What is Jackson-Weiss syndrome?

In 1976, a large family cohort was the first to be diagnosed with Jackson-Weiss syndrome. 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.

According to Jackson et al., an Amish relative was diagnosed with craniosynostosis, midfacial hypoplasia, and foot deformities. (1976). Pfeiffer’s syndrome was suspected due to enlarged big toes and cranial abnormalities, although thumb abnormalities were not evident. A total of 88 people were found to be affected, with another 50 people confidently claiming to be affected.

There was an autosomal dominant pedigree pattern with varying degrees of severity. Indeed, the phenotypic manifestation was so diverse in the kindred that it included the full range of craniofacial dysostoses and dominant hereditary acrocephalosyndactylies (excluding typical Apert syndrome).

Cross and Opitz (1969) identified a branch of the same family with webbing of the second and third toes as having generic craniosynostosis with recessive inheritance, according to Jackson et al. (1976). Other family members with second and third toe webbing were found by Jackson et al. (1976). They concluded that all family members suffered from the same dominant disorder.

Although Jackson et al. (1976) determined that learning disabilities were not a feature, Cross and Opitz asserted that they were present in some of the patients (1969). Escobar and Bixler’s report gave apparent corroboration of the Jackson-Weiss syndrome (1977).

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

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 result from abnormal growth of these bones. The most common symptom of Jackson-Weiss syndrome is deformity of the feet. Short and broad, the initial (big) toes point away from the other toes. Some toe bones may also be fused (syndactyly) or have an aberrant shape. Almost all the time the hands are normal.

The majority of patients with JWS present with a broad hallux phalanx, hypertelorism, midface retrusion, and turricephaly. Other commonly experienced symptoms include abnormal palate morphology, maxillary hypoplasia, mandibular prognathism, proptosis, strabismus, and convex nasal crest. Less than 30% of patients develop syndactyly of the 2 or 3 toes, a lobster claw foot deformity, fusion of the finger bones of the hand and an anomaly of the calf bone.

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.

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

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

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

Jackson-Weiss syndrome is a rare hereditary disease with no known incidence. It is known to afflict men and women in almost equal numbers.

Celie and. al (2019) described a patient who presented with delayed and rapidly increasing multisutural craniosynostosis and medical issues due to a de novo pathogenic FGFR2 mutation and a phenotype consistent with Jackson-Weiss syndrome.

After an easy pregnancy, the patient was born at 37 weeks gestation to healthy parents. A frontal hump, brachycephaly, midface hypoplasia, orbital bar retrusion, significant proptosis and an upturned nasal tip were all found during his medical examination at the time. There was strabismus and significant proptosis on ophthalmologic examination, but no lagophthalmos or exposure keratopathy. His phenotype was most consistent with Jackson-Weiss, Pfeiffer syndrome (PS), or Crouzon syndrome, and he was evaluated by medical genetics for facial abnormalities suggestive of craniosynostosis (CS) syndrome.

A de novo a heterozygous pathogenic variation of FGFR2 (c.1024T>A; p.C342S) was discovered using molecular testing. 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.

A thorough clinical evaluation, identification of typical physical characteristics, and a variety of specialized tests, including modern imaging techniques like CT scans, MRIs, and X-rays, can be used to diagnose or confirm JWS at birth. or throughout infancy. If the diagnosis is unclear, molecular genetic testing for FGFR2 gene mutations is available.

Treatment for JWS is tailored to the exact symptoms each person has. Symptomatic and supportive therapy is used to treat JWS. Craniostenosis and associated hydrocephalus can cause abnormally high pressure in the skull (intracranial pressure) and on the brain in some people. Surgery to treat craniosynostosis and other craniofacial and skeletal abnormalities that may be related to the disease may be recommended in such circumstances.

The type of surgery required is determined by the severity of the anatomical abnormalities, their symptoms, and other considerations. Physiotherapy 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 further their understanding of the condition.