Jacobsen Syndrome (11q Terminal Deletion Syndrome)

Etiology

Jacobsen syndrome is a contiguous gene deletion disorder caused by a partial deletion of the long arm of chromosome 11. The size of the deletion varies, typically ranging from 7 to 16 Mb.[3][4] Deletions larger than 20 Mb are expected to be lethal, but some cases of large deletions have been found in mosaic form, presenting as a severe phenotype.[5] Terminal deletions of chromosome 11 occur in 2 ways—a de novo pure terminal deletion (85% of cases) or an unbalanced familial translocation (15% of cases). Chromosomal breakage typically occurs within or beyond subband 11q23.3, often extending to the telomere. This partial chromosomal deletion results in the loss of all genes located distal to the breakpoint, which typically includes genes CBL2, FRA11B, TECTA, BSX, NRGN, FEZ1, CHK1, ETS1, FLI1, KCNJ1, BARX2, NFRKB, APLP2, ADAMTS8, ADAMTS15, OPCML, JAM3, and B3GAT1. Subband 11q23.3 includes FRA11B, a gene with a fragile site prone to double-stranded breakage, which serves as a breakpoint in some patients with Jacobsen syndrome. Smaller interstitial deletions within the Jacobsen syndrome region can also cause the condition, even without a full terminal deletion.[6][7][8] Regardless of the mode of pathogenicity, chromosomal deletions in Jacobsen syndrome can have incomplete penetrance and an unpredictable genotype-to-phenotype correlation.

Epidemiology

Jacobsen syndrome is a rare condition, affecting approximately 1 in 100,000 births and is more common in females, with a female-to-male ratio of 2:1. Accurately estimating its prevalence is challenging, as only 200 cases have been reported in the medical literature.[4][9] In addition, the actual incidence may be higher than described due to the variable presentation, which can reduce the initial diagnosis. Limited access to health care or genetic testing may further contribute to underdiagnosis, even in patients with severe symptoms.

Pathophysiology

Two genes, FLI1 and ETS1, are suspected to contribute to key symptoms of Jacobsen syndrome. Both are located on the long arm of chromosome 11. Loss of FLI1 and ETS1 has been linked to thrombocytopenia and cardiac defects, respectively. The loss of the transcription factor FLI1 leads to Paris-Trousseau syndrome and thrombocytopenia due to impaired hematopoiesis and megakaryocyte differentiation.[10][11] ETS1 is a transcription factor vital for angiogenesis and cardiac development. The loss of ETS1 leads to abnormal myocardial and coronary artery development in animal models.[12] The pathophysiology of immunodeficiency remains unclear; however, case reports indicate low immunoglobulin G levels, a decreased humoral response to pneumococcal vaccination, and reduced T-cell and natural killer cell numbers.[13][14]

History and Physical

Thrombocytopenia is present in 95% of patients and is most pronounced in the neonatal period, although it often improves with age. In addition to thrombocytopenia, all patients with Jacobsen syndrome have Paris-Trousseau syndrome, characterized by dysfunctional platelets with giant alpha granules. Platelets may be enlarged or abnormally large due to arrested development and premature release from the bone marrow into the bloodstream.[15] Laboratory evaluation of clotting activity typically shows a normal prothrombin time and activated partial thromboplastin time, but a prolonged bleeding time. Clinically, this can manifest as bleeding diatheses, spontaneous bleeding, or, in certain cases, signs of stroke secondary to intracranial hemorrhage, particularly in the setting of post-surgical anticoagulation.[16] 

Patients with Jacobsen syndrome may also have immunodeficiency, increasing their risk of ear and sinus infections, abnormal lymphocyte development, hypogammaglobulinemia, and poor response to vaccinations.[13][14]

Approximately 50% of patients are diagnosed with cardiac disease. However, post-mortem evaluations suggest that up to 95% of deceased children had cardiac malformations.[17] Among those with cardiac disease, approximately two-thirds have ventricular septal defects or left-sided heart lesions, such as hypoplastic left heart syndrome, aortic stenosis, mitral stenosis or regurgitation, and coarctation of the aorta. Although hypoplastic left heart syndrome is extremely rare in the general population (0.02%), it is found in 5% to 10% of patients with Jacobsen syndrome.[18]

