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The X factor: An overview of triple X syndrome
*Corresponding author: Ami Shah, Department of Pediatrics, Genetic Clinic, Bai Jerbai Wadia Hospital for Children, Mumbai, Maharashtra, India. drami.rajesh.shah@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Shah A, Bansal V. The X factor: An overview of triple X syndrome. Wadia J Women Child Health. 2025;4:96-9. doi: 10.25259/ WJWCH_25_2025
Abstract
Triple X syndrome (TXS) is a relatively common but underdiagnosed sex chromosomal abnormality since incidence / prevelance of normal phenotype is not defined. Available literature largely highlights the congenital abnormalities and post-natal morbidities associated with this condition. There has been an apparent rise in cases of TXS with increasing use of pre-natal genetic testing. Counseling can be difficult for medical professionals in view of extreme variability of the phenotype especially in prenatal cases. We describe our experience with TXS at the Genetic and Perinatology clinic, Wadia hospital and also review the available literature.
Keywords
47
XXX
Genetic counseling
Pre-natal diagnosis
Triple X syndrome
INTRODUCTION
Triple X syndrome (TXS) is a sex chromosome abnormality, with a 47,XXX karyotype, where a female carries an extra X chromosome. First reported in 1959, TXS has a worldwide incidence of 1/1000.[1] Only 10% cases are diagnosed, those with mild or normal phenotype usually remain undiagnosed.[2] Congenital malformations and post-natal neurodevelopmental delay are known but rare.[3] These aspects make counseling challenging, especially in pre-natal and/or incidental cases. Thus, it is important for reproductive and child healthcare professionals to have complete information regarding the diagnosis and management of TXS.
EXPERIENCE AT WADIA PERINATOLOGY CLINIC
We describe four families with TXS diagnosis [Table 1].
| Type of conception | Family 1 | Family 2 | Family 3 | Family 4 |
|---|---|---|---|---|
| IVF, Self gametes | Normal | Normal | Normal | |
| Consanguinity | Non-consanguineous marriage | |||
| Reason for testing | Dual marker high risk for aneuploidy NIPT high risk for trisomy of sex chromosome |
Last POC showed copy number variation−chromosome 22 deletion+duplication | Abnormal anomaly scan | Abnormal NT scan |
| USG | No major abnormality | - | TOF+mega cisterna magna | Absent NB at 12 weeks Normal NB in follow-up scan |
| Mode of testing | NIPT+Amniocentesis | Couple karyotype | Amniocentesis | Amniocentesis |
| Decision | Continued | Wife diagnosed at 33 years | Aborted | Lost to follow-up |
| Result | SGA baby, NICU stay+ | Conceived again | - | - |
NB: Nasal bone, NT: Nuchal translucency, NIPT: Non-invasive pre-natal test, NICU: Neonatal intensive care, TOF: Tetralogy of fallot, IVF:In vitro fertilization, POC: Product of conception, SGA: Small for gestational age, USG: Ultrasound sonography
Case 1
A 40-year-old female, conceived by in vitro fertilization (IVF) using self-gametes, showed an increased risk for trisomy 21, 18 on dual marker test. Later, non-invasive pre-natal test (NIPT) was positive for trisomy of sex chromosomes. Hence amniocentesis was done and Fluorescence in situ hybridization (FISH), Karyotype showed TXS. The ultrasound scans and fetal echo were normal. Post-counseling, they decided to continue the pregnancy. A female neonate was, delivered at 34 weeks by cesarean section, and required 3-week neonatal intensive care unit stay due to low birth weight (1.58 kg) and respiratory distress. She had no dysmorphism or congenital malformations. Post–discharge, she continued to have poor weight gain and was readmitted at 2 months for sepsis. She had a stormy course with bleeding issues and hepatic involvement likely secondary to the infection and succumbed to her illness.
Case 2
A 33 year old female and her 40 year old husband were referred for counseling and evaluation following detection of a deletion and duplication in chromosome 22q region in product of conception from missed abortion. Couple karyotype was done for structural defects such as translocation, which incidentally revealed TXS in her. On enquiry, she had a normal birth and development history and was a working professional. She had no dysmorphism or congenital malformations on evaluation.
Case 3
A 42-year-old female with spontaneous conception had a normal early pregnancy screening. At 28 weeks of scan, tetralogy of Fallot (TOF) was detected, which was confirmed on fetal echo. Amniocentesis showed TXS on FISH report. After counseling, the couple decided to discontinue in view of poor prognosis due to the cardiac anomaly.
Case 4
A 38-year-old female presented with delayed nasal bone (NB) ossification during their second spontaneous conception with normal serum markers. Amniocentesis showed TXS on FISH report. NB was visible on follow-up scan, and no other congenital abnormalities were seen. The couple was lost to follow-up thereafter.
