Opitz-Frias syndrome
Opitz-Frias syndrome, also known as Opitz G/BBB syndrome, is a genetic disorder characterized by developmental defects primarily affecting the midline of the body. It can be inherited in two forms: an X-linked dominant form (Type I) and an autosomal dominant form (Type II). Common symptoms include wide-spaced eyes (hypertelorism), swallowing difficulties due to esophageal malformations (dysphagia), breathing issues from laryngeal abnormalities, and penile malformations (hypospadias) in males. The frequency of Type I is estimated at 1 in 50,000 to 100,000, while Type II is more prevalent at approximately 1 in 4,000 to 6,000. The underlying genetic causes include mutations in the MID1 gene for Type I and a deletion on chromosome 22 for Type II. Symptoms can vary significantly among individuals and may also include developmental delays and heart defects. Diagnosis can occur prenatally through ultrasound or postnatally based on physical features, with fluorescence in situ hybridization (FISH) confirming genetic deletions. While there is no prevention for this syndrome, symptomatic treatments—such as surgeries and therapies—can improve quality of life.
Opitz-Frias syndrome
ALSO KNOWN AS: Opitz G/BBB syndrome Types I and II; 21q11.2 deletion syndrome; BBB syndrome; G syndrome; Opitz oculogenitolaryngeal syndrome; hypertelorism-hypospadias syndrome; telecanthus-hypospadias syndrome; hypertelorism with esophageal abnormality and hypospadias; hypospadias-dysphagia syndrome
DEFINITION Opitz-Frias syndrome can be inherited as either an autosomal dominant (Opitz G/BBB syndrome Type II) or X-linked dominant (Opitz G/BBB syndrome Type I). The most common symptoms are developmental defects mainly occurring along the midline of the body, usually including wide-spaced eyes (hypertelorism), esophageal malformations leading to swallowing difficulties (dysphagia), laryngo-tracheal abnormalities leading to breathing problems (pulmonary aspiration), and, in males, malformation of the penile urethra (hypospadias).
Risk Factors
There are no known risk factors for this disease. In Type I, males show more severe symptoms than females, who may only show mild hypertelorism. The frequency of Type I is 1 in 50,000 to 100,000. In Type II, males and females are equally affected. The frequency of type II is 1 in 4,000 to 6,000. According to Myriad Genetics in 2023, Type I syndrome was believed to affect some 1 in 50,000 to 100,000 males. Though the incidence of Type II is not known, it is part of 22q11.2 deletion syndrome, which has an estimated prevalence of 1 in 4,000 people.
Etiology and Genetics
The X-linked form of this disease is caused by a mutation in the MID1 gene (located at Xp22), which codes for the protein midin. This protein is involved in degradation of a protein phosphatase that is involved in microtubule formation. When the protein phosphatase is not degraded quickly enough, it builds up in cells and hyperphosphorylates microtubule-associated proteins. Because of this, microtubules are not formed properly, which interferes with cell division and with the cytoskeleton. In addition, nonfunctional midin in the cells coalesces into clumps. The relationship between these changes and the disruption of normal development is not yet understood. Many different mutations within the MID1 gene have been seen in patients including additions, deletions, and substitutions.
The autosomal form of the disease occurs when a portion of chromosome 22 is deleted (22q11.2). This deletion can be inherited (7 percent of patients) but is often seen as a new deletion in patients with no family history of the disease (93 percent of patients). Several other disorders including DiGeorge syndrome, velocardiofacial syndrome (Shprintzen syndrome), conotruncal anomaly face syndrome, and Cayler cardiofacial syndrome are now included with autosomal Opitz-Frias syndrome in 22q11.2 deletion syndrome since all seem to be variable expressions of this deletion. The region deleted is usually about three million base pairs long and contains thirty to forty genes, most of which are not well characterized. In a few patients, this deletion is significantly smaller. Two genes that may affect the disease symptoms are TBX1, the deletion of which may be responsible for many of the developmental deformities, and COMT , which, when deleted, may lead to increased mental instability.
Symptoms
A variably expressed group of symptoms is seen in this syndrome, the majority of which affect structures along the body’s midline. The most common symptoms are hypertelorism, dysphagia, tracheal abnormalities, and hypospadias. Other symptoms include developmental delay; mild mental disability; cleft lip and/or palate; heart defects; imperforate anus; structural abnormalities of the brain, especially the corpus callosum and pituitary; urinary/reproductive abnormalities such as cryptorchidism, bifid scrotum, and abnormal labia; flat nasal bridge; widows peak; lingual frenulum; and low-set ears. Approximately one-third of the affected families showed monozygotic twinning, a much higher rate than normal. The majority of the symptoms are common to both the X-linked and autosomal forms of the disease, but there are some differences. Cleft lip with or without cleft palate is more common in the X-linked form, while cleft palate alone is more common in the autosomal form. Anteverted nares and posterior pharyngeal cleft have only been seen in the X-linked form.
Screening and Diagnosis
Heart and craniofacial abnormalities and hypospadias can be diagnosed prenatally by ultrasound between eighteen and twenty-two weeks. Postnatally, the presence of hypertelorism and hypospadias are used to diagnose both X-linked and autosomal forms. Fluorescence in situ hybridization (FISH) is used to confirm 22q11.2 deletions in Type II. FISH can also be used on DNA from chorionic villus biopsy as early as ten weeks of pregnancy.
Treatment and Therapy
Symptomatic treatments include surgery to correct cardiac, palate, urethral, and respiratory abnormalities. Medications can help with reflux caused by esophageal defects.
Language assessment and speech therapy are often needed as is psychological evaluation and intervention. If the pituitary is involved, then growth hormone therapy may be needed.
Prevention and Outcomes
There is no way of preventing Opitz G/BBB syndrome. Many patients suffer from aspiration pneumonia, which can prove fatal. Symptomatic treatments must be continued throughout the patient’s life.
Bibliography
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Hunning, I, et al. "Exon 2 Duplication of the MID1 Gene in a Patient with a Mild Phenotype of Opitz G/BBB Syndrome." European Jour. of Medical Genetics 56.4 (2013): 188–191. Print.
Ji, X., et al. "A Novel Mutation in MID1 in a Patient with X-Linked Opitz G/BBB Syndrome." Gene 537.1 (2014): 140–142. MEDLINE. Web. 1 Aug. 2014.
McDonald-McGinn, Donna M., Beverly S. Emanuel, and Elaine H. Zackai. "22q11.2 Deletion Syndrome." GeneReviews. Ed. Roberta A. Pagon et al. Seattle: U of Washington, Seattle, 1993–2014. NCBI Bookshelf. Natl. Center for Biotechnology Information, 28 Feb. 2013. Web. 1 Aug. 2014.
Meroni, Germana. "X-Linked Opitz G/BBB Syndrome." GeneReviews. Ed. Roberta A. Pagon et al. Seattle: U of Washington, Seattle, 1993–2014. NCBI Bookshelf. Natl. Center for Biotechnology Information, 28 July 2011. Web. 1 Aug. 2014.
Migliore, Chiara, et al. "SPECC1L Mutations Are Not Common in Sporadic Cases of Opitz G/BBB Syndrome." Genes, vol. 13. no. 2, 2022, p. 252, doi.org/10.3390/genes13020252. Accessed 9 Sept. 2024.
Millichamp, J. Gordon. Neurological Syndromes: A Clinical Guide to Symptoms and Diagnosis. New York: Springer, 2013. Print.
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