Abstract
We present here, a case of a neonate with an unbalanced chromosomal translocation due to a maternal chromosomal translocation carriage that resulted in the presence of trisomy 9p combined with a partial trisomy 12p. Karyotype analysis was performed using conventional cytogenetic chromosomal analysis using the GTG-banding technique. The mother was a carrier of a balanced chromosomal translocation of 46, XX, t(9;12)(q13;p11.2), that resulted in an unbalanced translocation of the offspring, who had a karyotype 47, XX, +der(9)t(9;12)(q13;p11.2)dmat, featuring a combined trisomy of 9q13→9pter region and 12p11.2→12pter region. Clinical phenotype of the infant included cephalo-facial deformity, growth retardation, hypertonia, opisthotonus, laryngeal wheezing, foot deformity, and congenital heart disease.
Background
Unbalanced chromosomal translocation is a type of a structural chromosome abnormality that results mainly from the genetic effect of a parental balanced chromosomal translocation.1,2 Abnormal meiosis in the process of gamete formation leads to unbalanced chromosomal rearrangements in the offspring, where deletion or duplication of chromosomes affect the gene dosage balance and disrupt normal expression and regulation of genes, resulting in abnormal clinical phenotypes. 1 These may include, intrauterine and extrauterine growth retardation, unusual facial features, psychobehavioral disorders and congenital malformations. 1 Unbalanced chromosomal translocations can impose a substantial psychological and financial burden on patients and their families. We describe here, a neonate with an unbalanced chromosomal translocation due to a maternal chromosomal translocation carriage that resulted in the presence of trisomy 9p combined with a partial trisomy 12p.
Case report
The baby was born to a non-consanguineous couple, a 25-year-old mother and a 27-year-old father, who gave a history of three spontaneous abortions, no abnormal phenotypes, and no family history of genetic disorders. The baby girl was the fourth pregnancy, born at 39+3 weeks gestational age, with clear amniotic fluid at birth and no placental abnormalities. Routine maternity examinations had not been performed because the family lived in a remote mountainous area and had financial difficulties. The baby weighed 2.76 kg, had an Apgar score of 6 points at 1 minute (2 points for muscle tone and 1 point for respiratory complexion) and had a caput succedaneum. She was assessed as having a poor mental response, average nutritional status, mild yellowing of the skin, increased muscle tone in the limbs, and weak primitive reflexes. In addition, she had a deformed head with a prominent forehead, wide eye spacing, small eyelids, a low nasal bridge, and low positioning of her ears. She also had clenched fists in both hands and her thumbs were inward (Figure 1(a)). In addition, she had ankle valgus deformities (Figure 1(b)). A pulmonary computed tomography (CT) scan showed increased texture and inflammatory changes in both lungs and a cranial CT scan showed presence of a subarachnoid haemorrhage. Cardiac ultrasound showed congenital heart disease. The neonate had atrial septal defect (secondary foramen ovale), patent ductus arteriosus, and tricuspid valve insufficiency with pulmonary hypertension. Results from laboratory tests showed: direct bilirubin, 13.5 μmol/l (reference range 0–8 μmol/l); indirect bilirubin, 153 μmol/l (reference range 0–13 μmol/l); total bilirubin, 167 μmol/l (reference range 0–21 μmol/l); free triiodothyronine (FT3), 1.92 pmol/l (reference range 2.43–6.01 pmol/l). Following symptomatic treatment (i.e., treatment for lung inflammation, hyperbilirubinemia, and poor circulation) and improvement in her condition, the baby was discharged from hospital.
abnormal phenotype of the child. (a) Unusual facial features and (b) Ankle valgus deformity.
At the three-month assessment, the baby was observed to have growth retardation, malnutrition, and laryngeal stridor. At the four-month assessment, she had laryngeal wheezing, high muscle tone in her limbs, and still had clenched fists in both hands and her thumbs were inward. Moreover, she had limited ability to lift her head supine or support standing with both lower limbs. According to the Gesell Developmental scale, the baby was equivalent to a 4-week-old child with a developmental quotient (DQ) <25 (i.e., a severe deficit).
At seven months, the infant continued to have laryngeal wheezing, and high muscle tone in all four limbs, and she had a general developmental level equivalent to that of a 6-week-old child and a QD of 30 (i.e., a severe deficiency). At the eight-month assessment, she had laryngeal wheezing, high muscle tone in her extremities, and a general developmental level equivalent to that of a two-month-old child, and a QD of 37 (i.e., a severe deficit). She could roll over but not sit up.
