1 - Unidade de Genética Médica, Área de Pediatria Médica, Hospital Dona Estefânia, Centro Hospitalar e Universitário de Lisboa Central, Lisboa, Portugal;
2 - Unidade de Cuidados Paliativos, Área de Pediatria Médica, Hospital Dona Estefânia, Centro Hospitalar e Universitário de Lisboa Central, Lisboa, Portugal;
3 - Unidade de Endocrinologia, Área de Pediatria Médica, Hospital Dona Estefânia, Centro Hospitalar e Universitário de Lisboa Central, Lisboa, Portugal;
4 - Serviço de Neuropediatria, Área de Pediatria Médica, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal;
5 - Unidade de Doenças Metabólicas, Área de Pediatria Médica, Hospital Dona Estefânia, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
- Reunião internacional - American Society of Human Genetics Virtual Meeting 2021, publicação sob a forma de resumo, comunicação em poster
Resumo:
Introduction: Allan-Herndon-Dudley syndrome (AHDS, OMIM #300523) is an X-linked disorder caused by hemizygous pathogenic variants in the SLC16A2 gene. Clinically, AHDS is characterized by neurologic findings, dysthyroidism and pathognomonic thyroid test results (high free T3 and low reverse T3, low free T4, and normal or slightly elevated TSH). The neurocognitive phenotype includes hypotonia, feeding difficulties in infancy, developmental delay, intellectual disability ranging from mild to severe, pyramidal signs, extrapyramidal findings, and late-onset seizures. Dysthyroidism signs include poor weight gain, reduced muscle mass, cold intolerance, sweating, elevated heart rate and irritability. To date, over 100 different genetically confirmed cases were reported. Here, we present two newly identified patients harboring two novel SLC16A2 variants, aiming to expand the AHDS clinical and mutational spectrum.
Case report: Two unrelated boys were referred for genetic evaluation at 3 and 10 years of age, respectively. Both patients presented with severe global developmental delay, hypotonia, absence speech, and dystonia. The older child also had pyramidal signs, and dysthyroidism features including feeding difficulties, poor weight gain, reduced muscle mass and variable cold intolerance. Family history was suggestive of an X-linked inheritance pattern. Clinical exome sequencing revealed two hemizygous variants: SLC16A2 (NM_006517.3) c.1057A>C p.(Thr353Pro) in proband 1, and SLC16A2 (NM_006517.3) c.695C>T p.(Ser232Phe) in proband 2, classified as variants of unknown significance. Both variants were neither present in population databases nor reported in the literature. In silico analysis suggested that variants were disease causing. Segregation analysis revealed that mother and grandmother were carriers in both families. Further, retrospective evaluation confirmed abnormal thyroid function: normal TSH, low free-T4, high free T3 and low reverse T3. With the available evidence, we reclassified both variants as likely pathogenic, establishing the diagnosis of AHDS.
Conclusions: Here, we identified two previously unreported missense variants in SLC16A2 gene. Both patients’ phenotypes were consistent with other reported cases. Reverse phenotyping through thyroid hormonal profile and segregation analysis were essential for confirmation of variants pathogenicity and establishment of molecular diagnosis. Additionally, this report further broadens the AHDS genotypic spectrum, and provides additional information for genotype-phenotype correlations. From a practical standpoint of view, it highlights that molecular diagnosis not only directs accurate genetic counselling and reproductive options, but also offers therapeutic hope as ongoing clinical trials suggest encouraging response to T3 analogue Triac as a potential therapy.
Palavras Chave: Allan-Herndon-Dudley syndrome, SLC16A2 gene, hypotiroidism, reverse phenotyping