Hydrops fetalis, diffuse lung disease, lymphoedema and haemangiomas as leading symptoms in children with a biallelic pathogenic variants in the THSD1 gene

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Background: THSD1 (thrombospondin type 1 domain-containing protein 1) is a transmembrane protein belonging to the thrombospondin family. Heterozygous pathogenic variants in the THSD1 gene are associated with intracranial aneurysms. Biallelic pathogenic variants are additionally linked with lymphatic malformations, non-immune hydrops fetalis, heart defects and haemangiomas. However, childhood interstitial lung disease (chILD) and lymphedema have not previously been reported in association with pathogenic THSD1 variants. Methods: We describe seven patients with homozygous frameshift variants in THSD1, identified by exome or genome sequencing, who presented with hydrops fetalis and childhood-onset chILD. Results: All individuals (currently aged 3, 4, 13, 14, 20, 22 and 23 years) had non-immune hydrops fetalis and cutaneous haemangiomas. Pleural effusions and ascites resolved over time. However, asymmetric subcutaneous lymphedema of the face, extremities or genitals persisted. Four of the six patients were also diagnosed with chILD based on clinical, radiological and histological findings. One of them showed CT morphological signs of pulmonary fibrosis in the first year of life. Conclusions: The combination of hydrops fetalis, diffuse lung disease with early manifestation, the presence of asymmetric lymphoedema and hemangioma should prompt consideration of pathogenic biallelic variants in the THSD1 gene and genetic counselling.

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