RESUMO
Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down-slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha-fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype-phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.
Assuntos
Anormalidades Múltiplas/genética , Calcinose/genética , Otopatias/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Megalencefalia/genética , Atrofia Muscular/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , 3-Hidroxiacil-CoA Desidrogenases/genética , Anormalidades Múltiplas/patologia , Acetil-CoA C-Aciltransferase/genética , Adolescente , Adulto , Calcinose/patologia , Isomerases de Ligação Dupla Carbono-Carbono/genética , Criança , Pré-Escolar , Otopatias/patologia , Enoil-CoA Hidratase/genética , Face/anormalidades , Feminino , Estudos de Associação Genética , Heterozigoto , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Megalencefalia/patologia , Pessoa de Meia-Idade , Mitocôndrias/genética , Mitocôndrias/patologia , Atrofia Muscular/patologia , Mutação , Mutação de Sentido Incorreto/genética , Fenótipo , Racemases e Epimerases/genética , Neoplasias Testiculares , Adulto JovemRESUMO
Homozygosity for nonsense variants in CEP55 has been associated with a lethal condition characterized by multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, and hydranencephaly (MARCH syndrome) also known as Meckel-like syndrome. Missense variants in CEP55 have not previously been reported in association with disease. Here we describe seven living individuals from five families with biallelic CEP55 variants. Four unrelated individuals with microcephaly, speech delays, and bilateral toe syndactyly all have a common CEP55 variant c.70G>A p.(Glu24Lys) in trans with nonsense variants. Three siblings are homozygous for a consensus splice site variant near the end of the gene. These affected girls all have severely delayed development, microcephaly, and varying degrees of lissencephaly/pachygyria. Here we compare our seven patients with three previously reported families with a prenatal lethal phenotype (MARCH syndrome/Meckel-like syndrome) due to homozygous CEP55 nonsense variants. Our series suggests that individuals with compound heterozygosity for nonsense and missense variants in CEP55 have a different viable phenotype. We show that homozygosity for a splice variant near the end of the CEP55 gene is also compatible with life.