Prenatal Diagnosis of Unbalanced Translocation t(5;11)(q21;q22) With a Jacobsen Syndrome Clinical Phenotype

ABSTRACT

This case report describes a fetus with a Jacobsen syndrome phenotype, caused by an unbalanced translocation t(5;11)(q21;q22) resulting from an inherited balanced translocation from one of the parents; it underscores the importance of undertaking prenatal diagnosis and genetic counseling in parents to help plan for future pregnancies.

1. Introduction

Jacobsen syndrome, a chromosomal structural abnormality caused by a partial deletion of the long arm of chromosome 11, was first reported by Jacobsen et al. in 1973 [1]. It is a rare disease, with a reported incidence of 1 in 100,000 live births [2]. Eighty‐five percent of reported cases are de novo, and 15% are unbalanced translocations caused by familial balanced translocations or other chromosomal rearrangements [2]. Typical features of affected patients include facial malformations, cranial abnormalities, cardiac defects, and psychomotor developmental delay, but not all of these symptoms are always present [3]. Moreover, a study of the prenatal diagnosis of Jacobsen syndrome reported characteristic ultrasound findings of fetal growth retardation and cardiac malformation [4].

Partial duplication of the long arm of chromosome 5 is a very rare chromosomal abnormality. Although there are no reports of it as a syndrome, distal trisomy 5q is the most frequently reported abnormality of chromosome 5, being associated with fetal growth restriction, craniofacial dysplasia, and mental retardation [5, 6].

To date, Jacobsen syndrome and 5q trisomy have been described separately, and there has been only one report of an unbalanced translocation between chromosome 11 and chromosome 5 [7]. Furthermore, there are no known reports of prenatal diagnosis of this unbalanced translocation. Therefore, this is the first documentation of fetal growth restriction and cardiac malformation caused by an unbalanced translocation of chromosomes 11 and 5, which was diagnosed through amniotic fluid chromosome testing. Written informed consent was obtained from the parents, who were also the clients, for publication of this case.

2. Case Presentation

A 28‐year‐old primigravida woman was referred to our department at 22 weeks of gestation for perinatal management after fetal growth retardation was observed at 20 weeks of gestation. An ultrasound showed fetal growth restriction, and hypoplastic left heart syndrome was suspected. Genetic counseling was carried out regarding the possibility of a chromosomal abnormality, and chromosomal analysis by amniocentesis revealed 46,XX,der(11)t(5;11)(q21;q22) (Figure 1). Additional genetic counseling of the parents explained that the fetal ultrasound findings could be caused by either partial monosomy of chromosome 11q or partial trisomy of chromosome 5q. The possibilities of de novo unbalanced translocation and balanced translocation of chromosome 5 and 11 in either parent were also explained, but at this point, the couple did not wish to undergo chromosomal analysis.

FIGURE 1.

Chromosomal analysis by amniocentesis showing 46,XX,der(11)t(5;11)(q21;q22).

At 38 weeks of gestation, premature rupture of the membranes occurred, and an emergency cesarean section was performed because of non‐reassuring fetal status. The female infant weighed 1,680 g and had an Apgar score of 5 at 1 min and 6 at 5 min. The umbilical artery blood gas pH was 7.27, and the base excess was −13.5. The infant had hypoplastic left heart syndrome, thrombocytopenia, anorectal malformation, and a characteristic facial appearance including a flat nasal root, wide‐set eyes, low‐set ears (Figure 2A,B), and polydactyly (Figure 2C). The findings were considered to be characteristic of Jacobsen syndrome caused by a partial monosomy of chromosome 11. After birth, surgery was performed for hypoplastic left heart syndrome, and the infant's condition improved, but on the 78th day, she suddenly developed bradycardia and died on the same day.

FIGURE 2.

Neonatal facial features characteristic of Jacobsen syndrome. (A) Flat nasal root (White arrow) and hypertelorism (yellow arrow). (B) Auricular hypoplasia (white arrow). (C) Polydactyly (yellow arrow) in which the additional finger is connected by a thin stem on the side of the right phalanx.

