KBG syndrome (ORPHA:2332)
A rare congenital malformation syndrome characterized by a typical facial dysmorphism, macrodontia of the permanent upper central incisors, short stature, skeletal anomalies, developmental delay and behavioral abnormalities.
Epidemiology
The prevalence is unknown. More than 150 cases have been reported to date. ANKRD11 is one of the most frequently muted gene in patients with neurodevelopmental disorders diagnosed by whole exome sequencing.
Clinical description
KBG syndrome (KBGS) manifests in childhood with global developmental delay with short stature, mild-to-moderate intellectual disability, characteristic facies, macrodontia of the permanent upper central incisors and skeletal anomalies. Behavioral disturbances including hyperactivity, aggressiveness, attention deficit and autism spectrum disorders are recognized as constant clinical features. Developmental delay includes delayed motor milestones and markedly delayed speech and is almost always present in all patients. Characteristic facial dysmorphism is prominent in about half of the patients, consisting of triangular face, wide eyebrows with mild synophrys, hypertelorism, prominent ears and nasal bridge with bulbous nasal tip, long flat philtrum and thin upper lip. The hallmark feature, macrodontia, is observed in about 80% of cases; additional dental findings include oligo- or hypodontia, premature teeth loss in adults and enamel hypoplasia. Height below the 10th centile is observed in about two-thirds of cases. The most frequent skeletal anomalies are brachydactyly and fifth finger clinodactyly. Seizures, feeding difficulties, recurrent otitis media/hearing loss, palatal abnormalities and precocious puberty are notable additional features associated with KBGS.
Etiology
KBGS is caused by loss-of function alterations (pathogenic variants and copy number variations) affecting the ANKRD11 gene (16q24.3) which encodes ankyrin repeat domain-containing protein 11. The extent of ANKRD11 functions is yet to be determined, but it has been shown to be a crucial chromatin regulator that controls histone acetylation and gene expression during neural development.
Diagnostic methods
Diagnosis is based on clinical evaluation; there is no consensus on diagnostic criteria. The diagnosis is established by cytogenetic and molecular studies including a-CGH (array-comparative genome hybridization), targeted sequencing, gene panel, whole exome or genome sequencing.
Differential diagnosis
Differential diagnosis includes Cornelia de Lange syndrome, cleidocranial dysplasia, Robinow syndrome and 22q11.2 deletion syndrome.
Genetic counseling
The pattern of inheritance is autosomal dominant. Most cases occur sporadically due to de novo mutations. Intra-familial variability of the phenotype has been noted in familial cases.
Management and treatment
Management is symptom-based and requires a multidisciplinary approach. At diagnosis, systematic echocardiogram, palatal assessment, vision, hearing and dental assessment, pediatric assessment for developmental delay, autism spectrum disorders and behavioral anomalies are recommended. Additional investigations depends on the clinical presentation. Management and follow-up include educational support, surveillance of growth and puberty, screening for hearing loss (otitis media), educational and speech therapy, and treatment of seizures when needed.
Prognosis
Despite the history of developmental delay, many patients grow into autonomous adults.

                            Last update: 
                            September 2020


                            - Expert reviewer(s): 
                            Pr Nicole PHILIP | ITHACA* - Dr Florence RICCARDI | ITHACA*


                                * European Reference Network