OPITZ-G SYNDROME, TYPE I
OPITZ GBBB SYNDROME, TYPE I
OPITZ BBBG SYNDROME, TYPE I
OPITZ SYNDROME
TELECANTHUS-HYPOSPADIAS SYNDROME
HYPERTELORISM WITH ESOPHAGEAL ABNORMALITY AND HYPOSPADIAS
HYPERTELORISM-HYPOSPADIAS SYNDROME
OPITZ SYNDROME, X-LINKED
GGGB1
OGS1
OS
OSX
XLOS
BBBG1
X-linked Opitz BBB/G syndrome
X-linked Opitz syndrome
The Opitz GBBB syndrome is a congenital midline malformation syndrome characterized by hypertelorism, hypospadias, cleft lip/palate, laryngotracheoesophageal abnormalities, imperforate anus, developmental delay, and cardiac defects (So et al., 2005).
This disorder was first reported as 2 ... The Opitz GBBB syndrome is a congenital midline malformation syndrome characterized by hypertelorism, hypospadias, cleft lip/palate, laryngotracheoesophageal abnormalities, imperforate anus, developmental delay, and cardiac defects (So et al., 2005). This disorder was first reported as 2 separate entities, BBB syndrome and G syndrome; subsequent reports of families in which the BBB and G syndromes segregated within a single kindred suggested that they represent a single entity. Opitz GBBB syndrome is genetically heterogeneous, with both X-linked and autosomal dominant (145410) forms.
Hogdall et al. (1989) made the diagnosis of the BBB syndrome at 19 weeks' gestation by ultrasonographic demonstration of hypertelorism and hypospadias. The pedigree showed affected individuals in 3 generations in a pattern ... - Prenatal Diagnosis Hogdall et al. (1989) made the diagnosis of the BBB syndrome at 19 weeks' gestation by ultrasonographic demonstration of hypertelorism and hypospadias. The pedigree showed affected individuals in 3 generations in a pattern consistent with X-linked inheritance with minor expression in the heterozygous females.
Robin et al. (1996) compared the phenotypic features of the X-linked and autosomal (145410) forms of the Opitz syndrome. They found that anteverted nares and posterior pharyngeal cleft were seen only in the X-linked form. However, all other ... Robin et al. (1996) compared the phenotypic features of the X-linked and autosomal (145410) forms of the Opitz syndrome. They found that anteverted nares and posterior pharyngeal cleft were seen only in the X-linked form. However, all other manifestations of the syndrome, such as hypertelorism, swallowing difficulties, hypospadias, and developmental delay, were seen in both forms. For a discussion of clinical features in early reports of this syndrome, see 145410. Monozygotic twinning, which is unusually frequent in these families, may be a manifestation of the defect; unusually severe cases with early lethality occur as twins (Opitz, 1996). De Silva et al. (1998) reported a family with X-linked Opitz syndrome in which the diagnosis was established initially in the 64-year-old grandmother after she developed recurrent aspiration pneumonia due to esophageal reflux and pharyngeal dysmotility. Jacobson et al. (1998) reviewed the spectrum of congenital heart disease and genitourinary anomalies seen in Opitz syndrome. They reported an infant with this disorder and a combination of complex congenital heart disease (double outlet right ventricle with pulmonary atresia, malalignment ventriculoseptal defect, right-sided aortic arch with left ductus arteriosus) and bladder exstrophy. Neither of these defects had previously been reported in association with Opitz syndrome. Since both were midline defects, they further characterized Opitz syndrome as an impairment in midline development. Brooks et al. (1998) described pituitary macroadenoma and cranial osteoma in a 43-year-old woman, a mother of a boy with typical Opitz syndrome and herself a manifesting heterozygote. She had telecanthus, anteverted nares, and a history of frequent respiratory and urinary tract infections. Her son had hypertelorism, bilaterally cleft lip and palate, hypospadias, and dysphagia with multiple episodes of aspiration pneumonia. Linkage analysis had demonstrated X-linked inheritance in this family (Robin et al., 1995). Brooks et al. (1998) concluded that cranial osteomas are not associated with growth hormone hypersecretion and that therefore cranial osteomas and perhaps pituitary tumors should be included in the nosography of the Opitz GBBB syndrome. Reviewing all MID1-mutated Opitz syndrome patients thus far reported, De Falco et al. (2003) confirmed that hypertelorism and hypospadias were the most frequent manifestations, being present in almost all individuals. Laryngotracheoesophageal defects were also common anomalies, being manifested by all MID1-mutated male patients. Congenital heart and anal