Multiple congenital skull fractures as a presentation of Ehlers-Danlos syndrome type VIIC

We describe a newborn infant with multiple congenital skull fractures and intracranial hemorrhage. He also had multiple skin folds suggesting a connective tissue abnormality. Electron microscopy of the skin biopsy showed collagen abnormalities with a "hieroglyphic appearance." The analysis of the synthesis of collagen in the cultured dermal fibroblasts demonstrated an accumulation of procollagen I. Molecular analysis found a nonsense mutation Q225X in ADAMTS2 gene, which encodes procollagen I N-terminal proteinase. All these findings confirmed the diagnosis of Ehlers-Danlos syndrome type VIIC (MIM 225410). Family studies suggested a founder effect in Ashkenazi Jews originating from Belarus. Prenatal diagnosis in the subsequent pregnancy reassured the parents that the fetus was an unaffected carrier.     

Characterization by array-CGH of an interstitial de novo tandem 6p21.2p22.1 duplication in a boy with epilepsy and developmental delay

We report on a 6-years-old boy with psychomotor retardation, mild dysmorphic features and behavioral disturbances associated with epilepsy. Conventional cytogenetic analysis concluded to an interstitial de novo 6p21.2p22.3 duplication. Molecular cytogenetic analysis, including array-CGH technology, allows characterization of this 7.3Mb interstitial tandem duplication. The phenotype of this small 6p duplication reported to date is compared to other cases in the literature. Presence of epilepsy, although rare in patients with 6p duplication may be linked to genes involved in brain function and synaptic transmission in the 6p21.2p22.1 duplicated region (GABBR1, BRD2 and GRM4).     

A familial case of Keratitis-Ichthyosis-Deafness (KID) syndrome with the GJB2 mutation G45E

Keratitis-Ichthyosis-Deafness (KID) syndrome (OMIM 148210) is a congenital ectodermal defect. KID consists of an atypical ichthyosiform erythroderma associated with congenital sensorineural deafness. A rare form of the KID syndrome is a fatal course in the first year of life due to severe skin lesion infections and septicaemia. KID appears to be genetically heterogeneous and may be caused by mutations in connexin 26 or connexin 30 genes. GJB2 mutations in the connexin 26 gene are the main cause of the disease. Most of the cases caused by GJB2 mutations are sporadic, but dominant transmission has also been described. To date, the rare lethal form of the disease has been only observed in two Caucasian sporadic patients with the GJB2 mutation, with the p.Gly45Glu (G45E) arising de novo. We have reported an African family with dizygotic twins suffering from a lethal form of KID. The dizygosity of the twins was confirmed by microsatellite markers. The two patients were heterozygous for the G45E mutation of GJB2, whereas the mutation was not detected in the two parents. The unusual transmission of the disease observed in this family could be explained by the occurrence of a somatic or more probably a germinal mosaic in one of the parents.     

Deletion 18q21.2q21.32 involving TCF4 in a boy diagnosed by CGH-array

We report on a 12 year-old boy presenting with severe developmental delay, dysmorphic features, limb anomalies, growth retardation, hypoplastic vermis and corpus callosum. Conventional and high-resolution cytogenetic analyses were normal. CGH-array allowed characterisation of a de novo 6.2 Mb 18q21.2q21.32 interstitial deletion involving TCF4, the recently identified gene responsible for Pitt-Hopkins syndrome (PHS). No tachypnoea-apnoea paroxysms were observed. We discuss the dysmorphic features particularly involving the ears, which might be helpful towards PHS and 18q21 deletion diagnosis.     

Toward conceptual clarity in a critical parenting construct: parental monitoring in youth with chronic illness

Parental monitoring has been defined as "a set of correlated parenting behaviors involving attention to and tracking of the child's whereabouts, activities, and adaptations." This construct is of significant interest due to its relatedness to a broad range of youth risk behaviors, including risky sexual behavior, substance abuse, and poor adherence. However, to date, measures of parental monitoring are largely absent from the chronic illness literature. The present article focuses upon two key problems in the operationalization of the monitoring construct to date: (a) poor conceptual specificity in parenting constructs such as monitoring, overprotection, and over-involvement when used to date among youth with chronic conditions and (b) the confounding of existing measures of parental monitoring with items evaluating parental knowledge of youth activities, which has resulted in a lack of data regarding the mechanisms by which parents obtain their information. Recommendations for the future development of monitoring measures are discussed.     

