A number sign (#) is used with this entry because of evidence that VISS syndrome (vascular aneurysm, immune dysregulation, skeletal anomalies, and skin and joint laxity) is caused by homozygous or compound heterozygous mutation in the IPO8 gene (605600) on chromosome 12p11.

VISS syndrome is a generalized connective tissue disorder characterized by early-onset thoracic aortic aneurysm and other connective tissue findings, such as aneurysm and tortuosity of other arteries, joint hypermobility, skin laxity, and hernias, as well as craniofacial dysmorphic features, structural cardiac defects, skeletal anomalies, and motor developmental delay (Van Gucht et al., 2021). Immune dysregulation has been observed in some patients (Ziegler et al., 2021).

Van Gucht et al. (2021) reported 7 patients from 6 unrelated families presenting with a Loeys-Dietz (LDS; see 609192)/Shprintzen-Goldberg (SGS; 182212)-like syndrome and biallelic mutations in the IPO8 gene. Consistent features included facial dysmorphisms with dolichocephaly, frontal bossing, hypertelorism, eyelid ptosis, retrognathia, and a high-arched or cleft palate/bifid uvula. Skeletal findings included joint hypermobility and pectus excavatum in all, arachnodactyly, foot deformity, and scoliosis. Neuromuscular features included hypotonia and developmental delay, primarily motor, in all patients. Cardiovascular abnormalities included aortic root and/or ascending aortic aneurysm as well as structural heart disease in all, involving atrial or ventricular septal defects and patent ductus arteriosus. In addition, most patients had umbilical and/or inguinal hernias. No disproportionate body growth was observed. No dissection had occurred in the patients despite the severe aneurysm phenotype, which the authors suggested might be due to their young age (3 to 19 years). The authors also noted that marked arterial tortuosity, a typical LDS feature, was reported in only 2 affected individuals (2-II:1 and 6-II:1), but might have been overlooked in other patients because they had not undergone head-to-pelvis arterial imaging. Van Gucht et al. (2021) concluded that the phenotype fit into the spectrum of LDS/SGS-like disorders.

Through international collaboration facilitated by GeneMatcher, Ziegler et al. (2021) ascertained 12 patients from 9 families with biallelic mutations in the IPO8 gene who displayed a complex syndrome, reminiscent of LDS and SGS, that variably combined cardiovascular, neurologic, skeletal, and immunologic abnormalities as well as dysmorphic features. Early-onset dilatation of the ascending aorta was present in 7 individuals, occurring before 1 year of age in the youngest. The 2 oldest sibs (patients 1 and 2), who were 59 and 53 years old at the time of the first assessment, exhibited diffuse arterial frailty with multiple aneurysms involving the abdominal aorta, the iliac, coronary, and renal arteries and, in patient 1, the thoracic aorta. LDS-like arterial tortuosity was noted in 4 individuals. Patients 1 and 2 also experienced recurrent spontaneous pneumothorax, and pulmonary emphysema was present in patient 1 as well as in 2 younger patients. Facial dysmorphism was observed in 10 individuals, and 11 had joint hyperlaxity complicated by multiple joint dislocations. All displayed skeletal features, including scoliosis in 9, pectus excavatum or carinatum in 6, arachnodactyly in 6, and pes planus or talipes equinovarus in 6. Myopia was present in 8 individuals, complicated by retinal detachment in 2 of them and by early-onset cataract in 2 others, but none had lens dislocation. Consistent with a generalized connective tissue disorder, skin hyperextensibility and/or hernia were observed in 11 individuals. Delayed motor milestones, presumably due to joint instability, were observed in 7 individuals; 4 displayed impaired intellectual development, mild in 3 and severe in 1. Predisposition to allergic or inflammatory diseases, which had been reported in LDS, was seen in 6 individuals, some of whom also displayed immunologic parameters consistent with impaired TGF-beta (TGFB1; 190180) signaling, including hyper-IgE, hyper-IgG, hypo-IgA, and hypereosinophilia.

By combining exome/genome sequencing with data repository analysis, Bertoli-Avella et al. (2021) identified 9 unrelated patients with VISS syndrome. The patients exhibited dysmorphic features, hypotonia, and findings reminiscent of connective tissue disease, such as high palate, pectus deformities, hernias, gray-blue sclerae, cutis laxa, tortuosity of cerebral arteries, and congenital heart defects. In some patients, clinical suspicion included LDS and Ehlers-Danlos syndrome (see 130000).

The transmission pattern of VISS syndrome in the families reported by Van Gucht et al. (2021), Ziegler et al. (2021), and Bertoli-Avella et al. (2021) was consistent with autosomal recessive inheritance.

In 6 unrelated probands with VISS syndrome, who were negative for mutation in known thoracic aortic aneurysm-associated genes, Van Gucht et al. (2021) performed exome or genome sequencing and identified homozygosity or compound heterozygosity for truncating mutations in the IPO8 gene (see, e.g., 605600.0001-605600.0004). The mutations segregated with disease in the respective families and were not present or were present at very low minor allele frequency in the gnomAD database. Sanger sequencing of IPO8 in 50 more genetically unsolved Marfan syndrome (154700)-, LDS-, or SGS-like probands did not reveal additional individuals with biallelic variants.

Through international collaboration facilitated by GeneMatcher, Ziegler et al. (2021) ascertained 12 patients from 9 families with biallelic mutations in the IPO8 gene (see, e.g., 605600.0002 and 605600.0005-605600.0006) who displayed a syndromic association characterized by cardiovascular anomalies, joint hyperlaxity, and a variable degree of dysmorphic features and developmental delay, as well as immune dysregulation in some patients. Sanger sequencing confirmed segregation of the variants with disease within each family.

By combining exome/genome sequencing with data repository analysis, Bertoli-Avella et al. (2021) identified 9 unrelated patients with VISS syndrome and mutations in the IPO8 gene (see, e.g., 605600.0001 and 605600.0007).