A Novel Variant in the DIAPH1 Gene Causing Macrothrombocytopenia and Non-syndromic Hearing Loss in a Pediatric Saudi Girl.

Macrothrompocytopenia (MTP) is a rare group of hereditary disorders that lead to impaired hemostasis. Macrothrompocytopenia mostly results from genetic mutations in genes implicated in megakaryocyte differentiation and function. Diaphanous-related formin 1 (DIAPH1) is a protein-coding gene. Dominant gain-of-function DIAPH1 variants cause macrothrombocytopenia and sensorineural deafness (autosomal dominant non-syndromic hearing loss 1 (DFNA1)), while homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). This rare genetic disease is characterized by progressive and severe hearing loss with onset in the first decade of life, is associated with mild thrombocytopenia, and has no significant bleeding tendency. This case report presents the clinical findings of a 14-year-old Saudi pediatric girl. We investigated the potential association of DIAPH1 as a novel candidate gene linked to dominant MTP and autosomal dominant non-syndromic hearing loss (ADNSHL), which was evaluated through audiometry. Notably, a novel variant, c.3633_3636del, was identified in the DIAPH1 gene. To date, only a small number of mutations in this gene have been reported as the cause of MTP and ADNSHL.

LAD-III, a Mild Phenotype Resulting From a Novel Variant of FERMT3 Gene: A Case Report.

Leukocyte adhesion deficiency-III (LAD-III) is a rare recessive autosomal disorder characterized by bleeding syndrome of Glanzmann-type and life-threatening infections. The main etiology of this condition is variations in the FERMT3 gene, which encodes kindlin-3, an integrin-binding protein. This protein is responsible for the activation of fibrinogen receptors and integrin-mediated hematopoietic cell adhesion. So far, only limited cases of LAD-III have been reported. This case report discusses a two-year-old male infant from the Asir region, Saudi Arabia, who was referred to the pediatric hematology service due to recurrent ecchymosis and epistaxis. He was born at full term with a history of transient tachypnea of the newborn and recurrent bronchiolitis. The patient exhibited normal platelet count and coagulation profiles alongside a familial history of bleeding disorders, including a cousin with a similar condition. The patient also presented with hypospadias and café-au-lait spots. Laboratory findings revealed anemia, microcytosis, and hypochromia indicative of iron deficiency anemia. Whole exome sequencing (WES) identified a homozygous variant of uncertain significance in the FERMT3 gene, associated with autosomal recessive LAD-III. The patient was subsequently referred to an immunology subspecialty for further investigation and bone marrow transplant preparation. This case underscores the importance of comprehensive clinical and genetic evaluations in pediatric patients with unexplained bleeding tendencies.