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​Cihat Şen, ​Nicola Volpe

Cecilia Villalain, Daniel Rolnik, M. Mar Gil

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Jacobsen syndrome: a case report and clinical features of a rare genetic syndrome

Kazım Öztarhan, Talya Kaptaç, Mutlu Karkucak, Ece Öztarhan, Ali Gedikbaşı

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Jacobsen syndrome: a case report and clinical features of a rare genetic syndrome. Perinatal Journal 2022;30(3):320-325 DOI: 10.2399/prn.22.0303006

Author(s) Information

Kazım Öztarhan1,
Talya Kaptaç2,
Mutlu Karkucak3,
Ece Öztarhan4,
Ali Gedikbaşı5

  1. Department of Pediatric Cardiology, Demiroğlu Science University, İstanbul, Türkiye
  2. Demiroğlu Science University, İstanbul, Türkiye
  3. Genetic Diseases Assessment Center, İstinye University, İstanbul, Türkiye
  4. Yeditepe University, İstanbul, Türkiye
  5. Maternal & Fetal Medicine Unit, Department of Obstetrics & Gynecology, İstanbul Aydın University, İstanbul, Türkiye

Kazım Öztarhan, Department of Pediatric Cardiology, Demiroğlu Science University, İstanbul, Türkiye, [email protected]

Publication History

Manuscript Received: April 02, 2022

Manuscript Accepted: July 25, 2022

Earlyview Date: July 25, 2022

Publication date: November 07, 2022

Conflicts of Interest

Funding: This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Compliance with Ethical Standards: The authors stated that the standards regarding research and publication ethics, the Personal Data Protection Law and the copyright regulations applicable to intellectual and artistic works are complied with and there is no conflict of interest.

Jacobsen syndrome is an infrequent contiguous gene syndrome that involves the deletion of the long arm of chromosome 11. It is mostly accompanied by intellectual disability and other abnormalities. The majority of the patients are hospitalized or lost within the first two years of life.
We report a case of a fetus at 21 weeks of gestation with Jacobsen syndrome who presented with a conotruncal cardiac defect. Amniocentesis was performed, and karyotype analysis revealed that there was a de novo deletion of chromosome 11. The family decided to terminate the pregnancy.
Prenatal diagnosis of Jacobsen syndrome is not always possible, since the characteristic ultrasound findings vary greatly between patients. Additionally, existing symptoms and signs may not always be found with imaging techniques. However, if present, certain ultrasonographic findings should lead clinicians to consider the syndrome. The study aims to present a rare case of Jacobsen syndrome, inform the clinicians, and guide on this syndrome and its possible outcomes.

Jacobsen syndrome, deletion of chromosome 11, prenatal diagnosis.

