X-linked Opitz G/BBB Syndrome

Disease Overview

X-linked Opitz G/BBB syndrome is a rare genetic disorder characterized by facial differences, respiratory and genitourinary abnormalities and other midline abnormalities as well as developmental delay and intellectual disabilities. There is a wide variability in severity of this condition, even among members of the same family. X-linked Opitz G/BBB syndrome is an X-linked genetic condition associated with changes (pathogenic variants or mutations) in the MID1 gene.

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Synonyms

• hypertelorism-hypospadius syndrome (obsolete)
• Opitz BBBG syndrome
• Opitz-G syndrome
• telecanthus-hypospadius syndrome (obsolete)
• XLOS

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Signs & Symptoms

X-linked Opitz G/BBB syndrome is a rare genetic disorder mainly characterized by facial differences, respiratory and genitourinary abnormalities as well as developmental delay or intellectual disabilities.

Facial features 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 or the less severe laryngomalacia (soft larynx) 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 abnormalities 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 abnormalities 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.

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Causes

The MID1 gene is the only gene known to be associated with X-linked Opitz G/BBB syndrome.

X-linked Opitz G/BBB syndrome is inherited as an X-linked genetic condition. X-linked genetic disorders are conditions caused by a mutated gene on the X chromosome and mostly affect males. Females who have a mutated gene on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the mutated gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a mutated 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 can reproduce, he will pass the mutated gene to all 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 children.

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Affected populations

The prevalence of X-linked Opitz G/BBB syndrome is estimated to be 1/50,000-1/100,000 males.

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Disorders with Similar Symptoms

Chromosome 22q11.2 deletion syndrome is now known to include the autosomal dominant form of Opitz G/BBB syndrome. In addition to the different inheritance pattern, this condition can be distinguished from X-linked Opitz G/BBB syndrome by chromosome analysis that often shows a submicroscopic deletion of chromosome 22. (For more information on this disorder, choose “chromosome 22q11.2 deletion” as your search term in the Rare Disease Database.)

Variants in the SPECC1L gene located on chromosome 22 have been reported in some patients with autosomal dominant Opitz syndrome, suggesting that this is a cause of this form of this disease (Kruszka P, et al. 2015). However, publications that reviewed the spectrum of characteristics associated with SPECC1L variants indicated that some clinical features specific to Opitz syndrome are not seen in patients with variants in the SPECC1L gene (Bho, EJ, et al. 2015; Zhang, T., et al 2020). Further, a study confirmed that patients with a diagnosis of Opitz syndrome are not likely to have SPECC1L pathogenic missense variants (Migliore C, et al. 2022).

FG syndrome type 1 (FGS1) is an X-linked genetic disorder that is characterized by poor muscle tone (hypotonia), intellectual disability, constipation and or anal anomalies and complete or partial absence of the part of the brain that connects the two hemispheres of the brain (corpus callosum). Other features of the disorder are small and simple ears, tall and prominent forehead, wide and flat thumbs and great toes and down slanting eyes. FGS1 is an X-linked genetic disorder caused by a variant in the MED12 gene. The spectrum of disorders caused by variants in this gene is still being defined. (For more information on this disorder, choose “FG” as your search term in the Rare Disease Database.)

Craniofrontonasal dysplasia is a very rare inherited disorder characterized by differences of the head and face (craniofacial area), hands and feet and certain skeletal bones. Major symptoms of this disorder may include widely spaced eyes (ocular hypertelorism), a groove (cleft) on the tip of the nose, an unusually wide mouth, malformations of the fingers and toes and/or underdevelopment of portions of the face (midface hypoplasia), such as the forehead, nose and chin. In addition, the head may have an unusual shape due to premature closure of the fibrous joints (sutures) between certain bones in the skull (coronal synostosis). Craniofrontonasal dysplasia follows X-linked inheritance in most families, but females are more severely affected than males. An autosomal dominant form of the disorder has also been discussed in the medical literature. (For more information on this disorder, choose “craniofrontonasal” as your search term in the Rare Disease Database.)

