• Disease Overview
  • Synonyms
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • Resources
  • References
  • Programs & Resources
  • Complete Report

Nager Syndrome


Last updated: July 30, 2018
Years published: 1992, 1993, 2000, 2002, 2015, 2018


NORD gratefully acknowledges Elizabeth McPherson, MD, Department of Medical Genetic Services, Marshfield Clinic, Marshfield, WI, for assistance in the preparation of this report.

Disease Overview


Nager syndrome is a rare inherited disorder characterized by craniofacial malformations occurring in association with abnormalities of the thumb and forearm. Craniofacial malformations include underdevelopment of the cheekbones (malar hypoplasia) resulting in downward slanting palpebral fissures; incomplete development of the lower jaw (mandibular hypoplasia), causing the jaw to appear abnormally small (micrognathia); and small (microtia) and/or malformed (dysplastic) external ears (pinnae), often with a blind ending or absent external ear canals, resulting in hearing impairment (conductive hearing loss). Nager syndrome is distinguished from other forms of acrofacial dysostosis by the limb abnormalities, which are primarily on the thumb (radial) side of the hand and forearm including underdevelopment or absence of the thumbs and the radius bone in the forearm, and abnormal fusion of bones in the forearms (radioulnar synostosis). The fingers and the feet are usually normal. Intelligence is usually not affected. Nager syndrome is typically inherited in an autosomal dominant pattern and is caused by changes (mutations) in the SF3B4 gene. Although an individual with Nager syndrome can transmit the condition to his/her children, many cases occur randomly (sporadic) as a new gene change (de novo mutation) in the family.


Nager 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.

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  • acrofacial dysostosis, Nager Type
  • mandibulofacial dysostosis, Treacher Collins type, with limb anomalies
  • Nager acrofacial dysostosis
  • NAFD
  • preaxial acrofacial dysostosis
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Signs & Symptoms

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 which usually 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. Additional craniofacial findings in or around the eyes include downward-slanting palpebral fissures (which means that opening between the upper and lower lids slants downward), absence of tissue (colobomas) from the lower eyelids, partial or total absence of the eyelashes of the lower eyelids, and droopy or sagging of the upper eyelids (ptosis). In some patients, 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.

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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.

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 parent or to a parent having a gene change only in the ovary or testis (gonadal mosaicism).

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Affected populations

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.

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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).

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.

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).

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Standard Therapies

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 is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:

For information about clinical trials sponsored by private sources, in the main, contact:

For more information about clinical trials conducted in Europe, contact:

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Nager Syndrome Resources

Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.

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Jones KL, Jones MC, del Campo Casanelles. Eds. Nager Syndrome. In: Smith’s Recognizable Patterns of Human Malformation. 7th ed. Elsevier Saunders, Philadelphia, PA; 2013:344-345.

Wulfsberg EA. Nager Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:226.

Lansinger Y, Rayan G. Nager Syndrome. J Hand Surg Am. 2014;[Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/25543163

Petit F, Escande F, Jourdain AS, et al. Nager syndrome: confirmation of SF3B4 haploinsufficiency as the major cause. Clin Genet. 2014;86:246-251. http://www.ncbi.nlm.nih.gov/pubmed/24003905

McPherson E, Zaleski C, Ye Z, Lin S. Rodriguez syndrome with SF3B4 mutation: a severe form of Nager syndrome? Am J Med Genet A. 2014;164A:1841-1845. http://www.ncbi.nlm.nih.gov/pubmed/24715698

Nur BG, Bernier FP, Oztekin O, et al. Possible autosomal recessive inheritance in an infant with acrofacial dysostosis similar to Nager syndrome. Am J Med Genet A. 2013;161A;2311-2315. http://www.ncbi.nlm.nih.gov/pubmed/23913624

Gana S, Gentilin B, Bianchi V, et al. Prenatal phenotype of Nager syndrome and Rodriguez syndrome: variable expression of the same entity? Clin Dysmorphol. 2013;22:135-139. http://www.ncbi.nlm.nih.gov/pubmed/23811969

Czeschik JC, Voigt C, Alanav Y, et al. Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome. Hum Genet. 2013;132:885-898. http://www.ncbi.nlm.nih.gov/pubmed/23568615

Trainor PA, Andrews BT. Facial dysostosis: etiology, pathogenesis and management. Am J Med Genet C Semin Med Genet. 2013;163C:283-294. http://www.ncbi.nlm.nih.gov/pubmed/24123981

Wieczorek D. Human facial dysostoses. Clin Genet. 2013;83:499-510. http://www.ncbi.nlm.nih.gov/pubmed/23565775

Bernier FP, Caluseriu O, Ng S, et al. Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome. Am J Hum Genet. 2012;90:925-933. http://www.ncbi.nlm.nih.gov/pubmed/22541558

Schlieve T, Almusa M, Miloro M, Kolokythas A. Temporomandibular joint replacement for ankylosis correction in Nager syndrome: case report and review of the literature. J Oral Maxillofac Surg. 2012;70:616-625. http://www.ncbi.nlm.nih.gov/pubmed/21723020

Bernier F. Nager Syndrome. Orphanet Encyclopedia, February 2013. Available at: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=245 Accessed July 26, 2018.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:154400; Last Update: 03/25/2016. Available at: http://www.omim.org/entry/154400 Accessed July 26, 2018.

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Patient Organizations

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