Fatal accelerated-phase Chediak-Higashi syndrome caused by an in-frame LYST deletion: first documented case from Syria

Chediak-Higashi Syndrome (CHS) is a very rare genetic disorder that follows an autosomal recessive inheritance pattern. Biallelic mutations​ in the lysosomal trafficking regulator ( LYST ) gene cause abnormal granule formation, leading to clinical manifestations including organomegaly, immunodeficiency, and neurological dysfunction. A 9-year-old girl presented with a one-month history of fever, abdominal distension and jaundice. She had massive hepatosplenomegaly, pancytopenia, cholestatic liver dysfunction and a prolonged prothrombin time; infectious work-up was negative and duodenal biopsy showed coeliac disease. An older sister had died at the same age and had a history of​ ​splenomegaly that had not been investigated. She was discharged after splenectomy but returned two months later with left-sided ptosis and esotropia associated with a sphenoid sinus abscess, alongside recurrent dental abscesses, epistaxis and peripheral fundus hypopigmentation. Despite treatment with antibiotics and corticosteroids and supportive blood transfusions​, she developed multiple intracranial abscesses, recurrent pancytopenia and marrow features of myelodysplastic syndrome. Genetic testing identified a homozygous in-frame nine-base-pair deletion in the LYST gene, c.7029_7037delATCACCAGC, p.(Ser2344_Ala2346del), in exon 24. This variant had​ previously been reported as possibly disease-causing​ but was classified as a variant of uncertain significance in the current report. She died from gastrointestinal bleeding before transplantation could be arranged. CHS is a rare, potentially life-threatening ​​disorder. ​genetic testing can complement clinical and hematological findings and help establish the diagnosis​. This case highlights the importance of considering CHS in children presenting with recurrent infections, hepatosplenomegaly, and hematological abnormalities. Not applicable.