen doses and regimens, combined oral contraception and testosterone [28]. Hormone therapy for POI associated with trisomy X follows this guideline. The early reduction in AMH in 47,XXX girls raises the possibility of a narrow window for fertility preservation (oocyte cryopreservation), which should be discussed individually, acknowledging that the natural history of low AMH in this population has not yet been established [25].

7.4 Medical surveillance by entity

7.5 Disclosure of the diagnosis and family support

Disclosure of the karyotype on a “need-to-know” basis is generally advised, so that the child is not treated or viewed differently by others; communication to the child should be a gradual process over several years, with healthcare professionals supporting parents [4, 7, 29]. Young children should regularly be given simple, age-appropriate information, dispelling fears that the condition is lethal or contagious and explaining that it is not the parents' fault; with adolescents and young adults, discussion should be direct and complete [8]. The terms “sex” or “sex chromosome” should be used cautiously, because children and adolescents may confuse the diagnosis with their sexuality or interpret it as a “sexual abnormality” [8]. Patient associations (Unique in the United Kingdom and Europe; AXYS, Association for X and Y Chromosome Variations, in the United States) provide leaflets, conferences and regional groups [4, 7, 15]. At the 3rd International Workshop on Klinefelter, trisomy X and 47,XYY, the associations reported the enormous effort required of parents to explain their child's syndrome to healthcare and education professionals, and most countries do not have organised healthcare systems to diagnose and follow these conditions [78]. In the European Union, specialist follow-up may draw on the European Reference Network for rare congenital anomalies and intellectual disability (ERN ITHACA), particularly in forms with intellectual disability (tetrasomy and pentasomy X), and the European Reference Network for rare endocrine diseases (Endo-ERN), whose thematic group on sexual development and maturation covers gonadal and pubertal issues [79, 80]. In the United States, clinical programmes for X and Y chromosome variations maintain recruiting natural history studies, such as the eXtraordinarY Babies Study (NCT03396562) and the longitudinal GALAXY study (NCT06373861) [81].

7.6 Regulatory status and off-label use

No medicine has an approved indication for 47,XYY, 47,XXX, 48,XXXX or 49,XXXXX syndromes, nor are there ongoing authorisation applications in the United States or the European Union; the drugs used treat comorbidities, and their regulatory status relates to the comorbidity rather than the karyotype [2, 3]. The efficacy results cited in this article come from observational series (for example, the 78.6% response to psychostimulants in a clinical survey) rather than randomised trials in these populations [21]. The table summarises the status of the most commonly used drugs on 4 October 2026.

Off-label use is distinct from extrapolation of evidence. Applying surveillance recommendations formulated for trisomy X to 47,XYY and tetrasomy X, or applying evidence of psychostimulant efficacy obtained in ADHD in the general population to these syndromes, constitutes extrapolation of evidence, which is legitimate but should be explained to the patient [8, 15, 21]. Prescribing a psychostimulant below the labelled age, for an unapproved indication (such as hypersomnia) or during pregnancy depends on the label text and jurisdiction and constitutes off-label use, which should be justified and documented [82, 83].

7.7 Intervention studies and limitations of the evidence

There are no randomised trials of drugs targeting these syndromes; intervention data are observational, and registered studies are chiefly natural history studies or studies of non-pharmacological interventions [81].

These studies do not allow estimation of mutually comparable treatment effects: response to psychostimulants comes from clinical reports without a control group or blinding; series from specialist centres have ascertainment bias, particularly in postnatally diagnosed cases; and relative differences (for example, the odds ratio for low AMH) should be read alongside absolute values and the small number of patients [15, 21, 25]. The absence of published negative trials reflects the absence of trials and does not demonstrate the efficacy of the interventions in use.

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8. Reproductive Options and Family Counselling

8.1 Prenatal counselling following an NIPT finding or invasive diagnosis

Prenatal diagnosis of a sex chromosome aneuploidy is almost always incidental, arising, for example, in a karyotype requested to assess the risk of trisomy 21 [29]. Parents are usually distressed by the news, and information on the implications of the result becomes mixed with a sense of loss of the “normal” baby they expected; experienced, sensitive counselling is needed to help them assimilate information about conditions unfamiliar to most and make informed decisions [29]. As Barbara Biesecker wrote, as cited in the Oxford Desk Reference, the loss parents experience following a prenatal diagnosis is often not of the fetus that receives the diagnosis, but of the fetus they expected to have; grief is profound, but does not prevent the woman from welcoming the affected child [29].

