NORD gratefully acknowledges Zacory Kobylarz, NORD Editorial Intern from the University of Notre Dame, and Stephen Robertson, FRACP, DPhil, Curekids Professor of Pediatric Genetics, Dunedin School of Medicine, University of Otago, New Zealand, for assistance in the preparation of this report.
Individuals with OPD 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 OPD type II are 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 small chest, heart defects and occasionally intellectual disability. Less common symptoms may include split tongue-tip, clouded eyes, and Dandy-Walker syndrome (a brain malformation). OPD type II typically results in stillbirth or early infant death in males. Females do not have the full expression of OPD type II and 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.
OPD type I and II are caused by mutations in the FLNA gene on the X chromosome which is responsible for production of the filamin (FLNA) protein. Different mutations in the FLNA gene are responsible for the two syndromes. The filamin protein is normally responsible for helping with the formation and function of the cell’s cytoskeleton, and the mutations appear to give filamin a new function (referred to as a “gain-of-function” mutation) that leads to OPD type I and II.
OPD type I and II are inherited as X-linked traits with variable expression in carrier females.
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.
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 genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an altered gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the altered gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an altered gene he will develop the disease.
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.
If a male with an X-linked disorder is able to reproduce, he will pass the altered gene to all of his 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.
OPD type 1 and II are rare disorders affecting less than 1 in every 100,000 individuals. The specific incidence for these conditions is unknown.
The diagnosis of OPD type I or II is based on physical features and X-ray findings. Clinical molecular genetic testing for mutations in the FLNA gene is available to confirm the diagnosis. Skeletal abnormalities associated with these conditions can sometimes be seen on a prenatal ultrasound exam.
Treatment for OPD type I and II 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 recommended for patients and their family members.
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