Clinical characteristics.

MID1-related Opitz G/BBB syndrome (MID1-OS) is 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 30% of affected males. Cleft lip and/or palate are present in approximately half of affected males. Other malformations (present in <50% of affected males) 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 MID1-OS is established in a male proband with suggestive findings and a hemizygous pathogenic variant in MID1 identified by molecular genetic testing. Females with a heterozygous MID1 pathogenic variant usually have isolated hypertelorism and only rarely present with other manifestations of MID1-OS.

Management.

Treatment of manifestations: Management of anomalies by a multidisciplinary team; surgical treatment of cleft lip/palate and other craniofacial anomalies; standard treatments for hearing loss including PE tubes; speech therapy; standard dental treatments as needed for hypodontia; standard surgical management of hypospadias; surgical treatment for medically significant laryngotracheoesophageal abnormalities; anti-reflux therapy as needed; neuropsychological and educational support; surgical repair of congenital heart defects and imperforate anus; surgical treatment and/or refractive lenses as needed per ophthalmologist.

Surveillance: Follow up with craniofacial team for cleft lip/palate care; audiology evaluation annually or as needed; follow up with urologist as needed for those with significant hypospadias and/or other urinary tract defects; gastroenterology, pulmonology, and/or surgical team follow up for those with laryngotracheoesophageal defects; monitor developmental and educational needs at each visit; cardiology follow up per cardiologist; gastroenterology follow up as recommended for anal defects; ophthalmology evaluations as recommend by ophthalmologist; assess psychosocial and care coordination needs at each visit.

Genetic counseling.

MID1-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 heterozygote. If the mother of the proband has an MID1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and will usually manifest hypertelorism only. Once the MID1 pathogenic variant has been identified in an affected family member, heterozygote testing for at-risk female relatives and prenatal and preimplantation genetic testing are possible.

Suggestive Findings

MID1-related Opitz G/BBB syndrome (MID1-OS) should be suspected in a male with the following clinical and imaging findings and family history.

Clinical findings

• Hypertelorism and/or telecanthus (present in virtually all affected individuals)
• Hypospadias
• Laryngotracheoesophageal abnormalities, primarily laryngeal cleft, resulting in swallowing difficulties and respiratory dysfunction
• Cleft lip and/or palate
• Intellectual disability and developmental delay
• Congenital heart defects (e.g., ventricular septal defect, atrial septal defect, persistent left superior vena cava, patent ductus arteriosus)
• Imperforate or ectopic anus

Imaging findings

• Urinary tract abnormalities including vesicoureteral reflux and hydronephrosis
• Midline defects of the brain including agenesis of the corpus callosum and cerebellar vermis agenesis or hypoplasia

Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

Male proband. The diagnosis of MID1-OS is established in a male proband with suggestive findings and a hemizygous pathogenic (or likely pathogenic) variant in MID1 identified by molecular genetic testing (see Table 1).

Female proband. Females with a heterozygous MID1 pathogenic (or likely pathogenic) variant usually have isolated hypertelorism and only rarely present with other manifestations of MID1-OS.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) Identification of a hemizygous or heterozygous MID1 variant of uncertain significance does not establish or rule out the diagnosis.

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). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

MID1-related Opitz G/BBB syndrome (MID1-OS) is characterized by facial anomalies, genitourinary abnormalities, laryngotracheoesophageal defects, and congenital heart defects. Developmental delay and intellectual disability are common. Clinical manifestations are most evident in affected males, although wide clinical variability has been described, even among members of the same family. To date, 90 individuals have been identified with a pathogenic variant in MID1 and are reported together with their clinical synopsis [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, Hu et al 2012, Hüning et al 2013, Migliore et al 2013, Ji et al 2014, Li et al 2015, Maia et al 2017, Perea-Cabrera et al 2023].

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 [Maia et al 2017].

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 MID1-OS.

