Early detection of Emanuel syndrome: a case report

Introduction

Emanuel syndrome is rare inherited syndrome characterized by particular phenotype, due to an unbalanced t(11;22) (q23;q11.2) translocation [1], that usually arises through a meiosis and malsegregation during gametogenesis [2]. Emanuel syndrome is also described as derivative 22 syndrome, derivative 11;22 syndrome, partial trisomy 11;22, or supernumerary der (22)t(11;22) syndrome [2]. It may occur in offspring of carriers of balanced chromosomal translocation t(11;22)(q23;q11), these are phenotypically normal with physiological cognitive development [2]. Female balanced carriers use to have reproductive problems, including recurrent pregnancy loss with 3.7% risk of having children with Emanuel syndrome [2], [3]. Distinctive phenotype of affected individual consists of cranio-facial dysmorphism (including micrognathia, ear and palate anomalies), microcephaly, severe intellectual disability, developmental delay, renal anomalies, congenital cardiovascular defects, genital anomalies in males and growth retardation [4]. The complete non-mosaic type of trisomy 22 is rare: almost all pregnancies with affected foetuses end before the second or third trimester. The incidence of live births is 1:30,000 to 50,000 births. True mortality rate is unknown [5]. First trimester abortion rate is high, so little has been published: around 100 cases are reported [6]. Prenatal diagnosis of Emanuel syndrome is rarely reported in literature: little is known regarding prenatal biochemical characteristics or ultrasonographic features.

Here, we report a case of a complete non-mosaic trisomy 22, with several prenatal sonographic findings, that was diagnosed in utero at 15 weeks’ gestation and then it was confirmed with chromosomal analysis and postmortem examination.

Case presentation

A 35-year-old Caucasian woman, gravida 2, para 0, who already experienced a first trimester miscarriage. Her family history showed the presence of a cousin with a severe mental retardation that has not been further investigated. The patient and her partner were not relatives.

The first sonographic scan was performed at 5+3 weeks’ gestation because of a first trimester bleeding and because her previous miscarriage and it showed an intrauterine gestational sac with a yolk sac, no embryonic structures were seen. At eight weeks’ gestation the second scheduled scan showed a normal embryo, corresponding to amenorrhoea with a normal foetal heart rate. The patient was reassured and referred for the first trimester screening scan that was performed at 12+2 weeks’ gestation. Images revealed a nuchal translucency (NT) at 2.4 mm (percentile 90) with a normal crown-rump length (CRL = 65.1 mm). The foetus had a flat facial profile with an early image of retrognathia (Figure 1).

Figure 1:

Flat facial profile at the time of first trimester screening scan.

We first decided to perform a non-invasive prenatal testing (NIPT, Harmony™ Ariosa diagnostic) that was negative for T21, T13, and T18. At 15 weeks’ gestation an amniocentesis was performed: banding technique obtained by digesting the chromosomes with proteolytic trypsin followed by Giemsa staining (GTG)-banded karyotype analysis showed 47, XX, derivative +22 karyotype in all analysed cells. The Array Comparative Genomic Hybridization (CGH-array) showed two different genomic mutations: Arr (GRCh37) 11q23.3 q25(11663629_134928849)x3 and 22q11.1 q11.21(17532971_20246876)x3, these are duplication of the terminal region 11q23 q25 (qter) and duplication of the region 22q11.1 q11.21 (Figure 2).

Figure 2:

Foetal karyotype.

Second trimester screening scan was performed at 21+2 weeks’ gestation. The biometric measurements of the foetus were normal (biparietal diameter: 52.5 mm; head circumference: 184.7 mm; femoral length: 35.1 mm; abdominal circumference: 155.7 mm). A number of structural abnormalities were also revealed (Figures 3, 4): flat facial profile, long philtrum, retrognathia, hypotrophic cerebellar vermis with an unclear abnormal rotation of the cerebellum, that not clearly satisfied the Dandy Walker malformation pattern, border line ventriculomegaly with a normal cisterna magna, slightly bilateral hyperechogenic kidneys structures with a reduced biometry compared with the gestational age, low-set ears with pre-auricular tags and placentomegaly. After genetic counselling, the woman decided to terminate the pregnancy at 24+5 weeks’ gestation. According to parent’s wishes a postmortem examination was performed. On physical examination foetus was a girl with a flat facial profile, horizontal upper lid crease, low-set ears with pre-auricular tags and intrarotated left hand of Kidneys’ histology was normal. Both parents gave their consent for their own genetic test and their karyotype were analysed. Father’s karyotype was normal (46, XY), but a balanced reciprocal translocation between the long arm of the chromosome 11 and the long arm of the chromosome 22 resulted from mother’s karyotype analysis: 46,XX,t(11;22)(q23.3;q11.1).