Consultation structure [8, 15, 29]:

1. Take a brief history of the pregnancy and the indications for testing; if appropriate, emphasise that the information obtained was not what prompted the test.
2. Explain what chromosomes are and the unexpected finding.
3. Describe the specific aneuploidy and what the couple can expect if they continue the pregnancy: the baby will, in principle, look normal and most will attend mainstream school; present the follow-up plan.
4. For 47,XYY and 47,XXX, emphasise the rarity of diagnosis compared with the true frequency in the population (around 1:1,000), reflecting how infrequently these individuals require specialist medical care; convey that most girls and boys are never diagnosed.
5. Explore hopes and fears, assess information obtained from other sources (other professionals, the internet) and warn about outdated or biased information; show current photographs rather than those from old medical publications.
6. Explain that the occurrence is random, that nothing the parents did caused it or could have prevented it, and that prognosis also depends on the rest of the genetic background and the environment (family, educational support).
7. Explore the options (continuation or termination of pregnancy) and facilitate the decision, discouraging hasty decisions because the couple may need time to adjust.
8. Mention patient associations and, if the couple wishes, contact with other families.

Specific messages. For trisomy X: there is no known increase in miscarriage risk, and 99% of fetuses diagnosed by amniocentesis survive to term; physical appearance is usually normal or has very subtle findings; children diagnosed prenatally have higher verbal IQ, general ability index and adaptive functioning than those diagnosed after birth, but retain a risk of speech delay and learning disorder [8, 15]. For 47,XYY: boys detected prenatally have a milder phenotype, because there is no ascertainment bias, better cognitive outcomes and a lower likelihood of ASD, without a difference in physical phenotype [4, 38]. Girls with 46,XX/47,XXX mosaicism have better outcomes than non-mosaic girls [3, 8]. For tetrasomy X and pentasomy X, available information comes from postnatal cases with ascertainment bias, and there are no unbiased natural history data; the expectation of cognitive and language impairment of variable severity, and, in pentasomy, consistently present intellectual disability, should be conveyed, emphasising the uncertainty [9, 10, 44].

Couples' decisions. Pregnancy termination rates following prenatal diagnosis of trisomy X ranged from 25% to 40% in the more recent studies from the United States and France, lower than for other sex chromosome aneuploidies [8]. In an American series with positive screening, only 64.3% of pregnant women underwent confirmatory testing (prenatal or postnatal) [64]. For couples who continue the pregnancy, the counsellor should help identify resources for developmental assessment and early intervention and schedule postnatal confirmation of the karyotype with mosaicism testing [8, 15]. Tartaglia and colleagues recommend prenatal renal ultrasound in cases of trisomy X detected prenatally [7].

8.2 Recurrence risk for parents

Parents of 47,XYY or 47,XXX children are not usually karyotyped, and recurrence risk is low (< 1%) and probably no higher than the maternal age-specific risk [4, 7, 29]. The Brazilian handbook classifies recurrence risk for the parents of a 47,XYY boy as negligible [2]. Prenatal diagnosis may be offered in future pregnancies, but the indication is weak and there is a delicate balance between the very low recurrence risk and the procedure-associated risk of fetal loss; NIPT may be offered as an alternative where available [4, 7, 29]. The exception is parental mosaicism: if NIPT or testing of the child suggests maternal X mosaicism, maternal karyotyping is indicated [65].

8.3 Risk for the offspring of affected individuals

47,XYY men. Most spermatozoa are chromosomally normal, and no increased risk of 47,XYY or 47,XXY children has been demonstrated [4]; the Brazilian handbook states that offspring do not have an increased risk of chromosomal abnormality [2], whereas Smith's mentions that some increased risk of chromosomal abnormalities, miscarriage and perinatal death has been suggested [5]. In men with oligozoospermia or azoospermia, assisted reproduction techniques may be considered [24]. In a Chinese pilot study of 36 47,XYY men (including mosaics) with 43 in vitro fertilisation cycles, only 1.55% of the 129 embryos analysed had sex chromosome abnormalities, with autosomal errors more frequent, and rates of pregnancy, live birth and congenital abnormalities did not differ between transfers with and without preimplantation genetic testing; the authors conclude that this testing may not be necessary without another indication, a conclusion limited by the size and retrospective design [85].

