Nance-Horan syndrome is a rare genetic disorder that may be evident at birth (congenital). It is primarily characterized by abnormalities of the teeth and clouding of the lens of the eyes (congenital cataracts), resulting in poor vision. Additional eye (ocular) abnormalities are also often present, such as unusual smallness of the front, clear portion of the eye through which light passes (microcornea) and involuntary, rapid, rhythmic eye movements (nystagmus). In some cases, the disorder may also be associated with additional physical abnormalities and/or intellectual impairment. The range and severity of symptoms may vary greatly from one person to another, including among affected members of the same family.
Nance-Horan syndrome is inherited as an X-linked trait that it is usually fully expressed in males only. However, females who carry a single copy of the disease gene (heterozygotes) may manifest some of the symptoms and findings associated with the disorder. These may include microcornea and/or clouding of the lens of the eyes (posterior sutural cataract). Symptoms are less severe than those of affected males, potentially causing only slightly decreased clearness or clarity of vision (visual acuity). In some cases, abnormalities of the teeth may also be present. Intellectual impairment rarely occurs in females.
In affected males, the primary physical characteristic associated with Nance-Horan syndrome is the presence of dense clouding (opacities) of the lens of both eyes at birth (congenital bilateral nuclear cataracts). The lens of an eye is the small transparent flattened and elongated ball located behind the iris through which light passes. The light focuses on the retina, the thin nerve-rich membrane that lining the back of the eye. The retina converts the light into nerve impulses and relays the information along the optic nerve to the brain. Cataracts affect both eyes (bilateral) and usually result in blurred vision and severely decreased clearness or clarity of vision (visual acuity). Vision loss can potentially be profound.
Males with Nance-Horan syndrome may have additional eye abnormalities. The front (anterior), clear portion of the eye through which light passes (cornea) may be unusually small (microcornea). In addition, affected males with poor vision may have recurrent, involuntary, “to-and-fro” movements of the eyes (pendular nystagmus) and/or misalignment of the eyes (strabismus). In some cases, the entire eye may be abnormally small (microphthalmia) and/or the upper eyelid may droop (ptosis).
Males with Nance-Horan syndrome may also have several dental abnormalities such as unusually shaped, extra (supernumerary) teeth, absence of some teeth (dental agenesis), impacted teeth or unusually wide spaces (diastema) between some of the teeth. Front teeth (incisors) are tapered and “screwdriver-shaped” or are similar in appearance to a tooth abnormality often associated with congenital syphilis (i.e., Hutchinson’s teeth). Posterior teeth may be conical, rounded, cylindrical or with extra cusps (small bumps at the surface of the molar teeth). In some cases, affected males may have an extra (supernumerary), centrally located front tooth in the upper jaw (mesiodens). The tooth may be “cone-shaped” with an abnormally short root Such supernumerary incisors may prevent or disrupt the normal eruption of permanent incisors in some cases. Both the baby (deciduous) and permanent teeth are involved.
In many males with Nance-Horan syndrome, other physical findings may also occur. Distinctive facial features may be present, but may be subtle. The ears may be flared forward (anteverted) and unusually prominent, with folded lobes. Affected males may have a large, prominent nose with a high, narrow nasal bridge; a narrow prominent jaw (prognathism); and a long sometimes narrow face.
Some males with Nance-Horan syndrome may also experience delays in the acquisition of skills requiring the coordination of muscular and mental activity (psychomotor retardation). In addition, some reports suggest that approximately 20 to 30 percent of affected males may have varying levels of intellectual dysfunction. Intellectual dysfunction is usually mild or moderate, but in some cases can be severe.
As mentioned above, females who carry a single copy of the disease gene for Nance-Horan syndrome (heterozygotes) may develop some symptoms of the disorder. Such symptoms are usually milder and more variable than those associated with the fully expressed disorder. Affected females may have abnormally small corneas (microcornea) and/or Y-shaped clouding (opacities) in the back portion of the lens of the eyes at birth (congenital posterior sutural cataracts). Vision may be normal, or there may be slightly decreased clearness or clarity of vision (visual acuity). Without appropriate treatment, posterior sutural cataracts may progress to total clouding of the lens of the eyes (total cataracts) later in life. Heterozygous females often have some dental abnormalities, such as abnormally-shaped front teeth (incisors) and/or unusually wide spaces (irregular diastema) between some of the teeth. Affected females usually do not develop intellectual impairment.
