Clinical Diagnosis

X-linked Opitz G/BBB syndrome (XLOS) is diagnosed on the basis of clinical findings. The multiple clinical signs show variable expressivity in affected individuals, even within the same family.

The manifestations of XLOS are classified into major and minor findings based on frequency of occurrence. The clinical diagnosis of XLOS is suspected in males with ocular hypertelorism and at least one other major finding. A family history consistent with X-linked inheritance further supports the diagnosis of XLOS [Robin et al 1996, De Falco et al 2003, Fontanella et al 2008].

Major (more frequent) findings

• Ocular hypertelorism and/or telecanthus (found in virtually all affected individuals)
• All degrees of hypospadias that, in the most severe form, can be associated with renal malformations (85%-90%)
• Laryngotracheoesophageal abnormalities, primarily laryngeal cleft, resulting in swallowing difficulties and respiratory dysfunction (60%-70%)

Minor findings (found in <50% of individuals)

• Intellectual disability and developmental delay
• Cleft lip and/or palate
• Congenital heart defects including ventricular septal defect (VSD) or atrial septal defect (ASD), persistent left superior vena cava, patent ductus arteriosus
• Imperforate or ectopic anus
• Midline defects of the brain including agenesis of the corpus callosum and cerebellar vermis agenesis or hypoplasia

Molecular Genetic Testing

Gene. MID1 is the only gene in which mutations are currently known to cause X-linked Opitz G/BBB syndrome (XLOS) [Quaderi et al 1997].

Possible evidence for locus heterogeneity. A percentage of individuals with clinically diagnosed XLOS do not have identifiable mutations in MID1. The low mutation detection rate may reflect either genetic heterogeneity (i.e., the presence of other, as-yet unidentified loci associated with XLOS on the X chromosome) or the presence of mutations in regions of MID1 (e.g., promoter, introns, 5’ and 3' UTR) not routinely evaluated.

Clinical testing

• Sequence analysis. Sequence analysis of the coding exons and intron-exon boundaries detects small deletions/insertions and missense, nonsense, and splicing mutations in approximately 25% of males with clinically diagnosed XLOS [Gaudenz et al 1998, Cox et al 2000, De Falco et al 2003, Winter et al 2003, Pinson et al 2004, So et al 2005, Fontanella et al 2008].
  
  Note: Since the X-linked Opitz G/BBB syndrome and autosomal dominant Opitz G/BBB syndrome (see Differential Diagnosis) are clinically indistinguishable, the cohorts tested for MID1 mutations often include simplex cases (i.e., single occurrences in a family that cannot be defined as either X-linked or autosomal). In this case the mutation detection rate is approximately 15%. The mutation detection rate increases (i.e., >50%) when only those individuals with documented X-linked inheritance are tested.
• Deletion/duplication analysis. MID1 exonic and multiexonic deletions and duplications (including three whole-gene deletions) have been reported [Winter et al 2003, Ferrentino et al 2007, Fontanella et al 2008].

Table 1. Summary of Molecular Genetic Testing Used in X-Linked Opitz G/BBB Syndrome

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Rate by Test Method 1	Test Availability
MID1	Sequence analysis	Sequence variants 2	15%-50% 3,4,5	Clinical
	Deletion/ duplication analysis 6	Deletion/ duplication of one or more exons or the whole gene	Unknown 7

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis.

4. Includes the mutation detection frequency using deletion/duplication analysis

5. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

7. Three whole-gene deletions have been reported [Winter et al 2003, Ferrentino et al 2007, Fontanella et al 2008].

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis of XLOS is suspected based on clinical features; however, the variable expressivity of the manifestations requires identification of an MID1 mutation for confirmation.

• Sequence analysis of MID1 is performed first
• If a pathogenic mutation is not identified, deletion/duplication analysis is considered.

Carrier testing for at-risk female relatives requires prior identification of the disease-causing mutation in the family.

Note: (1) Carriers are heterozygotes for this X-linked disorder and may demonstrate hypertelorism or more rarely other clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotype is known to be associated with mutations in MID1.

