Alpelisib to treat CLOVES syndrome, a member of the PIK3CA-related overgrowth syndrome spectrum

CLOVES syndrome is a rare congenital overgrowth disorder caused by mutations in the phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) gene. It is part of the PIK3CA-related overgrowth syndrome (PROS) spectrum and its treatment is challenging. PROS malformations have traditionally been treated by surgery, but research into pharmacological treatments capable of blocking the PIK/AKT/mTOR pathway has increased over the past decade. Its favorable results in these settings suggest that its compassionate use in patients with PROS disorders could have clinical benefits. Another promising drug is Alpelisib, which is a selective inhibitor that competitively binds to the p110a subunit of PIK3 in the intracellular PI3K/AKT signaling pathway. A low dose of Alpelisib used on compassionate grounds was shown in an uncontrolled case series to have striking effects in a cohort of 19 PROS patients, several with life-threatening complications. Moreover, the low dose of Alpelisib provoked few side effects and did not impair linear growth of the often young patients. We present the case of a patient with CLOVES syndrome who was started on compassionate treatment with Alpelisib after surgical debulking of a cystic lymphangioma and treatment with sirolimus. This promising drug significantly reduced the size of the lymphangioma and prevented progression of the tissue overgrowth in the gluteal region. This case suggest that there may even be collateral benefits of low-dose PI3K inhibition beyond mitigating disease-specific features of PROS.

DNMT3A Overgrowth Syndrome is associated with the development of hematopoietic malignancies in children and young adults

DNMT3A Overgrowth Syndrome (DOS, also known as Tatton-Brown Rahman Syndrome/TBRS) is one of several overgrowth syndromes with complex phenotypes caused by constitutional mutations in genes encoding epigenetic regulators. The clinical features of DOS are variable but include overgrowth (tall stature and/or obesity) and intellectual disability. DNMT3A is essential for de novo DNA methylation and plays an important role in hematopoiesis. Somatic mutations in DNMT3A are among the most common initiating mutations in normal karyotype acute myeloid leukemia (AML) patients and in elderly people with clonal hematopoiesis. The natural history of DOS has not been fully explored since the first description of this rare condition in 2014. Because of the association of somatic DNMT3A mutations and leukemia development, we assessed information from the ~200 known DOS patients world-wide and were able to document eight with hematologic malignancies. Based on this prevalence, we suggest DOS is a cancer predisposition syndrome, especially for hematologic malignancies. Using recommendations from an expert panel, we suggest DOS patients should be prospectively monitored for hematologic malignancies, which may allow for early intervention and permit its natural history to be better defined.

Kosaki Overgrowth Syndrome: Report of a Family with a Novel PDGFRB Variant

Heterozygous activating missense variants of <i>PDGFRB</i> are associated with the phenotype of Kosaki overgrowth syndrome (KOGS). Here, we present a family including a father and 2 siblings with a novel variant, c.2567A&#x3e;T (p.Asn856Ile), localized in the cytoplasmic tyrosine kinase domain, exhibiting a KOGS phenotype. The coarsening of the facial features, enlargement of the hands/feet, and progressive scoliosis started to appear after an average age of 6. There were no signs of thin/fragile skin, premature aging appearance, myofibroma, white matter findings, and intellectual disability in any of them. Corneal pterygium and evidence of cerebral vasculopathy were only detected in the father. One sibling exhibited café-au-lait spots. Posterior fossa enlargement was revealed only in one sibling. KOGS is an extremely rare overgrowth syndrome. No familial cases of KOGS have been reported so far. Hereby, we demonstrated that the features of KOGS can show mild intrafamilial variability, and the risk of vascular complications may arise with age.

Bacterial overgrowth syndrome in adolescents with Сhronic viral hepatitis C

There is a close relationship between intestine and liver, so-called ‘gut liver’ axis, especially in patients suffered from chronic liver diseases with significant degree of fibrosis. Small intestinal bacterial overgrowth and disturbance in the microbiota composition lead to an increase in the permeability of the intestinal epithelium, the development of endotoxinemia, the activation of pro-inflammatory cytokines and, as a consequence, an additional damage to hepatocytes.Objective. To estimate the incidence of bacterial overgrowth syndrome (BOS) in the small intestine in adolescents with chronic hepatitis C (CHC), to identify the interaction between this syndrome and cytolytic activity, the degree of fibrosis.Materials and methods. There is a group of 33 patients aged 12—17 years old with CHC. All children underwent a hydrogen breath test with lactulose. The degree of fibrosis was assessed by the results of liver elastography (Fibroscan), cytolytic activity was determined by the level of alanine transaminase in serum.Results. The frequency of BOS was 81.8% in the study group. As a result of the correlation analysis, no relationship was found between the development of BOS and the degree of cytolytic activity of chronic hepatitis C (criterion χ2= 0.914, p > 0.05). Also, there was no correlation between excessive bacterial contamination and the degree of fibrosis in the liver tissue (criterion χ2= 0.914,p> 0.05).Conclusion. BOS in children with CHC occurs much more often than in adults. However, no relationship was found between this syndrome and the severity of cytolytic activity, the degree of fibrotic changes in the liver.