In the current observation, trisomy 8 was initially identified by cffDNA. Fetal US and MRI indicted hydronephrosis and irregular spine. T8M was suspected on the basis of the results of amniocentesis. After thoughtful considerations, the couple decided to continue the pregnancy and a male infant was delivered. FISH analysis on the uncultured neonatal cord blood cells verified the existence of T8M, with an percentage of 10%.Though the percentage was low, periodic fever as well as impaired speech was observed in the child in his follow up, indicating a poor prognosis. Our findings provided an insight into the identification of low level percentage of T8M with cffDNA screening.
CffDNA, originating from trophoblasts and circulating in the maternal plasma, is used to detect potential fetal chromosomal abnormalities 12. The analysis of cffDNA with the next-generation sequencing technology, also known as NIPS, provides a well-validated way to identify the aneuploid. CffDNA-based screening for trisomy21wassuperior to any other clinically available screening methods, with a detection rate (DR) of 99.2% 13. For other aneuploidies,suchastrisomy18,13, monosomy X and other sex chromosome aneuploidies, the DRs are relatively lower compared with trisomy 21, approximately 96.3%, 91.0%, 90.3% and 93.0%, respectively 13.
The observations about identification of RATs with cffDNA are available recently 5, 14. However, large-scale population data of RATs for genetic counseling remain limited 14, 15. Thus, whether the RATs identified by NIPS should be included in the final reports or not is still under debate 7. In fact, with an aggregate incidence of approximately 0.3%14, 16, RATs are not uncommon and associations between RATs and feto-placental diseases are increasingly reported. The ignorance of RATs may omit the increased risk of miscarriage, intrauterine growth restriction 17, 18, low birth weight19, small-for-gestational-age infants20, uniparental disomy16 and NICU admission 21. Therefore, early identification of RATs is necessary to notice therisks of adverse pregnancy outcomes 22.
Trisomy 8, one of the RATs, was known for its associations with the acute myeloid leukemia (AML) 23. T8M, also known as Warkany syndrome, is a rare chromosomal disorder, usually caused by a post zygotic non-disjunction. With an estimated prevalence ranging from 1:25000 to 1:50000, it is a disease affecting males more often than females24 25, 26 27. The clinical manifestations associated with T8M are extremely variable, including central nervous, ocular, cardiac, gastrointestinal, genitourinary and musculoskeletal abnormalities 25, 28. Patients with T8M present personalized pattern of features, ranging from no phenotypes to a variety of birth defects (Table 1) 28, 29 30 31 32 33 34 35 36 37 38 39 40. Thus, prenatal detection for T8M is still a challenge in the clinical practice and more evidences are required to estimate the outcome of T8M.
Table 1
Literature review and summary of the clinical manifestations in T8M patients
Study | mental retardation | dysmorphic facial feature | malformations of the kidneys | Developmental retardation | malformations of the bone | Fetual US abnormal |
(Kurtyka et al.,1988) | Patient 1 | Yes | Micrognathia, low set of auricles, funnel-breast, hyper- trichosis on the arms, cloudy cornea in right eye, severe contractures in fingers, moderatel extention impairment in joints, micrognathia, deep plantar skin furrows | bilateral moderate hydronephrosis | Yes | clinodactyly, bilateral absence patellae,V-shaped talipes valgus, narrow pelvis, right scoliosis of the thoracic segment of the vertebral column | Not mention |
Patient 2 | Yes | slight contractures of finger joints, bilateral arachnodactyly in hands and feet, Deep palmar and plantar furrows | Not find | Not find | deformed sternum, Narrow pelvis, right thoracic scoliosis | Not mention |
(Camurri et al.,1991) | Not find | prominent forehead, bulbous nose with a depressed bridge, everted lower lip | Not find | Not find | Not find | Not mention |
(Miller et al.,1997) | Yes | hypertelorism, micrognathia, large and dysplastic ears, deep palmar, plantar creases and corpus callosum agenesis | Yes | Not mention | Not mention | Not mention |
(de Pater et al., 2000) (10 patients) | Not find in 3 patients | 4 patients had dysmorphic facial feature; 3 patients were normal; 3 were not mention | Not mention | Not mention | 3 patients had skeletal anomalies; 4patients were normal; 3 were notmention | Not mention |
(Chen et al., 2011) | Not mention | the infant was grossly normal at birth | Not mention | normal at age 4 months | Not mention | Not find |
(Iwatani et al., 2014) | Not mention | Not mention | bilateral hydronephrosis | Not mention | Not mention | polyhydramnios and fetal left-sided congenital diaphragmatic hernia (CDH) |
(Tsai et al.,2014) | Not mention | asymmetrical cranium, small lids, deep palmar, plantar furrows, hypospadias, and corpus callosum agenesis | Not mention | Not find | Not mention | Not find |
(Ruland et al., 2017) | Not mention | Not mention | Not mention | Not mention | Not mention | agenesis of thecorpus callosum (ACC) |
(Sherer et al., 2017) | Not mention | Not mention | Not mention | Not mention | Not mention | ventricular septal defect (VSD) truncus arteriosus Type I |
(Cassina et al.,2018) (17 patients) | Not find in 17 patients | Not find in 17 patients | Not find in 17 patients | Prenatal and post-natal growth retardation in patient 14 | Clubfeet and clinodactyly of 3rd, 4th and 5th fingers in patient 17 | Prenatalgrowth retardation in patient 14 |
(Sun et al.,2019) | Mildmental retardation | Not find | Not find | Not find | Not find | Not find |
(Sanderson et al.,2020) | Not mention | Bilateral micropthalmia, Abnormal insertion of frenulum, Cleft palate, Low-set, posteriorly rotated ears, Frontal bossing | bilateral hydronephrosis and hydroureter | Not mention | small orbits, Bulging of the parietal plates, Steep sphenoid with abnormal configuration to stella, Obtuse mandibular angle, Formation/segment defects of lumbar vertebral bodies, Focal scoliosis convex right and kyphosis centered at L2 right congenital hemivertebral body, Dysraphic and segmentation defects of sacrum,13 sets of undulating ribs, Proximal fusion of ribs within the right lower hemithorax, Absence of anterolateral right sixth rib, Elongated and narrow thorax/sternum, Hook-like configuration of clavicles, Medial spurring of relatively flat acetabuli, Spurring at SI joints, Narrowing and straightening of interior Ilia. | noted enlargement of the lateral and third ventricles in the fetal brain |
Here in, low level percentage of T8M was identified by cffDNA. Findings in his follow up were recorded before 41, warning a poor prognosis. Therefore, the identification of RATs with cffDNA is essential for early diagnosis. In fact, some countries have embedded RATs into the detecting scope of cffDNA 42. Our findings provided another confirmation for its sensitivity to identify low level percentage of RATs. What’s more, invasive prenatal test ought to be performed afterwards when RATs are identified in NIPS as to exclude the possible false positive results.