19q13.11 microdeletion: Clinical features overlapping ectrodactyly ectodermal dysplasia-clefting syndrome phenotype.

We report a patient who was followed for a long time under an ectrodactyly ectodermal dysplasia-clefting (EEC) syndrome and was subsequently diagnosed with a 19q13.11 microdeletion. After a review of the related literature, we suggest testing patients with EEC for 19q13.11 microdeletion and include WTIP and UBA2 to a minimal overlapping region.

Analysis of mutations in EXT1 and EXT2 in Brazilian patients with multiple osteochondromas.

BACKGROUND: Multiple osteochondromas is a dysplasia characterized by growth of two or more osteochondromas. It is genetically heterogeneous, caused by pathogenic variants in EXT1 or EXT2 genes in 70%-90% of patients. The EXT1 is more often mutated than EXT2 gene, with a variable prevalence between populations. There are no data about EXT1 and EXT2 pathogenic variants in patients with multiple osteochondromas in Brazilian population. The aim of this survey is to characterize these to determine the genotype profile of this population. METHODS: DNA sequencing (Sanger Method) and MLPA analysis were performed to identify point mutations and deletions/duplications in the sample of 153 patients in 114 families. RESULTS: Germline variants were identified in 83% of families in which EXT2 variants were detected in 46% and EXT1 in 37% of cases. No variants were detected in 17% of them. We identified 50 different variants, 33 (13 frameshift, 11 nonsense, 5 missense, 2 splice site mutation, and 2 large deletions) in EXT1 and 17 (6 frameshift, 6 splice site mutation, 3 nonsense, 1 missense, and 1 large deletion) in EXT2. Of all 50 variants, 31 (62%) were novel, including 20 out of 33 (60,6%) EXT1 and 11 out of 17 (64.7%) EXT2 alleles. The vast majority of variants (88%) were "loss-of-function" and two novel hotspots in EXT2 gene were observed in our study. CONCLUSION: The prevalence of variants detected in the EXT2 gene differs from other researches from Latin America, European, and Asian population. This uncommon prevalence could be related with the newly characterized variant hotspot sites detected in EXT2 gene (p.Ala409Profs*26 and p.Ser290*). A high number of novel variants were also identified indicating that Brazilian population has a unique genetic profile. Characterizing this population and establishing its genotype is essential to understand the molecular pathogenesis of this disease in Brazil.

Avaliação de anticoagulantes naturais e de fatores da coagulação em pacientes com distúrbios congênitos de glicosilação (DCG) tipo I / An evaluation of natural anticoagulants and coagulation factors in patients with congenital disorders of glycosylation type I

Defeitos na incorporação de N-glicanos nas proteínas humanas ocasionam um grupo de doenças multissistêmicas denominadas coletivamente distúrbios congênitos de glicosilação (DCG). Os DCG manifestam-se na infância com sintomas neurológicos que incluem principalmente atraso psicomotor, ataxia, hipotonia e episódios de acidente vascular cerebral. Várias proteínas do sistema hemostático somente tornam-se biologicamente ativas após a glicosilação. O objetivo deste estudo foi avaliar os anticoagulantes naturais (proteína S livre, proteína C e antitrombina) e os fatores da coagulação (VIII, IX e XI) em pacientes com DCG tipo I. Foram avaliados 11 pacientes com diagnóstico positivo para DCG tipo I (três do gênero masculino e oito do gênero feminino), idade média de 5,6 anos; e oito pacientes com diagnóstico negativo para DCG(quatro do gênero masculino e quatro do gênero feminino), idade média de 4,5 anos (grupo-controle). O diagnóstico de DCG tipo I foi realizado pela identificação do padrão de hipoglicosilação da transferrina plasmática. Na avaliação dos anticoagulantes naturais pode-se observar redução dos valores de PS livre e PC e uma redução marcante de AT, quando comparados com o grupo controle. Em relação aos fatores de coagulação não houve diferença significativa para os fatores VIII e IX e houve redução marcante do fator XI. Os resultados do presente estudo sugerem que a deficiência combinada de anticoagulantes naturais é responsável pelo estado pró-trombótico observado em pacientes com DCG. Sugerimos também que a análise dos parâmetros hemostáticos seja realizada para pacientes com DCG quando apresentarem sintomas clínicos de alteração do sistema hemostático e antes de procedimentos invasivos.

Defects in the biosynthesis of N-linked human protein glycosylation leads to a group of multisystem disorders collectively called congenital disorders of glycosylation (CDG). CDG present in infancy with neurologic symptoms that include psychomotor retardation, ataxia, hypotonia and stroke-like episodes. Many haemostatic system proteins only present biological activity after glycosylation. The aim of this study was to evaluate coagulation inhibitors (free protein S, protein C and antithrombin) and coagulation factors (VIII, IX and XI) in CDG type I patients. Eleven patients with CDG type I (three males and eight females) with a mean age of 5.6 years old, and eight patients without CDG (four males and four females) with a mean age of 4.5 years old (control group) were evaluated. The diagnoses of CDG type I were confirmed by isoelectric focusing of serum transferrin. When coagulation inhibitors were evaluated, decreased activity of free protein S and protein C, and a pronounced reduction of antithrombin were observed compared to the control group. There was no significant difference for coagulation factors VIII and IX but a markedly decrease in factor XI. The present results suggest that a combined deficiency of coagulation inhibitors is responsible for the pro-thrombotic state observed in CDG patients. We recommend that a haemostatic analysis should be performed in CDG patients with clinical haemostatic manifestations before invasive procedures are performed.