abnormalities were less frequent than reported in the literature. De Falco et al. (2003) included limb defects in the clinical synopsis of Opitz syndrome, because they found MID1-mutated patients showing syndactyly. Pinson et al. (2004) found vermis hypoplasia or agenesis in 4 of 9 patients with MID1 mutations, including 1 patient with no developmental delay, and suggested that this is an important clinical feature that should be routinely sought even in patients without mental retardation. Funke et al. (2006) presented a case of Opitz syndrome complicated by congenital chylothorax (603523), a collection of lymph in the pleural space. The mother had marked hypertelorism. The boy also had bilateral cleft lip and palate, hypertelorism, hypospadias, right cryptorchidism, left hydrocele, widow's peak, prominent forehead, low-set and posteriorly angulated ears, and flat, broad nasal bridge. No mutation was detected in MID1. The patient was treated with octreotide, a somatostatin analog, which had proven to be effective for treatment of congenital cases of chylothorax (Goto et al., 2003; Young et al., 2004), intractable post-operative chylothorax (Clarke et al., 2005) and even intestinal lymphangiectasia in Noonan syndrome (163950) (Strehl et al., 2003).
Among 70 patients with clinically diagnosed Opitz syndrome, So et al. (2005) compared the phenotypes of patients with and without a MID1 mutation to determine if there were distinct clinical patterns in these groups. They identified 10 novel ... Among 70 patients with clinically diagnosed Opitz syndrome, So et al. (2005) compared the phenotypes of patients with and without a MID1 mutation to determine if there were distinct clinical patterns in these groups. They identified 10 novel mutations, of which 5 were detected in familial cases, 2 in sporadic cases, and 3 in families in which it was not clear whether the disorder was familial or sporadic. X-linked Opitz syndrome patients with MID1 mutations were less severely affected than patients with MID1 mutations reported in previous studies, particularly in terms of functionally significant neurologic, laryngotracheoesophageal (LTE), anal, and cardiac abnormalities. Minor anomalies were more common in patients with MID1 mutations compared to those without mutations. Female MID1 mutation carriers had milder phenotypes compared to male MID1 mutation carriers, with the most common manifestation being hypertelorism in both sexes. The authors found that most of the anomalies they observed did not correlate with MID1 mutation type, with the possible exception of LTE malformations. So et al. (2005) demonstrated the wide spectrum of severity and manifestations of Opitz syndrome, and they emphasized that X-linked Opitz syndrome patients with MID1 mutations may be less severely affected than previously reported.
Quaderi et al. (1997) identified mutations in the MID1 gene in 3 Opitz syndrome families: a 3-bp deletion involving a methionine codon (300552.0001), a 24-bp duplication causing addition of 8 amino acids (300552.0002), and a 1-bp insertion resulting ... Quaderi et al. (1997) identified mutations in the MID1 gene in 3 Opitz syndrome families: a 3-bp deletion involving a methionine codon (300552.0001), a 24-bp duplication causing addition of 8 amino acids (300552.0002), and a 1-bp insertion resulting in a frameshift and loss of 101 amino acid residues (300552.0003). All these mutations were in the C-terminal region of the MID1 gene. Among 15 patients with Opitz syndrome, Cox et al. (2000) identified 7 novel mutations in the MID1 gene, 2 of which disrupt the N terminus of the protein. The most severe of these, glu115 to ter (E115X; 300552.0005), is predicted to truncate the protein before the B-box motifs. Another mutation, leu626 to pro (L626P; 300552.0004), represented the most C-terminal alteration reported to date. Green fluorescent protein (GFP) fusion constructs of 2 N-terminal mutants showed no evidence of cytoplasmic aggregation, suggesting that this feature is not pathognomonic for X-linked Opitz syndrome. Pinson et al. (2004) identified 1 previously reported and 5 novel mutations in the MID1 gene in 14 patients with Opitz syndrome. Among 63 male individuals referred to De Falco et al. (2003) as instances of sporadic or familial X-linked Opitz syndrome, they found novel mutations of the MID1 gene in 11. The mutations were scattered throughout the gene, although more were represented in the 3-prime region. The low frequency of mutations in MID1 and the high variability of the phenotype suggested the involvement of other genes in the causation of OS.
