NORD gratefully acknowledges Nathaniel H. Robin, MD, Professor, Department of Genetics, University of Alabama at Birmingham, for assistance in the preparation of this report.
Jackson-Weiss syndrome (JWS) is a rare genetic disorder characterized by distinctive malformations of the head and facial (craniofacial) area and abnormalities of the feet. The range and severity of symptoms and findings may be extremely variable, even among affected members of the same family. Primary findings may include premature closure of the fibrous joints (cranial sutures) between certain bones of the skull (craniosynostosis), unusually flat, underdeveloped midfacial regions (midfacial hypoplasia) abnormally broad great toes, and/or malformation or fusion of certain bones within the feet. In some patients, JWS is an autosomal dominant genetic condition caused by a change (mutation) in the FGFR2 gene, although mutations in other genes (eg, FGFR3) can produce a similar appearing condition.
JWS was originally described in 1976 (C.E. Jackson) in a large Amish family (kindred). Within this kindred, 88 affected individuals were observed and an additional 50 were known to be affected. Several other families with the disorder have since been described. In addition, isolated cases have been reported in which there was no known family history.
JWS is now known to be a member of a group of conditions caused by mutations in the FGFR genes including Apert syndrome, Crouzon syndrome, Beare-Stevenson syndrome, FGFR2-related isolated coronal synostosis, Pfeiffer syndrome, Crouzon syndrome with acanthosis nigricans and Muenke syndrome.
JWS is typically characterized by craniofacial malformations occurring in association with skeletal abnormalities of the feet, but some affected individuals have no craniofacial abnormalities. The range and severity of associated findings may vary greatly among members of the same or other affected families.
In those with craniofacial abnormalities, such malformations may result in a distinctive facial appearance. For example, there may be premature closure of the fibrous joints (cranial sutures) between particular bones of the skull (craniosynostosis), causing the top of the head to appear pointed or conical (acrocephalic). In some patients, craniosynostosis may be associated with headaches, disturbances in vision, and hydrocephalus, a condition in which there is an abnormal accumulation of cerebrospinal fluid (CSF) in the skull. Hydrocephalus often results in increased fluid pressure and abnormal enlargement of the cavities (ventricles) within the brain.
Individuals with JWS may also have additional craniofacial abnormalities. These may include a relatively flat back region of the head (occiput), underdeveloped midfacial regions (midfacial hypoplasia), and widely spaced eyes (ocular hypertelorism). Affected individuals may also have downwardly slanting eyelid folds (palpebral fissures), drooping of the upper eyelids (ptosis), or abnormal deviation of one eye in relation to the other (strabismus). In some patients, additional features may also be present, such as a flat nasal bridge, an underdeveloped upper jawbone (maxillary hypoplasia), a highly arched roof of the mouth (palate), incomplete closure of the palate (cleft palate), and/or malformed ears.
JWS may also be characterized by various abnormalities of the feet. For example, affected individuals may have webbed or fused second and third toes (syndactyly) and/or abnormally short, broad great toes that may bend inward (varus deformities). There may also be malformation or fusion of certain bones within the body of the feet (metatarsals), the ankles (tarsal bones), and/or the heels (calcanei). Some individuals with JWS may also have additional physical abnormalities such as limitation of joint movements and/or a condition in which the legs are abnormally curved inward, with the knees close together and the ankles widely separated (genu valgum). In addition, although most individuals with the disorder have average or above average intelligence and a normal life span, varying levels of intellectual disability have been reported in a few patients.
JWS is an autosomal dominant genetic disorder. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
JWS is caused by a mutation in the FGFR2 gene. The FGFR2 gene regulates the production of a protein known as a fibroblast growth factor receptor (FGFR).Genetic mutations that disrupt the functioning of such proteins may result in certain abnormalities during embryonic development, such as premature fusion of the craniofacial area and the limbs. A number of syndromes have been identified that are associated with mutations of the FGFR2 gene including Crouzon, Pfeiffer, and Apert syndromes. (For further information on these disorders, please see the “Related Disorders” section of this report below.)
Most individuals with a FGFR2 gene mutation associated with JWS will have symptoms and findings associated with the disorder but range and severity may vary greatly from person to person).
JWS appears to affect males and females in equal numbers. The incidence rate is unknown.
JWS may be diagnosed or confirmed at birth or during early infancy based upon a thorough clinical evaluation, identification of characteristic physical findings, and a variety of specialized tests including advanced imaging techniques. For example, specialized x-ray imaging studies, such as computerized tomography (CT) scanning or magnetic resonance imaging (MRI), may help to confirm the presence and/or extent of certain craniofacial, foot, or other skeletal abnormalities. Molecular genetic testing for mutations in the FGFR2 gene is available if the diagnosis is uncertain.
In some children, a diagnosis of JWS may be suggested before birth (prenatally) based upon detection of certain characteristic physical findings during fetal ultrasound.
The treatment of JWS is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals who may need to systematically and comprehensively plan an affected child’s treatment. These professionals may include pediatricians; physicians who specialize in disorders of the skeleton, joints, muscles, and related tissues (orthopedists), physical therapists; and/or other health care professionals.
Specific therapies for JWS are symptomatic and supportive. In some affected individuals, craniosynostosis and associated hydrocephalus may result in abnormally increased pressure within the skull (intracranial pressure) and on the brain. In such cases, surgery may be advised to correct craniosynostosis and to insert a tube (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed. Surgery may also be recommended to correct other craniofacial and skeletal abnormalities potentially associated with the disorder. The surgical procedures performed will depend upon the severity of the anatomical abnormalities, their associated symptoms, and other factors. In some cases, physical therapy and additional orthopedic and supportive measures may also be recommended to help improve an affected individual’s mobility.
Early intervention may be important to ensure that children with JWS reach their potential. Special services that may be beneficial include special education and other medical, social, and/or vocational services.
Genetic counseling is recommended for affected individuals and their families. In addition, thorough clinical evaluations may be important in family members of diagnosed individuals to detect any findings that may be associated with JWS. Other treatment for this disorder is symptomatic and supportive.
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