Jacobsen Syndrome

Jacobsen syndrome is a contiguous gene deletion disorder caused by a terminal deletion of chromosome 11q (11q23 to qter), with intellectual disability, characteristic facies, congenital heart disease and a bleeding disorder called Paris-Trousseau thrombocytopenia. Most deletions are de novo, and females are affected about twice as often as males.

Pathophysiology. Hemizygosity for FLI1, a transcription factor needed for megakaryocyte maturation, causes thrombocytopenia with giant platelet alpha granules and platelet dysfunction. Loss of other genes in the region, including ETS1 for heart development, contributes to cardiac and other defects.

Deletion size varies from 7 to over 20 Mb, with larger deletions causing more severe disease.

Thrombocytopenia is present at birth and often improves in the first years, but platelet function stays abnormal.

• Thrombocytopenia from birth (Paris-Trousseau), with bruising and bleeding
• Developmental delay and intellectual disability, behavioural problems, ADHD and autism
• Characteristic face: hypertelorism, ptosis, epicanthal folds, broad nasal bridge, carp shaped mouth, low set ears
• Congenital heart disease (about half), including ventricular septal defect and hypoplastic left heart
• Short stature, macrocephaly or trigonocephaly
• Immune deficiency with low immunoglobulins and recurrent infection
• Renal, gastrointestinal and genital anomalies
• Ocular and hearing problems
• Pancytopenia and bone marrow failure in some

• Chromosomal microarray defining the size of the 11q deletion (preferred over karyotype), with FISH when needed.
• Platelet assessment: full blood count, blood film (giant platelets), and platelet function testing.
• Cardiac assessment: echocardiography at diagnosis.
• Immunology: immunoglobulins and vaccine responses.
• Developmental, ophthalmic, audiological and renal assessment.
• Parental testing to exclude a balanced translocation.

• Bleeding risk management: avoid aspirin and NSAIDs. For significant bleeding or before surgery, give platelet transfusion (10 to 15 mL/kg) based on count and function, and use antifibrinolytics: tranexamic acid 15 to 25 mg/kg orally three times daily or 10 mg/kg intravenously every 8 hours (maximum 1 g each dose).
• Desmopressin 0.3 microgram/kg intravenously over 30 minutes before procedures may improve platelet function in some patients, with fluid restriction to avoid hyponatraemia.
• Procedures: involve haematology before surgery, dental extraction or lumbar puncture, and plan platelet availability.
• Cardiac care: surgery or catheter intervention for significant defects, with endocarditis prophylaxis for high risk lesions.
• Immune deficiency: immunoglobulin replacement 0.4 to 0.6 g/kg intravenously every 3 to 4 weeks when low IgG is accompanied by recurrent infections, and vaccination.
• Developmental care: early intervention, speech therapy, special education, and behavioural support.
• Bone marrow failure: monitor the blood count, with stem cell transplant for severe failure.
• Other care: ophthalmology, audiology, renal surveillance, and growth review.
• Genetic counselling: recurrence risk is low if the deletion is de novo and higher if a parent carries a translocation.

Special groups.

• Neonates: check platelets and bleeding signs at birth, avoid intramuscular injections when platelets are low, and give vitamin K.
• Menstruating adolescents: consider tranexamic acid and hormonal control of heavy menses.

Monitoring. Full blood count every 3 to 6 months in infancy, then yearly. Echocardiography as cardiology advises, and developmental review every 6 to 12 months.

Referral and escalation. Refer to clinical genetics, haematology, cardiology and developmental paediatrics. Emergency for major bleeding, intracranial haemorrhage signs, or heart failure.