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. ...
DiagnosisClinical DiagnosisX-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) findingsOcular 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 TestingGene. 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 SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Rate by Test Method 1Test AvailabilityMID1Sequence analysisSequence variants 215%-50% 3,4,5ClinicalDeletion/ duplication analysis 6Deletion/ duplication of one or more exons or the whole gene Unknown 71. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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 analysis5. 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.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.Genetically Related (Allelic) DisordersNo other phenotype is known to be associated with mutations in MID1.
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. ...
Natural HistoryAffected 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. Table 2. Incidence of Main Clinical Features Seen in Males with XLOS with MID1 MutationsView in own windowFindingNumber of Males with Finding / Total Number of MalesHypertelorism68 / 69CL/P38 / 73LTE defects46 / 73Heart defects16 / 73Anal defects16 / 73Hypospadias63 / 73ID 1/developmental delay 25 / 73Brain abnormalities10 / 25 2Fontanella et al [2008]1. Intellectual disability2. Males with XLOS undergoing MRI examinationFacial 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].
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]. ...
Genotype-Phenotype CorrelationsIn 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].
X-linked Opitz G/BBB syndrome (XLOS; Opitz G/BBB syndrome, type I) and autosomal dominant Opitz G/BBB syndrome (ADOS; Opitz G/BBB syndrome, type II) (OMIM 145410) share the same clinical picture. ADOS maps to 22q11.2; the gene(s) implicated have not been identified [Robin et al 1995]. Robin et al [1996] compared the phenotypic features of the X-linked and autosomal forms of the Opitz syndrome. They found that anteverted nares and posterior pharyngeal cleft were seen only in the X-linked form, but this distinction was questioned by Cox et al [2000]. All other manifestations of the syndrome, such as hypertelorism, swallowing difficulties, hypospadias, and developmental delay can be seen in both forms. XLOS and ADOS can be distinguished by the mode of inheritance and by the fact that female carriers of XLOS are asymptomatic or show only ocular hypertelorism, whereas females with ADOS manifest a more complex phenotype [Robin et al 1995, Robin et al 1996]. ...
Differential DiagnosisX-linked Opitz G/BBB syndrome (XLOS; Opitz G/BBB syndrome, type I) and autosomal dominant Opitz G/BBB syndrome (ADOS; Opitz G/BBB syndrome, type II) (OMIM 145410) share the same clinical picture. ADOS maps to 22q11.2; the gene(s) implicated have not been identified [Robin et al 1995]. Robin et al [1996] compared the phenotypic features of the X-linked and autosomal forms of the Opitz syndrome. They found that anteverted nares and posterior pharyngeal cleft were seen only in the X-linked form, but this distinction was questioned by Cox et al [2000]. All other manifestations of the syndrome, such as hypertelorism, swallowing difficulties, hypospadias, and developmental delay can be seen in both forms. XLOS and ADOS can be distinguished by the mode of inheritance and by the fact that female carriers of XLOS are asymptomatic or show only ocular hypertelorism, whereas females with ADOS manifest a more complex phenotype [Robin et al 1995, Robin et al 1996]. Frequently, FG syndrome has been misdiagnosed as Opitz syndrome. FG syndrome is also characterized by facial dysmorphism, congenital heart defects, hypospadias, gastroesophageal reflux, and developmental delay/intellectual disability; however, features that distinguish the two conditions include the following findings not observed in Opitz G/BBB syndrome: Congenital hypotonia with joint hyperlaxity that evolves into spasticityChronic constipationCharacteristic personalityFG syndrome is genetically heterogeneous and includes several X-linked forms:FGS1 [Briault et al 1997, Graham