Prenatal Diagnosis of Williams-Beuren Syndrome Based on Suspected Fetal Hypotonia in Early Pregnancy

In this report, we describe a rare case of prenatal diagnosis of Williams-Beuren syndrome (WBS). While the prenatal diagnosis of WBS is very rare, in the current case, WBS was diagnosed in early pregnancy. The key element was the detection of fetal hands hypotonia and generalized fetal hypotonia at 17 weeks of gestation. This led to the diagnosis of WBS by molecular karyotyping, specifically array comparative genomic hybridization (arrayCGH) of the fetal DNA. The genetic material was acquired by extraction from the fetal cells which are abundant in the amniotic fluid drawn by amniocentesis. Clinical hypotonia of the affected individuals is a clinical characteristic that is widely associated with WBS; however, fetal hypotonia has not been described as a diagnostic criterion for the prenatal diagnosis of WBS.


Introduction
The examination of the fetal anatomy by ultrasound in early pregnancy is invaluable because it can help with the early detection of fetal abnormalities. This could serve as the basis for informed choices and possibly early termination of pregnancy, which in many cases is the optimal choice. Early rather than late termination can be the optimal management in terms of women's health, both physically and from a psychological perspective [1,2,3].
Williams-Beuren syndrome (WBS) is a chromosome microdeletion syndrome of a specific locus at chromosome 7 that includes the elastin (ELN) gene [4]. Its diagnosis is clinical and the first cases were described in the years 1961-1962 [5,6]. Individuals with WBS are diagnosed postnatally and a prenatal diagnosis is considered to be highly unlikely, albeit not impossible [7,8]. In this report, we present a rare case of prenatal diagnosis of WBS and we highlight the idea of prenatally diagnosing WBS based on suspected fetal hypotonia during a prenatal scan.
In the literature, studies on "normal fetal motility patterns" exist and the authors consider fetal motility as abnormal when immobility exceeds 13 minutes before 20 weeks of gestation [9].

Case Presentation
A primigravida aged 27 years with type 1 diabetes underwent a routine first-trimester scan by a fetal medicine specialist. The results of the first trimester tests are presented in Table 1  Due to the history of diabetes, a follow-up scan was booked at 17 weeks of gestation for the optimal assessment of the fetal heart and the spinal cord. Anatomically, the fetus appeared normal but there was a strong impression of fetal hypotonia, more profound in the upper extremities. The movements of the fetal core, extremities, and fingers appeared to be fewer than expected for the specific week of gestation. Based on extensive scanning (duration: >4 hours, over two consecutive appointments) and after a detailed discussion with the parents, it was decided to perform an amniocentesis. This specific finding is linked to WBS (#194050 in OMIM), which is characterized by cardiac anomalies, dysmorphic features, hypotonia, and neurodevelopmental impairment. A summary of the blood test results, ultrasound, and arrayCGH findings can be found in Table 1.
Following consultation, the couple opted for the termination of pregnancy. Termination was successfully performed by the "medical management pregnancy termination protocol", which is based on the use of misoprostol tablets. The procedure was successful and uneventful; there was no need for admission to the surgical theater and no need for a blood transfusion. An en bloc fetoplacental specimen was produced and the woman was discharged home after spending 48 hours in the hospital.

Discussion
In this report, we described a case of fetal hypotonia that led to the diagnosis of WBS early in pregnancy. The absence of fetal movements is considered abnormal when it exceeds 13 minutes before 20 weeks of pregnancy [9,10] and the nonspecific finding of reduced fetal motility/hands hypotonia, led to a rare identification and diagnosis of WBS prenatally. The incidence of the typical presentation of the syndrome is approximately 1/10,000 live births but atypical forms, of unknown incidence, have also been described [11].
In our literature search, we identified only nine cases of WBS that have been diagnosed prenatally (eight associated with deletion and one with duplication of genetic material). A summary of these studies and the indication for referral for invasive testing and molecular karyotyping are presented in Table 2.  WBS is usually diagnosed during childhood (median age: four years) and the diagnosis is clinical; the criteria include characteristic facial features that vary as per severity. Children often present with a flat nasal bridge, short upturned nose, periorbital puffiness, long philtrum, everted lower lip (dropping lower lip), widely spaced teeth, and delicate chin, whereas older patients have slightly coarse features, with full lips, wide mouth, and a full nasal tip [11].

Cases of prenatal diagnosis of WBS Referral reason -indication for prenatal invasive testing References
In the present case, bulbous nasal tip, long philtrum, malar hypoplasia, pointed chin, and large earlobes were observed in the affected WBS fetus (Figures 1, 2). Common medical conditions that coexist with WBS include cardiovascular, endocrine, and nervous system abnormalities. Of note, 75% of WBS cases present with clinical cardiac disease, with supravalvular aortic stenosis and pulmonary artery stenosis being the most common findings. Mental retardation, developmental delay, learning disability, and hypotonia are also among the common neurological features of WBS [11]. Furthermore, it has to be mentioned that the differential of hypotonia except for the WBS include T21/DOWN syndrome, T13/PATAU syndrome, Prader-Willi syndrome, Tay-Sachs disease, achondroplasia, and spinal muscular atrophy [16].
In our case, the pregnant woman was routinely offered first-trimester scanning by a fetal medicine specialist as per local practice. At the first trimester scan, the nuchal translucency and the maternal serum screening tests [beta chorionic gonadotropin (bHCG) and pregnancy-associated plasma protein A (PAPPA)] were normal, together with first-trimester anatomical scanning. Fetal crown-rump length (CRL) was showing a small-for-date fetus and, due to the mother being a type 1 diabetic, a 17-week scan was booked to reevaluate for cardiac anomalies.
During the scan and, specifically when scanning for the anatomy of the digits of the hands, the hand movements seemed to be very reduced for the gestational age. After scanning that lasted more than four hours on two consecutive days, there was a strong, albeit nonspecific, impression of inactivity of the fetal hands and overall hypotonia of the fetus.
Invasive prenatal testing was decided to be performed after counseling, and the repeat scan before termination of the pregnancy at 19 weeks classified the baby at the ninth centile of the growth chart (evidence of intrauterine growth restriction).
As for the genetic procedure, the actual molecular genetic analysis was performed by arrayCGH analysis as mentioned above. In more detail, the microarray used was the "8Χ60Κ G3 ISCA V2" (Agilent Technologies, Santa Clara, CA) and the software Cytogenetics (Agilent Technologies). The specific platform detects imbalances (deletions/duplications) of ~500kbases in the whole genome and imbalances of 50kbases in ~240 genetic regions of known clinical significance, which are related to ~512 genetic conditions