Clinical characteristics.

X-linked Opitz G/BBB syndrome (X-OS) is a multiple-congenital-anomaly disorder characterized by facial anomalies (hypertelorism, prominent forehead, widow's peak, broad nasal bridge, anteverted nares), genitourinary abnormalities (hypospadias, cryptorchidism, and hypoplastic/bifid scrotum), and laryngotracheoesophageal defects. Developmental delay and intellectual disability are observed in about 50% of affected males. Cleft lip and/or palate are present in approximately 50% of affected individuals. Other malformations (present in <50% of individuals) include congenital heart defects, imperforate or ectopic anus, and midline brain defects (Dandy-Walker malformation and agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis). Wide clinical variability occurs even among members of the same family. Female heterozygotes usually manifest hypertelorism only.

Diagnosis/testing.

The diagnosis of X-OS is established in a male proband most often by clinical findings. Identification of a hemizygous pathogenic variant in MID1 in a male proband by molecular genetic testing establishes the diagnosis if clinical features are inconclusive. The diagnosis of X-OS can be established in a female with suggestive clinical features by identification of a heterozygous pathogenic variant in MID1 on molecular genetic testing.

Management.

Treatment of manifestations: Management of anomalies by a multidisciplinary team; surgical treatment of medically significant laryngotracheoesophageal malformations; tracheostomy as needed; standard surgical management of hypospadias, cleft lip/palate, imperforate anus, heart defects; speech therapy; neuropsychological and educational support.

Prevention of secondary complications: Antireflux measurements to minimize risk of aspiration.

Surveillance: Based on the type of malformations present; regular monitoring of hearing for those with cleft lip/palate.

Genetic counseling.

X-OS is inherited in an X-linked manner. In a family with more than one affected individual, the mother of an affected male is an obligate carrier. If the mother of an affected male is a carrier, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Sons who inherit the pathogenic variant will be affected; daughters who inherit the pathogenic variant will be carriers and will usually manifest hypertelorism. Mildly affected males who have children will pass the pathogenic variant to all of their daughters and none of their sons. Prenatal and preimplantation genetic testing is possible for pregnancies at risk if the pathogenic variant in the family has been identified.

Suggestive Findings

The clinical diagnosis of X-OS should be suspected in a male with the following major and/or minor findings.

Major (more frequent) findings

• Hypertelorism and/or telecanthus (present 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%)
• A family history consistent with X-linked inheritance – although variable expressivity among affected individuals, even within the same family, should be taken into consideration

Minor findings (found in ≤50% of individuals)

• Intellectual disability and developmental delay
• Cleft lip and/or palate
• Congenital heart defects (e.g., ventricular septal defect, atrial septal defect, 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

Establishing the Diagnosis

Male proband. The diagnosis of X-linked Opitz G/BBB syndrome (X-OS) is established in a male proband with the above clinical findings. Identification of a hemizygous pathogenic variant in MID1 by molecular genetic testing can confirm the diagnosis if clinical features are inconclusive (see Table 1).

Female proband. The diagnosis of X-OS is established in a female proband with suggestive clinical features and identification of a heterozygous pathogenic variant in MID1 by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of X-OS is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of X-OS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Affected males. X-linked Opitz G/BBB syndrome (X-OS) is characterized by clinical abnormalities of primarily midline structures. These defects include facial anomalies, genitourinary abnormalities, laryngotracheoesophageal defects, and congenital heart defects. Developmental delay and intellectual disability are common. Wide clinical variability has been described; individuals with an MID1 pathogenic variant may manifest only some of the clinical features 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 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., vesicoureteral reflux, hydronephrosis) [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 [Pinson et al 2004].

Neurologic findings. More than one third of individuals with X-OS 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 50% of individuals with an MID1 pathogenic variant who underwent MRI examination [Fontanella et al 2008].

Congenital heart disease. Approximately 20% of individuals with X-OS present with congenital heart anomalies (e.g., ventricular septal defect, atrial septal defect, coarctation of the aorta, persistent left superior vena cava, patent ductus arteriosus, patent foramen ovale) [Robin et al 1996, Fontanella et al 2008].

Anal abnormalities are present in approximately 20% of individuals with X-OS (e.g., imperforate anus, ectopic anus) [Robin et al 1996, De Falco et al 2003, Pinson et al 2004, Fontanella et al 2008].

Ophthalmologic features. Refractive error and strabismus have been reported.

Heterozygous females usually have hypertelorism only, and rarely other manifestations (e.g., characteristic facial features [anteverted nares, short nose, short uvula, high arched palate, micrognathia], tracheoesophageal cleft or esophageal stenosis, anal malformations) [So et al 2005].

Genotype-Phenotype Correlations

In general, no genotype-phenotype correlations have been observed. Pathogenic missense, nonsense, splice site, and frameshift variants, insertions, and deletions all result in highly variable phenotypes even within the same family [Pinson et al 2004].

Two possible exceptions are:

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

Penetrance

Usually the presence of an MID1 pathogenic variant is associated with clinical findings of X-OS; 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 (X-OS; 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 1:50,000 to 1:100,000 males.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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 clinical geneticist) are recommended if they have not already been performed:

• Past medical history and physical examination with attention to palate, heart, genitourinary system, and lower respiratory system
• 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
• Developmental evaluation
• Referral of individuals with cleft lip/palate to a craniofacial surgeon
• Echocardiogram
• Assessment of anal position and patency
• Complete ophthalmology evaluation including assessment of visual acuity, refractive error, and ocular alignment for possible strabismus

Treatment of Manifestations

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

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

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:

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

Evaluation 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 in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

X-linked Opitz G/BBB syndrome (X-OS) 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 hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• 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 pathogenic variant. De novo pathogenic variants 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 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; female sibs who inherit the pathogenic variant will be carriers and will usually manifest hypertelorism only.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in DNA extracted from the leukocytes of the mother, the risk to sibs is low but slightly greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Mildly affected males transmit the pathogenic variant to:

• All of their daughters, who will be heterozygotes (carriers) and will usually manifest hypertelorism only;
• None of their sons.

Other family members. The proband's maternal aunts may be at risk of being heterozygotes (carriers) for the pathogenic variant, and the aunt's offspring, depending on their sex, may be at risk of being heterozygotes (carriers) or of being affected.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Heterozygote (Carrier) Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband.

Note: (1) Females who are heterozygous (carriers) for this X-linked disorder will usually manifest hypertelorism only. (2) Identification of female heterozygotes requires either (a) prior identification of the pathogenic variant in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis.

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/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the MID1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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Author Notes

Focus. 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

• 5 April 2018 (sw) Comprehensive update posted live
• 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 live
• 17 December 2004 (me) Review posted live
• 30 June 2004 (gm) Original submission