One year after the death of their first child, the couple became pregnant with their second child. They requested amniotic fluid chromosome analysis, which was performed following amniocentesis at 16 weeks and showed a normal karyotype. The pregnancy progressed without any problems, but at 23 weeks of gestation, a preterm premature rupture of the membranes occurred. An emergency cesarean section was performed at 27 weeks of gestation because of increased uterine contractions. A female neonate weighing 880 g (appropriate for the gestational age) was delivered, with Apgar scores of 4 and 7 at 1 and 5 min, respectively. At 2 years of age, no developmental abnormalities were noted.

Although the second child has a normal karyotype, the couple visited our genetic counseling department to request a chromosomal test for themselves because they had experienced premature labor. One of the parents was found to have a balanced translocation (Figure 3). They had requested that we keep the identity of the parent with the chromosomal abnormality confidential, so when presenting the chromosomal analysis to them, we concealed the sex chromosomes.

FIGURE 3.

Chromosomal analysis of one of the parents.

3. Differential Diagnosis

Partial trisomy 5q has rarely been documented, but there have been reports of phenotypes such as fetal growth restriction and craniofacial dysplasia that overlap with Jacobsen syndrome, which is a partial deletion of 11q [5, 6]. In this case, fetal growth restriction and cardiac malformation were observed, which together with the results of amniotic fluid chromosome testing led to a diagnosis of Jacobsen syndrome.

4. Outcome and Follow‐Up

We explained that the probability of the couple's next child having an unbalanced translocation was 38.6%, and the probability of miscarriage was 53.9%, in line with previously described content [8]. We are considering preimplantation genetic testing for structural rearrangements as an option for the third pregnancy.

5. Discussion

This case presented with partial trisomy of 5q and partial deletion of 11q, which have been rarely reported to date, and was diagnosed as Jacobsen syndrome based on clinical symptoms such as fetal growth restriction and craniofacial dysmorphism [5, 6].

Jacobsen syndrome occurs in approximately 1 in 100,000 births [2], and the incidence of partial trisomy of 5q is unknown. Therefore, this case, which combines both conditions, is considered extremely rare. Furthermore, there are no previous reports of prenatal diagnosis of 46,XX,der(11)t(5;11)(q21;q22), making this an even more valuable report. This unbalanced translocation derives from an adjacent‐1 separation pattern as indicated in the pachytene diagram of Figure 4. If the chromosomes in the upper half of the diagram above the dotted line separate and move to the daughter cell, and fertilization with a normal gamete occurs, it will result in the karyotype seen in this case. We calculated the haploid autosomal length (HAL)% for this unbalanced translocation using the International System for Human Cytogenomic Nomenclature 2020 [9] and a 550 bph ideogram to estimate the likelihood of birth. The HAL for partial trisomy 5 was 1.01%, and that for partial monosomy 11 was 0.282%, representing a possibility of birth according to previously reported thresholds of HAL < 2% for a deletion and < 4% for a duplication [10]. Determining the probability of a child being born with an unbalanced translocation was also attempted using the Stengel–Rutkowski method [11], although this was not possible because of the uncertainty of the 5qter → q21 translocation [12].

FIGURE 4.

Pachytene diagram in this case. The dotted lines represent the separation of chromosomes.

In the present case, we suspected a chromosomal abnormality from the ultrasound diagnosis, so undertook amniotic fluid chromosome testing. Because there is only one known report of an unbalanced translocation of chromosome 5 and chromosome 11, it was difficult to provide accurate information about potential complications or prognosis. This was in part because the fetal growth retardation and heart malformations observed during the fetal period can also occur following partial monosomy of chromosome 11 and partial trisomy of chromosome 5. Additionally, the region most frequently deleted in Jacobsen syndrome is the distal part of the long arm of chromosome 11, specifically 11q23.3 to 11q24.2 [13, 14]. In our case, the distal end from q22 of the long arm of chromosome 11 is partially monosomic. The 11q22‐q23 region contains important genes, including the ataxia–telangiectasia locus [15, 16]. Mutations at this locus can cause diseases such as ataxia–telangiectasia, telangiectasia, and immunodeficiency. Therefore, there was a possibility that a more serious phenotype than the previously reported Jacobsen syndrome would appear in this fetus. Previous reports show that 20% of patients with Jacobsen syndrome die within 2 years of birth, and the most common cause of death is complications of cardiac defects [2]. When attempting to determine the probability of birth using the Stengel–Rutkowski method [12], the presence of two translocations in the risk table would typically result in double segment imbalance. However, because the probability for the 5qter → q21 translocation was unknown, the probability of birth could not be calculated. If we estimate that the probability of 5qter → q21 is lower than that of 11qter → q22, the probability of a child being born with an unbalanced translocation is less than 1.3%, so this case can be considered to be a very rare birth.

