Generalized lymphatic anomaly (GLA) is a vascular disorder characterized by diffuse or multifocal lymphatic malformations (LMs). The etiology of GLA is poorly understood. We identified four distinct somatic PIK3CA variants (Glu542Lys, Gln546Lys, His1047Arg, and His1047Leu) in tissue samples from five out of nine patients with GLA. These same PIK3CA variants occur in PIK3CA-related overgrowth spectrum and cause hyperactivation of the PI3K–AKT–mTOR pathway. We found that the mTOR inhibitor, rapamycin, prevented lymphatic hyperplasia and dysfunction in mice that expressed an active form of PIK3CA (His1047Arg) in their lymphatics. We also found that rapamycin reduced pain in patients with GLA. In conclusion, we report that somatic activating PIK3CA mutations can cause GLA, and we provide preclinical and clinical evidence to support the use of rapamycin for the treatment of this disabling and deadly disease.

We describe for the first time the presence of somatic activating PIK3CA mutations in patients with CLAPO. We also report an update of the phenotype and natural history of the syndrome.

With the aim of providing better clinical characterisation of patients with a 1 -antitrypsin deficiency (AATD), we analysed the data of adult patients with severe AATD enrolled in the Spanish and Italian national registries.We assessed 745 subjects, 416 of whom were enrolled in the Spanish registry and 329 in the Italian registry. 57.2% were male and 64.9% were smokers or former smokers with a mean¡SD age of 49.9¡13.8 years. Most (81.2%) were index cases, mainly having the PI*ZZ genotype (73.4%), and the mean¡SD diagnostic delay was 9.0¡12.1 years.Patients with chronic bronchitis were younger, had better preserved lung function and lower tobacco consumption. Overlap patients (chronic obstructive pulmonary disease with asthma) were mainly females, more frequently never-smokers and received respiratory medications more often. 48% of emphysema, 27.5% of chronic bronchitis and 44.8% of overlap subjects were receiving augmentation therapy. Compared with PI*ZZ patients (n5547), the PI*SZ (n5124) subjects were older at diagnosis and had more preserved lung function, despite a higher mean smoking consumption.Early diagnosis of AATD is still an unmet need. Augmentation therapy is administered to similar proportions of patients with different clinical phenotypes. PI*ZZ patients in both registries had more severe respiratory disease than those with PI*SZ, despite lower smoking levels. @ERSpublications New characterisation of clinical phenotypes in patients with alpha-1 antitrypsin deficiency

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Severe alpha-1-antitrypsin (AAT) deficiency, phenotype Pi ZZ, is a rare condition with an estimated prevalence of 1/4500 individuals in Spain. Given this low prevalence, it seems useful to accumulate all the information derived from the care of these patients. In this context, the Spanish Registry of patients with AAT deficiency was founded in 1993; its main objectives were to establish guidelines adapted to our country for the treatment and management of AAT-deficient patients, offer expert support to physicians all over the country treating these patients, and provide technical support on the determination of Pi phenotyping and genotyping of individuals suspected of being AAT-deficient. From 1993 to January 1998 the number of enrollees increased from 48 to 223, of which 216 were Pi ZZ. Seventy-three per cent were male and only 31.5% were never smokers, mean age was 46 years (SD = 13 years) and mean FEV1 53% predicted (SD = 31%). 83% were index cases who, compared with non-index cases, were older (49 +/- 11 vs. 35 +/- 13 years, P < 0.001), more likely to have a smoking history (85% vs. 47%, P < 0.01) and displayed more severe impairment in pulmonary function (FEV1% = 40% +/- 19% vs. 96% +/- 23%, P < 0.001). Augmentation therapy was administered to 129 patients (58%). Treated patients had more severe impairment in pulmonary function than the untreated (FEV1% = 40% +/- 21% vs. 72% +/- 32%, P < 0.001) and were more likely to be index cases (81% vs. 43%, P < 0.001). Characteristics of the patients included are similar to those described for other Registries. The Registry has extended knowledge of the disease throughout the country and has established local guidelines for treatment and follow-up. It may be a valid database for future co-operation in international initiatives.

Based on the different mutations found, the authors propose a four-step protocol for the molecular diagnosis of CHM.

Background: CLAPO syndrome is a rare vascular disorder characterized by Capillary malformation of

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