47,XXX women. The risk of chromosomal abnormality in offspring is very low: some older studies suggested less than 5%, but more recent data support a risk below 1%, which should be presented independently of maternal age-related risk; these values apply only to non-mosaic trisomy X, and mosaicism should be assessed case by case [7, 8]. Counselling of adult women should include the risk of POI and its implications for family planning [8]. Prenatal diagnosis (or NIPT) should be offered to 47,XXX women [7]; a case of pregnancy through in vitro fertilisation after controlled ovarian stimulation in a woman with trisomy X and hypogonadotrophic hypogonadism has been described [86].

48,XXXX women. Although menstrual disorders are common and fertility is reduced, offspring tend to be normal [20].

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9. Special Considerations: Population Diversity and Epidemiology

9.1 Frequency at birth and underdiagnosis

In Leuven, Fryns and Kleczkowska found 75 47,XYY men in around 100,000 karyotypes, a frequency very close to neonatal incidence, indicating that intellectual disability and multiple congenital anomaly syndromes are generally not increased in 47,XYY men [4]. In Denmark, diagnostic activity increased over time for 47,XYY (and Klinefelter syndrome), whereas the incidence of trisomy X diagnosis remained stable [12]. Introduction of NIPT including sex chromosomes is changing these proportions in more recent generations, with increased diagnosis in infancy [43].

Tetrasomy X has an unknown prevalence, with around 100 cases reported worldwide [9] and an Orphanet class below 1 per 1,000,000 [1]. For pentasomy X, an approximate incidence of 1 in 85,000 is cited, estimated by comparison with 49,XXXXY, and the 2015 review brought together 26 postnatal and five prenatal cases [10, 11].

9.2 Geographic and ethnic variation

The Brazilian handbook reports an incidence of 47,XYY of around 1 per 1,000 male live births, depending on the region, more frequent in Europe than in Japan [2]. Evidence on phenotype and prognosis comes chiefly from populations of European ancestry: in Wigby's series, 89.9% of participants were non-Hispanic Caucasian [15], UK Biobank analyses included only men of European ancestry [13], and the biobank analysis of thromboembolism was restricted to participants self-identifying as white because samples from other groups were insufficient [41]. There are therefore no data allowing a statement on whether the phenotype or morbidity risks differ in other populations.

Portuguese-speaking and Latin American data. No population studies of the prevalence of these aneuploidies were identified in Portugal or Brazil, nor population-based cohort studies in Latin America; this gap should be acknowledged without extrapolation. Brazilian literature includes the study of 141 patients with amenorrhoea from Porto Alegre, in which trisomy X appeared among the causes of isolated ovarian failure [55], the study of X inactivation in a patient with pentasomy X from the Instituto Nacional de Câncer in Rio de Janeiro [18] and a report from São Luís (Maranhão) of an association between trisomy X and partial 21-hydroxylase deficiency [71]; references in the Brazilian handbook also include hospital cytogenetic series (Hospital Universitário da Universidade Federal de Santa Catarina, 2003–2008) and reports published in Brazilian journals [2, 3]. A report from Campinas (São Paulo) of a 47,XYY child with atypical genitalia, who proved to have 45,X/47,XYY mosaicism with mixed gonadal dysgenesis, accompanies the largest published review of the genital phenotype in 47,XYY (4403 cases) [69]. In China, a hospital series of 43 girls with trisomy X (2019–2024) found 72.1% non-mosaic cases and 20.9% with a 45,X cell line, the latter with delayed bone age and renal and skeletal abnormalities resembling those of Turner syndrome; the series describes a referred population and does not allow estimation of population frequencies [87]. Outside Europe, cases of tetrasomy X have been published in Sri Lanka, Turkey, Japan and Serbia [9, 17, 45, 88], as have Chinese prenatal screening series with tens of thousands of pregnant women [63].

