NORD gratefully acknowledges Dr. Germana Meroni, PhD, Group leader, Associate professor of Genetics, Department of Life Sciences, University of Trieste, Trieste, Italy, for assistance in the preparation of this report.
X-linked Opitz G/BBB syndrome is a rare genetic disorder mainly characterized by facial anomalies, respiratory and genitourinary abnormalities as well as developmental delay or intellectual disabilities.
Facial anomalies may include widely spaced eyes (hypertelorism), a prominent forehead, widow’s peak, broad nasal bridge, nostrils that are tipped forward, and cleft lip/palate.
Respiratory abnormalities can include laryngo-esophageal clefts that result in difficult swallowing and breathing. Genitourinary problems can include abnormal placement of the urethra in the penis (hypospadias), undescended testes and sometimes kidney abnormalities. Anal defects may also be present and include absent or mis-positioned anal opening. Congenital heart defects such as ventral septal defects and atrial septal defects might be present as well as brain defects such as agenesis or hypoplasia of the brain region that connects the two hemispheres (corpus callosum) and hypoplasia of the cerebellum also in the context of more complex defects such as Dandy-Walker malformation.
There is a wide variation in the presentation of the clinical signs and in the severity of this condition, even among members of the same family.
Approximately 50% of affected males have developmental delay or intellectual disability that can range from mild to severe. Carrier females usually have hypertelorism only.
X-linked Opitz G/BBB syndrome is inherited as an X-linked genetic condition. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and occur mostly in males. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease gene he will develop the disease. Females that have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display clinical signs because females have two X chromosomes and one is inactivated so that the genes on that chromosome are nonfunctioning. It is usually the X chromosome with the abnormal gene that is inactivated.
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.
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 to male offspring.
The MID1 gene is the only gene known to be associated with X-linked Opitz G/BBB syndrome.
The prevalence of X-linked Opitz G/BBB syndrome is estimated to be 1/50,000-1/100,000 males.
The diagnosis of Opitz G/BBB syndrome is usually made by clinical findings. It is not possible to distinguish this condition from chromosome 22q11.2 deletion syndrome (autosomal dominant Opitz G/BBB syndrome) based on physical features alone. Diagnosis of X-linked Opitz Syndrome can be done by way of inheritance and by molecular genetic testing for mutations in the MID1 gene that is available (15%-45% of affected males have been found to have a mutation).
Widely spaced eyes and cleft lip and palate associated with this condition can sometimes be visualized with prenatal ultrasound.
X-linked Opitz G/BBB syndrome is treated by a team of specialists including surgeons, speech therapists, neuropsychologists and early intervention specialists. Regular assessment of hearing is recommended for affected children with cleft lip and palate.
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