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Opitz G/BBB syndrome
Opitz G/BBB syndrome (OS) is a multiple congenital anomalies disorder characterized by malformations of the midline including hypertelorism, laryngo-tracheo-esophalgeal defects and hypospadias. There are two clinically indistinguishable genetic subtypes of Opitz G/BBB: X-linked Opitz G/BBB syndrome (XLOS), and autosomal dominant Opitz G/BBB syndrome (ADOS) (see these terms).
ORPHA:2745Classification level: Disorder
- Hypertelorism-oesophageal abnormality-hypospadias syndrome
- Hypospadias-dysphagia syndrome
- Hypospadias-hypertelorism syndrome
- Opitz syndrome
- Opitz-Frias syndrome
- Prevalence: 1-9 / 100 000
- Inheritance: Autosomal dominant or X-linked recessive
- Age of onset: Infancy, Neonatal
- ICD-10: Q87.8
- OMIM: 145410 300000
- UMLS: C1801950 C2936904
- MeSH: -
- GARD: 193
- MedDRA: -
The syndrome primarily affects males. The prevalence of X-linked OS ranges from 1/50,000 to 1/100,000. The prevalence of autosomal dominant OS is unknown; it is considered to be a part of 22q11.2 microdeletion syndrome (see this term) which has a prevalence of 1/4,000.
Opitz G and Opitz BBB (using the initials of the originally described families) were initially described as distinct phenotypes but were subsequently found to be the same syndrome. OS usually presents with characteristic facial defects including prominent forehead, hypertelorism and telecanthus, broad nasal bridge and cleft lip/palate, and anteverted nares, as well as hypospadias, cryptorchidism, and hypoplastic/bifid scrotum. A large number of additional variable features are also found: laryngo-tracheo-esophageal (LTE) abnormalities causing dysphagia, anal anomalies including imperforate or ectopic anus, syndactyly, congenital heart malformations such as ventricular or artrial septal defect, patent ductus arteriosus, or persistent left superior vena cava (see these terms), developmental delay with delay in onset of walking, and intellectual deficit with short attention span, learning difficulties, and speech disorders. Midline defects of the brain including corpus callosum agenesis and cerebellar vermis agenesis or hypoplasia have also been reported. Renal malformations have been reported in very severe cases. Female carriers mostly show only hypertelorism and rarely other manifestations.
XLOS is caused by mutations in the MID1 gene (Xp22) encoding the midline-1 protein which is an ubiquitin E3 ligase associated with microtubules. There is a wide variability in the presentation and severity of clinical manifestations even among patients harboring the same mutation. However, some patients with clinically diagnosed XLOS do not have identifiable mutations in MID1 suggesting that other genes or mutations in regulatory regions may also be involved. ADOS appears to be caused by a 22q11.2 deletion. The genes implicated have not been identified.
Opitz G/BBB syndrome is diagnosed on the basis of clinical findings and is suspected in males with ocular hypertelorism and at least one other of the major findings (hypospadias or LTE abnormalities). Molecular genetic testing is difficult due to the complicated etiology. Identification of a MID1 mutation confirms the diagnosis.
XLOS and ADOS can be differentiated based on the mode of inheritance. Differential diagnoses include FG syndrome, craniofrontonasal dysplasia, and Mowat-Wilson syndrome (see these terms).
Prenatal testing is possible for at-risk pregnancies if a MID1 mutation has been identified in a family member. Fetal sex determination can be performed by chromosome analysis, followed by DNA screening for disease-causing mutations.
Genetic counseling is recommended for young adults who are affected, are carriers, or are at risk of being carriers.
Management and treatment
Because of the nature of the syndrome, a multidisciplinary team including a craniofacial surgeon, ophthalmologist, pediatrician, pediatric urologist, cardiologist, pulmonologist, speech pathologist, and medical geneticist is required. Treatment primarily involves corrective surgical interventions. Regular follow-up is also needed depending on the type of malformations present.
The prognosis varies depending on severity which can vary considerably among affected patients.