9.3 Socioeconomic impact

Danish registry studies show that, compared with the general population, 47,XYY men have fewer marital relationships, a lower likelihood of fatherhood, lower income and educational attainment and earlier retirement, even in a country with universal free access to healthcare and education [53]. An epidemiological review of the four most frequent sex chromosome aneuploidies confirmed the association with poorer indicators of education, income, retirement, cohabitation and parenthood [89], and Ridder and colleagues' comparative review emphasises that early diagnosis appears to predict a lower comorbidity burden [6].

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10. Illustrative Clinical Case

10.1 Composite clinical vignette: NIPT suggestive of trisomy X

Teaching vignette constructed from the recommendations and data in the cited series; it does not correspond to a real patient.

A healthy 38-year-old pregnant woman undergoes NIPT at 11 weeks, which is low risk for trisomies 21, 18 and 13 and suggests fetal trisomy X. At the clinical genetics consultation, it is explained that this is a screening test whose positive predictive value for sex chromosome aneuploidies is around 40–50% in published series, and that some results are due to maternal aneuploidy or mosaicism [63–65]. The fetal anomaly ultrasound shows no abnormalities. After discussion, the couple opts for amniocentesis, whose karyotype confirms 47,XXX in all metaphases. The consultation follows the structure in section 8.1: frequency of 1 in 1,000 girls and diagnosis in only around 10%; usually normal physical appearance; increased risk of language delay, learning disorder, ADHD and anxiety, with a better cognitive and adaptive prognosis in girls diagnosed prenatally; usually preserved fertility, with an increased risk of POI [8, 15]. The couple decides to continue the pregnancy. After birth, karyotyping and FISH in 50 cells confirm trisomy X without mosaicism; renal ultrasound and echocardiography are normal. The child has mild hypotonia and epicanthic folds, is assessed at 6–9, 12–15, 18–24 and 30–36 months, starts speech and language therapy at 2 years for expressive delay and, at 7 years, neuropsychological assessment identifies predominantly inattentive ADHD, treated with educational intervention and a psychostimulant titrated from a low starting dose. At 10 years, annual thyroid function surveillance begins and, in adolescence, she is referred to adolescent gynaecology for assessment of ovarian function and discussion of fertility preservation [15, 25, 28].

10.2 Published case: tetrasomy X with hypersomnia

A 17-year-old young woman with tetrasomy X, a small muscular ventricular septal defect without haemodynamic impact and intellectual disability (overall IQ 69) was referred to paediatric neurology because of 5–6 episodes over 2 years of altered consciousness lasting around 15 minutes, during which she appeared to fall asleep, preceded by extreme fatigue, and excessive daytime sleepiness with a daily 2–3-hour nap despite 8–9 hours of sleep at night [59]. On examination, she had a long face, bilateral single palmar creases and mild diffuse hypotonia; her Epworth Sleepiness Scale score was 20. Laboratory studies excluded anaemia and thyroid dysfunction; magnetic resonance imaging showed subcortical white matter T2 hyperintensities of uncertain significance; two EEGs and polysomnography were normal, and the multiple sleep latency test showed a mean latency of 7.2 minutes without sleep-onset REM periods, consistent with hypersomnia. Treatment with a psychostimulant (extended-release mixed amphetamine salts, initially 10 mg in the morning according to the report; off-label use, because the American label for this medicine is limited to ADHD) resolved sleepiness and improved attention and school performance, without adverse effects [59]. The article has no figures and is open access (https://pmc.ncbi.nlm.nih.gov/articles/PMC5930223/); the management described is that of the authors and does not constitute a routine recommendation [59, 83]. The case illustrates that sleep disorders should be actively sought in X polysomies and that paroxysmal episodes require differential diagnosis with epilepsy.

10.3 Published cases: ovarian insufficiency in trisomy and tetrasomy X

A 15-year-old Turkish girl with intellectual disability and minor physical abnormalities presented with secondary amenorrhoea, elevated gonadotrophins and osteoporosis; blood karyotyping showed 48,XXXX/47,XXX mosaicism, but fibroblasts had a pure 48,XXXX constitution, and the supernumerary X chromosomes were maternal in origin [17]. The authors recommend screening for ovarian insufficiency in early adolescence in all girls with tetrasomy X. In Brazil, a 38-year-old woman with a history of premature ovarian failure and subsequent hyperandrogenism was found to have trisomy X associated with partial 21-hydroxylase deficiency, a reminder that trisomy X, frequently underdiagnosed, may coexist with other genetic diseases and that POI should always prompt karyotype testing [55, 71].