The most commonly reported partial trisomy of chromosome 5 is distal trisomy 5q (5q33‐qter) [5, 6]. Associated phenotypes include mental retardation, craniofacial abnormalities, growth failure, and cardiac malformations [17, 18, 19]. In some cases, craniosynostosis, a condition in which the skull fuses prematurely, has also been reported, and this is thought to be caused by an extra copy of the Msh homeobox 2 gene (MSX2) [19].

In the present case, although craniofacial abnormalities and fetal growth restriction were observed, the infant died 78 days after birth so it was not possible to know whether growth retardation or mental retardation would have occurred. However, there was no evidence of cranial fusion. Additionally, the observation of characteristics not previously reported in 5q trisomy, including thrombocytopenia, anorectal malformation, and facial features such as a flat nasal root and wide‐set eyes, suggest that the main phenotype was Jacobsen syndrome.

Although cardiac defects are the most likely cause of sudden death in this case, the surgery had been completed without any problems, and the direct cause of death is unknown. By diagnosing the fetal chromosomal abnormality before birth, the parents had sufficient time to undergo genetic counseling. It was also possible to provide relevant information to the pediatric department about the treatment of the newborn after birth, so resuscitation procedures could be performed promptly.

In consideration of the parents' wishes, we have not disclosed which of them has the balanced translocation. Preimplantation genetic diagnosis could be an option for their third pregnancy, and continued genetic counseling is thought to be necessary.

In conclusion, this is the first known case to be reported in which a prenatal amniotic fluid chromosome analysis diagnosed 46,XX,der(11)t(5;11)(q21;q22); the postnatal phenotype led to a diagnosis of Jacobsen syndrome. Although chromosomal findings suggested a very poor prognosis, the patient survived for 78 days. Prenatal diagnosis of the chromosomal abnormality allowed for sufficient time to provide comprehensive genetic counseling to the parents. Furthermore, sharing information with the pediatric team regarding the expected clinical course enabled prompt resuscitation and management of the neonate.

Author Contributions

Yuri Hasegawa: conceptualization, funding acquisition, investigation, methodology, resources, writing – original draft. Yuriko Kitajima: data curation, writing – review and editing. Koh Nagata: data curation, investigation, resources. Shoko Miura: investigation, resources, validation. Kiyonori Miura: supervision, writing – review and editing.

Disclosure

This article was previously presented as a poster at the 28th International Conference on Prenatal Diagnosis and Therapy on 9 July 2024.

Ethics Statement

This article was approved by the Institutional Review Board for Ethical, Legal, and Social Issues of Nagasaki University (ID: 12121777).

Consent

We obtained written informed consent from the parents of the patient regarding the publication of this case.

Conflicts of Interest

The authors declare no conflicts of interest.

Hasegawa Y., Kitajima Y., Nagata K., Miura S., and Miura K., “Prenatal Diagnosis of Unbalanced Translocation t(5;11)(q21;q22) With a Jacobsen Syndrome Clinical Phenotype,” Clinical Case Reports 13, no. 8 (2025): e70772, 10.1002/ccr3.70772.

Data Availability Statement

The data used in this case report are maintained as part of patient medical records at Nagasaki University Hospital and are not publicly available due to patient confidentiality. Access to data can be considered upon reasonable request and with appropriate permissions.