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Familial Beckwith-Wiedemann syndrome: Prenatal manifestation and a possible expansion of the phenotype
European Journal of Medical Genetics ( IF 1.9 ) Pub Date : 2021-01-06 , DOI: 10.1016/j.ejmg.2021.104137
Dana Brabbing-Goldstein 1 , Yuval Yaron 2 , Adi Reches 1
Affiliation  

We describe a case of Beckwith-Wiedemann syndrome (BWS) demonstrating pre- and post-natal intra-familial variability. Our first encounter with the family occurred in the 1990s following the birth of 3 affected offspring. The first two pregnancies presented with exomphalos and elevated second trimester maternal serum alpha-fetoprotein (msAFP, 3.43 and 4.01 MOM, respectively) as well as elevated maternal human chorionic gonadotrophin (mhCG, 4.33 and 8.8 MOM, respectively). The diagnosis of BWS was confirmed postnatally in both cases. The third ongoing pregnancy presented only with elevated mhCG (7.09 MOM) and no malformation. Nonetheless BWS was suspected. The diagnosis was confirmed postnatally with clinical manifestations including macroglossia and cleft palate. Two affected female siblings were also diagnosed with Mullerian agenesis in adulthood.

Suspecting a common genetic etiology, sequencing of the CDKN1C gene revealed a maternally inherited, likely pathogenic variant (NM_000076.2: c.367_385del; p.(Ala123Serfs*143)) causative of BWS. Chromosomal microarray and whole exome sequencing did not reveal any other pathogenic variant that would explain the Mullerian agenesis. One of the affected females underwent successful preimplantation genetic testing (PGT) with a surrogate and gave birth to a healthy female.

To the best of our knowledge, this is the first report of Mullerian agenesis as a possible rare expansion of the BWS phenotype. In addition, this case highlights the potential role of abnormal second trimester biochemical markers (msAFP, mHCG) as possible indicators of BWS, especially in familial cases.



中文翻译:

家族性Beckwith-Wiedemann综合征:产前表现和表型可能扩大

我们描述了一个Beckwith-Wiedemann综合征(BWS)的病例,该病例证明了出生前和出生后的家庭内部变异性。我们与家人的第一次相遇发生在1990年代,是3个受影响的后代出生。前两次怀孕表现为胎膜早孕和孕中期孕产妇血清甲胎蛋白升高(分别为msAFP,3.43和4.01 MOM)以及孕产妇绒毛膜促性腺激素升高(分别为mhCG,4.33和8.8 MOM)。两种病例均在产后确诊。第三次进行中的妊娠仅表现为mhCG升高(7.09 MOM),无畸形。尽管如此,还是怀疑BWS。产后证实诊断,临床表现包括巨舌症和c裂。两名受影响的女性同胞成年后也被诊断出患有苗勒氏不育。

怀疑是常见的遗传病因,对CDKN1C基因进行测序后发现了母体遗传的,可能的病原体变异(NM_000076.2:c.367_385del; p。(Ala123Serfs * 143))是造成BWS的原因。染色体微阵列和整个外显子组测序未发现任何其他致病性变异,可解释穆勒幼虫的无性繁殖。其中一名受影响的女性接受了成功的代孕前基因测试(PGT),并生下了一名健康女性。

据我们所知,这是穆勒无性繁殖的首次报道,认为是可能罕见的BWS表型扩展。此外,该病例突出了异常的中期妊娠生化指标(msAFP,mHCG)作为BWS的可能指标的潜在作用,尤其是在家族性病例中。

更新日期:2021-01-13
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