1 - Departamento de Genética Médica. Hospital Dona Estefânia, Unidade Local de Saúde São José, Lisboa, Portugal
- Comunicação oral, XII Reunião de Neurogenética 2024
Resumo:Allan-Herndon-Dudley syndrome (AHDS, MIM 300523) is a rare X-linked neurodegenerative disorder caused by pathogenic variants in the SLC16A2 gene. It is characterized by severe hypotonia, reduced muscle mass, progressive spastic paraplegia, global developmental delay, and moderate to severe intellectual disability. Affected males present with pathognomonic thyroid profiles (elevated T3, low-normal free T4, normal TSH) and dysthyroid-related symptoms (poor weight gain, cold intolerance, tachycardia, and irritability). Distinctive craniofacial features may include microcephaly, cup-shaped ears, an ogival palate, and decreased facial creases. Here we describe a 10-year-old boy referred for genetic evaluation due to severe intellectual disability, microcephaly (P<1; -2.5SD), axial hypotonia, limb hypertonia, dystonia, and oromandibular dyskinesia. Family history revealed early deaths among male members with a similar phenotype, suggesting an X-linked inheritance pattern. MRI showed cortico-subcortical atrophy and frontal demyelination. After extensive investigation, clinical exome sequencing revealed a hemizygous variant in the SLC16A2 gene, initially classified as a variant of unknown significance. Analysis of the endocrinologic profile confirmed abnormal thyroid function - normal TSH, low free T4 as well as the pathognomonic high free T3, and low reverse T3. These data allowed reclassification of the variant as likely pathogenic, establishing the diagnosis of AHDS. Segregation analysis identified the mother and grandmother as carriers. This case highlights the importance of reverse phenotyping, when interpreting inconclusive results. Genetic diagnosis permitted a precise genetic counselling, namely recurrence risk determination for family members, as well as personalized clinical management. Also, this report enlightens the importance of thorough phenotyping for genotype-phenotype correlations establishment and reinforces the importance of thyroid studies in individuals with delay development and intellectual disability.
Palavras Chave: Allan-Herndon-Dudley syndrome; Genetic counselling