Luciana Rodrigues-Jacy da Silva

CDH3 on 16q22.1 is responsible for two rare autosomal recessive disorders with hypotrichosis and progressive macular dystrophy: Hypotrichosis with Juvenile Macular Dystrophy and Ectodermal Dysplasia, Ectrodactyly and Macular Dystrophy. We present a new case of Hypotrichosis with Juvenile Macular Dystrophy. A Spanish male born in 1998 from non-consanguineous healthy parents with a suspected diagnosis of Keratosis Follicularis Spinulosa Decalvans and Retinitis Pigmentosa Inversa referred to our Genetics Department (IIS-Fundación Jiménez Díaz). Molecular study of ABCA4 was performed, and a heterozygous missense p.Val2050Leu variant in ABCA4 was found. Clinical revision reclassified this patient as Hypotrichosis with Juvenile Macular Dystrophy. Therefore, further CDH3 sequencing was performed showing a novel maternal missense change p.Val205Met (probably pathogenic by in silico analysis), and a previously reported paternal frameshift c.830del;p.Gly277Alafs*20, thus supporting the clinical diagnosis.. This is not only the first Spanish case with this clinical and molecular diagnosis, but a new mutation has been described in CDH3. Moreover, this work reflects the importance of joint assessment of clinical signs and evaluation of pedigree for a correct genetic study approach and diagnostic.

Background: The majority of Marfan syndrome (MFS) cases is caused by mutations in the fibrillin-1 gene (FBN1), mapped to chromosome 15q21.1. Only few reports on deletions including the wholeFBN1gene, detected by molecular cytogenetic techniques, were found in literature.Results: We report here on a female patient with clinical symptoms of the MFS spectrum plus craniostenosis, hypothyroidism and intellectual deficiency who presents a 1.9 Mb deletion, including theFBN1gene and a complex rearrangement with eight breakpoints involving chromosomes 6, 12 and 15.Discussion: This is the first report of MFS with a complex chromosome rearrangement involving a deletion ofFBN1and contiguous genes. In addition to the typical clinical findings of the Marfan syndrome due toFBN1gene haploinsufficiency, the patient presents features which may be due to the other gene deletions and possibly to the complex chromosome rearrangement.