SPECC1L-related hypertelorism syndrome (ORPHA:1519)
A rare autosomal dominant malformation syndrome characterized by hypertelorism, omphalocoele, cleft lip, ear pits, uterine malformation (bicornuate uterus), and more variably by diaphragmatic hernia and congenital heart defects.
Epidemiology
Unknown. Less than 40 patients reported with genetic confirmation. The clinical diagnostic is unreliable in older literature due to phenotypic confusion.
Clinical description
Presentation is typically with characteristic facial dysmorphism: prominent forehead, hypertelorism (>95%) and telecanthus, cleft lip/palate (25%), slightly downslanting palpebral fissures, long philtrum prominent nasal root, and a large nose with a large tip. Malformations include omphalocoele (50%), uterine malformations (>25%), congenital heart malformations (20%), ear pits (30%), dysphagia, reflux and other esophageal problems (30%) and, less commonly, diaphragmatic herniae (10%), inguinal herniae, aortic root dilation, and rarely CNS anomalies (ventriculomegaly, agenesis of the corpus callosum) and craniosynostosis. Learning disability affects 20% of patients, and intellectual disability (ID) is present in 10%.
Etiology
The disorder is due to heterozygous gain of function variants in SPECC1L (Sperm antigen with calponin homology and Coiled-Coil domains 1 Like) located in 22q11.23. The SPECC1L protein is a cytoskeletal protein that associates with both actin and microtubules to affect larger cytoskeletal function. It is involved in cell adhesion, actin cytoskeleton organization, microtubule stabilization, spindle organization and cytokinesis. Of note, heterozygous loss of function of SPECC1L causes Tessier IV oblique facial cleft.
Diagnostic methods
SPECC1L-related hypertelorism syndrome is suspected on clinical findings : ocular hypertelorism and at least one other of the characterstic findings (omphalocoele or diaphragmatic hernia, bicornuate uterus, ear pits). Diagnosis is confirmed by identification of a SPECC1L variant.
Differential diagnosis
Opitz GBBB syndrome is the main differential diagnosis of SPECC1L-related hypertelorism syndrome. Opitz GBBB syndrome has strikingly overlapping craniofacial phenotype, leading to confusion in the past literature between MID1-confirmed Opitz GBBG and various overlapping conditions. Earpits, uterine malformations, omphalocoele, diaphragmatic herniae are specific to SPECC1L, whereas laryngeal and anorectal defects are specific to Optiz GBBB. ID is more common in the latter. Baraitser-Winter cerebrofrontofacial syndrome (ACTB and ACTG1), craniofrontonasal dysplasia (EFNB1), frontonasal dysplasia and Aarskog syndrome (FGD1) share marked hypertelorism.
Antenatal diagnosis
Prenatal testing is possible for at-risk pregnancies if a SPECC1L mutation has been previously identified in a family member.
Genetic counseling
The pattern of inheritance is autosomal dominant and genetic counseling is recommended for young adults who are affected. The offspring of an affect individual have a 50% risk of also being affected.
Management and treatment
Multidisciplinary medical support with pediatricians, craniofacial, ENT (ear, nose and throat) and abdominal surgeons, cardiologists, and a medical geneticist is required. Neurodevelopmental support and speech therapy may be necessary. Uterine anomalies may cause fertility issues.
Prognosis
Prognosis is variable but usually favorable, depending on the severity of malformations and associated ID.

                            Last update: 
                            October 2020


                            - Expert reviewer(s): 
                            Pr Alain VERLOES | ITHACA*


                                * European Reference Network