Cutis laxa and excessive bone growth due to de novo mutations in PTDSS1

• Published in: American journal of medical genetics. Part A 2018-03, Vol.176 (3), p.668-675
• Main Authors: Piard, Juliette, Lespinasse, James, Vlckova, Marketa, Mensah, Martin A., Iurian, Sorin, Simandlova, Martina, Malikova, Marcela, Bartsch, Oliver, Rossi, Massimiliano, Lenoir, Marion, Nugues, Frédérique, Mundlos, Stefan, Kornak, Uwe, Stanier, Philip, Sousa, Sérgio B., Van Maldergem, Lionel
• Format: Article
• Language: English
• Subjects: Adult; Alleles; Bone dysplasia; Bone growth; Brachydactyly; Child; Child, Preschool; Clinical Report; Clinical Reports; cutis laxa; Cutis Laxa - diagnosis; Cutis Laxa - genetics; Dwarfism; Exons; Facies; Female; Genetic Association Studies; Genotype; Growth rate; Humans; Hyperostosis - diagnosis; Hyperostosis - genetics; hyperostotic skeletal dysplasia; Intellectual disabilities; Lenz–Majewski syndrome; Majewski syndrome; Male; Mutation; Neonates; Nitrogenous Group Transferases - genetics; Phenotype; Phenotypes; Phospholipids; PTDSS1; Radiography; Skeleton; Skin
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.38604

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.