LAUSR

Dear Editor, The authors present a detailed review aimed, as stated, at exploring “to which extent genetic syndromes can cause fetal growth restriction (FGR) in the absence of associated structural defects, mainly at early gestational ages.” The article is very interesting and worth reading for all specialists dealing with prenatal diagnostics. We did nevertheless like to point only some of the discrepancies that, from our perspective, are worth notifying in the correspondence. Meler and colleagues focused on (as one may expect from the title) “genetic syndromes associated with isolated fetal growth restriction” and analysed early FGR, which are defined as “gestational age at diagnosis below 32 weeks.” However, the text and tables (Tables 1-5) present and discuss genetic conditions that are mostly syndromic. Also, most examples listed in the paper are numerical chromosomal aberrations (Section 2) and submicroscopic aberrations (Section 3). The clinical manifestation of the latter may vary, but (a) in prenatal period, congenital heart defect (CHD) is frequently observed (as also noted in Table 3) and (b) as cited from the study of Schaeffer et al, among 259 fetuses with FGR, there were 46 associations with other non-structural anomalies and 137 FGR with structural abnormalities, what is nearly 53%. How can the authors mention them among “FGR in the absence of associated structural defects”? Referring to the monogenic aetiology of FGR (Section 4)—ignoring the main criticism (as in the sentence above), when other syndromic disorders are presented, thanatophoric dysplasia (TD), which is the most common skeletal dysplasia, should definitely be mentioned. This condition is lethal, and its prenatal recognition is essential for genetic counselling concerning subsequent pregnancies. It has to be acknowledged that the title of this paper suggests a review of genetic conditions apparent in “isolated growth restriction” and it does present many conditions fulfilling this criterion. On the other hand, most of the genetic conditions presented in the paper are not isolated whatsoever. There are numerous conditions where ultrasound markers or even anatomical abnormalities can be detected in the second or early third trimester. Moreover, in a large non-selected population of 10 414 fetuses, Rydberg et al concluded that fetuses with chromosomal abnormalities have a higher probability of prenatal detection than chromosomally normal fetuses with structural malformations (61% and 39%, respectively) due to more frequent or more pronounced ultrasound markers. Therefore, we believe the article focused on genetic conditions associated with truly isolated growth restriction would be much more interesting, easier to read and clinically more relevant. That is because the most difficult cases of early severe growth restriction are the cases without any other ultrasound abnormalities. Regarding the syndromes mentioned in Table 4 (eg, Cornelia de Lange or Smith-Lemli-Opitz)—Smith-Lemli-Opitz syndrome is a prototypic monogenic multiple malformation entity. From our clinical practice, its prenatal suspicion in primarily based on the spectrum of ultrasound anomalies (listed in Table 4—heart, external genitalia), and/or increased nuchal translucency (NT; of note, the authors mentioned it only once through the entire paper). Thus again, why these syndromes are described when “FGR in the absence of associated structural defects” is intended to be presented? Finally, taking into account data in Table 5—placing Noonan syndrome among the disorders with “extremely short long bones” is very doubtful. Firstly, the short femur is not a diagnostic feature and is rare in NS. Secondly, the diagnosis of Noonan syndrome is usually considered among euploid fetuses with increased NT (≥3 mm), but especially when NT is ≥3.5 mm and at least one of the following ultrasound anomalies: distended jugular lymphatic sac (JLS), hydrops fetalis, polyhydramnios, pleural effusion, ascites, cardiac defects, and renal anomalies. Also, the data presented in the review paper by Meler et al suggest severe growth restriction in conditions like trisomy 21 (Table 2). This conclusion is based on the article by Drummond et al, but it has to be underlined that the cited paper retrospectively summarized 171 cases of fetuses that underwent karyotyping due to structural defects (atrioventricular septal defect [AVSD], pleural effusion or corpus callosum agenesis). There were only three cases of trisomy 21 in the reported series. In 25 of the cases (19%), the indication was a moderate or severe IUGR, and in all fetuses, karyotype was normal. Moreover, Meler et al suggest that typical feature of Silver-Russel syndrome that is apparent in prenatal ultrasound is macrocephaly. The authors should explain whether macrocephaly here is defined as HC above 95 centiles, and add at least one reference. We believe the authors meant relative macrocephaly. Because of small triangular face, the head may appear large, although the head circumference is well within a normal range. It is confusing in the paper by Meler and colleagues and should be adequately clarified. Received: 20 January 2020 Accepted: 5 February 2020