THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome (ORPHA:363444)
A rare, autosomal recessive, syndromic intellectual disability disorder characterized by global development delay, mild microcephaly, mild to severe intellectual disability and non-specific facial dysmorphism in association with variable multiple congenital anomalies including congenital heart defects, dental anomalies, cryptorchidism, renal and cerebral malformations. Short stature is frequent.
Epidemiology
First described in two Hutterite families, there are now approximately 20 affected individuals reported worldwide.
Clinical description
Affected individuals have mild to severe intellectual disability and are non-verbal or have limited speech. The most relevant congenital anomalies include cardiac malformations (atrial and/or ventricular septal defects, patent ductus arteriosus), renal anomalies (unilateral agenesis or ectopic kidney), multiple teeth caries and/or malocclusion, cryptorchidism, anteriorly displaced anus, ventriculomegaly and corpus callosus dysgenesis. Short stature is reported in approximately half of individuals. Several recurrent craniofacial features have been described including mild microcephaly, tall forehead, high anterior hairline, short upslanting palpebral fissures, deep-set eyes, a long nose with low-hanging columella. The facial features are non-specific. More rarely, affected individuals could have hypergonadotropic hypogonadism (in females), seizures, low birth weight, feeding difficulties, hearing loss and/or eye abnormalities.
Etiology
The syndrome is caused by homozygous mutations in THOC6, encoding for a protein of the THO/TREX (transcription/export) complex, which is involved in the transcription of mRNA as well as the export of spliced mRNA from the nucleus; it is supposed to play a crucial role in both embryogenesis and human neurodevelopment.
Diagnostic methods
Diagnosis is based on molecular studies: for Hutterite communities, testing the specific c.136G>A variant can be considered; for non-Hutterite individuals, multigene panels for intellectual disability, chromosome microarray analysis, or exome array are indicated.
Differential diagnosis
Due to the non-specific characteristics of the syndrome, all disorders with intellectual disability and without other distinctive features should be investigated.
Antenatal diagnosis
Prenatal testing is possible when a pathogenic variant is already known in the family.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy. Carrier testing is possible where the pathogenic variant has been previously identified in a family member.
Management and treatment
Management requires a lifelong multidisciplinary approach, including a pediatrician, neurologist, otorhinolaryngologist (assessment for hearing loss), ophthalmologist, cardiologist, radiologist and gastroenterologist (to evaluate feeding problems and consider gastrostomy). Developmental assessments are needed to tailor medical services, develop an individualized education plan, and promote occupational therapy. Moreover, a behavioral assessment for signs of autism spectrum disorder is recommended. Annual evaluation of renal function should be considered in those with anomaly of kidney/urinary tract. Surgery is required in case of cryptorchidism while females older than 12 require an endocrine consultation. Need for family support (e.g. social work involvement, palliative care, home nursing) should be evaluated at each visit. No specific pharmacological therapy is available.
Prognosis
The course of the disease is non-progressive. Longitudinal data are insufficient to determine life expectancy, although survival into adulthood is possible. Need for life-long support from caregivers depends on the severity of intellectual disability.

                            Last update: 
                            November 2020


                            - Expert reviewer(s): 
                            Dr Andrea ACCOGLI | ITHACA* - Dr Valeria CAPRA | ITHACA* - Dr Gianluca PICCOLO | ITHACA*


                                * European Reference Network