To perform Mendelian analysis of 3 families with cold-induced urticaria and identify and elucidate immunologic pathways and mechanisms.Three families with a dominantly inherited complex of cold-induced urticaria, antibody deficiency, and susceptibility to infection and autoimmunity.Immunophenotyping, including flow cytometry, analysis of serum immunoglobulins and autoantibodies, lymphocyte stimulation, and enzymatic assays, was used. Genetic studies, including linkage analysis, targeted Sanger sequencing, and next-generation whole-genome sequencing, were performed.Cold-induced urticaria occurred in all affected subjects. Other, variable manifestations included atopy, granulomatous rash, autoimmune thyroiditis, antinuclear antibodies, sinopulmonary infections, and common variable immunodeficiency. Levels of serum IgM and IgA, circulating natural killer cells, and class-switched memory B cells were reduced. Linkage analysis led to the identification of an interval on chromosome 16q that included PLCG2, which encodes phospholipase Cγ2, a signaling molecule expressed in B cells, natural killer cells, and mast cells. Genomic sequencing identified 3 distinct in-frame deletions that co-segregated with disease. These deletions, located within a region encoding an inhibitory domain, result in protein products with constitutive phospholipase activity. PLCG2-expressing cells had diminished cellular signaling at 37oC but enhanced signaling at subphysiologic temperatures.Genomic deletions in PLCG2 cause gain of function of phospholipase Cγ2, leading to signaling abnormalities in multiple leukocyte subsets and a phenotype that includes both deficient and excessive immune function.This is a very interesting “experiment of nature” that provides a great deal of insight into phospholipase-mediated signaling. It is fascinating that the PLCG2 mutations identified in this report could lead to both impaired and excessive immune function and that this can be affected by temperature.
In their recent article, authors Donaldson, Forrest, and Gole describe their results after conventional management of consecutive exotropia. 1 Donaldson M.J. Forrest M.P. Gole G.A. The surgical management of consecutive exotropia. J AAPOS. 2004; 8: 230-236 Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar In one case, they describe a medial rectus “pseudotendon.” We previously reported a comprehensive series of clinical and laboratory studies of scar remodeling after strabismus surgery 2 Ludwig I.H. Scar remodeling after strabismus surgery. Trans Am Ophthalmol Soc. 1999; 97: 583-651 PubMed Google Scholar , 3 Ludwig I.H. Chow A.Y. Scar remodeling after strabismus surgery. J AAPOS. 2000; 4: 326-333 Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar that addressed these issues in depth. Using an animal model of scar stretch after strabismus surgery on rabbit eyes, we were able to demonstrate the need for direct repair of stretched scars (seen in greater than 50% of consecutive exotropia cases) with nonabsorbable sutures. The use of absorbable suture, especially with hang-back techniques, was shown to lead to a high rate of stretch recurrence. The authors have too short a follow-up period to detect all the potential recurrences, as stretching may occur during the course of years. Additionally, their practice of operating on fresh antagonist lateral recti will usually lead to balanced stretching of the medial and lateral recti, stabilizing the situation for a period of time. The medial recti usually prevail over their weaker opponents, and recurrent exotropia usually results. Authors’ replyJournal of American Association for Pediatric Ophthalmology and Strabismus {JAAPOS}Vol. 10Issue 3PreviewWe thank Drs. Ludwig and Chow for taking the time to comment on our paper and Drs. Wang and Campolattaro for also drawing our attention to Dr Ludwig’s work. Drs. Ludwig and Chow make several criticisms that we address here. Full-Text PDF
Clinical Professor of Medicine, Stanford University School of Medicine, Stanford, California, USA Correspondence to Glen A. Lillington, 1020 Siskiyou Drive, Menlo Park, CA 94025, USA E-mail: [email protected]
