title: Femoral facial syndrome associated with a de novo complex chromosome 2q37 rearrangement.
abstract: The femoral facial syndrome (FFS) is a rare congenital anomaly syndrome characterized by bilateral femoral hypoplasia and facial dysmorphism. The etiology of FFS is currently unknown but maternal/gestational diabetes has been proposed as a strong risk factor for syndromic femoral hypoplasia. In affected children born to non-diabetic mothers, a genetic contribution to FFS is suspected; however, no chromosomal anomalies or gene mutations have been identified so far. Here, we report on a girl with FFS and a de novo complex chromosome rearrangement of terminal chromosome 2q37.2. Radiographs of the pelvis and lower limbs showed bilateral shortening and bowing of the femur and radiographs of hands and feet revealed a brachydactyly type E (BDE). Using high resolution array-CGH, qPCR, and FISH, we detected a ~1.9 Mb duplication in the chromosomal region 2q37.2 and a ~5.4 Mb deletion on chromosome 2q37.3 that were absent in the parents. The duplication contains six genes and the deletion encompasses 68 genes; the latter has previously been shown to cause BDE (through haploinsufficiency for HDAC4) but not femoral hypoplasia. Therefore, we propose that the duplication 2q37.2 could be causative for the femur phenotype. To the best of our knowledge, our report is the first to propose a genetic cause in a case of FFS.
authors.affiliation: Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Max Planck Institute for Molecular Genetics, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Spielmann
authors.affiliation: Department of Pediatric Orthopedics, Schön Klinik Vogtareuth, Vogtareuth, Germany.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Marx
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: Gotthold
authors.initials: G
authors.lastname: Barbi
authors.affiliation: Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ricarda
authors.initials: R
authors.lastname: Flöttmann
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: Hildegard
authors.initials: H
authors.lastname: Kehrer-Sawatzki
authors.affiliation: Institute of Human Genetics, University of Frankfurt, Frankfurt/Main, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: König
authors.affiliation: Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
authors.affiliation: Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Max Planck Institute for Molecular Genetics, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.affiliation: Department of Pediatric Orthopedics, Schön Klinik Vogtareuth, Vogtareuth, Germany.
authors.forename: Sean
authors.initials: S
authors.lastname: Nader
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
mesh_terms: D000015:Abnormalities, Multiple / Q000000981:diagnostic imaging / Q000235:genetics*; D059327:Brachydactyly / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology / Q000601:surgery; D002648:Child; D002872:Chromosome Deletion; D058674:Chromosome Duplication; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D016640:Diabetes, Gestational / Q000235:genetics / Q000503:physiopathology; D005260:Female; D005269:Femur / Q000002:abnormalities* / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000601:surgery; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D010855:Pierre Robin Syndrome / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology / Q000601:surgery; D011247:Pregnancy; D012097:Repressor Proteins / Q000235:genetics; D012307:Risk Factors
chemical_list: D012097:Repressor Proteins; C400300:HDAC4 protein, human; D006655:Histone Deacetylases
keywords: HACNS1; array-CGH; de novo complex genomic rearrangement; femoral facial syndrome (FFS); femoral hypoplasia unusual face syndrome (FHUFS); limb enhancer element 921