The cutis laxa syndromes are multisystem disorders that share loose redundant inelastic and wrinkled skin as a common hallmark clinical feature. The underlying molecular defects are heterogeneous and 13 different genes have been involved until now, all of them being implicated in elastic fiber assembly. We provide here molecular and clinical characterization of three unrelated patients with a very rare phenotype associating cutis laxa, facial dysmorphism, severe growth retardation, hyperostotic skeletal dysplasia, and intellectual disability. This disorder called Lenz-Majewski syndrome (LMS) is associated with gain of function mutations in PTDSS1, encoding an enzyme involved in phospholipid biosynthesis. This report illustrates that LMS is an unequivocal cutis laxa syndrome and expands the clinical and molecular spectrum of this group of disorders. In the neonatal period, brachydactyly and facial dysmorphism are two early distinctive signs, later followed by intellectual disability and hyperostotic skeletal dysplasia with severe dwarfism allowing differentiation of this condition from other cutis laxa phenotypes. Further studies are needed to understand the link between PTDSS1 and extra cellular matrix assembly.

Centre de Génétique Humaine Université de Franche Comté Besançon France

Department of Biology and Medical Genetics Motol Hospital Charles University Prague Czech Republic

Faculty of Medicine Lucian Blaga University Sibiu Sibiu Romania

Genetics and Genomic Medicine UCL GOS Institute of Child Health London UK

Institut für Medizinische Genetik und Humangenetik Charité Universitätsmedizin Berlin corporate member of Freie Universität Berlin Humboldt Universität zu Berlin and Berlin Institute of Health Berlin Germany

Institute of Human Genetics Medical Center of the Johannes Gutenberg University Mainz Mainz Germany

Service d'Imagerie Pédiatrique Centre Hospitalier Universitaire Grenoble Alpes Grenoble France

Service de Cytogénétique Centre Hospitalier de Chambéry Hôtel Dieu Chambéry France

Service de Génétique Hospices Civils de Lyon Centre de Recherche en Neurosciences de Lyon Bron France

Service de Radiologie Pédiatrique et Imagerie de la Femme Centre Hospitalier Régional Universitaire de Besançon Besançon France

Serviço de Genética Medica Hospital Pediatrico Centro Hospitalar e Universitário de Coimbra Coimbra Portugal

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