ORIGINAL ARTICLE Femoral-facial syndrome: A review of the literature and 14 additional patients including a monozygotic discordant twin pair Maria Dora Jazmin Lacarrubba-Flores 1,2 | Daniel Rocha Carvalho 3 | Erlane Marques Ribeiro 4 | Carolina Araujo Moreno 1,2 | Ana Carolina Esposito 5 | Fernando Augusto Lima Marson 6 | Thereza Loureiro 7 | Denise Pontes Cavalcanti 1,2 1 Skeletal Dysplasia Group, Department of Medical Genetics, Faculty of Medical Sciences, University of Campinas [Unicamp], Campinas, São Paulo, Brazil 2 Perinatal Genetic Program, Department of Medical Genetics, Faculty of Medical Sciences, University of Campinas [Unicamp], Campinas, São Paulo, Brazil 3 Genetic Unit, SARAH Network of Rehabilitation Hospital, Federal District, Brasilia, Brazil 4 Department of Pediatrics, Children’s Hospital Albert Sabin, Fortaleza, Ceará, Brazil 5 Pediatric Division, Hospital Municipal Nossa Senhora do Loreto, Rio de Janeiro, Brazil 6 Department of Pediatrics, Faculty of Medical Sciences, University of Campinas [Unicamp], Campinas, São Paulo, Brazil 7 Unit of Medical Genetics, Department of Genetics, Faculty of Medicine, University of São Paulo, Riberão Preto, São Paulo, Brazil Correspondence Denise Pontes Cavalcanti, Grupo de Displasias Esqueléticas, Departamento de Genética Médica, FCM, Unicamp. R. Tessália V. de Camargo, 126, 13083-887; Campinas, São Paulo, Brazil. Email: denisepcavalcanti@gmail.com Funding information Conselho Nacional de Desenvolvimento Científico e Tecnológico, Grant/Award Number: 590148/2011-7; Fundação de Amparo à Pesquisa do Estado de São Paulo, Grant/Award Number: 2015/22145-698/16006-6 Femoral-facial syndrome (FFS, OMIM 134780), also known as femoral hypoplasia-unusual face syndrome, is a rare sporadic syndrome associated with maternal diabetes, and comprising femo- ral hypoplasia/agenesis and a distinct facies characterized by micrognathia, cleft palate, and other minor dysmorphisms. The evaluation of 14 unpublished Brazilian patients, prompted us to make an extensive literature review comparing both sets of data. From 120 previously reported individuals with FFS, 66 were excluded due to: not meeting the inclusion criteria (n = 21); not providing sufficient data to ascertain the diagnosis (n = 29); were better assigned to another diagnosis (n = 3); and, being fetuses of the second trimester (n = 13) due to the obvious difficult to confirm a typical facies. Clinical-radiological and family information from 54 typical patients were collected and compared with the 14 new Brazilian patients. The comparison between the two sets of patients did not show any relevant differences. Femoral involvement was most fre- quently hypoplasia, observed in 91.2% of patients, and the typical facies was characterized by micrognathia (97%), cleft palate (61.8%), and minor dysmorphisms (frontal bossing 63.6%, short nose 91.7%, long philtrum 94.9%, and thin upper lip 92.3%). Clubfoot (55.9%) was commonly observed. Other observed findings may be part of FFS or may be simply concurrent anomalies since maternal diabetes is a common risk factor. While maternal diabetes was the only common feature observed during pregnancy (50.8%), no evidence for a monogenic basis was found. Moreover, a monozygotic discordant twin pair was described reinforcing the absence of a major genetic factor associated with FFS. KEYWORDS cleft palate, femoral hypoplasia, maternal diabetes, micrognathia, unusual facies 1 | INTRODUCTION The femoral-facial syndrome (FFS; OMIM: 134780), was first described by Daentl, Smith, Scott, Hall, and Gooding (1975) in four unrelated patients with bilateral femoral hypoplasia, and distinct facies character- ized by micrognathia, cleft palate, frontal bossing, small and bulbous nose, long philtrum, and thin upper lip. Because of the patients’ features, the syndrome was initially called femoral hypoplasia-unusual facies syn- drome (FHUFS). Subsequently, other patients were reported (Gleiser, Weaver, Escobar, Nichols, & Escobedo, 1978; Lord & Beighton, 1981; Pitt, Findlay, Cole, & Rogers, 1982), and new features such as upper limbs defects (Lord & Beighton, 1981), hemivertebrae, and scoliosis Received: 18 July 2017 Revised: 4 June 2018 Accepted: 6 June 2018 DOI: 10.1002/ajmg.a.40425 Am J Med Genet. 2018;1–12. wileyonlinelibrary.com/journal/ajmga © 2018 Wiley Periodicals, Inc. 1