Temple-Baraitser syndrome (ORPHA:420561)
A rare, genetic, multiple congenital anomalies syndrome defined by global developmental delay and severe intellectual disability, epilepsy, hypoplasia/aplasia of the nails of the thumb and great toe, and facial dysmorphism.
Epidemiology
To date, 9 cases have been reported in the literature.
Clinical description
Temple-Baraitser syndrome (TBS) is defined by the association of developmental delay (neonatal hypotonia, delayed developmental milestones), and intellectual disability which is most often severe. The characteristic finding is the presence of distal hypoplasia of digits (mostly the distal phalanges), which is more pronounced at, and often limited to, the thumbs and halluces; nail aplasia or hypoplasia is observed in all patients. In some patients, thumbs and halluces are broad or elongated, and pseudoepiphysis may be observed on X-ray imaging. Facial dysmorphism is characterized by a pseudo-myopathic appearance. Other reported facial features include high anterior or low frontal hairline with central cowlick, flat forehead, ptosis, hypertelorism, downslanting palpebral fissures, epicanthal folds, thick helices, broad depressed nasal bridge with anteverted nares, short columella, long philtrum, high-arched palate, broad mouth with thick vermilion border of the upper or the lower lip and downturned corners. Seizures are reported in all patients, starting at a various ages. Poor visual contact and autistic behaviour are observed in most patients.
Etiology
TBS is due to heterozygous gain of function missense variants in the KCNH1 gene (1q32.2), lowering the activation threshold of the mutant voltage-gated potassium channel and delaying its deactivation. TBS is allelic to Zimmermann-Laband syndrome (ZLS), which differs from TBS by the presence of gingival fibromatosis, coarse facial features, hypertrychosis, hepato-splenomegaly, and more severe digital anomalies. As both syndromes have been described with the same variant, and some patients with KCNH1 variant but without full-blown TBS or ZLS have been reported, it is likely that TBS is part of a broader KCNH1-related disorder.
Diagnostic methods
Confirmation of clinical diagnosis is based on KCNH1 sequencing by targeted sanger sequencing, or via NGS (next generation sequencing) multigene panel including KCNH1.
Differential diagnosis
Differential diagnosis includes DOORS, Lynch Bushby and Zimmermann-Laband syndrome.
Antenatal diagnosis
For parents of an index individual, prenatal diagnosis in subsequent pregnancies should be discussed.
Genetic counseling
The disorder is autosomal dominant; however, most reported KCNH1 variants occur de novo. Mosaicism has been reported in two epileptic, but otherwise unaffected, mothers. Although not known, the recurrence risk to siblings is thus much higher than the usual theoretical 1% estimated risk in the presence of an apparent de novo variant.
Management and treatment
Management and treatment are based on the phenotype. Antiepileptic drugs, and physical and occupational therapy may be needed. Nutritional and feeding status should be evaluated.
Prognosis
Prognosis depends on the severity of the phenotype.

                            Last update: 
                            January 2021


                            - Expert reviewer(s): 
                            Pr Catheline VILAIN | ITHACA*


                                * European Reference Network