Inversia pericentrică a cromozomului 9: un fenotip anormal

Introduction

Pericentric inversion of chromosome 9 – inv(9) – is one of the most frequent chromosomal variations^(1-3), being described in 1-3% of the general population⁽¹⁾. The prevalence varies among different ethnic groups⁽³⁾. The minor rearrangement in the heterochromatic region of chromosome 9 has been considered a balanced structural anomaly, most often with no phenotypic impact. Despite being widely discussed, the clinical significance is still uncertain. As a relatively common part of the human karyotype, this heterochromatic variant has been correlated with intellectual disability^(4-7), schizophrenia^(3,4), growth failure^(3-5,7), skeletal, cardiac^(3,5,8) and genital malformations^(3,5,8,9). Moreover, contradictory studies can be found on the association between pericentric inversion of chromosome 9, infertility^(1,3-24) and cancer predisposition^(3-5,10,12).

Our paper aims at presenting the case of a 5-month-old male infant with an array of congenital abnormalities. We described the chromosomal rearrangement by karyotyping and the clinical usefulness of the correlation between an abnormal phenotype and pericentric inversion of chromosome 9, considered a balanced variation of the human karyotype. Additionally, we reviewed the literature for developmental delay and dysmorphic features similar to those present in our patient.

Case presentation

A couple of parents presented to our hospital with a 5-month-old male infant for poor feeding and loose stools. The infant was the fourth born to healthy non-consanguineous parents. There was no history of drug intake, radiation or chemical exposure during preg­nancy. No previous abortions and no older siblings with abnormal phenotypes were found. The antenatal period was uneventful. The routine ultrasounds reported normal findings during pregnancy, until the third-semester examination depicted oligohydramnios. The male child was delivered at 34 weeks of gestation by caesarean section, weighing 2100 g (under the third percentile), with a length of 47.9 cm (the 15^th percentile) and with a head circumference of 32 cm (the third percentile).

The physical examination revealed an underweight boy (6 kg, under the third percentile), average length (66 cm, the 50^th percentile), plagiocephaly, microcephaly, dysmorphic and low-set ears, hypertelorism, long philtrum, saddle nose and micrognathia. The abnormal phenotype (Figure 1a and b) included: long limbs, arachnodactyly, a fifth finger clinodactyly, camptodactyly of the fingers I, II and III, “sandal gap” deformity, pilonidal sinus and a systolic ejection murmur in the pulmonic area. Even unresponsive to auditory stimuli, he appeared cheerful and presented mild motor developmental delay.

The laboratory investigations revealed an increased alkaline phosphatase, immune globulin G deficiency and undigested fiber in the stool test. The ENT exa­mination described bilateral sensorineural hearing loss. Moreover, a patent foramen ovale was present on cardiac ultrasound, and renal ultrasound identified mild left hydronephrosis. Lactose intolerance genetic test resulted in 13910 C/T and 22018 G/A heterozygous genotype.

The karyotyping was performed due to the infant’s dysmorphic appearance. After 72-hour PHA-stimulation of peripheral blood lymphocytes and G-banding, the cultures were examined in light microscopy. The cytogenetic analysis was performed on twenty meta­phase plaques. The chromosomal imbalances were described according to the International System for Human Cytogenetic Nomenclature (ISCN) 2016. As a result of the karyotyping of peripheral, the case was classified as a pericentric inversion of chromosome 9 (p11q13). Parental karyotype could not be performed due to the father’s refusal of consent, while further investigation of the mother’s karyotype encountered no genomic abnormalities.

Presentation at 18 months

The evaluation at 18 months revealed an underweight boy (9 kg, the third percentile), with tall stature (90 cm, above the 95^th percentile), presenting the craniofacial dysmorphisms previously described, associating impaired dentition (delayed tooth eruption and cavities), pectus excavatum, thin and sparse hair (Figure 2a and b). In addition, he appeared cheerful but with moderate neurodevelopmental delay, walking difficulties and with severe speech delay. He suffered a traumatic (hot water chest-burn) anterior chest lesion. The head CT revealed the persistence of cavum septum pellucidum and cavum vergae.

Discussion

Pericentric inversion of chromosome 9 is one of the most common morphological chromosomal variations^(1-3). The frequency of inv(9) is variable among different ethnic groups, ranging from a high rate in the African population (3.57%) to a relatively low rate in Caucasians (0.73%)⁽³⁾. The incidence of this fetal disorder was higher in females than in males, without a specific explanation. Maternal origin was inclined (1.3 times) more often than paternal origin, with only one de novo event being described in the most extensive study on carriers of chromosome 9 variants⁽¹²⁾.

Developmental delay and dysmorphic features affect 2-3% of the pediatric population. In a limited number of cases, additional research is recommended for chromosomal imbalances using the G-banded karyotype and chromosomal microarray⁽²⁵⁾. After discovering the congenital abnormalities, the genetic test result concluded that our case was a minor rearrangement, namely a pericentric inversion of chromosome 9 (p11q13). This unifying diagnosis accounts for a part of the patient’s dysmorphic features, skeletal, cardiac and urological malformations.