Natural History

Affected males. X-linked Opitz G/BBB syndrome (XLOS) is characterized by clinical abnormalities of primarily midline structures [Opitz et al 1969a, Opitz et al 1969b]. These defects include facial anomalies, laryngotracheoesophageal (LTE) defects, genitourinary abnormalities, and heart defects. Developmental delay and intellectual disability are common. Wide clinical variability has been described; individuals with a mutant MID1 allele may manifest only some of the typical clinical signs with different degrees of severity, even among members of the same family.

Facial appearance and head anomalies. The facial appearance of affected males is characterized by ocular hypertelorism, which can also be accompanied by telecanthus, a prominent forehead, widow's peak, broad nasal bridge, anteverted nares, low-set and malformed ears, microcephaly, large fontanelle, and/or prominent metopic suture. Unilateral or bilateral cleft lip and/or palate is present in approximately 50% of affected individuals. Other oral manifestations include high-arched palate, ankyloglossia, micrognathia, hypodontia, and neonatal teeth [Robin et al 1996, Shaw et al 2006, Fontanella et al 2008].

Urogenital abnormalities. Hypospadias of varying severity is present in approximately 90% of males with X-linked Opitz G/BBB syndrome and is often associated with other genital anomalies such as cryptorchidism and hypoplastic/bifid scrotum. Severe hypospadias can be associated with urinary tract dysfunction, e.g. vesicoureteric reflux and hydronephrosis [Robin et al 1996, Pinson et al 2004, Fontanella et al 2008, Zhang et al 2011].

Laryngotracheoesophageal (LTE) defects. LTE abnormalities may result in coughing and choking with feeding, recurrent pneumonia, and life-threatening aspiration. In their most severe form, LTE defects are manifest as laryngeal and tracheoesophageal clefts and in more mild form as tracheoesophageal fistulae or LTE dysmotility. The incidence of respiratory and/or gastroesophageal symptoms is probably underestimated, because mildly affected individuals may only manifest functional swallowing difficulties that improve with age and eventually disappear during infancy [Robin et al 1996, De Falco et al 2003, Pinson et al 2004].

Neurologic findings. More than one third of individuals with XLOS show developmental delay and intellectual disability; they frequently manifest delay in onset of walking, short attention span, learning difficulties, and speech problems. In some cases, these delays are secondary to surgical interventions. Midline brain anatomic defects including agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis and Dandy-Walker malformations were identified in 40% of individuals with an MID1 mutation who underwent MRI examination [Gaudenz et al 1998, Cox et al 2000, De Falco et al 2003, Winter et al 2003, Pinson et al 2004, So et al 2005, Fontanella et al 2008].

Other malformations present in approximately one fifth of individuals with XLOS are congenital heart anomalies (ventricular septal defects, atrial septal defects, coarctation of the aorta, persistent left superior vena cava, patent ductus arteriosus, patent foramen ovale) and anal abnormalities (imperforate or ectopic anus) [Robin et al 1996, De Falco et al 2003, Pinson et al 2004, Fontanella et al 2008].

Carrier females. Female carriers usually show only ocular hypertelorism and rarely other manifestations [Robin et al 1996, De Falco et al 2003, So et al 2005].

Genotype-Phenotype Correlations

In general no genotype-phenotype correlations have been observed. Missense, nonsense, splice site, and frameshift mutations, insertions, and deletions all result in highly variable phenotypes even within the same family [Gaudenz et al 1998, Cox et al 2000, De Falco et al 2003, Winter et al 2003, Pinson et al 2004].

Two possible exceptions are:

• An association between truncating mutations and the presence of anatomic brain abnormalities, in particular cerebellar defects [Fontanella et al 2008];
• Possible correlation of a mild phenotype with mutations in the fibronectin type III domain of the protein [Mnayer et al 2006].

Penetrance

Usually the presence of an MID1 mutation is associated with clinical findings of XLOS; however, recently an instance of reduced penetrance has been reported [Ruiter et al 2010].

Nomenclature

Opitz G/BBB syndrome was first reported as two separate entities, BBB syndrome [Opitz et al 1969b] and G syndrome [Opitz et al 1969a]. Subsequently, it has become apparent that the two syndromes identified in 1969 are in fact a single entity, now named Opitz G/BBB syndrome.

Other names, no longer used, include hypospadias-dysphagia syndrome, Opitz-Frias syndrome, telecanthus with associated abnormalities, and hypertelorism-hypospadias syndrome.

