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.

Smith‐Kingsmore syndrome (SKS) OMIM #616638, also known as MINDS syndrome (ORPHA 457485), is a rare autosomal dominant disorder reported so far in 23 patients. SKS is characterized by intellectual disability, macrocephaly/hemi/megalencephaly, and seizures. It is also associated with a pattern of facial dysmorphology and other non‐neurological features. Germline or mosaic mutations of the mTOR gene have been detected in all patients. The mTOR gene is a key regulator of cell growth, cell proliferation, protein synthesis and synaptic plasticity, and the mTOR pathway (PI3K‐AKT‐mTOR) is highly regulated and critical for cell survival and apoptosis. Mutations in different genes in this pathway result in known rare diseases implicated in hemi/megalencephaly with epilepsy, as the tuberous sclerosis complex caused by mutations in TSC1 and TSC2, or the PIK3CA‐related overgrowth spectrum (PROS). We here present 4 new cases of SKS, review all clinical and molecular aspects of this disorder, as well as some characteristics of the patients with only brain mTOR somatic mutations.

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.

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

The increased speed and decreasing cost of sequencing, along with an understanding of the clinical relevance of emerging information for patient management, has led to an explosion of potential applications in healthcare. Currently, SNP arrays and Next-Generation Sequencing (NGS) technologies are relatively new techniques used to scan genomes for gains and losses, losses of heterozygosity (LOH), SNPs, and indel variants as well as to perform complete sequencing of a panel of candidate genes, the entire exome (whole exome sequencing) or even the whole genome. As a result, these new high-throughput technologies have facilitated progress in the understanding and diagnosis of genetic syndromes and cancers, two disorders traditionally considered to be separate diseases but that can share causal genetic alterations in a group of developmental disorders associated with congenital malformations and cancer risk. The purpose of this work is to review these syndromes as an example of a group of disorders that has been included in a panel of genes for NGS analysis. We also highlight the relationship between development and cancer and underline the connections between these syndromes.

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In the LS group, a moderate/strong dermal inflammation was frequently (70%) observed, comparing to non-LS cases, which showed mostly (82%) a mild/absent inflammation. This well defines the second most common diagnosis of our non-LS group, namely LSC, a consequence of chronic itch, without inflammatory background dermatosis. In one third of the LS cases, as previously reported, 2,8 the elastic fibres were lost within the zones of sclerosis or fibrosis. This is not specific for LS and may be found also in other conditions, such as LP. 9 We found apoptotic keratinocytes in the epidermis in up to 41% of the LS cases, mostly associated with a lichenoid inflammation (83% of those cases). Within 80% of the non-LS cases, single apoptotic keratinocytes were associated with a LSC/ chronic eczema and not with lichenoid inflammation. In conclusion, the diagnosis of female genital LS may be challenging, especially in its early stages, or when the typical histological features of LS are missing. We could define 10 histopathological criteria strongly associated with LS, which should be considered when distinguishing it from other vulvar dermatoses.