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

• Waardenburg Syndrome
• Imperforate Anus
• VACTERL Association

Facial anomalies include, among others, widely set eyes (hypertelorism), a broad flat nasal bridge, cleft lip, and cleft palate. Patients may also present with swallowing difficulties (choking, aspiration). Genital malformations may include, among others, undescended testicles (cryptorchidism), urinary opening (meatus) on the underside of the penis (hypospadias), and/or the absence of an anal opening (imperforate anus). Examination may disclose partial or total absence of the thick band of nerve fibers that connects the left and right hemispheres of the brain (hypoplasia or agenesis of the corpus callosum), and/or additional abnormalities.

SYMPTOMS COMMON TO BOTH OPITZ G AND OPITZ BBB SYNDROMES:
Individuals with both forms of Opitz Syndrome generally have unusually wide-set eyes (hypertelorism). Males often have abnormal placement of the urinary opening (meatus) on the underside of the penis (hypospadias), a cleft in the scrotum (bifid scrotum), and/or undescended testicles (cryptorchidism). Females usually have normal genitals or a minor malformation of the outer area of the genitals ("splayed" labia majora). The ears may be slightly rotated on the head (posterior angulation of auricle). Individuals may have a "widow's peak" of hair on the forehead. Mild mental retardation and/or hernias may also occur.

Occasionally, the following symptoms may occur in both forms of Opitz Syndrome: the anal opening may be absent (imperforate anus). There may be a split of the upper lip (cleft lip), and/or an abnormal fissure in the roof of the mouth (cleft palate). Sometimes the back of the mouth may have a fissure as well (cleft uvula). A shorter than average connection (membrane) between the floor of the mouth and the underside of the tongue (frenulum) may be present. In some patients, one eye may be crossed (strabismus). Eyelid abnormalities (downslanting palpebral fissures) may occur. There may also be an irregular shape to the head (cranial asymmetry).

Abnormalities of the heart (cardiac anomaly) or abdominal muscles (diastasis recti) are infrequent. Other uncommon symptoms include absence or inadequate development (agenesis) of the gallbladder or defects of the kidney (renal defects). Part of the small intestine may be narrower than normal (duodenal stricture) in some patients. Twins, especially identical twins, may occur more often in families having this disorder (increased monozygotic twinning).

SYMPTOMS SEEMINGLY LIMITED TO OPITZ G SYNDROME:
Babies with Opitz G Syndrome may have a weak, hoarse cry. Swallowing or breathing is usually difficult. In some babies, food may go into the lungs (recurrent aspiration) because of breathing and swallowing problems, possibly due to nerve and muscle dysfunction or malformations. These malformations may include a malformed larynx, a cleft between the larynx or "voicebox" and windpipe (laryngotracheal cleft), or an abnormal passage between the windpipe and upper digestive tract (tracheoesophageal fistula). Lungs may be underdeveloped (pulmonary hypoplasia). Below the vocal cords, the throat may narrow (subglottic stenosis) or there may be inability to relax muscles of the upper digestive tract (achalasia of esophagus). In addition, in some cases, affected individuals may have partial or total absence of the thick band of nerve fibers that connects the left and right hemispheres of the brain (hypoplasia or agenesis of the corpus callosum).

The bridge of the nose is usually broad and flat with the openings of the nose set more forward than usual (nares anteverted). The jaw may be unusually small (micrognathia) and the roof of the mouth (palate) may have a high arch.

SYMPTOMS SEEMINGLY LIMITED TO OPITZ BBB SYNDROME:
In Opitz BBB Syndrome, respiratory and swallowing difficulties or a hoarse voice are not present. Physical features of the face are different from those of Opitz G Syndrome. The bridge of the nose is often high and broad. Congenital heart disease such as coarctation of the aorta and atrial septal defect may occur in some patients. Abnormalities of the upper urinary tract, a twisted intestine (volvulus), or a small penis may also be present.

As mentioned above, Opitz G/BBB Syndrome was originally classified as two distinct disorders, known as Opitz G and Opitz BBB Syndromes. However, many researchers have since concluded that the two syndromes represent the same disease entity. The form of the disorder previously known as Opitz G Syndrome is transmitted as an autosomal dominant trait. The form previously designated Opitz BBB Syndrome has X-linked inheritance. Human traits, including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother.

In autosomal 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.