Jacobsen syndrome (JS) is a rare contiguous gene syndrome that presents with a large terminal or interstitial deletion of the long arm of chromosome 11.[1,2] This syndrome was first published in the literature by Petrea Jacobsen in 1973.[3] The incidence of JS is 1/100,000, and the female/male ratio is 2:1.[2]
The clinical manifestations of JS differ among patients and are highly related to the deletion’s size and the deleted genes in chromosome 11.[4,5] The most common clinical manifestations of JS are trigonocephaly, pre- and postnatal physical growth retardation, intellectual disability, psychomotor retardation, characteristic facial dysmorphism, visceral malformations, cardiac defects, dilatation of the renal pelvis, thrombocytopenia, pancytopenia, combined immunodeficiency, and antibody deficiency.[4–6]
A 25-year-old female patient (gravida 1, para 0) was admitted to the Department of Obstetrics & Gynecology at 21 weeks of gestation due to suspicion of hypoplastic left heart syndrome (HLHS). Ultrasonographic imaging revealed that the fetus had a 2.7 mm wide subaortic ventricular septal defect (VSD), dextroposition of the aorta, and persistent superior vena cava (PSVC), in addition to confirmed HLHS. In the gastrointestinal system examination of the patient, hyperechogenic intestines were present, and no additional anomalies were observed apart from cardiac and gastrointestinal system findings. The family had not undergone a screening test before. Therefore, for further evaluation, a karyotype test and gene analysis which would be done with the Array-CGH technique were recommended.
A deletion was detected in the q arm of chromosome 11 [46, XX, del(11)(q24-->qter)] in the chromosome analysis of the sample taken from the amniotic fluid. Array-CGH was applied to determine the size of the deletion and the genes affected as a result of it. In the SNP array (HumanCytoSNP-12 array, Illumina, Inc., San Diego, CA, USA) analysis of the patient, 55 OMIM genes [arr(GRCh37) 11q24.1-q25(123846864_134944006)x1], 19 of which were associated with the disease, were detected between chromosome 11 q24.1 and q25 regions with a size of 11097.143 bp. The patient was diagnosed with Jacobsen syndrome. The chromosome analysis of the patient’s parents revealed a normal karyotype and the syndrome detected in the patient was evaluated as “de novo” (Fig. 1).
The missing 19 genes in the patient were named morbid OMIM genes and associated with the disease. These genes were identified as ACAD8, CDON, DCPS, FL11, FOXRED1, HEPACAM, HYLS1, JAM3, KCNJ1, KCNJ5, NCAPD3, OPCML, PUS3, ROBO3, ROBO4, SIAE, ST14, STT3A, and TIRAP. According to the research conducted in the DECIPHER database, possible pathological changes that may be caused by the genes in the missing region were detected as follows: cognitive retardation, hyperactivity-attention deficit disorders, autistic features, hypertelorism, head-neck and ear anomalies, abnormal platelet morphology, atrioventricular canal defect, and musculoskeletal anomalies. The family was informed about the possible outcomes of the syndrome which led them to decide on the termination of the pregnancy. Dysmorphic findings consistent with Jacobsen syndrome were found on the examination of the 21-weeks-old fetus. The patient had skull and facial deformities, ocular hypertelorism, downslanting palpebral fissures, epicanthal fold, down-set ear, flat and wide nasal bridge, and long philtrum in addition to a short and webbed neck (Fig. 2). An autopsy was not performed after the termination.
Jacobsen syndrome is a contiguous gene syndrome that results from the partial deletion of the long arm of chromosome 11.[1,2] First, in 1973, a family with translocation t(11,21) was investigated by Petrea Jacobsen in three generations.[3] JS is a rare syndrome, and more than 200 cases have been reported to date. The prevalence of JS is 1/100,000 with a female to male ratio of 2:1. In 85% of the cases, the deletion is de novo, it is inherited in 15% and JS may develop due to hereditary transmission of the unbalanced separation of a familial balanced translocation.[5] In our case, the family had no known history of translocation, and no deletion was detected in the karyotype examination of the parents, consequently, the deletion was evaluated as “de novo”.
In JS, the size of the deletion can range from 7 to 20 Mb, with the breakpoint occurring at 11q23.3. In most cases, it extends from the distal to the lower band and usually to the telomere. Terminal deletions that are longer and extend to the proximal of 11q23.3 usually result in the loss of the embryo. Terminal deletion of the 11q21 band may cause a complex phenotype in mosaic form, holoprosencephaly, and cyclopia.[2]
60% of the patients are born at term and 30% are born preterm. Complications such as premature rupture of membranes and abnormal fetal presentation may occur during delivery. The research conducted by Mattina et al. indicated that 60% of the patients had a normal birth weight and 37% of the patients had a birth weight below the 10th percentile. In the first two years of life, 20% of children die, usually due to congenital cardiac anomalies, and more rarely due to bleeding disorders.[2] BSX, NRGN, ETS-1, FLI-1, and RICS are considered to be the genes that cause mortality and morbidity the most. The genes in question can often cause intellectual disability, behavioral and bleeding problems, congenital heart diseases, and immunodeficiency.[7]
Jacobsen syndrome can be diagnosed easier in the postnatal period; however, ultrasonographic findings are seen less frequently in the prenatal period. More than 200 cases of JS have been reported to date, most of which were diagnosed postnatally. There are approximately 11 cases that have been reported with prenatal diagnosis, the oldest was published in 1995 and the newest in 2020.[8,9] Different publications state that some prenatal findings should be suspected regarding Jacobsen syndrome. Findings such as nuchal thickening, trigonocephaly, micrognathia, anterior and protruding nostrils, protruding forehead, open frontonasal angle, and parieto-frontal overlap can be seen. The cardiac findings common in JS include hypoplastic right heart syndrome, double outlet right ventricle, interventricular septal defect, and the presence of a cardiac shunt. In addition to these findings, intrauterine growth restriction, short femur, ductus venosus agenesis, single umbilical artery, bent toes, oligohydramnios, decreased fetal movements, cerebral ventricular dilatation, hydronephrosis or polyhydramnios should suggest 11q deletion and examination should be done accordingly.[5,6,10]
Children with severe symptoms may be diagnosed in the first year of life, while those with milder symptoms may be diagnosed at an advanced age if the prenatal diagnosis is not possible. The patients often have malformations affecting the skeletal, cardiac, renal, gastrointestinal, genital, and central nervous systems. After birth, abnormal platelet function is often accompanied by thrombocytopenia and pancytopenia. In the postnatal period, growth retardation can be seen in the measurement of height, weight, and head circumference. Moderate or severe intellectual disability is seen in 97% of cases, and the size of the deletion is considered to be an important determinant of its severity.[2] In addition, dysmorphic features that may suggest Jacobsen syndrome should also be considered which are often accompanied by congenital heart diseases (Table 1).
In the presented case of the fetus at 21 weeks of gestation, there were several ultrasound abnormalities detected, suggesting a possible case of Jacobsen syndrome: HLHS, 2.7 mm wide subaortic VSD, PSVC, and aortic dextroposition. The growth of the fetus was consistent with the weeks of gestation; however, due to cardiac anomalies, amniocentesis and karyotype examination were recommended. In the karyotype examination, it was found that there were mutations and deletions in the long arm of chromosome 11 which were compatible with Jacobsen syndrome. In the region of deletion, 19 out of 55 OMIM genes were associated with the disease. The family was informed that the child to be born may have pathologies such as autistic features, intellectual disability, hyperactivity-attention deficit disorders, ear anomalies, hypertelorism, head-neck anomalies, abnormal platelet morphology, atrioventricular canal defect, and musculoskeletal anomalies. After extensive perinatal counseling, the parents decided to terminate the pregnancy.
In Jacobsen syndrome, the size of the deletion of chromosome 11 and the number of deleted genes affect the severity of the syndrome closely. In the case of multiple fetal anomalies with congenital cardiac anomalies, the Jacobsen syndrome must be suspected and the deletion of chromosome 11 needs to be evaluated. The families of the patients with Jacobsen syndrome should be informed broadly and the decision of termination must be given accordingly.
  1. Conrad S, Demurger F, Moradkhani K, Pichon O, Le Caignec C, Pascal C, et al. 11q24.2q24.3 microdeletion in two families presenting features of Jacobsen syndrome, without intellectual disability: Role of FLI1, ETS1, and SENCR long noncoding RNA. Am J Med Genet A 2019;179:993–1000. [PubMed] [CrossRef