Most patients have developmental delays and facial dysmorphism, and all have some form of intellectual disability. A common cranial vault abnormality, metopic craniosynostosis, results in trigonocephaly, characterized by a triangularly shaped forehead and narrow temples. Facial features in Jacobsen syndrome can vary but commonly include hypertelorism, down-slanting palpebral fissures, strabismus, ptosis, sparse eyebrows, epicanthal folds, and eyelid coloboma. Other characteristic features include a flat or prominent nasal bridge, a short upturned nose, anteverted nares, prominent columella, a long or flat philtrum, a V-shaped mouth, and a thin upper lip. Skull and facial structures may also be affected, leading to micrognathia; retrognathia; or small, low-set, posteriorly rotated ears.[2][19] Developmental disorders may manifest as attention deficit hyperactivity disorder, autism spectrum disorder, or severe behavioral disturbances. About 65% of patients have structural brain abnormalities, such as ventriculomegaly, cerebral atrophy, or agenesis of the corpus callosum. In addition, patients may experience hearing and vision deficits, necessitating a comprehensive ophthalmologic evaluation to assess for coloboma, cataracts, or retinal vessel abnormalities.[2]

Affected infants often experience intrauterine growth restriction and postnatal growth restriction. In childhood, 75% of patients fall below the 10th percentile for height, and 58% fall below the 10th percentile for weight. Growth restriction is typically asymmetric, with normal head circumference in infancy and childhood.[2] Some infants may have low levels of insulin-like growth factor 1 (IGF-1) and thyroid-stimulating hormone (TSH).

Patients with Jacobsen syndrome may have gastrointestinal malformations, such as pyloric stenosis, anal atresia or stenosis, duodenal atresia, or malrotation. Patients may also be affected by chronic constipation, feeding difficulties, and inguinal hernias. In addition, they have a higher risk of urinary tract malformations, including multicystic kidneys, hydronephrosis, and dysplastic kidneys. Cryptorchidism occurs in 36% to 60% of male patients with Jacobsen syndrome.[20]

Orthopedic abnormalities are common in Jacobsen syndrome, including joint dislocations, clubbed feet, and scoliosis. Hand abnormalities may include cutaneous syndactyly, flat finger pads, hypoplastic thenar and hypothenar regions, and abnormal palmar creases. The feet are often stubby and flat, with a long first toe, brachydactyly, and syndactyly of the second and third toes.[2]

Evaluation

Jacobsen syndrome is diagnosed through a combination of clinical examination, imaging studies, and genetic testing. Approximately 50% of patients are diagnosed within the first year of life, whereas those with milder presentations may not receive a diagnosis until later.

Prenatal genetic assessment is recommended for fetuses with a thickened nuchal fold, cardiac defects, or genitourinary abnormalities. Molecular diagnosis, chromosomal microarray, or fluorescence in situ hybridization (FISH) can be performed prenatally through amniocentesis or chorionic villus sampling.

Postnatally, Jacobsen syndrome should be suspected in infants with congenital heart disease and extracardiac anomalies, particularly if thrombocytopenia or easy bleeding is present. Jacobsen syndrome should also be considered in patients with hypoplastic left heart syndrome, as the incidence of hypoplastic left heart syndrome is higher in Jacobsen syndrome.

Postnatal genetic testing can be performed using FISH or chromosomal microarray.[2]

Treatment / Management

There is no cure for Jacobsen syndrome, so treatment focuses on symptom management and supportive care. A multidisciplinary team is often required, including geneticists, pediatricians, cardiologists, hematologists, audiologists, ophthalmologists, endocrinologists, orthopedists, and other specialists.

Recommended Evaluations and Specialist Referrals

Given the risk of multiorgan involvement, patients with suspected or confirmed Jacobsen syndrome should undergo:

• Abdominal ultrasound: To assess for intestinal obstruction, kidney disease, and urinary malformations
• Endocrine testing: Including TSH and IGF-1 levels
• Hematologic and coagulation studies: To evaluate thrombocytopenia, platelet dysfunction, and other cytopenias
• Auditory testing: To detect hearing loss

In addition, referrals should be made for further assessment:

• Cardiology: For electrocardiogram and echocardiogram 
• Ophthalmology: To screen for retinal artery malformations or cataracts
• Immunology: For immunodeficiency testing
• Neurology: To evaluate for structural brain abnormalities or cerebral hemorrhage

Management of Jacobsen syndrome may also include surgery for orthopedic and skeletal abnormalities, the use of hearing and vision aids, and cardiac surgery for congenital heart defects. Many patients benefit from physical, occupational, and speech therapy, in addition to special education and behavioral therapy.

Cardiac Involvement in Jacobsen Syndrome

Congenital heart disease is common in Jacobsen syndrome, with ventricular septal defects, left-sided malformations, and hypoplastic left heart syndrome being the most frequent findings. Depending on disease severity, cardiac defects may require surgical intervention within the first few months to years of life.