et al 1998] caused by mutations in MED12 (locus [Risheg et al 2007]. See MED12-Related Disorders. FGS2 (OMIM 300321) [Briault et al 1999, Briault et al 2000] associated with mutations in FLNA (locus Xq28) [Unger et al 2007] FGS3 (linked to Xp22.3) (OMIM 300406) [Dessay et al 2002] FGS4 (OMIM 300422) [Piluso et al 2003] caused by mutations in CASK (locus Xp11.4) [Piluso et al 2009]FGS5 (linked to Xq22.3) (OMIM 300581) [Jehee et al 2005] Other malformation syndromes that share overlapping features with X-linked Opitz G/BBB syndrome:Craniofrontonasal dysplasia (OMIM 304110). In addition to some midline defects in common with Opitz G/BBB syndrome, craniofrontonasal dysplasia has skeletal, skin, nail, and hair defects. A significant proportion of individuals with craniofrontonasal dysplasia have a mutation in EFNB1. Mowat-Wilson syndrome. Mowat-Wilson syndrome has ocular and gastrointestinal abnormalities that are not usually observed in X-linked Opitz G/BBB syndrome. It is characterized by intellectual disability, microcephaly, distinct facial features, and often Hirschshprung disease. It is caused by mutation in ZEB2. See also Hirschshprung Disease OverviewNote to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
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:...
ManagementEvaluations Following Initial DiagnosisTo 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 strabismusAssessment 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 surgeonAge-appropriate assessment of development and intellectual abilitiesAssessment of anal position and patency Echocardiogram Cranial imaging Treatment of ManifestationsManagement 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 ManifestationsAll primary manifestations are present at birth. To date no factors that can influence their expression have been identified. Prevention of Secondary ComplicationsAntireflux pharmacologic therapy minimizes the risk for aspiration until laryngeal competence is assured. SurveillanceRegular 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 Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. X-Linked Opitz G/BBB Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDMID1Xp22.2Midline-1MID1 @ LOVDMID1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for X-Linked Opitz G/BBB Syndrome (View All in OMIM) View in own window 300000OPITZ GBBB SYNDROME, X-LINKED 300552MIDLINE 1; MID1Normal allelic variants. MID1 is composed of nine coding exons and variable and alternative 5' untranslated regions [Quaderi et al 1997, Gaudenz et al 1998, Perry et al 1998, Van den Veyver et al 1998, Cox et al 2000, Landry & Mager 2002]. Polymorphic variants are not common. Pathologic allelic variants. To date, mutations in MID1 have been found in approximately 80 individuals with X-linked Opitz G/BBB syndrome (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, Mnayer et al 2006; Ferrentino et al 2007; Fontanella et al 2008]. No mutations are recurrent with the exception of p.Arg495X, which was identified in five unrelated individuals and p.Arg277X, identified in three unrelated individuals. The other mutations are missense and nonsense mutations, small deletions, or insertions located along the entire length of the gene, the majority in the most 3' portion of the gene. A duplication of the first coding exon leading to a premature stop codon has been detected in one individual with XLOS [Winter et al 2003]. Three whole-gene deletions have been reported [Winter et al 2003, Ferrentino et al 2007, Fontanella et al 2008]. Normal gene product. The normal gene product is the midline-1 protein that is anchored to the microtubules [Cainarca et al 1999, Schweiger et al 1999, Cox et al 2000], acting as an E3 ubiquitin ligase that regulates the degradation of phosphatase 2A [Liu et al 2001, Trockenbacher et al 2001, Short et al 2002]. The role of this protein function within the cell and during development is yet to be clarified. Abnormal gene product. The missense and truncated forms lower their affinity for the microtubular apparatus. The pathogenic mechanism is likely to be caused by the loss of midline-1 protein function on the microtubules.