Figure 3:

Second trimester screening scan: facial appearance.

Figure 4:

Second trimester screening scan: foetal findings and placenta.

Conclusions

Emanuel syndrome is due to a chromosomal abnormality that consists of a derivate chromosome 22 as a supernumerary chromosome. Female karyotype 47 XX, +der(22)t(11;22)(q23;q11) and male karyotype 47 XY,+der(22) t(11;22)(q23;q11) were named Emanuel syndrome in 2004 [7]. In almost every case one of the parents is the balanced carrier, who is phenotypically normal. Pregnancies of a balanced carrier could develop in four different ways: (a) spontaneous abortion; (b) genetically normal offspring; (c) supernumerary der(22) syndrome, that is Emanuel Syndrome; (d) balanced t(11;22) carrier [7].

No characteristic prenatal patterns appear from literature analysis [6] probably because of short number of cases (no more than 40 cases worldwide have been recording from 1980 to date [5]). The development of pregnancies, which survive after the first trimester, used to be uneventful [4].

Despite little possibilities to produce valuable sonographic images due to high rate of early abortion, Stressing et al. in 2005 summarized prenatal sonographic features, recognizable from 12–14 weeks’ gestation: intrauterine growth restriction, hypoplastic femurs, nuchal thickening, cerebellar defects, and oligohydramnios [8]. Schwendemann et al. in 2009 correlated Emanuel Syndrome with oligohydramnios, increased NT and cystic hygroma [9]. Other studies link also cardio-vascular diseases, cranio-facial anomalies, gastrointestinal tract malformations (as diaphragmatic hernia), kidney anomalies and neural tube closure defects to Emanuel syndrome [1], [2], [4], [5].

The above case has shown discrete ultrasound findings. The first trimester screening scan at 12+2 weeks’ gestation revealed a NT at 2.4 mm (percentile 90) with a flat facial profile and retrognathia. However hypotrophic cerebellar vermis with an unclear abnormal rotation of the cerebellum, border line ventriculomegaly slightly bilateral hyperechogenic kidneys structures with a reduced biometry and placentomegaly were detected at 21+1 weeks’ gestation during second trimester screening scan.

Thanks to the high accuracy of sonographic images flat facial profile, retrognathia and low-set ears were detected in uterus and confirmed by autopsy.

According to literature no abnormal biochemical values were recorded [6].

The time between amniocentesis to the termination of pregnancy was necessary to process foetal genome and to provide a complete genetic counselling to the family that is essential for future procreation planning.

Being aware that a confirmation test Fluorescence in situ hybridization (FISH) is actually recommended in order to ascertain the presence of the chromosome 11, as the detection of breaking points was clearly showed by the CGH-array and as the higher number of metaphases analysed on the karyotype allowed us to exclude a mosaicism, we decided not to carry on because of the high costs generated by these procedures and because the couple finally decided for an elective termination of pregnancy after the second trimester screening scan was done.

Karyotyping has been performed for both parents, as literature’s recommendations suggest. After identifying the mother as a balanced carrier, pre-implantation genetic diagnosis has been recommended for future pregnancies.

Emanuel syndrome is usually diagnosed after birth. In utero diagnosis of Emanuel Syndrome is established by karyotyping embryo’s DNA that is obtained by invasive procedures. Non invasive Prenatal Testing (NIPT) is not useful for the diagnosis. The chorionic villus sampling is not recommended as well because of possible false positive results due to a placental mosaicism.

Only above 16% of affected foetuses show abnormal ultrasound findings [4], [10]. In the presence of either these abnormalities or every slightest anatomical variation observed with scheduled ultrasound scan, the amniocentesis should be offered because literature data fail to suggest a characteristic prenatal pattern for Emanuel syndrome.

When Emanuel syndrome is diagnosed a complete genetic counselling for family is important for planning prenatal cytogenetic test for future pregnancies and testing unaffected sibling should be offered.

All this to underline that every anatomical difference should always be further investigated in order to achieve the correct diagnosis to best manage the present and the coming’ pregnancies.