CD40 Ligand Deficiency in Latin America: Clinical, Immunological, and Genetic Characteristics.

CD40 ligand (CD40L) deficiency is a rare inborn error of immunity presenting with heterogeneous clinical manifestations. While a detailed characterization of patients affected by CD40L deficiency is essential to an accurate diagnosis and management, information about this disorder in Latin American patients is limited. We retrospectively analyzed data from 50 patients collected by the Latin American Society for Immunodeficiencies registry or provided by affiliated physicians to characterize the clinical, laboratory, and molecular features of Latin American patients with CD40L deficiency. The median age at disease onset and diagnosis was 7 months and 17 months, respectively, with a median diagnosis delay of 1 year. Forty-seven patients were genetically characterized revealing 6 novel mutations in the CD40LG gene. Pneumonia was the most common first symptom reported (66%). Initial immunoglobulin levels were variable among patients. Pneumonia (86%), upper respiratory tract infections (70%), neutropenia (70%), and gastrointestinal manifestations (60%) were the most prevalent clinical symptoms throughout life. Thirty-five infectious agents were reported, five of which were not previously described in CD40L deficient patients, representing the largest number of pathogens reported to date in a cohort of CD40L deficient patients. The characterization of the largest cohort of Latin American patients with CD40L deficiency adds novel insights to the recognition of this disorder, helping to fulfill unmet needs and gaps in the diagnosis and management of patients with CD40L deficiency.

Acquired Angioedema due to C1-Inhibitor Deficiency: A Challenging Condition.

BACKGROUND: Acquired deficiency of C1 inhibitor (AAE-C1-INH) is a very rare cause of recurrent angioedema, with few cases reported in the literature. We aimed to describe a series of patients with AAE-C1-INH who were diagnosed and received care at angioedema reference centers in Brazil, affiliated to the Brazilian Group of Studies on Hereditary Angioedema. METHODS: Fourteen patients from 8 Brazilian Angioedema Reference Centers, diagnosed with AAE-C1-INH, were included in this study. Clinical data collected included sex, date of birth, date of onset of symptoms, date of diagnosis, plasma levels of antigenic and/or functional C1-INH, levels of C4 and C1q, location and treatment of angioedema attacks, long-term prophylaxis, associated diseases, and definitive treatment. RESULTS: Fourteen patients were identified with AAE-C1-INH. Most patients (10/14; 71.4%) were female. The median age at onset of symptoms was 56.5 years (range, 14-74 years; interquartile range [IQR], 32-64 years), and median age at diagnosis was 58.0 years (range, 20-76 years; IQR, 38-65 years), with a median time until diagnosis of 2 years (range, 0-6 years; IQR, 1-3 years). The most common manifestations were cutaneous (face, eyelids, lips, trunk, hands, feet, and genitals). Most patient had low levels of C4 (13/14; 92.8%) and of antigenic C1-INH (8/14; 57.1%). Four had decreased functional activity of C1-INH (4/7; 57.1%) and C1q levels were low in 5 patients (5/12; 41.6%). Underlying diseases were identified in all 14 patients, with lymphoma of the splenic marginal zone and monoclonal gammopathy of undetermined significance being the most frequent. Nine patients (64.2%) needed long-term prophylactic treatment for recurrent angioedema and 5 patients (46.7%) required treatment for angioedema attacks. Most of them (12/14; 85.7%) had resolution of angioedema. CONCLUSION: Therapy of AAE-C1-INH aims to control symptoms; however, diagnosis and treatment of the underlying disease, when present, should be an important target and may lead to the resolution of angioedema in patients with AAE-C1-INH.

Síndrome de Melkersson-Rosenthal como diagnóstico diferencial de edema labial / Melkersson-Rosenthal syndrome as a differential diagnosis of lip swelling

A síndrome de Melkersson-Rosenthal é uma condição rara caracterizada pela tríade clássica: edema orofacial, língua fissurada e paralisia facial. Pode haver apenas uma ou duas manifestações por tempo prolongado, dificultando o diagnóstico. É denominada queilite de Miescher quando a única manifestação é o edema orofacial, com histologia característica. O presente relato tem como objetivo alertar para o diagnóstico da síndrome de Melkersson- Rosenthal em casos de angioedema labial crônico, com revisão da literatura. Mulher de 40 anos apresentando edema labial desde os 23 anos de idade, sem regressão há cinco anos, sem prurido, sem desencadeantes. Observou-se língua fissurada ao exame físico. Sem alterações aos exames complementares. O edema orofacial persistente, a língua fissurada, a biópsia de lábio inferior evidenciando queilite crônica (hiperqueratose e infiltração linfocítica perivascular) e a exclusão de diagnósticos diferenciais através de exames complementares permitiram o diagnóstico da síndrome de Melkersson-Rosenthal. A paciente foi então encaminhada à Cirurgia Plástica, que orientou retirada cirúrgica do excesso labial. O diagnóstico da síndrome é essencialmente clínico. O tratamento deve ser individualizado, visando o alívio das manifestações clínicas apresentadas em cada caso. É importante o acompanhamento multiprofissional tentando minimizar danos psicológicos e melhorar o prognóstico. A síndrome de Melkersson- Rosenthal pode apresentar-se como angioedema labial crônico e língua fissurada, sem paralisia facial, podendo retardar o diagnóstico, como no presente caso. É necessária a lembrança da síndrome para o diagnóstico e conduta mais precoce, para melhor qualidade de vida destes pacientes.

Melkersson-Rosenthal syndrome is a rare condition characterized by the classic triad: orofacial edema, fissured tongue, and facial paralysis. Only 1 or 2 manifestations of the triad may be present for a prolonged time, making diagnosis difficult. It is called Miescher's cheilitis when the only manifestation is orofacial edema, with characteristic histology. The present report aims to alert to the diagnosis of Melkersson-Rosenthal syndrome in cases of chronic lip angioedema, with a review of the literature. A 40- year-old woman presented with lip swelling since the age of 23, with no regression of the swelling for 5 years, without pruritus or triggers. A fissured tongue was observed on physical examination. Complementary tests showed no abnormalities. Persistent orofacial edema, fissured tongue, lower lip biopsy showing chronic cheilitis (hyperkeratosis and perivascular lymphocytic infiltration) and the exclusion of differential diagnoses through complementary tests led to the diagnosis of Melkersson-Rosenthal syndrome. The patient was then referred to the Plastic Surgery Service, which recommended surgical removal of excess lip tissue. The diagnosis of the syndrome is essentially clinical. Treatment should be individualized, aiming to alleviate the clinical manifestations in each case. Multidisciplinary follow-up is important to minimize psychological damage and improve prognosis. Melkersson- Rosenthal syndrome can present as chronic lip angioedema and fissured tongue, without facial paralysis, which may delay the diagnosis, as in the present case. It is necessary to consider the syndrome to allow earlier diagnosis and management and to provide a better quality of life for these patients.