A baby with craniosynostosis - one of the main symptoms of the syndrome. Image Credit: In The Light Photography/Shutterstock

What is Jackson-Weiss Syndrome?

Introduction
History
Cause and Symptoms
FGFR2 gene
Epidemiology
case report
Diagnosis and Treatment
References
Read further


A genetic disorder, Jackson-Weiss syndrome (JWS), is characterized by specific deformities of the head, face and foot abnormalities. Symptoms and findings can vary widely in terms of range and severity.

In 1976, a large family cohort was the first to be diagnosed with Jackson-Weiss syndrome. The premature fusion of the skull bones causes many of the facial features associated with Jackson-Weiss syndrome. The majority of people with Jackson-Weiss syndrome are intelligent and live a typical lifespan.

History

An Amish relative was diagnosed with craniosynostosis, midface hypoplasia, and foot deformities, according to Jackson et al. (1976). Pfeiffer syndrome was suspected because of enlarged big toes and cranial abnormalities, although thumb abnormalities were not evident. In total, 88 people were found to be affected, while another 50 people confidently claimed to be affected.

There was an autosomal dominant pedigree pattern with varying degrees of severity. Indeed, the phenotypic manifestation was so diverse across the sex that it encompassed the full range of dominantly inherited craniofacial dysostoses and acrocephalosyndactylies (excluding the typical Apert syndrome).

A baby with craniosynostosis – one of the main symptoms of the syndrome. Image Credit: In The Light Photography/Shutterstock

Cross and Opitz (1969) identified one branch of the same family with bands of the second and third toes as generic craniostenosis with recessive inheritance, according to Jackson et al. (1976). Other relatives with bands of the second and third toes were found by Jackson et al. (1976). They concluded that everyone in the family had the same dominant disorder.

Although Jackson et al. (1976) found that learning disabilities were not a feature, Cross and Opitz argued that it was present in some patients (1969). The Escobar and Bixler report provided clear confirmation of the Jackson-Weiss syndrome (1977).

Causes and Symptoms

JWS is caused by mutations in the FGFR2 gene and is inherited in an autosomal dominant manner; however, it can also be caused by a new mutation that happens randomly.

The premature fusion of the skull bones causes many of the facial features associated with Jackson-Weiss syndrome. A deformed skull, widely set eyes and a protruding forehead are the result of abnormal growth of these bones. The most common symptom of Jackson-Weiss syndrome is deformed feet. Short and wide, the first (big) toes bend away from the other toes. The bones of some toes may also be fused (syndactyly) or have an abnormal shape. The hands are almost always normal.

Image credit: EmmaDeformity of the feet and/or toes is a common symptom of Jackson-Weiss syndrome. Image credit: Emma’s Photos/Shutterstock

A majority of patients with JWS exhibit broad hallux phalanx, hypertelorism, midface retrusion, and turricephaly. Other common symptoms include abnormal palate morphology, maxillary hypoplasia, mandibular prognathism, proptosis, strabismus, and convex nasal bridge. Less than 30% of patients develop 2-3 toe syndactyly, lobster claw foot deformity, fused finger bones of the hand, and fibula deformity.

Hearing loss affects some people with Jackson-Weiss syndrome. The majority of people with Jackson-Weiss syndrome have normal intelligence and live a typical lifespan.

FGFR2 gene

The FGFR2 gene encodes a protein called fibroblast growth factor receptor 2 (FGFR2). Fibroblast growth factor receptors are related proteins that play a role in, among other things, proliferation, cell maturation/differentiation, bone development, angiogenesis, wound healing and embryonic development. The FGFR2 protein comes in different forms (isoforms). These isoforms are found in specific patterns in the tissues of the body, which can vary during growth and development.

The FGFR2 gene.  Image credit: ibreakstock/ShutterstockThe FGFR2 gene† Image credit: ibreakstock/Shutterstock

The FGFR2 protein is critical for bone formation, especially in the early stages of development before birth (embryonic development). For example, this protein instructs certain immature cells in the developing embryo to differentiate into bone cells and construct the skull, hands, feet and other tissues.

The protein is also involved in bone remodeling, which is a natural process in which old bone is broken down and new bone is formed to replace it. A mutation in a specific part of the FGFR2 gene causes the FGFR2 protein to overstimulate signaling, causing premature fusion of cranial bones and impairing bone formation in the foot.

Epidemiology

Jackson-Weiss syndrome is a rare hereditary condition whose incidence is unknown. It is known to affect both men and women in almost similar numbers.

Read next: What is oculodentodigital dysplasia?

case report

Celie et. al (2019) described a patient presenting with delayed, rapidly increasing multisutural craniosynostosis and medical problems due to a the new pathogenic mutation of FGFR2 and a phenotype compatible with Jackson-Weiss syndrome.

After an easy pregnancy, the patient was born at 37 weeks gestational age to healthy parents. Frontal bulge, brachycephaly, midface hypoplasia, orbital rod retrusion, significant proptosis, and a bent nose tip were all found during his medical examination at the time. There was strabismus and significant proptosis on ophthalmic examination, but no lagophthalmos or exposure keratopathy. His phenotype was most consistent with Jackson-Weiss, Pfeiffer syndrome (PS), or Crouzon syndrome, and he was assessed by medical genetics for facial abnormalities suggestive of craniosynostosis syndrome (CS).

A the new heterozygous pathogenic variation of FGFR2 (c.1024T>A; p.C342 S) was discovered using molecular assays. They show that this mutation caused aberrant dimerization and constitutive activation of FGFR, resulting in the Jackson-Weiss phenotype, using three-dimensional modeling of the FGFR protein.

Knowing the relationship between genotype and phenotype in people with FGFR2-related craniosynostosis should lead to earlier detection of medical problems, more effective therapy and better clinical outcomes.

Molecular genetic testing can be used to facilitate the diagnosis of Jackson-Weiss syndrome.  Image Credit: Salov Evgeniy/ShutterstockMolecular genetic testing can be used to facilitate the diagnosis of Jackson-Weiss syndrome. Image Credit: Salov Evgeniy/Shutterstock

Diagnosis and Treatment

A thorough clinical evaluation, identification of typical physical features, and a variety of specialized tests, including modern imaging techniques such as CT scan, MRI, and X-rays, can be used to diagnose or confirm JWS at birth or during early childhood. If the diagnosis is unclear, molecular genetic testing for mutations in the FGFR2 gene is available.

The treatment of JWS is tailored to the exact symptoms each person exhibits. Symptomatic and supportive therapy are used to treat JWS. Craniosynostosis and related hydrocephalus can cause unusually high pressure in the skull (intracranial pressure) and on the brain in some people. In such circumstances, surgery to treat craniosynostosis and other craniofacial and skeletal abnormalities that may be related to the disease may be recommended.

The type of surgery needed is determined by the severity of the anatomical anomalies, their symptoms, and other considerations. Physical therapy and other orthopedic and supportive interventions may be recommended in some circumstances to help improve an affected person’s mobility. Early intervention may be needed to help children with JWS reach their full potential. Affected individuals and their families may opt for genetic counseling to deepen their understanding of the condition.

References

Further Reading

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