Prenatal Diagnosis of Mosaic Tetrasomy 18p in a Case without Sonographic Abnormalities.

A 26-year-old, gravida 2 (para 1) was referred for amniocentesis at 16 weeks of gestation because of her own personal request; the latter was justified by a concern for Down syndrome based on borderline maternal serum screening risk assessment and consanguineous marriage. Anomaly scan ultrasound and echocardiography were unremarkable. Her husband was 36 years old, and there was no family history of congenital malformations. Unexpectedly an abnormal karyotype of 47,XX,+mar dn[36]/46, XX[4] was found after GTG banding analyzes from two separate amniocyte cultures ( Fig. 1A ). C banding revealed a centeric marker and parental karyotypes were normal (results not shown). After genetic counseling, she underwent umblical cord blood sampling (cordocentesis) at 26 weeks of gestation and again an abnormal karyotype of 47,XX,+ mar dn[18]/46,XX[22] was found. Fluorescence in situ hybridization (FISH) using subtelomeric and centromeric probes (Abbott, USA) confirmed the karyotype results and identified the sSMC as an i(18)(pter- >q11.1: q11.1- >pter), in short I (18p) ( Fig. 1B ). Molecular karyotyping was performed using CYTOCHIP ISCA 8x60k whole genome oligo array version 2. An 18.4 Mb gain on chromosome 18p11.32q11.2 was confirmed, compatible with tetrasomy for the mentioned region ( Fig. 1C ). Cytogenetic analyzes. A: GTG-banding result after initial amniocentesis; the aberrant clone with the extra marker chromosome (arrow) is shown; B:FISH-result identifying the sSMC (arrow) as a i(18p); probes used were subtleomeric probe for 18pter (subtel 18pter) and centromirc probe for chromosome 18 (cen 18); C: Array-CGH-result showing the gain of copy numbers of the whole short arm of chromosome 18 Photographs of the index patient after abortion. The extra finger on the right hand is highlighted by an arrow The parents decided to terminate the pregnancy after genetic counseling and agreed in post mortem examination. Weight, length and head circumfe-rence were normal according to age of pregnancy and there was no indication for intrauterine growth retardation (IUGR). However, facial features included low anterior hairline, large philtrum, mild retrognathia and low- set posteriorly rotated malformed ears with prominent antihelix. In limb examination, joint contracture of the lower limbs and digital anomalies including long and narrow toes with clinodactyly of the 1 st and 5 th  toes and postaxial polydactyly of one hand was seen ( Fig. 2 ).

The authors declared no conflict of interest.

Among supernumerary isochromosomes, those derived from the short arm of chromosome 18 are the ones most commonly observed ( 2 , 3 ). Tetrasomy 18p-syndrome due to sSMC-formation is de novo in the overwhelming majority of the reported patients, like in the here presented one. However, exceptionally there are also familial cases ( 3 , 10 ). The latter supports again what was mentioned before, i.e. i(18p)-cases may have a high clinical variability ( 3 , 5 , 6 ). This makes the de novo occurrence of an i(18p), especially when being present as a mosaic state, a considerable challenge in prenatal settings. In the case of i(18p) this could be even more substantial from this point of view that as we saw, sonographic signs and expected phenotypes can be so mild that they are overlooked. In addition, the fact that the present case had no remarkable echocardiogram made the problem worse, although this fits well to the fact that cardiac anomalies are present in only 12.3% of such patients ( 5 , 6 ). For comparable cases with normal sonography a cordocentesis has been regarded as a useful step to get further insights into the fetal situation. Chen et al. reported in a prenatally detected mosaic tetrasomy 18p, a cytogenetic discrepancy between amniocytes (mosaic) and cord blood lymphocytes (no i(18p) detectable) ( 11 ). After genetic counseling the pregnancy was carried to the term and a normal male baby was delivered. In another case Jung et al. did cordocentesis at 32 weeks of gestation because of congenital heart disease, IUGR, cardiomegaly, and imperforate anus observed in prenatal ultrasound, with tetrasomy 18p detected in karyotyping and FISH analysis ( 12 ). What can be implied from our case and the other cases is that, de novo i(18p) can be considered as a special case in the sense that the major relevant phenotypes mentioned for it, i.e. feeding difficulties, abnormalities in muscle tone and developmental/ mental retardation, cognitive and behavioral characteristics, recurrent otitis media and seizures, are mostly postnatal ( 5 , 6 ). This emphasizes the necessity to determine the nature of a de novo euchromatic marker chromosome, especially in cases with normal ultrasound result, and highlights that studying a second fetal tissue (e.g. cordocentesis) can help the parents to better understand the situation they are in.