10.4 Published case: pentasomy X detected by NIPT

In 2022, the first case of pentasomy X detected by non-invasive prenatal screening and confirmed by QF-PCR and fetal karyotyping was published [11]. In the original open-access article (https://pmc.ncbi.nlm.nih.gov/articles/PMC9321121/), Figure 1 shows QF-PCR analysis of amniotic fluid, with X chromosome counting markers, and cytogenetic characterisation [11]. The case illustrates both that NIPT can identify rare X polysomies and that an NIPT result indicates only an X imbalance and requires invasive diagnosis to distinguish trisomy, tetrasomy and pentasomy, whose prognoses differ substantially [10, 11].

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11. Prognosis and Long-Term Follow-Up

11.1 Prognosis

47,XYY. Prognosis is considered good, with prospects of independence and employment in most [2, 4], but life expectancy is reduced (67.5 vs. 77.9 years in the Danish registry), with excess mortality from cancer, pulmonary and neurological diseases and trauma, partly explained by socioeconomic factors [39, 53]. Adult morbidity burden includes type 2 diabetes, venous thromboembolism and chronic obstructive pulmonary disease [13, 41]. Psychiatric vulnerability may increase in adolescence and adulthood [52]. Swerdlow and colleagues' cohort assessed mortality and cancer incidence in numerical sex chromosome aneuploidies [56].

47,XXX. Prognosis is variable, ranging from women with minimal manifestations to women with significant cognitive and psychological involvement, and depends on the severity of manifestations and the quality and timeliness of treatment [3, 8]. Outcomes are better in girls diagnosed prenatally and in 46,XX/47,XXX mosaics [8, 15]. Most adults live independently [36], but mortality is increased (a 7.7-year difference in median survival) [40].

48,XXXX. Intellectual disability and speech and behavioural problems are frequent, but there is no evidence of intellectual deterioration with age, and physical health may be good in the sixth decade [20]. Some patients will require support throughout adulthood [9].

49,XXXXX. Intellectual disability is consistently present, and malformations and susceptibility to infections influence prognosis; there are no survival data [1, 10].

11.2 Follow-up plan by age

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12. Summary and Final Considerations

47,XYY and 47,XXX syndromes each occur in around 1 in 1,000 births of the corresponding sex and are the most underdiagnosed aneuploidies in human genetics: fewer than one fifth of affected individuals are diagnosed [12]. The physical phenotype is subtle — tall stature, macrocephaly, hypotonia, hypertelorism and macro-orchidism in 47,XYY; tall stature, epicanthic folds, clinodactyly and hypotonia in 47,XXX — and the clinical burden lies in neurodevelopment: language delay, learning disorders, ADHD (76% in 47,XYY and around half in 47,XXX), ASD in 47,XYY and anxiety and mood disorders in 47,XXX [8, 21, 22, 38]. The myth of the “aggressive super-male” does not withstand unbiased studies: the excess of convictions disappears after socioeconomic adjustment [35].

In adulthood, both conditions are associated with increased mortality and greater morbidity; testicular function is subtly compromised in 47,XYY, and in trisomy X ovarian reserve declines early, with a risk of POI warranting gynaecological assessment and discussion of fertility preservation [25, 39, 40, 47]. Tetrasomy X and pentasomy X follow the dosage gradient, with increasing cognitive and language impairment, dysmorphism and malformations, and short stature in pentasomy [10, 19, 20].

The spread of NIPT makes prenatal counselling the decisive moment: balanced information on phenotypic variability, the better prognosis of prenatally diagnosed cases, confirmation by invasive diagnosis, exclusion of maternal aneuploidy and planning of early intervention [15, 29, 65]. Recurrence risk is below 1%. There is no targeted treatment; follow-up is multidisciplinary, anticipatory and age-directed, and early diagnosis appears to reduce the comorbidity burden [6]. Relevant gaps remain: the absence of international guidelines dedicated to 47,XYY and 47,XXX, scarce population data outside Northern Europe and, in particular, the absence of prevalence and phenotype studies in Portugal and Brazil [78].

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