Gonadal mosaicism in hereditary angioedema

To the Editor: Hereditary angioneurotic edema (HAE; OMIM #106100) is a rare autosomal dominant disorder resulting from the congenital deficiency of functional C1 esterase inhibitor protein (C1INH). Patients affected with HAE clinically are characterized by recurrent episodes of swelling of the extremities, face, trunk, airways or abdominal viscera, occurring either spontaneously or following stress and/or trauma. Laryngeal manifestations are often life threatening (1–3). Affected individuals carry a mutation in the C1-INH gene (C1-INH, SERPING1; OMIM #606860) (4, 5). C1-INH encodes for an esterase, which is the only inhibitor of the first component of the complement system (6). The C1-INH gene maps onto chromosome 11q12-q13.1, and it is organized into eight exons and seven introns (7). A large spectrum of mutations have been described in the C1-INH gene, leading to a failure in secretion or production of C1-INH protein (8, 9). Approximately 25% of these mutations occur de novo (10). We describe here the molecular genetic analysis of a family in which only the sons but not the parents show either clinical or laboratory findings typical of HAE and provide evidence for the first time of gonadic mosaicism in this disease. In 2003, two brothers, aged respectively, 4 and 1 years, were referred to the Department of Rheumatology/Allergology and Clinical Immunology of the University of Rome, Tor Vergata, for the continued presentation of repeated bouts of edema. The first child had his first attack at the age of 2 (in 2001) localized in periorbital region. The attack spontaneously resolved in few hours. In 2002, he had a new severe episode of edema localized at the left foot, which required hospitalization. He was screened for allergies and infectious diseases with no positive result, and neither treatment with steroids and antihistaminics brought any improvement. At the same time, the younger brother manifested flares in periorbital region. We decided to study both children for angioedema assaying C1-INH and C4. C1-INH plasma concentrations were less than 0.048 g/dl in both sibs (normal value 0.15– 0.35 g/dl); functional C1-INH was 17% and 30%, respectively (n.v. 70–130%). C4 levels were 7 and 3 mg/dl, respectively (n.v. 10–40 mg/dl). A critical laryngeal edema episode that occurred in one of the children was successfully treated by administration of C1-INH concentrate, confirming HAE diagnosis. Surprisingly, no clinical and laboratory findings were detected in parents and relatives. Genomic DNA was isolated from peripheral blood lymphocytes, buccal cells, hair roots, and urinary cells. PCR amplification of C1-INH gene was carried out on 200 ng of DNA using primers reported in Table 1 (11). Each amplicon was analyzed using Denaturing High Performance Liquid Chromatography (DHPLC) in a WAVE DNA Fragment Analysis System (Transgenomic Inc., Crewe, UK). Amplicons exhibiting a heterozygous pattern were purified and directly sequenced using an ABI Prism 3100 Genetic