X-linked disorders are conditions that are coded on the X chromosome. Females have two X chromosomes, whereas males have one X chromosome and one Y chromosome. In females, certain disease traits on the X chromosome may in some cases be "masked" by the normal gene on the other X chromosome (random X-chromosome inactivation). However, since males have only one X chromosome, if they inherit a gene for a disease present on the X, it is more likely to be fully expressed.

Therefore, in females who inherit a copy of a disease gene for an X-linked disorder, expression of the disorder may be more variable and less severe than in affected males. Males who inherit such a disease gene are more likely to fully express the spectrum of abnormalities associated with the disorder (full phenotype) and therefore are typically more severely affected.

Males with an X-linked trait transmit the gene to all their daughters but none of their sons. Females with one copy of such a gene have a 50 percent risk of transmitting the gene to their daughters and their sons.

The autosomal dominant form of Opitz Syndrome (formerly known as Opitz G Syndrome) appears to result from minute deletions of genetic material from the long arm (q) of chromosome 22 (22q11.2). 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.

The X-linked form of the disorder (previously designated Opitz BBB Syndrome) is thought to result from changes (mutations) of a gene located on the short arm (p) of chromosome X (Xp22). The gene, known as MID1 (meaning "midline-1") appears to play a role in the control of cellular reproduction (proliferation) and development.

The primary abnormalities associated with Opitz G/BBB Syndrome, known as midline defects (such as hypertelorism, hypospadias, cleft lip and palate, and imperforate anus) result from abnormal development of midline structures of the body during fetal growth. Accordingly, researchers suggest that disruption or mutation of the MID1 gene in some affected individuals implicates its function in midline structural development.
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Opitz Syndrome is a rare genetic disorder that is typically apparent at birth. Because one form of the disorder has X-linked inheritance, Opitz Syndrome appears to more commonly affect males than females. In addition, males are more likely to fully express the spectrum of abnormalities associated with the disorder and therefore are typically more severely affected. However, it is important to note that, in some instances, the disorder may be expressed with equal severity in affected females.

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

Waardenburg Syndrome is characterized by displacement of the inner folds of the eyelids, prominence of the nose, and overdevelopment of the eyebrows. The patient may have two different colored eyes or two colors in one iris of the eye. Congenital (present at birth) nerve deafness may also occur. A white streak of hair in the front (forelock) of the head or early graying of the hair are characteristic of this disorder. A thin nose with flaring nostrils, a "cupid bow" configuration of the lips, wide-set eyes, inflammation of the tear sac and drooping of the upper eyelids may occur. A lack of an indent between the nose and the forehead, prominent lower jaw and a clefted or high-arched palate may also be present. (For more information on this disorder, choose "Waardenburg" as your search term in the Rare Disease Database.)

Imperforate Anus is a rare congenital abnormality characterized by the absence or abnormal location of the anus. The rectum or colon may be connected to the vagina or the bladder by a tunnel (fistula). With surgical correction, normal fecal elimination can become possible. Imperforate Anus can occur alone or as a symptom of another disorder. (For more information on this disorder, choose"imperforate anus" as your search term in the Rare Disease Database.)

VACTERL Association is an acronym for (V)ertebral anomalies, (A)nal atresia (absence of a normal anal opening), congenital (C)ardiac disease, (T)racheo(E)sophageal fistula (abnormal openings or passages between the windpipe and/or upper digestive tract), (R)enal anomalies, radial dysplasia, and other (L)imb defects. These abnormalities are present at birth. (For more information on this disorder, choose "VACTERL" as your search term in the Rare Disease Database.)

Ultrasound testing (a technique which uses sound waves to form pictures) before birth may indicate the presence of Opitz Syndrome. If there is swelling of the fetus before birth due to a build-up of fluids, this can be treated while the baby is still in the womb.

Treatment of Opitz Syndrome often includes corrective surgery for malformations. Special education and related services may be helpful for children with this disorder. Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.

Some researchers believe conditions of the baby's environment before birth may influence the severity of symptoms present in Opitz Syndrome. Research on Opitz Syndrome and its heredity is ongoing.

Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 145410; 4/30/99. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?145410.

Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 300000; 8/17/99. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim? 300000.

Jones KL. Smith’s Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA; W.B. Saunders Company; 1997:132-135.

Tolmie JL, et al. Congenital anal anomalies in two families with the Opitz G syndrome. J Med Genet. 1987;24:688-691.