CBM-opathies for the dermatologist: a rapidly expanding delineated spectrum of heterogeneous phenotypes

CBM [Caspase recruitment domain (CARD) protein–B cell lymphoma/leukaemia 10 (BCL10)–MALT1 paracaspase (MALT1)] complex proteins regulate critical signalling of innate and adaptive immunity. They cause a spectrum of primary immunodeficiency disorders, primary atopic disorders and immunodysregulatory syndromes. Germline mutations associated with CBM-opathies can cause antifungal immunodeficiency, CADINS, BENTA, atopic dermatitis, psoriasis, pityriasis rubra pilaris, and CARD14-associated papulosquamous eruption. Genes related to human germline CBM-opathies include CARD9, CARD11, CARD14, BCL10 and MALT1. We have reviewed key dermatological phenotypes related to human germline CBM-opathies. A notable example includes autosomal dominant hypomorphic CARD14 mutations associated with severe atopic dermatitis. Patients tend to be in their first year of life (between 3 and 12 months) with severe atopy, recurrent pyogenic and viral skin infections, and chest infections, as a consequence. CARD14 mutations may impair nuclear factor-κB activation, decreasing inflammatory gene expression, and impact epidermal secretion of antimicrobial peptides. Although hypomorphic mutations in CARD11 and CARD14 cause atopic dermatitis, gain of function mutations are associated with BENTA and inflammatory psoriatic skin disease. Psoriasis or pityriasis rubra pilaris diagnosed in individuals with earlier onset may warrant a high suspicion for sequencing of CARD14 in patients and families to aid therapeutic decisions. Genetic diagnoses can be made using next-generation sequencing techniques, such as whole-exome sequencing, whole-genome sequencing, or an immunodeficiency gene panel. For diagnostic confirmation, novel variants for CBM-opathies may be identified using methods to assess expression of proteins such as CARD11, phosphorylation of nuclear factor-κB, and degradation of IkBa.