Information on the following diseases can be found in the Related Disorders section of this report:

• Miller Syndrome
• Treacher Collins Syndrome
• Goldenhar-Gorlin Syndrome
• Oral-Digital-Facial Syndrome
• Juberg-Hayward Syndrome
• Hemifacial Microsomia

Nager Syndrome is characterized by underdevelopment of the bones of the cheek and jaw area of the face. The eyes may slant downward and there may also be an absence of eyelashes. A smaller than normal jaw, and internal and external ear deformities may also be present. Clefting of the soft and hard palate may occur as well as deformities of the thumbs and arms. Missing, overlapping or webbing of the toes may occur. Clubfeet, hip dislocation and underdeveloped ribs may occasionally be present. Some patients may have heart problems related to the syndrome. There may be hair growing on the sides of the face in an elongated sideburn effect. Feeding, breathing, hearing and speech problems need to be taken care of as soon as possible in order to aid in proper development of the child.

This syndrome is very closely related to Miller Syndrome and in some cases has also been misdiagnosed as Treacher Collins Syndrome.

The exact cause of Nager Syndrome is not known. However, scientists believe that it may be a genetic disorder inherited either through autosomal recessive or dominant inheritance.

Human traits, including the classic genetic diseases,are the product of the interaction of two genes, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed "dominating" the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.

Nager Syndrome is a very rare disorder that affects males and females in equal numbers. It is apparent at birth and may also be detected prenatally by ultrasound screening.

Symptoms of the following disorders can be similar to those of Nager Syndrome. Comparisons may be useful for a differential diagnosis:

Miller Syndrome is a very rare genetic disorder. Major symptoms may include shortening of the upper and lower limbs, cupped ears, lower eyelid abnormalities (coloboma) and lack of development of the lower jaw. There is a lack of development of the long bones in the arms and legs causing shortening of those limbs. There is sometimes clefting of the soft palate or lip. (For more information on this disorder, choose "Miller" as your search term in the Rare Disease Database.)

Treacher Collins Syndrome is characterized by underdevelopment of the cheek (malar), the lower jaw (mandibular) and jaw bones, slanted eyes, notching of lower eyelids, and a receding chin. Underdevelopment of the jaw may cause problems in swallowing or breathing for the newborn. Tubes may have to be inserted to aid the infant in feeding and breathing. The outer upper area of the ear (pinna) may be malformed as well as the external hearing canal (auditory meatus). The eardrum (tympanic membrane) may be replaced with a bony plate. The combination of a longer than normal face with a beaklike nose, receding chin and acute deafness, are characteristic of people with Treacher Collins Syndrome. (For more information on this disorder, choose "Treacher Collins" as your search term in the Rare Disease Database.)

Goldenhar-Gorlin Syndrome is a rare congenital disorder that involves unusual facial characteristics. The facial structure of people with Goldenhar Syndrome may include partial absence of the upper eyelid or an unusual slant of the eyelid, abnormal shape of the skull (asymmetry), the forehead may be sharply prominent, the nostrils may be absent or closed, the roof of the mouth may be clefted (cleft palate), and there may be abnormal growth of the jaw. Paralysis of the eye muscles may occur. Unusual cysts on the eyeball, cysts in fatty tissue at the edge of the eye and skin growths around the ears (skin tags) may also occur. Malformations of the spinal column including open spine (spina bifida), fusion of the top of the spine to the lower edge of the skull, incomplete development of one side of the spinal column and more than the normal number of vertebrae may also be present. (For more information on this disorder, choose "Goldenhar" as your search term in the Rare Disease Database.)

Oral-Facial-Digital Syndrome is a rare genetic disorder characterized by episodes of neuromuscular disturbances, split tongue, splits in the jaw, midline cleft lip, overgrowth of the membrane that supports the tongue (frenulum), a broad based nose, vertical folds of skin covering the inner angle where the eyelids meet (epicanthic folds), more than the normal number of fingers and/or toes, and shorter than normal fingers and/or toes. (For more information on this disorder, choose "Oral-Facial-Digital" as your search term in the Rare Disease Database.)

Juberg-Hayward Syndrome (Orocraniodigital Syndrome) is a rare hereditary disorder characterized by cleft lip and palate, a smaller than normal sized head, deformities of the thumbs and toes, and growth hormone deficiency resulting in short stature.

Hemifacial Microsomia (HFM) is a syndrome that affects one in 5,000 births. It can be confused with a Treacher Collins-like Syndrome. However, it is not genetic. Although it can cause abnormalities on both sides of the face, they are always uneven whereas in Treacher Collins Syndrome both sides of the face appear equally affected. The facial nerve is frequently paralyzed in Hemifacial Microsomia. The variety of features of HFM include: underdevelopment of the lower jaw, tilting of the face to one side, ear deformities (microtia), facial nerve weakness in forty percent of patients, cleft-like notching of the affected corner of the mouth (macrostomia), and underdevelopment of the cheek and eye on the affected side of the face. Other common abnormalities include fatty tumors over the eye, abnormalities of the vertebrae and ribs, cleft lip/palate, and heart and kidney abnormalities which are very rare.

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.

Scientists are studying various surgical methods to improve the appearance of patients with craniofacial and other birth defects affecting the head, eyes and jaw.

Clinical researchers and Johns Hopkins University School of Medicine are engaged in fundamental studies of the gene(s) responsible for Nager Syndrome. Patients with Nager syndrome willing to contribute blood for this study should contact:

Ethlyn Wang Jabs, MD
Director, Center for Craniofacial Development and Disorders
Institute of Genetic Medicine
Tel: 410-955-4160
e-mail ewjabs@jhmi.edu
.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 154400; Last Update:5/12/1999.

TEXTBOOKS
Jones KL. ed Smith’s Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W.B. Saunders Co: 1997:258-59.

REVIEW ATRICLES
Opitz C, Stoll C, Ring P. Nager syndrome. Problems and possibilities of therapy. J Orofac Orthop. 2000;61:226-36.

Vargervik K., Mandibular malformations: growth characteristics and management in hemifacial microsomia and Nager syndrome. Acta Odontol Scand. 1998;56:331-38.

Preis S, Raymakers-Buntinx I, Majewski F. et al., Acrofacial dysostosis of unknown type: nosology of the acrofacial dysostoses. Am J Med Genet. 1995;56:155-60.

Friedman RA, Wood E, Pranksy SM, et al., Nager acrofacial dysostosis: management of a difficult airway. Int J Pediatr Otorhinolaryngol. 1996;35:69-72.

JOURNAL ARTICLES
Denny AD, Talisman R, Hanson PR, et al. Mandibular distraction osteogenesis in very young patients to correct airway obstruction. Plast Reconstr Surg. 2001;108:302-11.

Delb W, Lipfert S, Henn W. Mandibulofacial dysostosis, microcephaly and thorax deformities in two brothers: a new recessive syndrome? Clin Dysmorphol. 2001;10:105-09.

Norris RA, Scott KK, Moore CS, et al. Human PRRX1 genes: cloning, expression, genomic localiation, and exclusion as disease genes for Nager syndrome. Mamm Genome 2000;11:1000-05.

Waggoner DJ, Ciske DJ, Dowton SB et al., Deletion of 1q in a patient with acrofacial dysostosis. Am J Med Genet. 1999;82:301-04.


Zori RT, Gray BA, Bent Weilliams A, et al., Preaxial acrofacial dysostosis (Nager Syndrome) associated with an inherited and apparently balanced X;9 translocation: prenatal and postnatal late replication studies. Am J Med Genet. 1993;46:379-83. Am J Med Genet. 1993;46:379-83.