Mosaic trisomy 12 diagnosed in a female patient: clinical features, genetic analysis, and review of the literature

Abstract

Mosaic trisomy 12 is a rare genetic condition with a highly variable phenotype. Clinical features associated with this condition include developmental delay, intellectual disability, dysmorphic facial features, short stature, pigmentary dysplasia, complex congenital heart defects and hypotonia (Table 1). To date, 20 patients have been described in which mosaic trisomy 12 was observed in both extraembryonic and neonatal/infant tissues. Chen et al. reported two cases without phenotypic abnormalities [1]. Of the 20 previously reported cases, 4 resulted in neonatal or infant death. Those findings support the hypothesis that mosaic trisomy 12 manifests across a wide spectrum of phenotypes and that predicting the degree of abnormalities is quite difficult [2–4]. In several cases, trisomy 12 mosaicism was detected prenatally in amnion fluid, but not postnatally [5–8]. Even if the mosaicism is not confirmed in one tissue, it may still be present in other tissues of the child. The described patient is the second child of a 37-year-old mother. The healthy parents already had a healthy son. Upon prenatal screening, amniocentesis was performed owing to fetal abnormalities including muscular ventricular septal defect, aberrant right subclavian artery and unbalanced ventricles with hypertrophy of the right ventricle detected by ultrasound examination at gestational week 21. Chromosome analysis revealed in 18/55 metaphases (33%) mosaicism for trisomy 12 in cultured amniocytes. Fluorescence in situ hybridization (FISH) analysis on 58 uncultured amniocytes found 24 cells with trisomy 12 consistent with 41% mosaicism for trisomy 12. An array-CGH analysis (arraycomparative genomic hybridization) of fetal DNA displayed an additional chromosome 12 in 30–40% of all analyzed cells (Fig. 1). The parents decided to continue the pregnancy. Ultrasound in gestational week 24 confirmed the abnormalities listed above and additionally showed an increased vascular resistance of the left uterine artery. In gestational week 28, the development of polyhydramnios was discovered. The following ultrasound examinations showed no deterioration of the previously stated findings. After birth, cytogenetic analysis of neonatal lymphocytes revealed a 46,XX karyotype. Metaphase and interphase FISH analysis on 10 metaphases and 200 interphase cells did not give evidence for trisomy 12. Following these results, interphase FISH analysis on uncultured urinary cells was conducted at five weeks of age and revealed 28% (28/100 cells) mosaicism for trisomy 12. Thereafter, interphase FISH on lymphocytes was repeated showing three signals in 7/200 cells consistent with 3.5% mosaicism for trisomy 12 (Fig. 2). Repetitive chromosome analysis confirmed the normal karyotype of the neonatal blood sample. The varying results described above are shown in Table 2. The female baby was delivered spontaneously at 38 weeks of gestation with a birth weight of 3820 g (91th percentile), length of 52 cm (72th percentile), and head circumference of 38 cm (> 99th percentile). She showed multiple dysmorphic features, such as the prominent forehead, broad flat nasal bridge, low-set ears, prominent cheeks, flat profile, single transverse palmar crease on both sides, camptodactyly of the fifth finger on both sides, clinodactyly of the fourth finger on both sides, overlapping toes, deep plantar crease on both sides, short neck, and anteriorly placed anus (Fig. 3). The ophthalmologic examination displayed a missing upper eyelid crease and coloboma of the right eye as well as blepharophimosis, ptosis, epicanthus, and tapetoretinal abnormalities * Julia Hoefele [email protected]