Affiliations: Department of Obstetrics & Gynecology, Ziekenhuis Oost-Limburg, Genk, Belgium.
E-mail correspondence: ingrid.witters@skynet.be

Case report

A primigravid, consanguineous couple was referred at 18 weeks with multiple anomalies including bilateral cheilognathopalatoschisis (Image 1 and 2, Video 1), cerebral ventriculomegaly, cerebellar hypoplasia, left-sided hydroureteronephrosis (Video 2), right-sided dysplastic kidney, genital hypospadias (Image 3), and a complex cardiopathy with univentricular right-sided heart, DORV (Double Outlet Right Ventricle), TGA (Transposition of the Great Arteries) and pulmonary stenosis (Video 4 and 5).

Amniocentesis revealed an unbalanced de novo reciprocal translocation with terminal 1p36 deletion (3.68 Mb) and terminal 3q duplication (32.43 Mb).  Parents were counseled regarding the poor prognosis of the fetus by the clinical geneticist and neonatologist, and elected to continue the pregnancy with neonatal comfort care.

The remainder of the pregnancy was uncomplicated a male newborn was delivered spontaneously at 36 weeks of gestation with the following neonatal measurements: weight of 2310 g (10th percentile), length of 44 cm (5th percentile), and head circumference of 33.5 cm (50th percentile). APGAR score was 1/1 at 1 and 5 minutes (Image 4).  Newborn’s recovery was fast with normal heart action after ten minutes and was admitted to the neonatal unit for comfort care.

The newborn managed to drink and swallow, but twelve hours after delivery his breathing worsened, and the baby died in the presence of the parents.

Parental karyotypes were normal, thus recurrence risk is low.

Discussion

The unbalanced translocation was a 1p36 deletion and a 3q duplication.

1p36 deletion is common, occurring in 1/5000 births. The size of the deletion can be very variable and therefore its phenotypic expression also varies widely.  Typically, these terminal deletions present with growth restriction, epilepsy and dysmorphic features.  Cerebral malformations are also described including polymicrogyria, leukoencephalopathy, cerebral atrophy, and ventriculomegaly. Cardiac malformations, such as patent ductus arteriosus, ventricular septal defects (VSD), and atrial septal defects (ASD) have been reported in patients with 1p36 deletion.

The 3q duplication is much less common and has most frequently been reported as a part of unbalanced translocations. Therefore, scarce data are available about the phenotype of pure 3q duplication. Features of a pure duplication can include:

• Cerebral malformations such as corpus callosum agenesis, cortical dysgenesis, macro-microgyria, Dandy-Walker malformation, and vermian hypoplasia
• Cardiac malformations including tetralogy of Fallot, ASD, VSD, and patent foramen ovale
• Cleft palate
• Genitourinary malformations such as cryptorchidy, hypospadias, and micropenis
• Renal malformations including renal cysts and hydronephrosis
• Skeletal malformations such as brachydactyly, clinodactyly, and ulnar deviation of the hands

Most reciprocal translocations are unique to a family since the breakpoint can occur randomly throughout the genome. Therefore, in unbalanced translocations, it is difficult to differentiate which malformations can be ascribed to the deletion, and which to the duplication. In this case report, heart and cerebral malformations have been described in 1p36 deletion as well as in 3q duplication.  Due to the lack of similar reported cases, it is difficult to ascribe each malformation seen in our patient to the particular genetic defect.

References

[1] Abreu-González M, García-Delgado C, Cervantes A, et al. Clinical, Cytogenetic, and Biochemical Analyses of a Family with a t(3;13)(q26.2;p11.2): Further Delineation of 3q Duplication Syndrome. Case Rep Genet. 2013, Epub 2013 Sep 18. PMID 24151567

[2] Dworschaka GC, Crétolle C, Hilgera A, et al. Comprehensive review of the duplication 3q syndrome and report of a patient with Currarino syndrome and de novo duplication 3q26.32-q27.2. Clin Genet 2017 May;91(5):661-671.  PMID: 27549440

[3] Gajecka M, Mackay KL, Shaffer LG. Monosomy 1p36 deletion syndrome. Am J Med Genet Part C Semin Med Genet. 2007, 145C:346–356.

[4] Rocha CF, Vasques RB, Santos SR, et al. Mini-Review: Monosomy 1p36 syndrome: reviewing the correlation between deletion sizes and phenotypes. Genet Mol Res. 2016 Feb 22;15(1).  PMID: 26910004