Constitutional chromosomal abnormalities are an important cause of miscarriage, infertility, congenital anomalies, and mental retardation in humans.1 Constitutional chromosomal abnormalities include numerical chromosome aberrations that cause aneuploidy and structural chromosome aberrations such as translocations, inversions, deletions, and duplications. The frequency of structural chromosomal abnormalities has been estimated as 0.25% in live-born infants.2 Chromosomal polymorphisms of constitutive heterochromatin regions of chromosomes 1, 9, 16, and the Y chromosome have been reported.3 The pericentric inversion of the heterochromatic region of chromosome 9 [inv(9)], inv(9)(p11q13), or inv(9)(p12q13), is the most common pericentric inversion found in the human karyotype.4

Because the inv(9) has been found in - 3.57% of human samples without apparent phenotypic consequences, inv(9) is considered to be a structural chromosomal variant in the general population.3,5-7 In this study we re-evaluated cases with congenital anomalies associated with de novo inv(9).

We investigated the clinical profiles of 431 newborn cases with congenital anomalies including: age, gender, history of consanguinity, maternal and paternal factors, family history, pedigree, and associated diseases. The clinical characteristics of the patients are listed in Table 1. To confirm the existence of chromosomal aberrations in the patients, we carried out cytogenetic studies on all patients. As shown in Table 2, among the 431 neonates, chromosomal aberrations were found in 60 patients (13.9%). Numerical abnormalities were found in 34 patients (7.9%). The numerical abnormalities included Down syndrome among 28 patients (6.5%), Edward syndrome, Klinefelter syndrome, 47,XXX, and mosaicism. Structural abnormalities were found in 26 patients (6.0%). Inversions, translocations, deletions, addition, insertion, ring chromosome, 16qh+, and 21ps+ were found. Two inversions, inv(8)(q13q24.1) and inv(9)(p11q13), were detected.

We focused further study on the pericentric inversion of chromosome 9, inv(9)(p11q13), because it was the most common type of structural abnormality (8 cases) identified in this study. No other chromosomal abnormalities were found in these patients with inv(9)(p11q13), and represen-Normal karyotypes were obtained in the parents of the affected patients, indicating that all cases with inv(9)(p11q13) were de novo.

The patients with inv(9)(p11q13) had various dysmorphic features and/or congenital anomalies including: polydactyly, club foot, microtia, deafness, asymmetric face, giant Meckel's diverticulum, duodenal diaphragm, small bowel malrotation, pulmonary stenosis, atrial septal defect, tricuspid regurgitation, cardiomyopathy, arrhythmia, intrauterine growth restriction, and oligohydramnios (Table 3) (Fig. 2). The patient with polydactyly had a thumb duplication on standard X-ray (Fig. 2A). In the patient with a giant Meckel's diverticulum, barium filled the large cystic mass at the distal part of the ileum (Fig. 2B). In the patient with the duodenal diaphragm and small bowel malrotation, a dilated duodenal bulb and obstructed lower portion of the duodenum was observed on an upper gastrointestinal study (Fig. 2C). In the patient with hypertrophic cardiomyopathy, atrial septal defect, arrhythmia, club foot, and oligohydramnios, and cardiomegaly were identified (Fig. 2D). In the patient with unilateral microtia and an asymmetric face, the external auditory canal of the right ear was absent on three-dimensional reconstruction images of the computed tomography (Fig. 2E). Brain stem-evoked audiometry responses were tested in all patients. One patient (case 7) was found to have severe hearing difficulty in both ears, and in the patient with microtia, the affected ear was non-responsive to stimuli. We followed these patients for 6 to 32 months and performed developmental assessments with the Bayley and social maturity scales. All patients showed normal progress in motor, language, and social development.

Chromosomal inversion is a common structural rearrangement that originates from two breaks on the same chromosome followed by reinsertion of the 180° rotated broken fragment. Human chromosome 9 is highly susceptible to structural chromosomal rearrangement and various types of pericentric inversions have been reported including: inv (9)(p11q13), inv(9)(p11q12), inv(9)(p11q21), inv(9) (p12q13), inv(9)(p13q13), and inv(9)(p13q21); the variable breakpoints are preferentially located in the 9p12 or 9q13-21.1 regions.9 Among them, inv(9)(p11q13) and inv(9) (p12q13) cannot be distinguished on karyotypes and 'inv(9)' represents these two karyotypes.

The inv(9) is one of the most common structural balanced chromosomal variations. The incidence of inv(9) has been found to differ among ethnic groups and the overall incidence has been estimated to be - 3.57% in various populations by antenatal cytogenetic analysis and peripheral blood karyotype analysis.3-6 A previous study reported that in 6,250 referred antenatal cases of four major ethnic groups, the incidence of inv(9) was highest in the Black population (3.57%), slightly above average in Hispanics (2.42%), and relatively low in Whites (0.73%) and Asians (0.26%).3 In another study of Asian populations, the overall incidences of inv(9) were estimated to be 1.2% in antenatal groups in Singapore and 1.95% among normal and patient populations in Japan.5,6 In this study, inv(9) was observed in 1.9% of the total referred newborn cases (n = 431) and this data is similar to that of a previous report in Korea (1.7%).10 As shown in the previous study, the incidence of inv(9) in fetuses was significantly higher in females than males;7 our data also showed more females (7 : 1).

In this study, we detected various abnormalities in eight patients with inv(9), including polydactyly, club foot, microtia, deafness, asymmetric face, giant Meckel's diverticulum, duodenal diaphragm, small bowel malrotation, pulmonary stenosis, atrial septal defect, cardiomyopathy, arrhythmia, and intrauterine growth restriction (Table 3)(Fig. 2). There were no commonly shared clinical features; however, polydactyly was found in cases 1 and 2, gastrointestinal abnormalities in cases 3 and 4, atrial septal defect and oligohydramnios in cases 5 and 6, and unilateral microtia in cases 7 and 8. In the literature, a few reports have shown that inv (9) was detected in patients with various congenital anomalies such as a dysmorphic face, congenital cataract, blindness, deafness, cleft palate, congenital heart anomalies, hydronephrosis, amenorrhea, short stature, short toes, microcephaly, and urogenital anomalies.11-15 There were no overlapping clinical phenotypes. This indicates that inv(9) was not pathogenic.

Recently complex chromosomal rearrangements, with more than two chromosomal breaks, have been identified more frequently than it had been expected before the human genome project era. This was supported by a higher prevalence of inv(9) in the Down syndrome population in comparison to the normal population.16 A higher prevalence of inv(9) has been reported in couples with habitual abortion and a history of more than two spontaneous first trimester abortions,6 aborted fetuses,6 and among the schizophrenia population.17 Although no specific or common manifestations have been identified in these populations, a few studies have reported that inv(9) is sometimes associated with various clinical phenotypes related to fertilization,18 fetal development,19 morphogenesis,11,12 growth,15 acute leukemia,20 and ovarian cancer.21

The cytogenetic analysis of the parents revealed that all cases were de novo heterozygous inv(9)(p11q13). Karyotypes of peripheral blood lymphocytes from the patients demonstrated that no other chromosomal aberrations except inv(9)(p11q13) were present (Fig. 1). However, there is the possibility of microdeletions or duplications that could not be detected by the karyotypes in these patients. Unlike the inherited inv(9) found in normal populations, de novo pericentric inversions would be expected to have other cryptic genomic abnormalities. This may explain why de novo inv(9) is associated with various clinical features.