Trinh Hermanns-Lê

Classical Ehlers-Danlos syndrome caused by a mutation in type I collagen

Classical Ehlers-Danlos syndrome (EDS) is characterized by skin hyperelasticity, joint hypermobility, increased tendency to bruise, and abnormal scarring. Mutations in type V collagen, a regulator of type I collagen fibrillogenesis, have been shown to underlie this type of EDS. However, to date, mutations have been found in only a limited number of patients, which suggests genetic heterogeneity. In this article, we report two unrelated patients with typical features of classical EDS, including excessive skin fragility, in whom we found an identical arginine-->cysteine substitution in type I collagen, localized at position 134 of the alpha1(I) collagen chain. The arginine residue is highly conserved and localized in the X position of the Gly-X-Y triplet. As a consequence, intermolecular disulfide bridges are formed, resulting in type I collagen aggregates, which are retained in the cells. Whereas substitutions of glycine residues in type I collagen invariably result in osteogenesis imperfecta, substitutions of nonglycine residues in type I collagen have not yet been associated with a human disease. In contrast, arginine-->cysteine substitutions in type II collagen have been identified in a variety of chondrodysplasias. Our findings show that mutations in other fibrillar collagens can be causally involved in classical EDS and point to genetic heterogeneity of this disorder.

Acanthosis nigricans associated with insulin resistance : pathophysiology and management.

AbstractThe association of acanthosis nigricans, skin tags, diabetes mellitus due to insulin resistance, and obesity in adolescents and young adults represents a well defined syndrome. Hyperandrogenism may also be present. The endocrine origin of this condition is beyond doubt. Insulin and insulin-like growth factor-1, and their receptors on keratinocytes are obviously involved in the complex regulations leading to the peculiar epidermal hyperplasia. This condition is unrelated to other types of acanthosis nigricans, including the congenital and the paraneoplastic types.Control of obesity contributes largely to reverse the whole process, essentially by reducing both insulin resistance and compensatory hyperinsulinemia. Several drugs including metformin, octreotide, retinoids and topical colecalciferol (vitamin D3) analogs are also beneficial in clearing acanthosis nigricans.

Musculocontractural Ehlers-Danlos Syndrome (former EDS type VIB) and adducted thumb clubfoot syndrome (ATCS) represent a single clinical entity caused by mutations in the dermatan-4-sulfotransferase 1 encoding CHST14 gene.

We present clinical and molecular findings of three patients with an EDS VIB phenotype from two consanguineous families. The clinical findings of EDS kyphoscoliotic type (EDS type VIA and B) comprise kyphoscoliosis, muscular hypotonia, hyperextensible, thin and bruisable skin, atrophic scarring, joint hypermobility and variable ocular involvement. Distinct craniofacial abnormalities, joint contractures, wrinkled palms, and normal urinary pyridinoline ratios distinguish EDS VIB from EDS VIA. A genome‐wide SNP scan and sequence analyses identified a homozygous frameshift mutation (NM_130468.2:c.145delG, NP_569735.1:p.Val49*) in CHST14, encoding dermatan‐4‐sulfotransferase 1 (D4ST‐1), in two Turkish siblings. Subsequent sequence analysis of CHST14 identified a homozygous 20‐bp duplication (NM_130468.2:c.981_1000dup, NP_569735.1:p.Glu334Glyfs*107) in an Indian patient. Loss‐of‐function mutations in CHST14 were recently reported in adducted thumb–clubfoot syndrome (ATCS). Patients with ATCS present similar craniofacial and musculoskeletal features as the EDS VIB patients reported here, but lack the severe skin manifestations. By identifying an identical mutation in patients with EDS VIB and ATCS, we show that both conditions form a phenotypic continuum. Our findings confirm that the EDS‐variant associated with CHST14 mutations forms a clinical spectrum, which we propose to coin as “musculocontractural EDS” and which results from a defect in dermatan sulfate biosynthesis, perturbing collagen assembly.

Dermal Ultrastructure in Low Beighton Score Members of 17 Families with Hypermobile-Type Ehlers-Danlos Syndrome

The distinction between the Ehlers-Danlos syndrome hypermobile type (EDSH) and the benign joint hypermobility syndrome (BJHS) is unclear. The aim of the present study was to compare skin ultrastructural abnormalities of EDSH and BJHS among different families. Skin of 23 EDSH, 27 BJHS, and 41 asymptomatic subjects from 17 families was examined using transmission electron microscopy. Similar ultrastructural abnormalities were found irrespective of the Beighton score. Flower-like collagen fibrils represented the key change and elastic fibers were altered as well. Beighton score is a clinical parameter rating joint mobility that appeared unrelated to quantitative and qualitative collagen ultrastructural alterations in the skin. Some EDSH family members fit with BJHS diagnosis. BJHS possibly represents a mild variant of EDSH.

