IntroductionNager syndrome was first described in the medical literature in 1948 by doctors Nager and De Reynier. Nager syndrome belongs to a group of disorders collectively known as acrofacial dysostoses or AFDs. These disorders are characterized by craniofacial and limb abnormalities. AFDs are generally broken down into preaxial and postaxial types. Nager syndrome is a preaxial form; the term preaxial refers to the bones of the arms and legs that are on the thumb and big toe sides of the body.
The specific symptoms that occur may vary from one person to another, even among members of the same family. Affected individuals may develop a variety of craniofacial and limb abnormalities. Some abnormalities are noticeable at birth (congenital).
Common craniofacial abnormalities include underdevelopment of the cheekbones (malar hypoplasia); an abnormally small lower jaw (micrognathia); incomplete closure of the roof of the mouth (cleft palate) and/or velopharyngeal insufficiency, in which the soft palate of the mouth does not close properly during speech; narrowing of the back of the nasal cavity (choanal atresia); malformation of the internal or external ears that can range from mild abnormality to absence of the external portion of the ear; and/or absence of tissue (colobomas) from the lower eyelids. Additional craniofacial findings can occur including downward-slanting palpebral fissures (which means that the opening between the eyelids slants downward), partial or total absence of the eyelashes of the lower eyelids, and droopy or sagging of the upper eyelids (ptosis). In some cases, scalp hair may extend onto the cheek.
Micrognathia is caused by underdevelopment (hypoplasia) of the lower jaw bone (mandible). Severe mandibular hypoplasia along with cleft palate and choanal atresia can result in feeding difficulties and/or severe breathing difficulties during infancy. In some cases, if left untreated, breathing difficulties can cause life-threatening complications. Affected individuals may have temporomandibular joint dysfunction (TMJD); the temporomandibular joint connects the jaws to the side of the head. TMJD can cause pain of the jaw, face and neck, stiff jaw muscles, and upper and lower teeth that do not meet properly when closing the mouth (malocclusion).
Malformation of the ears can contribute to affected individuals developing conductive hearing loss. Conductive hearing loss occurs due to lack of conduction of sound from the outer or middle ear to the inner ear. Degree of hearing loss can vary. Hearing impairment may cause speech development to be delayed.
Individuals with Nager syndrome also have abnormalities affecting the arms and hands including underdevelopment or absence of the thumbs, the presence of an extra (third) copy of a bone known as the phalange within the thumb (triphalangeal thumbs), and underdevelopment of the forearm bone on the thumb side of the arm (radius). Less often, webbing (syndactyly) of the fingers may occur, or certain fingers may be fixed or stuck in a bent position (camptodactyly). The formation of an abnormal bone or soft tissue connection between the ulna and the radius, two main bones of the forearm (radioulnar synostosis) may also occur. Because of these abnormalities, the forearms may appear abnormally short. Some individuals may have difficulty fully straightening their arms because the range of motion of the elbow is limited. A few very severely affected individuals have severely shortened upper limbs (phocomelia).
Although abnormalities of the hands and forearms are more common, some affected individuals have abnormalities affecting the feet and lower legs including underdeveloped or absent toes, webbing of the toes, clubfeet, and the abnormal turning inward of the big toe towards the index toe (hallux valgus).
While most individuals with Nager syndrome are healthy, a few severely affected individuals have serious internal malformations involving the kidney and/or the heart. Additional rare symptoms that have been reported in the medical literature include diaphragmatic hernia (an abnormal connection between the chest and abdomen), and underdevelopment of the larynx which can contribute to respiratory problems, as well as additional skeletal abnormalities such as underdevelopment of the first rib, abnormal curvature of the spine (scoliosis), or dislocation of the hip.
Most cases of Nager syndrome are cause by mutations in the SF3B4 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
Investigators have determined that the SF3B4 gene is located on the long arm (q) of chromosome 1 (1q12-q21). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1q12-q21” refers to bands q12 through q21 on the long arm of chromosome 1.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the 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 affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Because individuals with Nager syndrome have a change in only 1 copy of the SF3B4 gene we know that Nager syndrome is inherited as an autosomal dominant condition. Most cases occur as a new (sporadic or de novo) mutation at the time of the formation of the egg or sperm for that child only, and no other family members are affected. An individual who is the first one in the family to have Nager syndrome does, however, still have a 50% risk to transmit it to his or her children. Previous reports of siblings with Nager syndrome born to apparently unaffected parents could represent a different recessive form of Nager syndrome, but are more likely due to failure to recognize the condition in a mildly affected parents or to a parent having a gene change only in the ovary or testis (gonadal mosaicism).
Nager syndrome affects males and females in equal numbers. The exact incidence and prevalence in the general population is unknown. Many cases go misdiagnosed or undiagnosed, making it difficult to determine the true frequency in the general population. More than 100 cases have been reported in the medical literature. Although rare, Nager syndrome is the most common form of acrofacial dysostosis.
A diagnosis of Nager syndrome is based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic physical findings. Most of the associated abnormalities are present at birth (congenital).
Treatment of Nager Syndrome may consist of surgery to insert breathing and feeding tubes in infants who are unable to breath or eat due to deformities of the palate or jaw. Surgery may be needed on the ears to aid in hearing in those with ear defects. There may be a need for multiple plastic surgeries to correct eye and jaw defects and cleft palate. Physical therapy often is necessary to improve use of hands and feet. Orthopedic surgery may also be necessary to try and correct deformities of the arms, hands, feet or toes. Speech therapy may be needed to aid in hearing and language development.
Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.
Clinical Testing and Workup
Specialized x-ray studies will confirm the presence and/or extent of certain observed craniofacial abnormalities. For example, such imaging tests show the abnormally small jaw (micrognathia) due to underdevelopment of the lower jaw bone (mandibular hypoplasia) as well as the underdeveloped cheekbone (malar hypoplasia).
Molecular genetic testing can confirm a diagnosis of Nager syndrome. Molecular genetic testing can detect a mutation the SF3B4 gene, but is available only as a diagnostic service at specialized laboratories.
The treatment of Nager syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, oral surgeons, plastic surgeons, pediatric ear, nose and throat specialists (pediatric otolaryngologists), specialists in diagnosing and treating eye disorders (ophthalmologists), specialists in diagnosing and treating ear disorders (otologists), specialists in treating hearing loss (audiologists), psychologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Affected individuals may benefit from referral to a craniofacial center.
Specific treatment may consist of surgery to create a small opening in the throat, through which a small tube is inserted to assist with breathing (tracheostomy). Surgery may also be necessary to create a small opening in the stomach to allow the insertion of a feeding tube in infants experiencing difficulty eating in order to maintain proper nutrition.
Surgery may be required to correct abnormalities of the jaws, limbs, and eyes. Surgery and/or speech therapy may be necessary when cleft palate or cleft lip is present. Skeletal malformations such as rib abnormalities, limited range of motion of the elbows, and scoliosis may require surgical intervention. Congenital heart defects often require surgery.
Early intervention with appropriate physical, occupational, and speech therapy services is important in ensuring that affected children reach their full potential. Physical and occupational therapy may be necessary to aid in walking and using one’s hands. Speech therapy may be of benefit for individuals with speech development delays due to hearing loss. Hearing loss may require tubes to be implanted in the ears or the use of a hearing aid.
Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.
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