Prenatal phenotype of 47, XXY (Klinefelter syndrome)

Abstract

Objective: There is a paucity of knowledge regarding the prenatal presentation of Klinefelter syndrome, or 47, XXY. Accurate prenatal counseling is critical and in utero diagnosis is currently limited by a poor understanding of the prenatal phenotype of this condition.Methods: This is a case series of fetuses with cytogenetically confirmed 47, XXY in the prenatal period or up to age 5 years, with prenatal records available for review from four academic institutions between 2006 and 2019. Ultrasound reports were reviewed in detail to assess for increased nuchal translucency and structural abnormalities. Additionally, we reviewed results of cell-free DNA and serum analyte testing when performed to inform our understanding of the detection of fetal 47, XXY through standard genetic screening tests.Results: Forty-one cases with confirmed cytogenetic diagnosis of 47, XXY and prenatal records available for review were identified: 37 had a prenatal diagnosis and 4 had a postnatal diagnosis. Nuchal translucency was increased ≥3.0 mm in 23.1% (6/26) of cases with a documented measurement. In 29.2% (7/24) of cases with a second trimester anatomical ultrasound available for review, a fetal abnormality was identified (3 brain anomalies, 1 cardiac abnormality, 1 echogenic bowel, and 2 limb abnormalities). Among those who had cell-free DNA and serum analytes performed, 92.6% (25/27) and 36.3% (4/11) had an abnormal result respectively. Conclusion:This case series expands our knowledge of the prenatal presentation of 47, XXY by identifying first and second trimester fetal sonographic abnormalities.

The burden of disease for children diagnosed with Klinefelter syndrome – a European cohort

“…A multicentre cohort study analysed the frequency of abnormal pregnancy ultrasound ndings in children diagnosed with Klinefelter syndrome pre-or postnatally and found that nearly one third of the cases had structural abnormalities, most commonly intracranial and skeletal abnormalities (29). The inclusion criteria for the children with Klinefelter syndrome were similar to our study.…”

A systematic review and meta‐analysis of cell‐free DNA testing for detection of fetal sex chromosome aneuploidy

“…52 While 45,X may present with a prenatal phenotype such as cystic hygroma or bicuspid aortic valve, the prenatal phenotypes for 47,XXY, 47,XYY or 47,XXX are more likely to be normal. 53 Prenatal detection of SCAs is important, as it allows for genetic counseling and preparation for an infant that may have physical differences and unique health needs. For patients with 47,XXX, this may include assessment for hypotonia, monitoring of developmental milestones or evaluation for seizure activity.…”

Unique Challenges of NIPT for Sex Chromosome Aneuploidy

“…13 For 47,XXY, a fetal phenotype is also emerging, which includes increased firsttrimester nuchal translucency ( >3.0 mm) noted in 6/26 (23.1%) and second-trimester anomalies (CNS, cardiac, echogenic bowel, and limb abnormalities) in 7/24 (29.2%). 16 Of note, the degree of maldevelopment of the systems is variable with CNS findings ranging from mild ventriculomegaly to holoprosencephaly and the skeletal findings including a unilateral clubfoot to shortened long bones. 16 Further work is needed to develop the 47, XXY fetal phenotype as these observations are from a cohort of 41 fetuses.…”

“…16 Of note, the degree of maldevelopment of the systems is variable with CNS findings ranging from mild ventriculomegaly to holoprosencephaly and the skeletal findings including a unilateral clubfoot to shortened long bones. 16 Further work is needed to develop the 47, XXY fetal phenotype as these observations are from a cohort of 41 fetuses. Although children with 47,XXY have higher incidences of developmental delay, learning disability, and behavioral issues, and in the adult, the effects of gonadal dysgenesis include infertility and osteoporosis, structural anomalies have not been associated with the overall phenotype.…”