Fetal Beckwith-Wiedemann syndrome associated with abnormal quad test, placental mesenchymal dysplasia and HELLP syndrome

Discussion

BWS is a rare disease and can be prenatally suspected or diagnosed by ultrasonogram. The most common prenatal findings are polyhydramnios and visceromegaly, accounting for 50% of cases followed by omphalocele (43%),7 as seen in this case. However, these features are not specific to BWS. Others features included overgrowth, macroglossia, and renal malformation. The abnormal appearance of a placenta, including placentomegaly, PMD, chorioangioma and extravillous trophoblastic cytomegaly, is common in BWS.8 9 It is of note that, in this case, abnormal placenta could be detected as early as at 16 weeks of gestation, characterised by increased thickness, hyperechoic parenchymal tissue with multiple small lacunae, highly suspicious for PMD at the first visit. Interestingly, although among cases of omphalocele, the chance of BWS is approximately 20%, the omphalocele together with PMD and elevated levels of the four serum biomarkers enabled us to make a provisional diagnosis of BWS. The diagnosis was even more reliable, especially when the specific markers like macroglossia and visceromegaly were demonstrated on the follow-up scans. In summary, prenatal diagnosis of BWS in this case was based on the major findings, including: (1) omphalocele, (2) macroglossia, (3) hepatomegaly, (4) nephromegaly and (5) outer ear abnormality. Additionally, PMD, which is one of the minor criteria of BWS, was highly suspected, with postnatal pathological confirmation. It is of note that DNA analysis was unfortunately not performed in this case due to unavailability. Nevertheless, the diagnosis could be reliably made based on clinical criteria.

Omphalocele is the earliest and reliable prenatal sonographic finding. Although, other signs might not present at the time of diagnosis of omphalocele, it should be underlined that follow-up ultrasound is important for detection of the late-occurring signs, such as macroglossia and overgrowth, that can be strongly supportive of the correct diagnosis.

Interestingly, we noticed the abnormal increase of all serum markers of quad test (markedly high MSAFP, inhibin-A and uE3 levels, and also relatively high beta-hCG level). High levels of MSAFP and uE3 may be associated with the visceral organ enlargement (liver and adrenal gland) and placentomegaly may probably cause an increase in inhibin-A and beta-hCG levels. These findings were consistent with observations in previous reports,7 10 which showed high serum levels of the triple screen biomarkers (MSAFP, uE3 and beta-hCG) during 15–18 weeks of gestation. Moreover, in our case, inhibin-A levels were also markedly increased. An increase in inhibin-A associated with BWS has never been described elsewhere. To the best of our knowledge, elevation of all biomarkers of quad test is very rarely reported to be specific to any certain disorders. This finding may be clinically useful for early detection of BWS. Unexplained elevation of inhibin-A along with any other biomarkers of quad test may warrant the possibility of BWS. In other words, the quad test can facilitate early detection of fetal BWS. Accordingly, this characteristic is clinically important, since approximately one out of four cases of BWS had no structural abnormality detected by prenatal ultrasound. This emphasises that for negative ultrasound finding in cases of unexplained elevated serum biomarkers, BWS should be kept in mind and DNA analysis may probably be warranted.

Of a limited number of case reports, several cases with fetal BWS developed preeclampsia, possibly associated with abnormal placentation, which tended to be early-onset and more severe. Of them, HELLP syndrome may develop in as many as 9% of pregnancy with fetal BWS.11 Likewise, the case presented here strongly supports such association. In our case, preeclampsia was early-onset and progressive to be HELLP syndrome. Placentomegaly or PMD is likely involved in the development, especially in the cases that display mutations in 9CDKN1C and associated with PMD.12 Therefore, the parents should be counselled about the risk of preeclampsia and surveillance. Early detection will help provide suitable management and avoid serious maternal and obstetric outcomes. Based on this case and literature review, we suggest the cases diagnosed early with fetal BWS receive ASA for preeclampsia prophylaxis.

In conclusion, this study provides new prenatal feature of BWS (elevated inhibin-A level), which can facilitate early detection. Additionally, this case adds important findings to the limited existing data in literature, which can strengthen the previous observations as follows: (1) unexplained elevated levels of the triple test biomarkers are strongly related to BWS; (2) omphalocele and abnormal placenta (thickened and multiple lacunae) can be detected early in gestation and the combination is strongly suggestive of BWS; (3) prenatal late-occurring sonographic signs may include macroglossia, macrosomia, visceromegaly (hepatomegaly and renal enlargement) and ear abnormality; (4) pregnancy with fetal BWS, especially involving PMD, is at higher risk for preeclampsia with a tendency to be more severe, particularly HELLP syndrome, and earlier onset.