Mowat-Wilson syndrome (MWS) is a rare genetic disorder that may be apparent at birth or in the first year of life. MWS is characterized by intellectual disability, distinctive facial features and seizures. Other congenital anomalies occur in some individuals and can include a gastrointestinal disease known as Hirschsprung disease in which a narrowing of a portion of the colon is present, heart (cardiac) defects, kidney (renal) abnormalities, male genital abnormalities and short stature. Some affected individuals may not be recognized until childhood or adulthood, especially when Hirschsprung disease is not present. Mowat-Wilson syndrome is caused by a variant in the ZFHX1B gene that is usually not inherited. (For more information on this disorder, choose “Mowat-Wilson” as your search term in the Rare Disease Database.)

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Diagnosis

The diagnosis of Opitz G/BBB syndrome is usually suspected based on 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 confirmed by molecular genetic testing for variants in the MID1 gene and 15%-45% of affected males have been found to have a MID1 gene variant.

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Standard Therapies

Treatment
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.

Genetic counseling is recommended for affected individuals and their family members.

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Clinical Trials and Studies

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 web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

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

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS
Opitz JM. GBBB Syndrome (Opitz Syndrome). In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:198-99.

JOURNAL ARTICLES
Migliore C, Vendramin A, McKee S, et al. SPECC1L mutations are not common in sporadic cases of Opitz G/BBB syndrome. Genes (Basel). 2022;13(2):252. Published 2022 Jan 28. doi:10.3390/genes13020252

Zhang T, Wu Q, Zhu L, et al. A novel SPECC1L mutation causing Teebi hypertelorism syndrome: Expanding phenotypic and genetic spectrum. Eur J Med Genet. 2020;63(4):103851. doi:10.1016/j.ejmg.2020.103851

Bhoj EJ, Li D, Harr MH, et al. Expanding the SPECC1L mutation phenotypic spectrum to include Teebi hypertelorism syndrome. Am J Med Genet A. 2015;167A(11):2497-2502. doi:10.1002/ajmg.a.37217

Kruszka P, Li D, Harr MH, et al. Mutations in SPECC1L, encoding sperm antigen with calponin homology and coiled-coil domains 1-like, are found in some cases of autosomal dominant Opitz G/BBB syndrome.J Med Genet. 2015 Feb;52(2):104-10. doi: 10.1136/jmedgenet-2014-102677. Epub 2014 Nov 20. PMID:25412741

Fontanella B, Russolillo G, Meroni G. MID1 mutations in patients with X-linked Opitz G/BBB Syndrome. Human Mutation 2008 May; 29(5):584-94.

So J, Suckow V, Kijas Z, et al. Mild phenotypes in a series of patients with Opitz G/BBB syndrome with MID1 mutations. Am J Med Genet. 2005;132A:1-7.

DeFalco F, Cainarca S, Andolfi G, et al. X-linked Opitz syndrome: novel mutations in the MID1 gene and redefinition of the clinical spectrum. Am J Med Genet. 2003;120A:222-228.

Cox TC, Allen LR, Cox LL, et al. New mutations in MID1 provide support for loss of function as the cause of X-linked Opitz syndrome. Hum. Mol. Genet. 2000;17: 2553-2562.

Robin NH, Opitz JM, Muenke M. Opitz G/BBB syndrome:clinical comparisons of families linked to Xp22 and 22q, and a review of the literature. Am J Med Genet.1996;62:305-317.

Robin NH, Feldman GJ, Aronson AL, et al. Opitz syndrome is genetically heterogeneous with one locus on Xp22 and a second locus on 22q11.2. Nature Genet. 1995;11:459-61.

Verloes A, David A, Odent S, et al. Opitz GBBB syndrome: chromosomal evidence of an X-linked form. Am J Med Genet. 1995;59:123-28.

INTERNET
Meroni G. X-Linked Opitz G/BBB Syndrome. 2004 Dec 17 [Updated 2018 Apr 5]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1327/ Accessed July 25, 2023.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:30000; Last Update: 04/07/2022 https://omim.org/entry/300000 Accessed July 25, 2023.

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