ABSTRACT
Ras-associated autoimmune leukoproliferative disorder (RALD) is a clinical entity initially identified in patients evaluated for an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype. It remains a matter of debate whether RALD is a chronic and benign lymphoproliferative disorder or a pre-malignant condition. We report the case of a 7-year-old girl diagnosed with RALD due to somatic KRAS mutation who progressed to a juvenile myelomonocytic leukemia phenotype and finally evolved into acute myeloid leukemia. The case report prompted a literature review by a search for all RALD cases published in PubMed and Embase. We identified 27 patients with RALD. The male-to-female ratio was 1:1 and median age at disease onset was 2 years (range 3 months-36 years). Sixteen patients (59%) harbored somatic mutations in KRAS and 11 patients (41%) somatic mutations in NRAS. The most common features were splenomegaly (26/27 patients), autoimmune cytopenia (15/16 patients), monocytosis (18/24 patients), pericarditis (6 patients), and skin involvement (4 patients). Two patients went on to develop a hematopoietic malignancy. In summary, the current case documents an additional warning about the long-term risk of malignancy in RALD.
Subject(s)
Autoimmune Diseases/diagnosis , Autoimmune Diseases/etiology , Autoimmunity/genetics , Disease Susceptibility , Myeloproliferative Disorders/diagnosis , Myeloproliferative Disorders/etiology , ras Proteins/genetics , Adolescent , Adult , Alleles , Autoimmune Diseases/therapy , Autoimmune Lymphoproliferative Syndrome/diagnosis , Autoimmune Lymphoproliferative Syndrome/etiology , Child , Child, Preschool , Combined Modality Therapy , Diagnosis, Differential , Disease Management , Female , Genetic Predisposition to Disease , Genotype , Humans , Infant , Karyotype , Male , Mutation , Myeloproliferative Disorders/therapy , Phenotype , Prognosis , Skin/immunology , Skin/metabolism , Skin/pathology , Treatment Outcome , Young AdultABSTRACT
Childhood-onset chronic and refractory cytopenias are rare and may be genetic in etiology. We report three pediatric cases of severe autoimmune thrombocytopenia or anemia associated with growth retardation and spastic diplegia with intracranial calcification. The identification of platyspondyly and metaphyseal lesions suggested a potential diagnosis of spondyloenchondrodysplasia (SPENCD), which was confirmed with the identification of biallelic ACP5 mutations. Two patients demonstrated elevated serum interferon alpha levels. Our report highlights ACP5-associated disease as a cause of childhood-onset autoimmune cytopenia, particularly combined with growth retardation and/or spasticity. Furthermore, a role for type I interferon in the pathogenesis of autoimmune cytopenias is supported.
Subject(s)
Autoimmune Diseases/complications , Autoimmune Diseases/genetics , Mutation/genetics , Osteochondrodysplasias/complications , Osteochondrodysplasias/genetics , Purpura, Thrombocytopenic, Idiopathic/complications , Purpura, Thrombocytopenic, Idiopathic/genetics , Tartrate-Resistant Acid Phosphatase/genetics , Age of Onset , Alleles , Autoimmune Diseases/therapy , Child , Child, Preschool , Female , Humans , Male , Osteochondrodysplasias/therapy , Prognosis , Purpura, Thrombocytopenic, Idiopathic/therapyABSTRACT
Constitutional trisomy 21 inherent to Down syndrome (DS) is associated with several hematological disorders occurring at different ages. Neonates with DS may present with transient asymptomatic blood count abnormalities such as neutrophilia, thrombocytopenia and polycythemia. Within 1-2 months of life, 3-10% of DS infants develop transient myeloproliferative disease. Despite a spontaneous regression in most of the cases, TMD can be fatal or lead to the subsequent development of myeloid leukemia in 20% of DS children (DS ML). DS ML has clinical and biological features that define a unique entity with a high sensitivity to chemotherapy and a favorable outcome. Children with DS also have an increased risk of developing acute lymphoblastic leukemia (ALL) characterized by a more heterogeneous pattern of genetic findings and by a higher rate of treatment-related toxicities. These features highlight the role of trisomy 21 in leukemogenesis and confirm the need of specific and adapted therapeutic approach for DS children with leukemia.
