Frail Silk: Is the Hughes-Stovin Syndrome a Behçet Syndrome Subtype with Aneurysm-Involved Gene Variants?

Abstract

Hughes-Stovin syndrome is a rare disease characterized by thrombophlebitis and multiple pulmonary and/or bronchial aneurysms. The etiology and pathogenesis of HSS are incompletely known. The current consensus is that vasculitis underlies the pathogenic process, and pulmonary thrombosis follows arterial wall inflammation. As such, Hughes-Stovin syndrome may belong to the vascular cluster with lung involvement of Behçet syndrome, although oral aphtae, arthritis, and uveitis are rarely found. Behçet syndrome is a multifactorial polygenic disease with genetic, epigenetic, environmental, and mostly immunological contributors. The different Behçet syndrome phenotypes are presumably based upon different genetic determinants involving more than one pathogenic pathway. Hughes-Stovin syndrome may have common pathways with fibromuscular dysplasias and other diseases evolving with vascular aneurysms. We describe a Hughes-Stovin syndrome case fulfilling the Behçet syndrome criteria. A MYLK variant of unknown significance was detected, along with other heterozygous mutations in genes that may impact angiogenesis pathways. We discuss the possible involvement of these genetic findings, as well as other potential common determinants of Behçet/Hughes-Stovin syndrome and aneurysms in vascular Behçet syndrome. Recent advances in diagnostic techniques, including genetic testing, could help diagnose a specific Behçet syndrome subtype and other associated conditions to personalize the disease management.

Keywords: Behçet syndrome; Hughes-Stovin syndrome; MYLK; myosin light chain kinase; personalized medicine; pulmonary artery aneurysm; thoracic aortic aneurysms and dissections; vascular cluster.

Figure 1

A graphic illustration of the full-length human MYLK gene, structural model consisting of 1915 amino acids with domains; this gene, a muscle member of the immunoglobulin gene superfamily, encodes myosin light chain kinase (a calcium-calmodulin dependent enzyme). Also regulates actin-myosin interaction through a non-kinase activity. Depicted are the actin-binding domain, catalytic core, the regulatory segment containing the inhibitory and calmodulin-binding domains, and the kinase-related protein (KRP) domain. The region where the patient’s variant c.1472A>G (p.Asn491Ser) is located is indicated by the blue triangle. In our case, the MYLK mutation interests the codon 491, localized in the exon 11, in the Ig-like domain 3, involved in the EC cytoskeletal functions based on [23].

Figure 2

Myosin Light Chain Kinase gene (MYLK) products; schematic representation of each protein and its domain structure. The gene MYLK encodes 3 proteins: MLCK210 (210–220 kDa), MLCK108 (110–140 kDa), and telokin/kinase-related protein (KRP) (based on [44,46]).

Figure 3

MLCK210 is a signal integrator molecule containing several interaction sites for cytoskeletal and regulatory proteins (based on [44,45]). Adapted with permission from Ref. [44], Shirinsky, V.P. (2012). MYLK (Myosin Light Chain Kinase). In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, New York. https://link.springer.com/referenceworkentry/-10.1007/978-1-4419-0461-4_248#citeas, license number 5481371185567/2023, Legend: CaM—calmodulin, KRP—kinase-related protein domain, MT—microtubules, PK+ARD1—Protein kinases and ARD1 acetylase that modify MLCK210 residues, SV—supervillin (a membrane-associated scaffolding protein interacting with MLCK210 N-terminus and with myosin II).