Surfactant-induced dermatitis: Comparison of corneosurfametry with predictive testing on human and reconstructed skin

BACKGROUND Surfactants elicit alterations in the stratum corneum. Predictive tests that avoid animal experimentation are needed. OBJECTIVE This study compares three methods of rating and predicting shampoo-induced irritation. METHODS Corneosurfametry entails collection of stratum corneum followed by brief contact with diluted surfactants and measurement of variations in staining of samples. RESULTS Corneosurfametry appears to correlate well with in vivo testing in volunteers with sensitive skin. However, corneosurfametry presents less interindividual variability than in vivo testing and allows better discrimination among mild products. Morphologic information about surfactant-induced loosening of corneocytes may be increased by testing surfactants on human skin equivalent. Results are similar to those provided by specimens used for corneosurfametry. CONCLUSION The corneosurfametric prediction of surfactant irritancy correlates with in vivo testing and with in vitro evaluation on human skin equivalent.

Age- and body mass index-related changes in cutaneous shear wave velocity

BACKGROUND The in vivo visco-elastic characteristics of skin depend on a series of physiopathological parameters. Among them, the age-related intrinsic tensile properties and the preconditioning of the tissues set under tension by the hypodermal volume might be of importance. AIMS To revisit the influence of age and body mass on the firmness and mechanical anisotropy of the skin as determined by the velocity of the shear wave propagation. METHOD Resonance running time measurements (RRTM) were performed on the mid volar forearm in 110 adults of both sexes. In each subject 16 RRTM were collected at four different precise angles with regard to the limb axis. We recorded the lowest, the highest and the mean multidirectional RRTM as well as the coefficient of variation (CV) of the latter value. In addition, the body mass index (BMI) was calculated. RESULTS Age and BMI did not influence the minimum RRTM. In contrast, the maximum RRTM as well as the mean and CV of the multidirectional RRTM, significantly rose in a progressively increasing proportion of the subjects older than 60 years. These changes were only encountered in subjects with a normal BMI ranging from 18 to 25. Sex-related differences were not disclosed. CONCLUSIONS The intrinsic skin tension lines identified by the minimum RRTM are not significantly altered with age and BMI variations. In contrast, skin laxity identified by larger maximum and mean multidirectional RRTM may increase after 60 years of age in subjects with a normal BMI. This is accompanied by increased skin mechanical anisotropy identified by CV values of the multidirectional RRTM over 40%.

The RIN2 syndrome: a new autosomal recessive connective tissue disorder caused by deficiency of Ras and Rab interactor 2 (RIN2)

Defects leading to impaired intracellular trafficking have recently been shown to play an important role in the pathogenesis of genodermatoses, such as the Ehlers–Danlos and the cutis laxa syndromes. A new genodermatosis, termed macrocephaly, alopecia, cutis laxa and scoliosis (MACS) syndrome has been described, resulting from a homozygous 1-bp deletion in RIN2. RIN2 encodes the Ras and Rab interactor 2, involved in the regulation of Rab5-mediated early endocytosis. We performed a clinical, ultrastructural and molecular study in a consanguineous Algerian family with three siblings affected by a distinctive autosomal recessive genodermatosis, reported in 2005 by Verloes et al. The most striking clinical features include progressive facial coarsening, gingival hypertrophy, severe scoliosis, sparse hair and skin and joint hyperlaxity. Ultrastructural studies of the skin revealed important abnormalities in the collagen fibril morphology, and fibroblasts exhibited a dilated endoplasmic reticulum and an abnormal Golgi apparatus with rarefied and dilated cisternae. Molecular analysis of RIN2 revealed a novel homozygous 2-bp deletion in all affected individuals. The c.1914_1915delGC mutation introduces a frameshift and creates a premature termination codon, leading to nonsense-mediated mRNA decay. These findings confirm that RIN2 defects are associated with a distinct genodermatosis and underscore the involvement of RIN2 and its associated pathways in the pathogenesis of connective tissue disorders. The current family displays considerable phenotypic overlap with MACS syndrome. However, our family shows a dermatological and ultrastructural phenotype belonging to the Ehlers–Danlos rather than the cutis laxa spectrum. Therefore, the MACS acronym is not entirely appropriate for the current family.

Juvenile Acanthosis Nigricans and Insulin Resistance

Acanthosis nigricans in obese adolescents is frequently associated with hyperinsulinemia and insulin resistance. We report three cases of this condition. In the early stage the skin lesions appeared to be erythematous and pruritic, mimicking an inflammatory dermatitis. Dietary control and oral metformin hydrochloride markedly improved the lesions. Topical calcipotriol may also help to control the skin condition.

Cervical artery dissection An atypical presentation with Ehlers–Danlos-like collagen pathology?

The authors took skin biopsies of the macroscopically normal skin of seven consecutive patients with spontaneous cervical artery dissection (SCAD). Histologically, alterations of the collagen and elastic fiber networks were found in six patients. In five, the histologic, immunohistochemical, and ultrastructural changes were similar to those usually found in Ehlers–Danlos syndrome (EDS). This suggests that SCAD is frequently associated with the dermal alterations seen in EDS.

Skin tensile properties revisited during ageing. Where now, where next?

Skin and its subcutaneous layer represent a complex composite of tissues, whose mechanical characteristics depend upon the mutual interdependence of their constituent parts. The molecular and microanatomical structures of skin allow it to meet normal mechanical demands. They also determine the orientation both of Langers lines and of relaxed skin tension lines. Ageing, photodamage, hormones, drugs, cosmetic products and dermatological interventions may modify the skins overall tensile properties. In turn, any variation in mechanical stresses and strains imposed upon the skins connective tissue influences the metabolic activity and phenotypic expression of fibroblasts and dermal dendrocytes.