Samples of peripheral venous blood for karyotyping were collected from the infant when she first attended our hospital. After finding unexplained chromosomal abnormalities in her samples, we decided to investigate the parents’ karyotype and so subsequently took blood samples from her mother and father. T-lymphocyte culturing, metaphase chromosome preparation and GTG-banding were carried out as described previously. 2 GTG-banded chromosome analysis of 50 cells was performed at 320–400 band resolution. Images were captured using a fully automated scanning chromosomal image analysis system (Zeiss Axio Imager system) to monitor the prepared gene chips and analyse the karyotypes. The karyotypes were described in accordance with the international system of cytogenetic nomenclature 2020 (ISCN 2020).
Karyotype analysis of the baby’s blood showed an extra chromosome, but it was difficult to determine its source and structure. Therefore, a preliminary diagnosis was made as 47,XX + mar karyotype. Chromosomal analysis of the parents' blood showed the karyotype of the child's mother was 46,XX,t(9;12)(q13;p11.2), which showed a balanced translocation between chromosomes 9 and 12, with chromosome breakpoints located in the 9q13 and 12p11.2 region, respectively (Figure 2(a)). The karyotype of the child's father was 46,XY, and no abnormalities were observed. The extra chromosome 9 formed in the child due to maternal balanced translocation and was morphologically consistent with a marker chromosome. Combined with the karyotype of the parents, the final diagnosis of the child's karyotype was 47,XX,+der(9)t(9;12)(q13;p11.2)dmat, and the structural composition of the marker chromosome could be described as der(9)t(9;12)(q13;p11.2) (Figure 2(b)). Therefore, this child was diagnosed as a patient with trisomy 9q13→9pter combined with trisomy 12p11.2→12pter syndrome.
(a) Karyotype of the child's mother and (b) Karyotype of the child. The black arrows indicate the abnormal chromosome.
The reporting of this study conforms to CARE guidelines. 3 The child's parents provided written informed for publication of their anonymised data. Publication of this case report was approved by the Medical Ethics Committee of Wuzhou Gongren Hospital.
Discussion
Parents with balanced chromosomal translocations may transmit unbalanced chromosomes to their offspring, resulting in partial monosomy and partial trisomy. 4 The degree of clinical expression of segmental aneuploidy will vary according to the size of chromosomal region involved. Trisomy of the short arm of chromosome 9 (trisomy 9p) is the fourth most frequent chromosome aberration seen in newborn infants after trisomy 21, 18, and 13. 5 The relatively few genes in the 9p region may be the reason why a foetus with trisomy 9p is well suited for survival. 6 The main clinical features of patients with trisomy 9p include growth retardation, mental retardation, speech impairment, and cephalo-facial deformity (i.e., microcephaly, forehead projection, drooping eyelids, low nasal bridge, nostrils facing skyward, drooping corners of the mouth, low-lying ears), limb deformities, congenital heart disease and, to a lesser extent, kidney disorders. 6 The severity of the clinical symptoms has been reported to be related to the size of the 9p repeated segment. 7 Most children with trisomy 9p syndrome are easily recognized because of their obvious abnormal facial signs. It has been reported that the 9p22→9p24 region may be the critical region for typical symptoms 5 and partial duplication of the 9p21.2→9p21.3 region may be associated with a speech development disorder. 8 In addition, the 9q12→9pter segmental duplication has been associated with skeletal malformations, cardiac defects, and abnormal craniofacial features. 8 Within the 9q12→9pter region, the contained JMJD2C, CPSQ2, DOCK8, jVIRD2, VLDLR, and CARMQ1 genes have been reported to be closely associated with mental retardation. 9 Researchers have suggested that VLDLR influences specific learning and memory functions in the hippocampus by regulating synaptic plasticity through the transduction of multiple extracellular signals across the neural cell membrane into the nervous system. 9 In addition, the GLIS3 gene has been found to be associated with congenital hypothyroidism and intrauterine and extrauterine growth retardation. 10 Furthermore, SMARCA2 gene mutations are reported to be associated with autosomal dominant Nicolaides-Baraitser syndrome, clinical manifestations of which include dwarfism, microcephalus, language disorders, epilepsy, and learning disabilities. 11 The increase in the number of copies of these genes may affect the expression and function of the relevant proteins, thus causing the corresponding clinical symptoms.