Nance-Horan syndrome is caused by mutations of the NHS gene, which is located on the X chromosome. Nance-Horan syndrome is inherited as an X-linked trait. 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.
X-linked disorders are conditions that result from changes (mutations) of a gene on an X chromosome. Females have two X chromosomes, but males have one X chromosome and one Y chromosome. In females, disease traits resulting from the abnormal copy of a gene on one X chromosome can be “masked” by the normal copy of the gene on the other X chromosome. (For more, see below.) In the opposite, since males only have one X chromosome, if they inherit an abnormal copy of a gene for a disease present on the X, it will likely be fully expressed. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a 50 percent risk of transmitting the carrier condition to their daughters and a 50 percent risk of transmitting the disease to their sons.
As mentioned above, in females who carry a copy of a disease gene for an X-linked trait, disease traits on the X chromosome may essentially be “masked” by the normal gene on the other X chromosome. More specifically, because only one functioning X chromosome is required in males and females, one of the X chromosomes in each cell of a female is essentially “turned off”, usually in a random pattern (random X chromosome inactivation). Therefore, if the X chromosome with the gene mutation is activated in some cells, female carriers may manifest certain, typically more variable or mild features of the disorder as previously discussed (see Symptoms section above).
Investigators have determined that Nance-Horan syndrome is caused by mutations of the NHS gene. The function of this gene is not fully understood. The gene has been mapped to the short arm (p) of chromosome X (Xp22.31-p22.13). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. Therefore, “Xp22.13″ refers to band 22.13 on the short arm of chromosome X.
As discussed above, Nance-Horan syndrome is usually fully expressed in males only, although females who carry a single copy of the disease gene (heterozygotes) may develop certain features. The disorder is present at birth (congenital). Nance-Horan syndrome was described in 1974 by two research teams independent of each other. Fewer than 50 families (kindreds) have been described in the medical literature. The exact incidence of the disorder is unknown. Researchers believe that cases may go unrecognized or misdiagnosed, making it difficult to determine the true frequency of Nance-Horan syndrome in the general population.
Nance-Horan syndrome may be diagnosed based upon a thorough clinical evaluation, detection of characteristic physical findings such as congenital cataracts and dental abnormalities, and specialized testing, including the use of an illuminated microscope to examine the interior of the eyes (slit-lamp examination) and dental x-ray series. Molecular genetic testing for the NHS gene is available to confirm the diagnosis.
The treatment of Nance-Horan syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists, such as pediatricians; physicians who diagnose and treat diseases of the eye (ophthalmologists); dental specialists who diagnose, prevent, and/or correct misalignment (malocclusion) and other abnormalities of the teeth (orthodontists); and other health care professionals.
A variety of methods may be used to treat, prevent, and/or correct eye defects associated with Nance-Horan syndrome, depending upon the specific combination of abnormalities present, their severity, and/or other factors. In affected males with cataracts, surgery may be recommended to remove the cataracts and, in some cases, to implant artificial lenses. Significant vision loss may still occur despite surgical removal of cataracts. In addition, corrective glasses, contact lenses, and/or other measures may be used to help improve vision.
Approximately 50 percent of males with Nance-Horan syndrome develop glaucoma, which results from cataract surgery during infancy. Glaucoma is a condition marked by a rise in the pressure within the eyeball preventing the normal drainage of fluid from the eye and potentially causing characteristic damage to the optic nerve, which relays nerve impulses from the retina to the brain. Glaucoma may be treated medically or surgically.
Carrier females and at-risk females should receive regular examinations from an ophthalmologist to ensure early detection of eye abnormalities potentially associated with the disorder. Infrequently, cataract surgery may be recommended to improve or preserve visual acuity.
In affected individuals with extra front teeth (supernumerary incisors), surgery may be advised to remove the additional incisors. Braces, dental surgery, and/or other corrective procedures may also be undertaken to correct other dental abnormalities, such as unusually wide spaces (diastema) between some of the teeth.
Early intervention is important in ensuring that affected children reach their potential. Special services that may be beneficial may include special remedial education and other medical, social, and/or vocational services. Affected individuals may need to attend a school for the visually impaired.
Genetic counseling will be of benefit for affected individuals, at-risk females, and their families. Family members of affected individuals should also receive regular clinical evaluations to detect any symptoms and physical characteristics that may be potentially associated with Nance-Horan syndrome or heterozygosity for the disorder.
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