Fibromuscular dysplasia (FMD) is a heterogeneous group of non-atherosclerotic and non-inflammatory arterial diseases that primarily involves the renal and cerebrovascular arteries. Grange syndrome is an autosomal-recessive condition characterized by severe and early-onset vascular disease similar to FMD and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Exome-sequencing analysis of DNA from three affected siblings with Grange syndrome identified compound heterozygous nonsense variants in YY1AP1, and homozygous nonsense or frameshift YY1AP1 variants were subsequently identified in additional unrelated probands with Grange syndrome. YY1AP1 encodes yin yang 1 (YY1)-associated protein 1 and is an activator of the YY1 transcription factor. We determined that YY1AP1 localizes to the nucleus and is a component of the INO80 chromatin remodeling complex, which is responsible for transcriptional regulation, DNA repair, and replication. Molecular studies revealed that loss of YY1AP1 in vascular smooth muscle cells leads to cell cycle arrest with decreased proliferation and increased levels of the cell cycle regulator p21/WAF/CDKN1A and disrupts TGF-β-driven differentiation of smooth muscle cells. Identification of YY1AP1 mutations as a cause of FMD indicates that this condition can result from underlying genetic variants that significantly alter the phenotype of vascular smooth muscle cells.

PURPOSESmooth muscle dysfunction syndrome (SMDS) due to heterozygous ACTA2 arginine 179 alterations is characterized by patent ductus arteriosus, vasculopathy (aneurysm and occlusive lesions), pulmonary arterial hypertension, and other complications in smooth muscle-dependent organs. We sought to define the clinical history of SMDS to develop recommendations for evaluation and management.METHODSMedical records of 33 patients with SMDS (median age 12 years) were abstracted and analyzed.RESULTSAll patients had congenital mydriasis and related pupillary abnormalites at birth and presented in infancy with a patent ductus arteriosus or aorto-pulmonary window. Patients had cerebrovascular disease characterized by small vessel disease (hyperintense periventricular white matter lesions; 95%), intracranial artery stenosis (77%), ischemic strokes (27%), and seizures (18%). Twelve (36%) patients had thoracic aortic aneurysm repair or dissection at median age of 14 years and aortic disease was fully penetrant by the age of 25 years. Three (9%) patients had axillary artery aneurysms complicated by thromboembolic episodes. Nine patients died between the ages of 0.5 and 32 years due to aortic, pulmonary or stroke complications, or unknown causes.CONCLUSIONBased on these data, recommendations are provided for the surveillance and management of SMDS to help prevent early onset life-threatening complications.

Moyamoya disease (MMD) is a progressive vasculopathy characterized by occlusion of the terminal portion of the internal carotid arteries and its branches, and the formation of compensatory moyamoya collateral vessels. Homozygous mutations in GUCY1A3 have been reported as a cause of MMD and achalasia. Probands (n = 96) from unrelated families underwent sequencing of GUCY1A3. Functional studies were performed to confirm the pathogenicity of identified GUCY1A3 variants. Two affected individuals from unrelated families were found to have compound heterozygous mutations in GUCY1A3. MM041 was diagnosed with achalasia at 4 years of age, hypertension and MMD at 18 years of age. MM149 was diagnosed with MMD and hypertension at the age of 20 months. Both individuals carry one allele that is predicted to lead to haploinsufficiency and a second allele that is predicted to produce a mutated protein. Biochemical studies of one of these alleles, GUCY1A3 Cys517Tyr, showed that the mutant protein (a subunit of soluble guanylate cyclase) has a significantly blunted signaling response with exposure to nitric oxide. GUCY1A3 missense and haploinsufficiency mutations disrupt nitric oxide signaling leading to MMD and hypertension, with or without achalasia.

SUMMARYEmotional distress is the subjective sensation of diminishment in wellbeing which manifests itself in a number of unspecific symptoms. It might be a risk factor for the development of mental illness, especially among individuals with psychosocial or biological vulnerability. Recent studies show that primary health care services receive a growing number of patients who suffer distress, but do not fulfill the diagnostic criteria of a mental or physical illness. This phenomenon is more frequent among women. The objective of this paper is to analyze the emotional distress experienced by a group of women who attended primary health care institutions in Mexico City, as well as their perceptions and experiences around the attention received, in order to identify their treatment needs. Data was gathered through techniques and instruments pertaining qualitative methodology. The information was coded and analyzed according to the meaning categorization method developed by Kvale. The results show that the main triggers of emotional distress are associated to daily life worries (lack of money, problems with children, domestic violence, among others). In some cases, it is associated as well with traumatic events, such as violence and sexual abuse in the past or at present. Data also suggest that women do not talk about emotional distress directly during medical consultations and that health care professionals do not identify distress or minimize its importance. These aspects are related to the current characteristics of the service, which lacks a comprehensive approach and a psychosocial point of view.Key words: Emotional distress, mental health, gender, primary health care. RESUMENLa presencia de malestar emocional -que se define como el conjunto de sensaciones subjetivas que percibe una persona de que su bienestar sufre una merma y que se manifiesta por síntomas inespecíficos-puede constituir un factor de riesgo para la aparición de enfermedades mentales, sobre todo en personas con vulnerabilidades biológicas y psicosociales. Estudios recientes señalan que los servicios de atención primaria reciben un número, cada vez mayor, de personas con malestares que no cubren los criterios diagnósticos de una enfermedad, ya sea mental o física, fenómeno que es más frecuente en las mujeres.El objetivo de este trabajo es analizar los malestares emocionales de un grupo de mujeres que acude a instituciones de atención primaria de la Ciudad de México, así como sus percepciones y vivencias sobre la atención recibida, con el propósito de identificar necesidades de atención. Para recopilar la información se utilizaron técnicas e instrumentos propios de la metodología cualitativa.La información se codificó y analizó conforme al método de "categorización de significados" propuesto por Kvale. Los resultados mostraron que los principales detonantes de los malestares emocionales en las participantes se asocian con las preocupaciones que enfrentan cotidianamente (como falta de dinero, problemas con los hijos y violencia intrafamiliar) y, en...

Women with BRCA1 or 2 mutations are at high risk for breast cancer. For BRCA1, a trend of increasing risk has been associated with increasing downstream (3′) location for mutations compared to the upstream (5′) mutations in the gene. For BRCA2, an increased risk of breast cancer has been associated with mutations outside of the ovarian cancer cluster region (OCCR). We sought to determine the mutation position in BRCA-associated breast cancers and whether or not there was a genotype-phenotype correlation. Breast cancer patients with BRCA1/2 mutations were identified by a search of a prospectively maintained data base. Mutation site, patient, and tumor characteristics were determined through retrospective review. One hundred and sixty-four patients with BRCA1-associated breast cancer and 109 patients with BRCA2-associated breast cancer were identified. Among patients with BRCA1-associated cancers, 86 (52%) had mutations in the 5′ half of the gene. Among patients with BRCA2-associated breast cancers, 40 (37%) had OCCR mutations. Although BRCA1-associated tumors were more likely to be ER/PR- than BRCA2-associated cancers (p < 0.0001), there was no difference in the tumor characteristics among BRCA1 or BRCA2-associated cancers based on mutation location. In this single-institution study, over half of BRCA1-associated and over a third of BRCA2-associated breast cancers were associated with putative lower risk mutations. Although we cannot exclude the possibility that mutations in these regions confer a lower relative risk for breast cancer, vigilance in cancer screening and prevention remains necessary. Further studies in genotype/phenotype correlation are needed to individualize prevention strategies.