Genetic Diagnostic Elucidation of a Patient With Multiorgan Granulomas, Facial Peculiarities, and Psychomotor Retardation

• Main Authors: Daniel Soukup, Alma Kuechler, Joachim Roesler, Leopold Pichlmaier, Maximillian Eckerland, Margarete Olivier, Florian Stehling
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2018-09-01
• Series: Frontiers in Genetics
• Subjects: chronic granulomatous disease; lip; swelling; Williams–Beuren syndrome; microdeletion; compound heterozygosity
• Online Access: https://www.frontiersin.org/article/10.3389/fgene.2018.00355/full

We report the case of a 19-years-old patient who presented with a perplexing variety of symptoms which included remarkable facial features, intellectual disability, granulomatous upper lip swelling (previously diagnosed as Melkersson–Rosenthal syndrome), Crohn’s-like disease, non-productive cough, and a granulomatous mass localized in the left lung. Chronic granulomatous disease (CGD) was diagnosed using dihydrorhodamine 123 assay that showed low levels of phagocytic NADPH-oxidase. DNA sequencing revealed a heterozygous mutation in the NCF-1 gene on chromosome 7. As remarkable facial features and psychomotor retardation are not associated with CGD, a more detailed genetic work-up using fluorescence in situ hybridization was performed. A microdeletion in 7q11.23 on one allele indicated Williams–Beuren syndrome (WBS). The NCF-1 gene and its two pseudogenes are part of a highly repetitive region within 7q11.23 and are prone to recombination events and deletions. Such deletions can involve both the WBS critical region and the NCF-1 wildtype gene, as was the case for our patient. The second allele of the NCF-1 gene was affected by the frequent c.75.76delGT mutation that stems from a recombination of the NCF-1 wildtype gene with one of its pseudogenes. In conclusion, patients with NCF-1-deficient CGD may also harbor microdeletions that result in WBS or other hereditary disorders; therefore, it is important to perform a thorough genetic analysis in order to initiate appropriate therapy for these patients.