ABOUT TXS
The literature for TXS is biased, with most of the cases having rare findings being reported. With increase in NIPT and prenatal testing, unsuspecting pregnancies with TXS are being diagnosed more frequently. Long-term outcome studies following pre-natal diagnosis and incidental TXS are limited.
Pathophysiology
TXS occurs due to non-disjunction in meiosis I, with 90% being maternal in origin.[4] The phenotype is a medley of X inactivation and overexpression of genes that escape inactivation. Although the exact cause for abnormal phenotype in TXS is yet to be determined, it is known that there are multiple genes for neurodevelopmental, behavioral issues, and other systemic function on X chromosome, which can manifest individually or in combination.[5,6]
Diagnosing TXS
Cytogenetic tests such as karyotype, FISH, and quantitative fluorescent polymerase chain reaction QF-PCR are test of choice. Antenatal testing is usually advised for advanced maternal age, abnormal serum markers like alpha fetoprotein, screen positive NIPT, and ultrasound abnormalities. This is like our group where a positive NIPT[1] and abnormal fetal ultrasound scan[3,5] resulted in testing. Behavioral and intellectual disabilities are common indication for post-natal testing. Rarely, dysmorphisms such as Pierre Robin sequence, hemihypertrophy, and congenital heart defects may prompt evaluation.[5]
Phenotype
Our case 2 represents the large subset of TXS without any congenital defects, developmental or intellectual abnormalities. The incidence of this normal phenotype is unknown since they are rarely detected as in our case.
Pre-natal features: though rare, they have been reported, the most common being fetal hydrops and septal cardiac defects.[7,8] There are many single case reports for various other findings like oligohydramnios, intraoral mass, cleft lip and palate, post-axial polydactyly, syndactyly, bronchogenic cyst, dysplastic kidneys, and duodenal atresia.[4] Complex heart defects such as TOF and delayed appearance of NB seen in our series have not been reported.
Post-natal features
Physical
Postnatally growth parameters range from below average to average at birth, but with age, they tend to be taller. Ambiguous genitalia, club foot, and cardiac defects have been reported. Some may have subtle but minor dysmorphisms such as hypertelorism, epicanthal folds, clinodactyly, and pes planus.[5]
Development
Majority of TXS women have normal neurocognitive development.[8] Speech and language difficulties are common childhood delays, followed by academic difficulties such as learning disorders. Intelligent quotient can range from slow learner to above average, and intellectual disability is rare. Behavioral issues such as attention deficit hyperactivity disorder (ADHD) and autism are more common in postnatally diagnosed cases.[5,9] Prenatally diagnosed TXS women undergo early testing and intervention, resulting in better developmental outcomes. Psychiatric disorders are common in TXS women.[8]
Medical
Urogenital and neurological disorders are the most common post-natal systemic findings. Ovarian, renal dysgenesis, and epilepsy of various types have been reported in respective systems. Rare findings include dental abnormalities, spinal abnormalities, immunodeficiency, and endocrine disorders.[3,4]
Reproduction
Most TXS women have normal sexual development and fertility. They can conceive and give birth to healthy babies since the extra X chromosome is generally not passed on.[3] There have been few reports of early or delayed puberty, ovarian abnormalities, and premature ovarian failure.[4,10] Risks of non-sex chromosomal aneuploidies in their progenies like in our family 2 are the same as normal age-matched population risk and cannot be attributed to TXS.
Points for counseling
Genetic counseling for TXS is same as for other disorders and should include complete information of the condition - How and why it occurs, source i.e. inherited or de novo, spectrum of clinical features, treatment options if any and prognosis. Pre-natal counseling should be non-directive, highlighting the extreme phenotypic variability and that most are normal females, just like their peers. Discuss the management, prognosis of congenital abnormalities if detected in fetal period and post-natal neurodevelopmental outcomes. How these should be suspected and monitored postnatally should also be expanded upon.
Outcomes of pre-natal counseling - Couples with incidental fetal diagnosis of TXS commonly struggle in understanding the condition and to take an appropriate reproductive decision. Most TXS pregnancies without congenital anomalies are continued following appropriate counseling.[3] A favorable outcome was reported in these cases, with parents satisfied by their decision to continue.[8]
CONCLUSION
TXS is a common disorder. The cause for its vast but skewed phenotypic spectrum is yet to be determined, but is likely to be multifactorial. With increasing pre-natal and incidental diagnosis, medical professionals need to share objective information regarding the disorder and its outcome during counseling.
Ethical approval:
Institutional review board approval is not required.
Declaration of patient consent:
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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