Primary Cutaneous Clonal CD8+ T-Cell Lymphoproliferative Disorder Associated With Immunodeficiency due to RAG1 Mutation.

The development of T-cell lymphomas, granulomatous reactions, and autoimmunity has been observed in immunodeficiency due to milder forms of recombination activating gene (RAG) deficiency. A few cases of cutaneous clonal papulonodular CD8 lymphocytic infiltrates and cutaneous CD8 granulomatous T-cell lymphoma have been described in association with common variable immunodeficiency, and with X-linked agammaglobulinemia. We describe a 15-year-old girl with several autoimmune disorders and recurrent infections that presented with several nodules on her cheek. Histopathological studies demonstrate histological, immunohistochemical, and molecular findings compatible with a primary cutaneous clonal CD8 T-cell lymphoproliferative disorder. Vacuolar interface changes were also seen in the involved skin, reminiscent of cutaneous lupus erythematosus. Molecular genetic analysis revealed a germline novel homozygous missense mutation in RAG1 (T1003>C). The parents were heterozygous carriers. The facial cutaneous lesions recurred despite local radiation therapy. Because of recurrent life-threatening systemic infections, allogeneic bone marrow transplantation was performed. The pathogenesis of this primary cutaneous clonal CD8 T-cell lymphoproliferative disorder may have been related to a chronic stimulation of autoreactive T cells in the involved skin paired with reduced RAG1 activity.

Transformation of Sézary syndrome into CD30+ anaplastic large T-cell lymphoma after alemtuzumab therapy with evidence of clonal unity.

Alemtuzumab is a humanized mouse antibody targeting the CD52 cell surface, which has been effective in patients with advanced stage mycosis fungoides (MF) including erythrodermic MF and Sézary syndrome. There are a few descriptions of large cell transformation after its administration. A young patient with an acute onset of Sézary syndrome treated initially unsuccessfully with fludarabine and cyclophosphamide and later on successfully with alemtuzumab has been described. Three weeks after the beginning of therapy, however, she developed transformed T-cell lymphoma indistinguishable from CD30 anaplastic large-cell lymphoma. After bone marrow transplantation, the transformed CD30 cutaneous T-cell lymphoma recurred as a transformed CD30 plaque MF. All 3 types of lesions showed the same T-cell receptor clonal gene rearrangement, which supports the notion that Sézary syndrome, CD30 anaplastic large-cell lymphoma, and MF are interrelated.

Atrophic skin patches with abnormal elastic fibers as a presenting sign of the MASS phenotype associated with mutation in the fibrillin 1 gene.

IMPORTANCE: Marfan syndrome (MFS) is a dominantly inherited disorder of connective tissue caused by mutations in the fibrillin 1 gene (FBN1). The most common skin finding in MFS is striae distensae. Particular individuals referred for suspected MFS who do not completely fulfill the MFS diagnostic criteria are classified as having a MASS phenotype. The acronym represents the following manifestations: a prolapsed mitral valve, myopia, aortic root enlargement, and skeletal and skin manifestations. Mutations in FBN1 have been shown to be associated in some cases with the MASS phenotype. Skin manifestations may be an important clue to the diagnosis of these disorders. OBSERVATIONS: We studied a patient referred for unusual atrophic skin patches on the buttocks. Results of histopathological examination and electron microscopy demonstrated markedly abnormal elastic fibers. Subsequent medical genetics evaluation led ultimately to the diagnosis of the MASS phenotype and the discovery of an underlying FBN1 mutation. CONCLUSIONS AND RELEVANCE: Although the clinical suspicion and diagnosis of MFS and related disorders are usually established by its main associated clinical features, including ophthalmologic, skeletal, and vascular involvement, clinicians should be aware of the associated skin manifestations, including unusual atrophic patches with abnormal elastic fibers that can sometimes be the first noted sign of the genetic disorder.