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

• Craniometaphyseal Dysplasia
• Frontometaphyseal Dysplasia
• Larsen Syndrome
• Oro-Facial-Digital Syndrome
• Osteopetrosis

Individuals with otopalatodigital syndrome type I typically have short stature, an incomplete closure of the roof of the mouth (cleft palate), a downward slant of the opening between the upper and lower eyelids, hearing loss due to a defect of the middle ear (conductive hearing loss), and abnormal shortness of the fingers and toes. Symptoms that are sometimes seen in OPD type I are: short, broad thumbs and great toes; wide spaces between the toes; one or more fingers bent to the side; two or more digits united (syndactyly); short fingernails; dislocation of the head of the radius (one of the bones of the forearm); a broad bridge of the nose; underdeveloped bones of the face; and/or slow speech development. Females with the disorder may have an overhanging brow, a depressed nasal bridge, a wide space between the eyes, and a flat midface. The symptoms expressed in females vary and are fewer. Females do not have the full expression of this disorder.

Individuals with otopalatodigital syndrome type II are typically more severely affected. Major characteristics in males with this disorder may be a small head, broad forehead, flat bridge of the nose, wide space between the eyes, small mouth, cleft palate, downward slant of the opening between the upper and lower eyelids, small mouth, small jaw, fingers that are bent and overlap, short fingers and toes, curved long bones of the forearms and legs and occasionally mental retardation. OPD type II typically results in stillbirth or early infant death. Females with OPD type II may have mild symptoms such as an arched palate in the mouth, broad face, low-set ears, split uvula (the fleshy lobe in the middle of the back border of the soft palate), fingers bent to the side, short stature, and a downward slant of the opening between the upper and lower eyelids. Females do not have the full expression of this disorder.

Otopalatodigital syndrome type I and II are inherited as X-linked traits with variable expression in carrier females. Different mutations in the gene for the filamin protein (FLNA) are responsible for the two syndromes. The FLNA gene has been mapped to chromosome Xq28.

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, "chromosomeXq28" refers to band 28 on the longt arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

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 recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is "turned off" and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is turned off. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.

Otopalatodigital syndrome type I and II affect males and females but males are more severely affected.

Symptoms of the following disorders can be similar to those of otopalatodigital syndrome type I and II. Comparisons may be useful for a differential diagnosis:

Craniometaphyseal dysplasia is a rare genetic disorder that is characterized by head and facial abnormalities, hearing loss and bone deformities of the legs. The nose is abnormally small with narrow nasal passages and the eyes are widely spaced and bulging. The limbs may be affected by a hardening or broadening of the shaft of the long bones close to the growth center. Craniometaphyseal dysplasia is thought to be inherited as an autosomal dominant trait, but may also be inherited as a recessive genetic trait. (For more information on this disorder, choose "craniometaphyseal" as your search term in the Rare Disease Database.)

Frontometaphyseal dysplasia is a rare genetic disorder characterized by coarse facial features that include a wide nasal bridge, widely spaced eyes, overgrowth of the bone over the eyes, a small jawbone and incomplete development of the sinuses. Multiple deformities of the teeth and bones may also be present. Occasionally mental retardation may occur.

Larsen syndrome is a multi-system genetic disorder that is present at birth. It is characterized by multiple bone dislocations and abnormalities, an extremely high arch of the foot, non-tapering cylindrically shaped fingers, and an unusual facial appearance. In some cases short stature, heart problems, cleft palate or lips, deafness and/or mental retardation may occur. This disorder is inherited through an autosomal dominant or recessive trait. (For more information on this disorder, choose "Larsen" as your search term in the Rare Disease Database.)

Orofacialdigital syndrome is a rare genetic disorder in which there have been four types identified. Symptoms common to all types include episodes of neuromuscular disturbances, split tongue, splits in the jaw, midline cleft lip, overgrowth of the membrane that supports the tongue, a broad based nose, vertical folds of the skin covering the inner angle where the eyelids meet (epicanthic folds), more than the normal number of fingers and/or toes, shorter than normal fingers and/or toes, and more than the normal number of divisions between skull sections. (For more information on this disorder, choose "orofacialdigital" as your search term in the Rare Disease Database.)

Osteopetrosis is a rare genetic bone disorder inherited through an autosomal dominant or autosomal recessive trait. Initial symptoms of the dominant form may include bone fragility leading to easy fractures and unusual dental problems. Bone pain may occur in the spine, and cranial nerves may be affected. Some vision defects or facial palsy may also be symptomatic of the dominant form of osteopetrosis. (For more information on this disorder choose "osteopetrosis" as your search term in the Rare Disease Database.)

Diagnosis
The diagnosis of OPD type I or II is based on physical features and X-ray findings. Skeletal abnormalities associated with theses conditions can sometimes be seen on a prenatal ultrasound exam. Clinical molecular genetic testing is available for mutations in the FLNA gene.

Treatment
Treatment for OPD is symptomatic. Infants may have difficulty breathing and require long-term respiratory care. Orthopedic and surgical procedures may be used to correct skeletal deformities. Treatment of hearing loss may be limited due to the severity of deformities within the ear.

Genetic counseling is appropriate for patients and their families.

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 website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

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

Savarirayan R. Oto-Palato-Digital Syndrome. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:239-240.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University; Entry No. 311300; Last Update: 3/19/03; Entry No. 304120; Last Update; 3/19/03.

Fitch N, Jequier S, and Papageorgiou A. A familial syndrome of cranial, facial, oral and limb abnormalities. Clin Genet 1977;10:226-231.

Robertson SP, Walsh S, and Oldridge M, et al. Linkage of otopalatodigital syndrome type 2 (OPD2) to distal Xq28: evidence for allelism with OPD1. Am J Hum Genet 2001;69:223-227.

Savarirayan R, Cornmier-Daire V, Unger S, et al. Oto-palato-digital syndrome, type II: report of three cases with further delineation of the chrondro-osseous morphology. Am J Med Genet 2000;95:193-200.