Since it was first reported in 1970, more than 200 cases of trisomy 9p have now been documented. 12 However, to our knowledge, trisomy 9p combined with partial trisomy 12p due to t(9;12) is a rare occurrence. Moreover, trisomy of the short arm of chromosome 12(trisomy12p) is a rare structural chromosomal abnormality with an incidence of approximately 1 in 50,000. 13 Most cases derive from the genetic effect of a parental balanced chromosomal translocation. 14 Cases of duplication 12p have been divided into five categories based on the extent of the region duplicated and whether other chromosomal aneusomies were present. 13 The main clinical features of trisomy 12p include, growth retardation, unusual facial features (i.e., round face, protruding forehead, medial canthus, low nasal bridge, long philtrum, lower lip ectropion, ear deformity), mental and speech delay, congenital heart disease, epilepsy. 15 In addition to the above symptoms, the patients may have syndactyly, hair thinning, cataracts, and abnormal skin pigmentation. 16 Several researchers have attempted to correlate karyotype with genotype and phenotype. 13 Interestingly, the clinical phenotype and severity of symptoms we observed in our case study were consistent with previous reports of patients with trisomy 12p. Furthermore, in accordance with previous cases, the duplication of the 12p13.3 region was characterized by foot deformities.17,18 The addition of the duplication of the 9q13→9pter region may have further complicated the patient’s symptoms. Moreover, our neonate had small eyelids, and it has been reported that this may be associated with duplication and overexpression of related genes that interfere with normal embryonic eyelid development. 19 In the case we documented here, there were duplications of the 9q13→9pter and 12p11.2→12pter regions of the chromosome. Therefore, the clinical features of growth retardation, unusual facial features, congenital heart disease, and foot deformities may have been due to the overlap of trisomy 9p with trisomy 12p.
The GTG-banding approach is the classic cytogenetic technique and ‘gold standard’ for diagnosing chromosomal disorders. Compared with molecular genetic techniques, such as high-throughput sequencing, GTG-banding is an excellent technique for detecting chromosomal number abnormalities and structural aberrations, especially in cases involving balanced chromosomal translocations. 20 However, the technique has limitations, particularly with regard to the detection of deletion or duplication of small chromosomal segments. 20 Indeed, current research suggests that lineage analysis based on GTG-banding chromosome karyotyping and high-throughput sequencing-based molecular genetic techniques are essential for determining the origin and structural composition of small supernumerary marker chromosomes (sSMCs).1,21
In the case reported here, molecular genetic testing services were not available in the patient’s regional location. In addition, the child's parents were concerned about the high costs associated with molecular genetic testing and so further testing and verification of chromosome breakpoints and copy number variants were not performed. However, although the study of genotype-phenotype relationships, in this case was limited, GTG-banding karyotypic analysis of blood from the child and her parents showed that the cause of the child's abnormal phenotype was due to the genetic effect of balanced chromosomal translocation of the mother. It is generally accepted that balanced translocation carriers tend to be phenotypically normal because there is no gain or loss of genetic material. 22 However, their germ cells can produce 18 different types of gametes during meiosis of which only one type is normal, one type is balanced and the rest carry unbalanced chromosomal changes. 22 Fertilization of unbalanced gametes may lead to miscarriage, stillbirth, or even giving birth to a child with chromosomal disorders due to changes in gene dosage. In the present case, the abnormal karyotype of the mother, 46,XX,t(9;12)(q13;p11.2), was probably the reason for her previous recurrent miscarriages. For this couple, prenatal diagnosis by chorionic villus or amniocentesis, should be recommended for their subsequent pregnancies to avoid recurrence of the abnormal karyotype. Alternatively, third-generation assisted reproductive technology may be a suitable choice for this couple; pre-implantation genetic testing to screen for chromosomally normal embryos would avoid the physical and psychological damage caused by recurrent miscarriages.
In summary, we examined the correlation between chromosomal abnormalities and clinical phenotypes for this patient, and in reporting our findings have hopefully provided clinicians with a broader diagnostic perspective. In addition, we described diagnostic methods and techniques for chromosomal disorders that tend to be available in economically underdeveloped areas where access to molecular genetic testing services is limited. We suggest that, in the event of a patient presenting at clinic with unusual facial features, growth retardation, mental retardation, and/or congenital anomalies, clinicians may initially wish to perform routine cytogenetic chromosomal analysis and, if necessary, obtain a maternal and paternal history. If chromosomal abnormalities are found, further cytogenetic chromosomal analysis of the parents’ blood should be performed to determine structural composition and origin of any abnormal chromosomes. If the patient's cytogenetic chromosomal analysis is negative, other disease causes could be investigated. We believe this is an economical and effective diagnostic strategy.
