RESUMO
Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only.
Assuntos
Anormalidades Múltiplas/genética , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/genética , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Fatores de Transcrição NFI/genética , Síndrome de Sotos/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/fisiopatologia , Criança , Pré-Escolar , Deleção Cromossômica , Hipotireoidismo Congênito/fisiopatologia , Anormalidades Craniofaciais/fisiopatologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Éxons/genética , Feminino , Deformidades Congênitas da Mão/fisiopatologia , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Megalencefalia/genética , Megalencefalia/fisiopatologia , Mutação de Sentido Incorreto/genética , Fenótipo , Displasia Septo-Óptica/genética , Displasia Septo-Óptica/fisiopatologia , Síndrome de Sotos/fisiopatologia , Adulto JovemRESUMO
Interferon-stimulated gene 15 (ISG15) was the first ubiquitin-like modifier protein identified that acts by protein conjugation (ISGylation) and is thought to modulate IFN-induced inflammation. Here, we report a new patient from a non-consanguineous Argentinian family, who was followed for recurrent ulcerative skin lesions, cerebral calcifications and lung disease. Whole Exome Sequencing (WES) revealed two novel compound heterozygous variants (c.285del and c.299_312del, NM_005101.4 GRCh37(hg19), both classified as pathogenic according to ACMG criteria) in the ISG15 gene, resulting in a complete deficiency due to disruption of the second ubiquitin domain of the corresponding protein. The clinical phenotype of this patient is unique given the presence of recurrent pulmonary manifestations and the absence of mycobacterial infections, thus resulting in a phenotype distinct from that previously described in patients with biallelic loss-of-function (LOF) ISG15 variants. This case highlights the role of ISG15 as an immunomodulating factor whose LOF variants result in heterogeneous clinical presentations.