Nomenclature

The title of this GeneReview, MID1-related Opitz G/BBB syndrome, is based on the dyadic naming approach proposed by Biesecker et al [2021], in which mendelian disorders are designated by combining the mutated gene and resulting phenotype.

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 became 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, MID1-OS is distinct from autosomal dominant Opitz G/BBB syndrome.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MID1-related Opitz G/BBB syndrome (MID1-OS), the evaluations summarized in Table 4 by a multidisciplinary team (including craniofacial surgeon, ophthalmologist, pediatrician, pediatric urologist, cardiologist, pulmonologist, speech-language pathologist, and clinical geneticist) are recommended if they have not already been performed.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves management of anomalies by a multidisciplinary team (including craniofacial surgeon, ophthalmologist, pediatrician, pediatric urologist, cardiologist, pulmonologist, speech-language pathologist, and clinical geneticist) to help assure coordination of care (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

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

MID1-related Opitz G/BBB syndrome (MID1-OS) is inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder, nor will he be hemizygous for the MID1 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. Note: If a woman has more than one affected child and no other affected relatives and if the MID1 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a de novo MID1 pathogenic variant (in which case the mother is not a heterozygote), or the mother may have somatic/germline mosaicism. De novo pathogenic variants have been detected in several affected males [Pinson et al 2004, Ferrentino et al 2007, Fontanella et al 2008, Maia et al 2017].
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has an MID1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
  • Males who inherit the pathogenic variant will be affected. (Note: Wide variability in clinical manifestations has been described among affected members of the same family.)
  • Females who inherit the pathogenic variant will be heterozygotes and will usually manifest hypertelorism only (see Clinical Description, Heterozygous Females).
• If the proband represents a simplex case and if the MID1 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but slightly greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of a male proband. Mildly affected males transmit the MID1 pathogenic variant to:

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

Other family members. The maternal aunts and maternal cousins of a male proband may be at risk of having an MID1 pathogenic variant.

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 Detection

Heterozygote testing for at-risk female relatives requires prior identification of the MID1 pathogenic variant in the family.

Note: Females who are heterozygous for this X-linked disorder will usually manifest hypertelorism only.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk 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 heterozygotes, or are at risk of being heterozygotes.

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.

Molecular Pathogenesis

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]. MID1 encodes E3 ubiquitin-protein ligase Midline-1, which is anchored to the microtubules [Cainarca et al 1999, Schweiger et al 1999, Cox et al 2000] and acts 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 fully clarified, and possible roles in common non-genetic diseases have also been reported; the findings available are reviewed in Baldini et al [2020].

The pathogenic variants are missense and nonsense variants, small deletions, intronic splicing variants, or insertions located along the entire length of the gene – the majority in the most 3' portion of the gene. MID1 whole-gene deletions as well as single-exon deletions and duplications have been reported [Winter et al 2003, Ferrentino et al 2007, Fontanella et al 2008, Hüning et al 2013, Migliore et al 2013, Micale et al 2023].

Mechanism of disease causation. The missense and truncated forms lower their affinity for the microtubular apparatus. The pathogenic mechanism is likely to be caused by the loss of E3 ubiquitin-protein ligase Midline-1 function on the microtubules.

Author Notes

Germana Meroni, PhD, focuses on basic research on the molecular basis of X-linked Opitz syndrome, including functional studies of MID1 and proteins belonging to the TRIM/RBCC family.

Contact Dr Meroni to inquire about review of MID1 variants of uncertain significance.

Acknowledgments

This chapter is dedicated to the memory of Dr John M Opitz, whose passion and dedication for children and families affected by MID1-related Opitz G/BBB syndrome has inspired the work of many geneticists, including Dr Germana Meroni.

Revision History

• 19 October 2023 (sw) Comprehensive update posted live
• 5 April 2018 (sw) Comprehensive update posted live
• 28 July 2011 (me) Comprehensive update posted live
• 18 January 2007 (me) Comprehensive update posted live
• 17 December 2004 (me) Review posted live
• 30 June 2004 (gm) Original submission

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