Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections.

Gene mutations that lead to decreased contraction of vascular smooth-muscle cells (SMCs) can cause inherited thoracic aortic aneurysms and dissections. Exome sequencing of distant relatives affected by thoracic aortic disease and subsequent Sanger sequencing of additional probands with familial thoracic aortic disease identified the same rare variant, PRKG1 c.530G>A (p.Arg177Gln), in four families. This mutation segregated with aortic disease in these families with a combined two-point LOD score of 7.88. The majority of affected individuals presented with acute aortic dissections (63%) at relatively young ages (mean 31 years, range 17-51 years). PRKG1 encodes type I cGMP-dependent protein kinase (PKG-1), which is activated upon binding of cGMP and controls SMC relaxation. Although the p.Arg177Gln alteration disrupts binding to the high-affinity cGMP binding site within the regulatory domain, the altered PKG-1 is constitutively active even in the absence of cGMP. The increased PKG-1 activity leads to decreased phosphorylation of the myosin regulatory light chain in fibroblasts and is predicted to cause decreased contraction of vascular SMCs. Thus, identification of a gain-of-function mutation in PRKG1 as a cause of thoracic aortic disease provides further evidence that proper SMC contractile function is critical for maintaining the integrity of the thoracic aorta throughout a lifetime.

A family with Classical Ehlers-Danlos Syndrome (cEDS), mild bone fragility and without vascular complications, caused by the p.Arg312Cys mutation in COL1A1.

The Ehlers-Danlos syndromes (EDS) are heritable disorders of connective tissue (HDCT) with joint hypermobility, skin hyperextensibility and tissue fragility, which were recently re-classified (2017 International Classification). Most patients (>90%) with Classical Ehlers-Danlos syndrome (cEDS) have a mutation in the COL5A1 or COL5A2 genes encoding type V procollagen. A small number of patients with the p.Arg312Cys mutation in COL1A1 have been reported with overlapping features of both cEDS and vascular EDS (vEDS). In this report, we describe two patients from a large family with this mutation and clinical features consistent with cEDS without vascular complications. The proband presented with congenital hip dislocation (previously reported in one patient), the mother of the proband with multiple fractures in childhood, and dental defects (novel findings). The small number of patients reported with this mutation and proportion with vascular complications suggests that vascular surveillance should still be recommended.

Successful outcome in pregnancy with arterial tortuosity syndrome.

BACKGROUND: Arterial tortuosity syndrome is a rare, autosomal recessive, severe, connective tissue disorder caused by a mutation in the SLC2A10 gene. We describe the pregnancy and delivery with this high-risk connective tissue disorder involving generalized abnormalities of the vasculature. CASE: A woman with an undefined connective tissue disorder was referred for tertiary prenatal care. Diagnostic imaging demonstrated multiple pulmonary artery aneurysms and arterial tortuosity, consistent with a clinical diagnosis of arterial tortuosity syndrome. With a team considering all potential complications, a delivery plan was undertaken involving cesarean delivery and intensive perioperative and postpartum monitoring. The outcome was optimal for mother and neonate. Concurrent molecular testing demonstrated homozygosity for the SLC2A10 gene. CONCLUSION: Optimal maternal, fetal and neonatal outcomes were obtained with comprehensive multidisciplinary care and close maternal and fetal surveillance.

A Practical Guide to Clinical Management of Thoracic Aortic Disease.

Physicians and surgeons faced with patients with thoracic aortic disease (TAD) need to determine the underlying diagnosis to facilitate decisions regarding appropriate investigations as well as which other specialists to involve, when to start medical therapy, when to refer for surgery, and how to plan follow-up and family screening. Increased understanding of conditions predisposing to thoracic aortic aneurysm (TAA) provides the opportunity for more personalized care. However, given advances in the genetics of TAD, clinicians are now faced with an expanded and often confusing list of associated differential diagnoses. We present a practical guide to managing patients with TAD based on current knowledge and guidelines. Important "flags" on history taking and "tips" to diagnosis on physical examination along with what investigations to order and what referrals to request are discussed. Need for medical therapy, indications for surgical repair, and planning long-term follow-up of TAD are determined by age, the underlying TAD diagnosis, previous vascular history in the patient or other family members (or both), aortic dimensions and growth rate, and any coexisting cardiovascular disease. Although medications may slow the progression of TAA, effective aortic surveillance and timely elective surgical repair remain the mainstays of prevention of acute aortic complications. Emergent repair of acute aortic dissection carries a far worse prognosis. Taking a practical approach to the management of TAD allows for standardized assessment and implementation of current best practice clinical guidelines. Ongoing discovery of new genes, better medical therapies, and innovative surgical techniques necessitate constantly adapting knowledge and integrating it into everyday clinical practice.