Identification of human CD4 T-cell epitopes on the VP1 capsid protein of enterovirus 71

The identification of human CD4 T-cell epitopes within a protein vaccine candidate is of great interest,as it provides a better understanding of the mechanisms involved in protective immunity and may therefore help in the design of effective vaccines and diagnostic tools. The entire amino acid sequence of the VP1 capsid protein from enterovirus 71 (EV 71) strain 41 was submitted to analysis by the ProPred algorithm for the identification of potential promiscuous human CD4 T-cellepitopes. Three regions spanning amino acids 66-77, 145-159, and 247-261 of VP1 were predicted to bind more than 25 HLA-DR alleles. The corresponding synthetic peptides (SP1 to SP3) were then tested for their abilities to induce proliferation of CD4 T cells isolated from five human volunteers screened positive for previous EV 71 exposure and one EV 71-negative volunteer. Upon stimulation with either peptide, CD4 T-cell proliferative responses were observed for all EV 71-positive volunteers,indicating the presence of EV 71-specific memory CD4 T cells. The amplitude of the proliferative responses was peptide- and HLA-DR-dependent, and correlated well with the ProPredpredicted binding efficiencies. Moreover, CD4 T cells from EV 71-positive volunteers produced significant levels of IL-2 and IFN- upon stimulation, indicative of a T-cell differentiation into Th-1-type subset. Among the three peptides, SP2 induced the highest proliferative response and cytokine production. Moreover, SP2-induced proliferative response could be inhibited with anti-major histocompatibility complex (MHC) class II antibody, indicating that SP2 represents a MHC class II-restricted CD4 T-cell epitope. This study demonstrates that the ProPred algorithm can accurately predict the presence of human CD4 T-cell epitopes within the VP1 capsid protein of EV 71, and therefore represents a useful tool for the design of subunit vaccines against EV 71.     

IL-21 promotes survival and maintains a naive phenotype in human CD4+ T lymphocytes

IL-21 is a key T-cell growth factor (TCGF) involved in innate and adaptive immune response. It contributes to the proliferation of naive, but not memory T lymphocytes. However, the full spectrum of IL-21 activity on T cells remains unclear. Here, we demonstrate that IL-21 primarily maintains the expression of specific naive cell surface markers such as CD45RA, CD27, CD62L and CCR7 on human CD4(+) T lymphocytes and that the expression of CCR7 induces cell migration by means of CCL21 chemoattraction. These effects contrast with those of IL-2 which induced the marked proliferation of CD4(+) T lymphocytes, leading to an activated-memory phenotype. Nevertheless, IL-21 maintained cell cycle activation and expression of proliferation markers, including proliferating cell nuclear antigen and Ki-67, and triggered T-cell proliferation via TCR and co-stimulation pathways. Unlike IL-2, IL-21 decreased the expression of the anti-apoptotic Bcl-2 protein, which correlated with the absence of activation of the phosphatidylinositol 3'-kinase/Akt signaling pathway. Thus, IL-21 is a TCGF whose function is the preservation of a pool of CD4(+) T lymphocytes in a naive phenotype, with a low proliferation rate but with the persistence of cell cycling proteins and cell surface expression of CCR7. These findings strongly suggest that IL-21 plays a part in innate and adaptive immune response owing to homeostasis of T cells and their homing to secondary lymphoid organs.     

Population history and infrequent mutations: how old is a rare mutation? GUCY2D as a worked example

The mosaic pattern of haplotypes observed around a single mutation results from one or several founder events. The difficulties involved in calculating the age of the variant are greatly reduced by assuming a single event, but this simplification may bias analysis of the genealogy of the mutation. However, if it is assumed that more than one founder event occurred, the number of genealogies is very large and the likelihood of every possible tree could not be realistically calculated. A multipoint approach is required, given the number of independent variables needed to describe a complex bifurcating genealogy. Starting from the observation that a limited number of parameters is needed for calculation of the simplest models of bifurcating genealogies, we show that the probability density of a two-ancestor model genealogy can be simply described as an algebraic function in a closed form, two coalescence times being calculated simultaneously without compromising accuracy. Implementation in a Bayesian framework is facilitated by the simplicity of the function, which describes the reciprocal relationship between the region of complete linkage disequilibrium and the branch length of the tree. We illustrate the use of haplotype information about allele-sharing decay around a mutation as a genetic clock, using data for two GUCY2D mutations in Mediterranean populations.