Of note, X-linked Opitz G/BBB syndrome (XLOS; OSX; type I) is distinct from autosomal dominant Opitz G/BBB syndrome (ADOS; type II).

Prevalence

The prevalence of X-linked Opitz G/BBB syndrome ranges from one in 50,000 to one in 100,000 males.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with X-linked Opitz G/BBB syndrome, the following evaluations by a multidisciplinary team (including craniofacial surgeon, ophthalmologist, pediatrician, pediatric urologist, cardiologist, pulmonologist, speech pathologist, and medical geneticist) are recommended:

• Past medical history and physical examination with attention to head and facial measurements, palate, heart, genitourinary system, and lower respiratory system
• Complete eye evaluation including assessment of visual acuity, refractive error, and ocular alignment for possible strabismus
• Assessment of hypospadias by a urologist, including ultrasound examination to evaluate for renal/urinary tract abnormalities in males with severe hypospadias
• Laryngoscopy and chest x-ray in individuals who have choking with feeding, recurrent pneumonia, and/or aspiration
• Assessment of cleft lip/palate (CLP) by a craniofacial surgeon
• Age-appropriate assessment of development and intellectual abilities
• Assessment of anal position and patency
• Echocardiogram
• Cranial imaging

Treatment of Manifestations

Management of anomalies by a multidisciplinary team (including craniofacial surgeon, ophthalmologist, pediatrician, pediatric urologist, cardiologist, pulmonologist, speech pathologist, and medical geneticist) to help assure coordination of care is indicated.

• Treatment as needed by an ophthalmologist
• Surgical intervention as needed for hypospadias
• Surgical treatment of medically significant laryngotracheoesophageal (LTE) abnormalities; often tracheostomy is necessary initially to assure an adequate airway.
• Surgical management for cleft lip/palate and other craniofacial anomalies; therapy for speech problems secondary to the cleft lip and palate
• Neuropsychological support; many males with X-linked Opitz G/BBB syndrome require special educational programs.
• Surgical intervention for imperforate anus
• Surgical repair as needed for heart defects

Prevention of Primary Manifestations

All primary manifestations are present at birth. To date no factors that can influence their expression have been identified.

Prevention of Secondary Complications

Antireflux pharmacologic therapy minimizes the risk for aspiration until laryngeal competence is assured.

Surveillance

Regular follow-up depending on the type of malformations present:

• Craniofacial team follow-up for those with cleft lip/palate, including regular monitoring of hearing
• Urology follow-up for those with significant hypospadias and/or renal defects
• Cardiac follow-up for those with cardiac defects
• Gastroenterology, pulmonary, and/or surgical follow-up for those with LTE defects
• Gastroenterology and/or surgical follow-up for those with anal defects

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

X-linked Opitz G/BBB syndrome (XLOS) is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

• The father of an affected male will not have the disorder nor will he be a carrier of the mutation.
• In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
• If pedigree analysis reveals that the proband is the only affected family member, the mother may be a carrier or the affected male may have a de novo gene mutation. De novo mutations have been detected in several affected males [Pinson et al 2004, Ferrentino et al 2007, Fontanella et al 2008].

Sibs of a proband

• The risk to sibs depends on the carrier status of the mother.
• If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will usually only manifest hypertelorism.
• If the disease-causing mutation cannot be detected in DNA extracted from the leukocytes of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Mildly affected males will pass the disease-causing mutation to all of their daughters and none of their sons.

Other family members of a proband. The proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the mutation has been identified in the proband.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

If the MID1 mutation has been identified in a family member, prenatal testing is possible for pregnancies at increased risk. The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation or by amniocentesis usually performed at about 15 to 18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Knowing before delivery that a child has XLOS may help families to prepare emotionally and physicians to prepare for the medical needs of a child with birth defects.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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Author Notes

Basic research on the molecular basis of X-linked Opitz syndrome, functional study of MID1 and proteins belonging to the TRIM/RBCC family.

Revision History

• 28 July 2011 (me) Comprehensive update posted live
• 20 June 2007 (cd) Revision: deletion/duplication analysis available clinically
• 18 January 2007 (me) Comprehensive update posted to live Web site
• 17 December 2004 (me) Review posted to live Web site
• 30 June 2004 (gm) Original submission