Fatal lung fibrosis associated with immunodeficiency and gonadal dysgenesis in 46XX sisters—A new syndrome

Abstract

Inherited immune deficiencies are a heterogeneous group of diseases that can be either isolated, with the immune defect being the exclusive manifestation, or associated with other abnormalities. We report on two sisters, born to consanguineous parents of Sri-Lankan descent, who presented in infancy with immunodeficiency, gonadal dysgenesis, and fatal lung fibrosis. Immune studies demonstrated combined humoral and cellular abnormalities including reduced immunoglobulin production, an absence of lymphoid tissue, markedly reduced T-lymphocyte numbers and function and reduced newly thymus-derived T-cells. Both infants succumbed to rapidly progressive lung fibrosis. Autopsy showed dysgenetic gonads bearing no discernible oocytes. In both, karyotypes were normal female (46,XX). Comparative genome hybridization and analysis of genes known to be associated with severe immune defects in infancy or gonadal dysgenesis showed no abnormality. The distinct findings in these two sisters have not been reported before and thus suggest a hitherto unknown autosomal recessive condition that includes immune dysfunction, gonadal dysgenesis, and pulmonary fibrosis.

Cutting edge: FasL+ immune cells promote resolution of fibrosis

“…In addition, pulmonary fibrosis has been linked to several immune deficiency-related diseases, including HIV [46] and adenosine deaminase (ADA) deficiency, which typically cause SCID in infants [47], as well as ataxia telangiectasia, and common variable immune deficiency [48]. In addition, a new syndrome of fatal lung fibrosis was reported to be clearly associated with immunodeficiency [49].…”

Molecular Assessment of Thymus Capabilities in the Evaluation of T-Cell Immunodeficiency

“…Significant T-cell immunodeficiency should, however, be considered in clinically immunodeficient patients who present with an atypical immunologic phenotype as a result of residual autologous T cells (17,18), maternal T-cell engraftment (19), a leaky thymus with release of some T-cell clones (11), or of being part of combined immunodeficiency syndrome. In cases such as these, elaborate and intensive studies of the thymus, including assessment of recent thymic emigrant cells or analysis of the TCR repertoire, are required to estimate the severity and nature of the immune disorder (20). Indeed, in the three cases presented herein, these assays were able to distinguish between patients with normal and abnormal T-cell immunity regardless of the normal numbers of lymphocytes/T cells that were found in each of them.…”

Perspectives in Pediatric Pathology, Chapter 5. Gonadal Dysgenesis

“…Rare associated somatic anomalies include neurosensory hearing loss (a phenotype known as Perrault syndrome) [81,82], achondroplasia [83], and fatal lung fibrosis with immunodeficiency [84].…”