A particularly severe form, hypoplastic left heart syndrome, occurs in up to 10% of patients with Jacobsen syndrome, compared to 0.2% in the general population. Hypoplastic left heart syndrome is fatal without intervention, requiring single ventricle palliation, which includes:

• Norwood operation
• Bidirectional Glenn anastomosis
• Fontan operation

Although the Norwood procedure carries high morbidity and mortality risks, survival rates stabilize around 60% after completion of the Fontan operation. Although certain genetic disorders, such as trisomy 21, have poorer outcomes with single ventricle palliation, studies indicate that patients with Jacobsen syndrome and hypoplastic left heart syndrome tend to have favorable outcomes. Therefore, all 3 stages of single ventricle palliation should be offered to patients and their families. For shunt-dependent patients, such as those with a Blalock-Taussig-Thomas shunt, low-dose aspirin may be used cautiously despite thrombocytopenia, as observed in hypoplastic left heart syndrome cases.[18][21][22][21]

Surgical Considerations

Jacobsen syndrome presents unique risks for cardiopulmonary bypass and cardiothoracic surgery that should be carefully managed.[23]

• Bleeding and coagulation risk 
  • Thrombocytopenia and platelet dysfunction are present in nearly all patients, increasing the risk of uncontrolled bleeding and intracranial hemorrhage.[16][17][24][17]
  • Cardiothoracic surgery requires significant anticoagulation to prevent stroke and disseminated clotting during cardiopulmonary bypass. Platelet counts should be maintained >100×10³/μL via transfusions to mitigate bleeding risk.
  • Activated clotting time is typically used to assess heparinization in cardiothoracic surgery, but it may underestimate bleeding risk in Jacobsen syndrome due to platelet dysfunction.
  • Intraoperative thromboelastography (TEG 6s PlateletMapping®) has been proposed as a more accurate method for evaluating clot formation and stability, helping guide anticoagulation management in real time during and after surgery.[25]
(B2)

• Airway and intubation challenges
  • Patients with Jacobsen syndrome may experience difficult intubation or airway obstruction due to:
    • Retrognathia or micrognathia
    • Anterior laryngeal opening
    • Scoliosis
  • Extubation timing should be carefully planned, as reintubation carries a higher risk in these patients.[23]

• Immunodeficiency and infection risk 
  • Many patients have hypogammaglobulinemia, increasing their risk for infections.
  • If prior immunodeficiency testing has not been performed, healthcare providers should have a low threshold for antibiotic therapy with any sign of infection.
  • Prophylactic antibiotics or empiric intravenous immunoglobulin may be considered in patients with confirmed hypogammaglobulinemia.[17]
(B3)

Differential Diagnosis

The physical presentation of Jacobsen syndrome can resemble other genetic syndromes, including:

• Turner syndrome is associated with an increased incidence of bicuspid aortic valve and coarctation of the aorta, which can present with cardiogenic shock, similar to hypoplastic left heart syndrome. Patients with Turner syndrome may also have a short neck and low-set ears, overlapping features with Jacobsen syndrome.

• Trisomy 21 (Down syndrome) shares several facial features with Jacobsen syndrome, including a flat nasal bridge; small, low-set ears; and epicanthal folds. In addition, patients with trisomy 21 may present with heart failure due to atrioventricular septal defects.

• Noonan syndrome also presents with down-slanting palpebral fissures, epicanthal folds, hypertelorism, and an increased bleeding risk. However, cardiac defects in Noonan syndrome are typically right-sided, in contrast to the left-sided defects more commonly observed in Jacobsen syndrome.

• Neonatal thrombocytopenia, a common finding in Jacobsen syndrome, can also be an essential sign of sepsis, TORCH infections (toxoplasmosis, other agents, rubella, cytomegalovirus, and herpes simplex), or necrotizing enterocolitis in neonates.[26]

Prognosis

As there is no curative therapy for Jacobsen syndrome, prognosis is often determined by the severity of cardiac or hematologic disease. There is a 20% risk of mortality within the first 2 years of life, often due to complications of cardiac defects or after high-risk cardiothoracic surgery. The overall life expectancy is largely unknown, although the oldest documented patients have reached 45 years of age.[2] Patients with Jacobsen syndrome may require surgical and medical interventions throughout their lifetime, reflecting the ongoing need for specialized care and management.

Complications

Complications associated with Jacobsen syndrome include developmental and intellectual delays, heart failure from severe cardiac disease, stroke secondary to intracranial hemorrhage, uncontrolled bleeding due to platelet dysfunction or thrombocytopenia, bowel obstruction due to intestinal atresia or malrotation, or skull or skeletal abnormalities. Surgical repair of cardiac disease, craniosynostosis, intestinal obstruction, or scoliosis involves the typical risks associated with surgery and anesthesia. In addition, there is an increased risk of hemorrhage due to thrombocytopenia or platelet dysfunction, or a heightened risk of infection due to immunodeficiency.