D1.354 - Possible Association of a MYOF Loss-of-Function Variant With Recurrent Angioedema: Overlap Between Chronic Spontaneous Urticaria and Normal-C1 Hereditary Angioedema? A Case Report

Background:Hereditary angioedema with normal C1 inhibitor (HAE-nC1INH) represents a diagnostically challenging entity due to its heterogeneous genetic basis and clinical overlap with mast cell–mediated angioedema. Recently, novel gene-disease associations have been discussed in the context of disease susceptibility or phenotype modulation.

Case Presentation:

We report a 27-year-old woman with recurrent swelling of the extremities and face, accompanied by intermittent abdominal complaints. Symptoms started in childhood and showed partial regression under antihistamine therapy with fexofenadine, but not with rupatadin. Due to frequent episodes, anti-IgE therapy with omalizumab was initiated, resulting in marked clinical improvement, but persistent recurrent attacks of abdominal pain, mainly triggered by stress, infections and menstruation and not responding to antihistamines. 

Genetic testing identified a heterozygous loss-of-function mutation in the MYOF (myoferlin) gene. To date, only one similar case has been described, involving a gain-of-function MYOF variant associated with HAE-nC1INH. The same variant detected in our patient was also found in her father and sister, both of whom report recurrent swelling responsive to antihistamines. The asymptomatic mother and brother did not harbor the variant in MYOF. We obtained written informed consent from the patient to publish her case.

Discussion:The clinical response to antihistamines and omalizumab argues for a predominantly mast cell–mediated mechanism. However, the presence of intermittent abdominal symptoms under omalizumab  raises suspicion for a possible bradykinin-mediated component. To clarify this, on-demand treatment with bradykinin-targeted therapy (icatibant or C1-inhibitor concentrate) during a future abdominal episode is planned. The relevance of the MYOF loss-of-function variant therefore remains uncertain but may represent a novel mechanism – however in an oligogenic rather than a monogenic context. 

Conclusion:This case highlights the diagnostic complexity of recurrent angioedema and suggests a possible overlap between chronic spontaneous urticaria and HAE-nC1INH. Variants in MYOF may warrant further investigation as potential contributors to angioedema susceptibility and phenotype variability.