X-Linked Opitz G/bbb Syndrome
Summary
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.
Diagnosis
X-linked Opitz G/BBB syndrome (X-OS) is diagnosed most often on the basis of clinical findings. There is variable expressivity among affected individuals, even within the same family. The manifestations of X-OS are classified into major and minor findings based on frequency of occurrence. Formal diagnostic criteria for X-OS have not been established.
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).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of X-OS, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of MID1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
- A multigene panel that includes MID1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of X-OS is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in X-Linked Opitz G/BBB Syndrome
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| MID1 | Sequence analysis 3, 4 | ~25% 5 |
| Gene-targeted deletion/duplication analysis 6 | 10 individuals 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
- 5.
The detection of an MID1 pathogenic variant in an individual without a family history of X-OS is approximately 15%. The pathogenic variant detection rate in individuals with documented X-linked inheritance is >50%. [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].
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
Three whole-gene deletions have been reported [Winter et al 2003, Ferrentino et al 2007, Fontanella et al 2008]. In addition, single-exon deletions and duplications have been reported [Winter et al 2003, Hüning et al 2013, Migliore et al 2013].
Clinical Characteristics
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.
Table 2.
Incidence of Clinical Features in Males with X-OS with an Identified MID1 Pathogenic Variant
| Clinical Feature | # of Males with Clinical Feature / Total # of Males |
|---|---|
| Hypertelorism | 82/82 |
| Hypospadias | 65/85 |
| Laryngotracheoesophageal defects | 46/85 |
| Intellectual disability and/or developmental delay | 28/85 |
| Cleft lip//palate | 42/85 |
| Congenital heart defects | 20/85 |
| Anal defects | 18/85 |
| Brain abnormalities | 18/35 1 |
Fontanella et al [2008], Li et al [2015]
- 1.
Includes males with X-OS who have undergone MRI examination
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.
Differential Diagnosis
Table 3.
Disorders to Consider in the Differential Diagnosis of X-OS
| Differential Disorder | Gene(s) / Genetic Mechanism | MOI | Clinical Features of the Differential Disorder | |
|---|---|---|---|---|
| Overlapping w/X-OS | Distinguishing from X-OS | |||
| AD Opitz G/BBB syndrome (ADOS; Opitz G/BBB syndrome, type II) | SPECC1L 22q11.2 deletion 1 | AD |
|
|
| FG syndrome 2 | MED12 FLNA CASK | XL |
|
|
| Craniofrontonasal dysplasia (OMIM 304110) | EFNB1 | XL |
|
|
| Mowat-Wilson syndrome | ZEB2 | AD |
|
|
AD = autosomal dominant; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
- 1.
AD Opitz G/BBB syndrome can be caused either by a heterozygous pathogenic variant in SPECC1L [OMIM 145410] or by deletion on the chromosome region 22q11.2.
- 2.
FG syndrome is genetically heterogeneous and includes several X-linked forms: FGS1, caused by pathogenic variants in MED12 (see MED12-Related Disorders); FGS2 (OMIM 300321), associated with pathogenic variants in FLNA (locus Xq28); FGS3 (linked to Xp22.3) (OMIM 300406); FGS4 (OMIM 300422), caused by pathogenic variants in CASK (locus Xp11.4); FGS5 (linked to Xq22.3) (OMIM 300581).
Management
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.