X-linked intellectual disability, Cabezas type (ORPHA:85293)
An X-linked syndromic intellectual disability characterized by developmental delay, intellectual disability (ID) with severe speech impairment, and short stature. Variable additional clinical features have been associated, including behavioral disturbances, gait abnormalities, tremor, seizures, hypogonadism, truncal obesity, unspecific facial dysmorphism, and small hands and feet.
Epidemiology
The prevalence of Cabezas syndrome (CS) is unknown. It is estimated that CS accounts for 3% of X-linked intellectual disability. To date, around 120 cases have been reported in the literature. Males are predominantly affected.
Clinical description
CS typically presents in childhood and the penetrance of CS is age-dependent, with less specific clinical features in early childhood which progress over time. It is characterized by mild to severe intellectual disability with disproportionate, severe speech impairment. Other neurologic problems include behavioural disturbances (mainly hyperactivity and aggressive behaviour), gait abnormalities, tremors, seizures (more common in young children), and variable and unspecific cerebral abnormalities (such as malformations of cortical development, including polymicrogyria, ventriculomegaly, and decreased white matter volume). Most of the described patients also have short stature, truncal obesity, hypogonadism, and small hands and feet. The facial phenotype is unspecific and evolves with age. The most frequent facial dysmorphisms are prominent lower lip and low-set ears. Additional features include urogenital anomalies (such as undescended and/or small testes, hypospadias, and small penis), gynecomastia, kyphosis, pes cavus and sandal gap. Females are mainly asymptomatic but in rare cases can present learning disability, attention deficit disorder, or tremor.
Etiology
This syndrome is caused by pathogenic variants in CUL4B gene (Xq24), encoding a scaffold protein of the cullin 4B-RING ubiquitin ligase (E3) complex, which is crucial in the regulation of the degradation of cellular proteins.
Diagnostic methods
Molecular genetic testing approaches can include a combination of chromosomal microarray and Next Generation Sequencing-based multigene panel or a comprehensive genomic testing (whole-exome sequencing or genome sequencing).
Differential diagnosis
Differential diagnosis includes Börjeson-Forssman-Lehmann syndrome, Wilson-Turner syndrome and Smith-Fineman-Myers syndrome.
Antenatal diagnosis
Prenatal diagnosis can be offered if the disease-causing mutation has been identified in a family member.
Genetic counseling
Genetic counselling should be proposed to parents of affected individuals. It is inherited in an X-linked manner. If the mother is a carrier of the pathogenic variant, the chance of transmitting the pathogenic variant at each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers. Female carriers are usually asymptomatic but in rare cases can exhibit a mild phenotype.
Management and treatment
Management is symptomatic and should be multidisciplinary, usually addressing developmental delay. It can include physical, occupational and speech therapy, including nonverbal methods of communication. In patients with seizures, anticonvulsant medication is needed. Medication may also be required in patients with behavioural disturbances and/or hypogonadism.
Prognosis
Longitudinal data are insufficient to determine life expectancy. However, it is not a life-threatening condition and survival into adulthood is expected. Autonomy is limited and depends on the severity of intellectual disability.

                            Last update: 
                            January 2021


                            - Expert reviewer(s): 
                            Dr Marcia RODRIGUES | ITHACA* - Dr Marta P. SOARES | ITHACA*


                                * European Reference Network