Molecular studies suggest that the complex structural organization of the pericentric region of chromosome 9 may contain susceptible breakpoints with a higher potential of generating pericentric inversions, deletions, duplications and other types of variations. The pathogenesis of this disorder involves the heterochromatic region of chromosome 9, leading to a variety of clinical presentations. Among these heterochromatic variants, the pericentric inv(9) is considered a balanced structural anomaly^(2,4).

Although firstly described more than four decades ago⁽²⁶⁾, the clinical significance of chromosome 9 variants is still uncertain. More often cited as a relatively common part of the normal human karyotype, this chromosomal rearrangement could be associated with dysmorphic features: growth failure^(3-5,7), synophrys, low hairline⁽⁵⁾, microcephaly^(3,5) and micrognathia⁽⁵⁾.

A few studies have drawn the correlation between inv(9) and various anomalies such as intellectual disability^(4-7), schizophrenia^(3,4), bipolar disorder⁽⁴⁾, skeletal, cardiac^(3,5,8) and genital malformations^(3,5,8,9). The heterochromatin polymorphism of chromosome 9 has been mentioned in patients with hematological malignancies^(3-5,10,12). It is still uncertain whether inv(9) and malignant diseases could be regarded as a familial inheritance or due to acquired conditions⁽¹⁰⁾.

Previous literature has mentioned the association between structural chromosomal anomalies and reproductive failure^(1,3-24). A prospective study carried out over more than fifteen years in 895 individuals with a history of infertility observed that the most common abnormal karyotype contained the pericentric inversion of chromosome 9⁽¹¹⁾. Some authors report the heterochromatin variants and underlying reproductive failure with a higher incidence in females^(11,13), while others describe a frequent correlation between inv(9) and azoospermia^(14,15). We found the malformations mentioned before in our present case, but other clinical conditions could still develop.

We encountered various similarities regarding the phenotypic anomalies between our patient and a case of pericentric inversion of chromosome 9 and a de novo 6-Mb 9 (p13.1p11.2) duplication reported by Malinverni et al.⁽⁷⁾: hypertelorism, low set ears, long philtrum, dysmorphic nose, “sandal gap” deformity, a fifth finger clinodactyly, neurodevelopmental and growth delay. The aforementioned study described the father’s karyotype with the same positive C-banding as the child⁽⁷⁾.

One study analyzed the frequency of chromosomal polymorphisms among high-risk cases by performing maternal serum screening followed by amniocentesis. Inv(9) was the second most common polymorphic variant, specifically inv(9) (p11q13). In almost half of the parents who underwent chromosomal karyotype analysis, it was shown that fetal inv(9) was inherited from one parent and did not present an abnormal clinical phenotype. In this regard, the authors mentioned that inv(9) could be associated with abnormal clinical phenotype only if pregnant couples present other disorders that can lead to infertility or to an unfavorable pregnancy outcome⁽²⁴⁾.

There are various similarities between our present case and the various malformations associated with de novo inv(9) mentioned in a study in 431 neonates with congenital disorders⁽³⁾. Similar malformations were also described in another study which listed 157 cases of inv(9), with inversions inherited from one of the parents⁽⁴⁾. A significant key point in our complete diagnosis would have been the chromosomal analysis of both parents. We were able to investigate only the mother’s karyotype, which encountered no genomic abnormalities, while the father’s consent was not obtained. Parental chromosomal analysis is essential to assess the origin of the rearrangement to offer more accurate genetic counseling. We emphasized the clinical features of our case compared to other studies regarding the dysmorphic anomalies of the heterochromatic region of chromosome 9 (Table 1).

Numerous studies have described developmental delay and dysmorphic features similar to those present in our patient. Marfan syndrome is a rare disorder diagnosed in infants, although a few skeletal findings may be encountered from birth, including arachnodactyly, dolichocephaly, long bones and joint laxity, micrognathia and pectus deformity. A broad range of malformations complete this syndrome, ranging from cardiac and aortic disease to ocular, pulmonary and skin abnormalities⁽²⁷⁾. VACTERL association is a disorder that often includes vertebral defects, digestive tract and cardiac defects, renal and limbs malformations⁽²⁸⁾. Congenital craniofacial anomalies are connected to defects associated with neural crest cells. Treacher Collins syndrome is a severe congenital disorder that implies craniofacial malformations, such as cleft palate, hypoplastic facial bones, malformation of the external and middle ear⁽²⁹⁾. The chromosome 17q21.31 deletion syndrome, also known as Koolen-De Vries syndrome, is characterized by particular facial features, including long face and philtrum, bulbous nasal tip, spaced teeth and dysmorphic ears. Other relevant component manifestations are growth failure, intellectual disability, hypotonia and friendly behavior. Furthermore, epilepsy, heart defects and kidney anomalies are attributed to subjects with this chromosome deletion and KANSL1 mutation⁽³⁰⁾.

Conclusions

This case highlights the combination of an abnormal phenotype and one of the most common balanced structural anomalies. Despite being categorized as a clinically insignificant variant to a cytogenetic finding, further research is still needed for the few cases where specific pathologies were associated with pericentric inversion of chromosome 9. Additional investigations of the breakpoint region could provide a better understanding of how to differentiate a common heteromorphism from an abnormal aberration. More awareness should be given towards various studies that continue to draw a correlation between this chromosomal inversion and an array of abnormalities. 

Conflict of interests: The authors declare no con­flict of interests.