RESUMEN
POU3F3 variants cause developmental delay, behavioral problems, hypotonia and dysmorphic features. We investigated the phenotypic and genetic landscape, and genotype-phenotype correlations in individuals with POU3F3-related disorders. We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals. Trio exome sequencing or single exome sequencing followed by segregation analysis were performed in the novel cohort. Functional effects of missense variants were investigated with 3D protein modeling. We included 28 individuals (5 previously published) from 26 families carrying POU3F3 variants; 23 de novo and one inherited from an affected parent. Median age at study inclusion was 7.4 years. All had developmental delay mainly affecting speech, behavioral difficulties, psychiatric comorbidities and dysmorphisms. Additional features included gastrointestinal comorbidities, hearing loss, ophthalmological anomalies, epilepsy, sleep disturbances and joint hypermobility. Autism, hearing and eye comorbidities, dysmorphisms were more common in individuals with truncating variants, whereas epilepsy was only associated with missense variants. In silico structural modeling predicted that all (likely) pathogenic variants destabilize the DNA-binding region of POU3F3. Our study refined the phenotypic and genetic landscape of POU3F3-related disorders, it reports the functional properties of the identified pathogenic variants, and delineates some genotype-phenotype correlations.
Asunto(s)
Trastorno Autístico , Epilepsia , Discapacidad Intelectual , Humanos , Niño , Discapacidad Intelectual/genética , Trastorno Autístico/genética , Fenotipo , Epilepsia/genética , Mutación Missense/genética , Discapacidades del Desarrollo/genética , Factores del Dominio POU/genéticaRESUMEN
Background: Thyroid hormone resistance due to pathogenic variants in thyroid hormone receptor alpha (THRA) is rare and descriptions of patients are sparse. The disorder is probably underdiagnosed as patients may have normal thyroid function tests. Treatment with thyroxine in childhood improves clinical symptoms. However, it is not clear if treatment has beneficial effects if started in adulthood. Cases: We investigated 4 previously untreated Caucasian adult first-degree-related patients with the THRA c.788C > T, p.(Ala263Val) variant identified by a gene panel for intellectual disability in the index patient. Clinical data and previous investigations were obtained from medical reports. Results: During childhood and adolescence, short stature, short limbs, metacarpals, and phalanges, and delayed bone age maturation were observed. Delayed motor and language development and decreased intellectual and learning abilities were described. Abdominal adiposity, round face, and increased head circumference were common features. All individuals complained of tiredness, constipation, and low mood. While thyrotropin (TSH) and free thyroxine (FT4) were within the reference range, free triiodothyronine (FT3) was high. FT4/FT3 ratio and reverse T3 were low. Other main features were low hemoglobin and high LDL/HDL ratio. Conclusion: Investigation of 4 first-degree-related adult patients with untreated resistance to thyroid hormone alpha (RTHα) revealed more pronounced phenotype features and hypothyroid symptoms than previously described in patients treated with levothyroxine from childhood or adolescence. The delay in diagnosis is probably due to normal thyroid function tests. We suggest that THRA analysis should be performed in patients with specific clinical features, as treatment in early childhood may improve outcomes.