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Whilst epidemiological data is limited, the prevalence of X-linked Optiz GBBB syndrome (GBBB) has been suggested to range from 1/50,000 to 1/100,000. Males are more severely affected. More than 150 patients are reported with MID1 mutation. The clinical diagnostic is unreliable in older literature due to phenotypic confusion.

GBBB syndrome usually presents with characteristic facial dysmorphism: prominent forehead, hypertelorism (>95% of cases) and telecanthus, cleft lip/palate (50%), broad nasal bridge, broad nasal tip and anteverted nares. Malformations include hypospadias (80%), imperforate or ectopic anus (20%), laryngeal cleft (50%), dysphagia, reflux and other esophageal problems (30%) and, less commonly, congenital heart malformations (20%) and agenesis of the corpus callosum or hypoplasia of the vermis. Developmental delay or intellectual deficiency (ID) affect one-third of males. Female carriers mostly show only hypertelorism (>90%) and rarely other manifestations. A mild form of GBBB has been reported in a single family with a MID2 variant.

Opitz GBBB is caused by mutations in the MID1 gene (Xp22) encoding the midline-1 protein which is an ubiquitin E3 ligase associated with microtubules. The original report described two distinct X-linked midline defects either with (G syndrome) or without (BBB syndrome) laryngeal malformations. Both phenotypes were later assigned to the same gene, without genotype/phenotype correlation; a wide variability in clinical manifestations is noted even among patients harboring the same mutation.

Opitz GBBB syndrome is suspected on clinical findings: boy with ocular hypertelorism and at least one other of the major findings (hypospadias or laryngo-tracheoesophageal abnormalities). Diagnosis is confirmed by identification of a MID1 mutation.

SPECC1L syndrome (Teebi hypertelorism syndrome) is the main differential diagnosis of GBBB syndrome. SPECC1L syndrome has strikingly overlapping craniofacial phenotype, leading to confusion in the past literature between MID1-confirmed GBBB and various overlapping conditions. Earpits, uterine malformations, omphalocoele, diaphragmatic herniae and, rarely, craniosynostosis and aortic root dilation are specific to SPECC1L, whereas laryngeal and anorectal defects are specific to GBBB. ID is more common in the latter. Further nosologic confusion came from exceptional observation of ''BBBG-like'' phenotype in patients with 22q11.2 deletion syndrome. Baraitser-Winter cerebrofrontofacial syndrome (ACTB and ACTG1), craniofrontonasal dysplasia (EFNB1), frontonasal dysplasia and Aarskog syndrome (FGD1) share marked hypertelorism.

Prenatal testing is possible for at-risk pregnancies if a MID1 mutation has been identified in a family member.

The pattern of inheritance is X-linked. Genetic counseling is recommended for young adults who are affected, are carriers, or are at risk of being carriers. Where the female is the carrier, there is a 50% risk of future male offspring being affected and a 50% risk for future female offspring to be a carrier. For affected males, future male offspring are always unaffected, whereas future female offspring are always a carrier.

Multidisciplinary medical support with a pediatrician, craniofacial, ENT (ear, nose and throat) and urologic surgeons, cardiologist, and medical geneticist is required. Neurodevelopmental support and speech therapy may be necessary.

Prognosis is variable but usually favorable, depending on the severity of malformations and associated ID.

Last update: November 2020 - Expert reviewer(s): Pr Alain VERLOES | ITHACA*

* European Reference Network