Keywords
sex chromosome aneuploidy - NIPT - prenatal diagnosis - screening
The advent of noninvasive prenatal screening (NIPS, sometimes abbreviated as NIPT
or NIPS) for aneuploidy has made a substantial impact in maternal–fetal medicine practice
by significantly decreasing the number of second-trimester invasive diagnostic tests
performed.[1] Nevertheless, the American Congress of Obstetricians and Gynecologists (ACOG) continues
to recommend judicious use of NIPS, as this is a nondiagnostic tool and a “negative”
(more accurately, low-risk) result does not ensure an unaffected pregnancy.[2]
Pentasomy 49,XXXXY is a rare sex chromosome abnormality with an incidence of 1 in
85,000 male births.[3] The mechanism of this condition is thought to occur due to maternal nondisjunction
during both meiosis I and II.[4] Typical characteristics of boys with this condition include short stature, intellectual
disability, and various congenital malformations including radioulnar synostosis,
hip dysplasia, genitourinary malformation, cleft palate, inguinal hernia, clubfoot,
and cardiac anomalies.[3] Prenatal diagnosis of this condition by ultrasound alone is generally difficult
due to limited studies describing the sonographic prenatal findings and the nonspecific
nature of such. However, reported prenatal features described in the literature include
cystic hygroma, microgenitalia, clubfoot, epignathus, nonimmune hydrops, and hypoplastic
right heart syndrome.[5] Confirmatory prenatal diagnosis relies on amniocentesis and fetal chromosomal studies.
A single nucleotide polymorphism (SNP)–based NIPS method has been proposed as an accurate
method to screen for sex chromosome aneuploidy (with an average calculated accuracy
of 99.78%).[6] In this report, we describe a patient with pentasomy 49,XXXXY with false low-risk
results (consistent with a normal male fetus) using a SNP-based NIPS.
Case Report
We present a case of 30-year-old gravida 1 para 0 woman presented to our institution
for genetic counseling and amniocentesis at 336/7 weeks of gestation, secondary to ultrasound-detected fetal anomalies. She had previously
undergone SNP-based NIPS at 136/7 weeks through her primary obstetric care provider. Results reported a low risk for
trisomy 21, trisomy 18, trisomy 13, monosomy X, and triploidy/vanishing twin in a
male fetus. Per the patient's report, she elected not to attend an 18- to 20-week
anatomy ultrasound; NIPS had screened for fetal sex, and she had had an early bedside
ultrasound at her obstetric care provider office to establish her estimated due date.
The patient underwent anatomy survey at 306/7 weeks, at which time multiple congenital anomalies were noted, including bilateral
clubfeet, clinodactyly of the left fifth digit, micropenis, echogenic bowel, and fetal
growth restriction (FGR) ([Fig. 1]). During the genetic counseling session, she reported a family history of a brother
with bilateral clubfeet, abnormal hands, and multiple severe impairments of unknown
etiology despite extensive genetic work-up.
Fig. 1 Sonographic findings of pentasomy 49,XXXXY in our patient. (A) Right fifth digit clinodactyly, (B) micropenis, and (C) and (D) bilateral club feet.
The patient consented to late-gestation amniocentesis following the genetic consultation.
Fetal karyotype and chromosome microarray revealed pentasomy 49,XXXXY syndrome. Ultimately,
the couple decided to terminate the pregnancy at ∼36 weeks. Physical exam after delivery
revealed micropenis and bilateral clubfeet, consistent with prenatal sonographic finding.
Autopsy was declined.
Discussion
We present prenatal diagnosis of fetus with pentasomy 49, XXXXY following a false-positive
SNP-based NIPS. This report also highlights third-trimester sonographic features of
a fetus with pentasomy 49, XXXXY including bilateral clubfeet, clinodactyly of the
left fifth digit, micropenis, echogenic bowel, and FGR. Clubfoot was previously noted
in four reports.[5] Micropenis was also previously reported.[5] These findings are ultimately nonspecific and should trigger further investigation,
including invasive diagnostic testing with prenatal chromosome microarray, as in this
case.
Sex chromosome anomaly screening has previously been reported to be difficult using
massively parallel shotgun sequencing NIPS methods; however, SNP-based NIPS has been
reported to be highly accurate for detection of these particular aneuploidies.[6] Some experts have also alluded to the use of routine NIPS to screen for sex chromosome
anomalies, as maternal serum screening does not provide a risk assessment for these
conditions.[7] However, in this case, we report a false “low-risk” NIPS result, which ultimately
delayed ultrasound screening and resulted in delay of diagnosis.
Although the company was not validated to diagnose pentasomy cases, it did report
“male” as the fetal sex. Due to the suspected maternal origin of the extra X chromosomes
in pentasomy 49, XXXXY,[4] we would have expected the SNP profile to at least be suggestive of Klinefelter's
syndrome (as both of the maternally derived X chromosome SNP profiles would be represented
in the fetoplacental circulating cell-free DNA). If the SNP profiles were indeed reflective
of at least Klinefelter's syndrome, we would expect at the very least a “noninformative”
or “no-call” result. This false low-risk result could theoretically result from confined
placental mosaicism involving aneuploidy rescue in an early trophoblastic progenitor.[6]
[8] Placental pathology with karyotyping was not performed to explore this theory in
this case.
Our report also highlights the importance of thorough pre- and posttest counseling
for noninvasive DNA screening. It is a common misconception among patients (and even
providers) that NIPS is diagnostic or “near diagnostic”; to mitigate this, pretest
counseling points have been suggested to assist clinicians in performing this important
task.[9]
[10] Emphasizing the screening nature of NIPS is paramount prior to undergoing testing,
and it should not replace the use of routine ultrasound to evaluate for fetal anomalies.
Routine anatomy ultrasound may have resulted in earlier detection in this case.
It is worth noting that some commercial companies who provide NIPS will return “noninformative,”
“no-call,” or “failed” results in the event of an unexpected cell-free DNA profile.
In this case, such result could have prompted an anatomy ultrasound or invasive diagnostic
testing and thus an earlier diagnosis. Noninformative results have been reported to
be associated with an increased risk of aneuploidy; amniocentesis is often recommended
by the reference laboratory in these cases. In addition, it is important to mention
that ACOG and Society of Maternal-Fetal Medicine have also continued to recommend
conventional screening methods for the low-risk population given limited data of accuracy
among them.[2]