  2. Mattina T, Perrotta CS, Grossfeld P. Jacobsen syndrome. Orphanet J Rare Dis 2009;4:9. [PubMed] [CrossRef

  3. Jacobsen P, Hauge M, Henningsen K, Hobolth N, Mikkelsen M, Philip J. An (11;21) translocation in four generations with chromosome 11 abnormalities in the offspring. A clinical, cytogenetical, and gene marker study. Hum Hered 1973;23:568–85. [PubMed] [CrossRef

  4. Nalbantoğlu B, Donma MM, Nişli K, Paketçi C, Karasu E, Ozdilek B, et al. Jacobsen syndrome without thrombocytopenia: a case report and review of the literature. Turk J Pediatr 2013;55:203–6. [PubMed

  5. Chen S, Wang R, Zhang X, Li L, Jiang Y, Liu R, et al. Ultrasonographic findings and prenatal diagnosis of Jacobsen syndrome: A case report and review of the literature. Medicine (Baltimore) 2020;99:e18695. [PubMed] [CrossRef

  6. Grossfeld PD, Mattina T, Lai Z, Favier R, Jones KL, Cotter F, et als. The 11q terminal deletion disorder: a prospective study of 110 cases. Am J Med Genet A 2004;129A:51–61. [PubMed] [CrossRef

  7. Favier R, Akshoomoff N, Mattson S, Grossfeld P. Jacobsen syndrome: advances in our knowledge of phenotype and genotype. Am J Med Genet C Semin Med Genet 2015;169:239–50. [PubMed] [CrossRef

  8. Wax JR, Smith JF, Floyd RC, Eggleston MK. Prenatal ultrasonographic findings associated with Jacobsen syndrome. J Ultrasound Med 1995;14:256–8. [PubMed] [CrossRef

  9. Chen S, Wang R, Zhang X, Li L, Jiang Y, Yiu R, et al. Ultrasonographic findings and prenatal diagnosis of Jacobsen syndrome: a case report and review of the literature. Medicine (Baltimore) 2020;99:e18695. [PubMed] [CrossRef

  10. Lo JO, Feist CD, Hashima J, Shaffer BL. Jacobsen syndrome detected by noninvasive prenatal testing. Obstet Gynecol 2015;125s:387–9. [PubMed] [CrossRef
Fig. 1.
G banding and Array-CGH images of the q arm terminal deletion of chromosome 11. (a) G-banding revealed that the chromosome anomaly was due to a terminal deletion of chromosome 11 (arrow). (b) Array-CGH analysis revealed a deletion of 11q24.1-q25 (arrow).
Fig. 2.
Autopsy of the 21-weeks-old fetus. (a, b) Dysmorphic features include skull deformities, ocular hypertelorism, flat and wide nasal bridge in addition to a short and webbed neck.
Table 1.
Dysmorphic features of Jacobsen syndrome.[2]