Jacobsen Syndrome

Original Editor - Rania Nasr Top Contributors - Rania Nasr, Rucha Gadgil, Audrey Brown and Kim Jackson

This article is currently under review and may not be up to date. Please come back soon to see the finished work! (25/03/2022)

Introduction

Jacobsen syndrome (JS) is a rare congenital gene syndrome caused by partial deletion of the long arm of chromosome 11. It was first described by Danish geneticist Petrea Jacobsen in 1973. It is also known as 11q terminal deletion disorder because the deletion occurs at the end of the long (q) arm of chromosome 11.

Incidence and Prevalence

Jacobsen syndrome is an uncommon genetic syndrome, with around 200 cases reported worldwide to date. The prevalence of JS has been estimated to be at 1 in 100,000 newborns with a female/male ratio of 2:1. Around 8-15% of cases are caused by a deletion from a balanced parental chromosome translocation or rearrangement and 85-92% of cases are of a de novo origin. When one parent is affected by JS, the recurrence risk is 50%.

The severity of symptoms depends on the location and size of the deletion. The prevalence of intellectual disability in individuals with JS is 97%. 68-75% of those diagnosed with JS experience developmental delays, 88.5-94% have platelet anomalies, and 56% will have congenital cardiac malformations. Around 20% of children die during the first two years of life, the main causes of mortality being complications of CHD and bleeding disorders caused by thrombocytopenia.

Etiology

Jacobsen Syndrome is caused by the loss of genetic material in chromosome 11 as an entirely random error in cell division in most cases. It can occur during the formation of reproductive cells or early on during fetal development. The number of genes deleted from the chromosome will determine how severe the disorder is.

The majority of JS cases are not inherited. 5-10% of cases will inherit it from the unaffected parent who have genetic material that is rearranged but still present in chromosome 11. This is called balanced translocation.<section> ADVERTISEMENT

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Clinical Presentation

An individual with Jacobsen Syndrome displaying characteristic facial features of the syndrome.

1. Growth delay: weight and height below the 10^th percentile in over 50% of cases.
2. Craniofacial dysmorphism: trigonocephaly, facial asymmetries, high prominent forehead, flat occiput, thin and brittle hair, down slanting palpebral fissure, palpebral ptosis, epicanthal folds, iris coloboma, arched eyebrows, hyper-telorism, small and low set ears, short nose with large and depressed nasal bridge, anteverted nostrils, down turning corners of the mouth, large mouth, high palate, dental anomalies, micrognathia.
3. Limb anomalies: brachydactyly, clinodactyly, comptodactyly, bilateral simian crease, clubfoot, muscular atrophy, stiff joints, pectus excavatum, dorsal scoliosis, lumbar lordosis.
4. Visceral Malformations: 56% of those diagnosed with JS have congenital heart malformations. The most frequent heart defects are ventricular septal defects or left heart obstructive malformations, such as abnormalities of the aortic or mitral valves, coarctation of the aorta, Shone's complex, or hypo plastic left heart syndrome. 18% of cases have gastrointestinal tract malformations. Functionally, these malformations may include feeding difficulties in newborns and chronic constipation. 65% of individuals diagnosed with JS have some sort of structural abnormality of the brain such as enlarged ventricles, cerebral atrophy, and agenesis of the corpus callosum.
5. Cognitive Impairments
6. Neuromotor and psychiatric disabilities: delayed standing and walking, compulsive, hetero-aggressive and auto-aggressive behavior. Increased possibility of autism spectrum disorder characterized by impaired socialization and communication skills.
7. Syndromic primary immune deficiency (SPID).
8. Additional signs and symptoms appears in puberty: primary amenorrhea, genital infantilism, repeated episodes of sinusitis.
9. May also be diagnosed with ADHD and learning disabilities.

Complications:

1. Platelet disorders, such as Paris-Trousseau Syndrome, are a serious but common complication of Jacobsen syndrome
2. Heart conditions: abnormalities on the left side of the heart, hypoplastic left heart syndrome, holes between the left and right lower chambers
3. Kidney problems: having a single kidney, double ureters (the tubes leading from the kidneys to the bladder), hydronephrosis, or swelling cysts
4. Gastrointestinal problems like pyloric stenosis causes forceful vomiting because of a narrowed or blocked outlet from the stomachs to the intestines. Other complications include blocked or narrow anus, constipation, intestinal obstruction, missing parts of the GI tract, abnormal positioning of the gut.
5. Cataracts
6. Ear and sinus infections

Diagnostic Procedures

Diagnosis is based on clinical findings (thrombocytopenia, intellectual deficit, and facial dysmorphic features) and must be confirmed by cytogenetic analysis. 

Differential Diagnosis

Some of the clinical features of children with Jacobsen Syndrome are shared with Tuner and Noonan syndrome, such as a short and wide neck, short stature, ptosis, pulmonary or aortic stenosis, and down-slanting palpebral fissure. Some children with JS have had clinical diagnosis of Kabuki syndrome due to mental retardation, unusual palpebral fissures, short stature, and finger-pads.

Medical Management

Post diagnosis, a complete evaluation needs to be performed by a multidisciplinary team which includes a pediatrician, cardiologist, neurologist, physical therapist, ophthalmologist etc. Newborns diagnosed with JS often require specialized assistance and treatment. Medications may be used to manage complications of heart defects and platelet abnormalities.

Children with JS may also require surgery, especially for those with cardiac malformations, and hematologic complications need to be taken into consideration preoperatively.

Physiotherapy Management

Jacobsen syndrome is a chromosomal disorder in which children with JS will have a global developmental delays, presented by delayed motor and speech milestones. Those with JS should be referred to physical and/or occupational therapy for early intervention in order to overcome motor developmental delays. Physical therapy can help children with JS improve their coordination and mobility.

In physical therapy, each child should be assessed in terms of individual movement expression and the potential to maximize their movement efficiency. Treatment cannot be repetitive or stereotype as it has to continuously adapt to the individual's progression.

Integrating play within Neurodevelopmental treatment (NDT) is proven to have many benefits in improving developmental delay. NDT may improve cognitive and perceptual skills and can act as a stimuli for normal movement patterns by providing appropriate, engaging activities.

The adaptation of children with activity is essential for an effective play activity. That involves:

1. Adapting the shape, size and consistency of the used material.
2. Modifying the procedure and rules of the play activity.
3. Adjusting the position of materials and the child.
4. Controlling the degree of interpersonal interaction. If the motor demand is high, the cognitive demand has to be lowered to meet the changing needs of the child.

Intensive neurodevelopmental treatment (Bobath approach) three times weekly, 60 minutes a day, for 3 months is recommended as it shows improved gross motor function and higher compliance than conventional NDT.

Prognosis

A proportion of children with JS die in the neonatal period, due to severe heart malformations and bleeding. Surviving patients require long-term care including surgical and medical interventions. Life expectancy is unknown, however, the oldest living patient with JS is 45 years old.