CLINICAL REPORT Microform Holoprosencephaly with Bilateral Congenital Elbow Dislocation; Increasing the Phenotypic Spectrum of Steinfeld Syndrome Gabriela E. Jones, 1 * Lisa Robertson, 2 Amit Maniyar, 3 Christos Shammas, 4 Marie M. Phelan, 5 Pradeep C. Vasudevan, 1 and George A. Tanteles 6 1 Department of Clinical Genetics, University Hospitals Leicester NHS Trust, Leicester, United Kingdom 2 North of Scotland Clinical Genetics Service, Aberdeen, United Kingdom 3 Department of Radiology, University Hospitals Leicester NHS Trust, Leicester, United Kingdom 4 Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus 5 NMR Centre for Structural Biology, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom 6 Clinical Genetics Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus Manuscript Received: 8 September 2015; Manuscript Accepted: 29 November 2015 Steinfeld syndrome (MIM #184705) was first reported in 1982. It is characterised by holoprosencephaly and limb defects, however other anomalies may also be present. Following the initial description, three further cases have been reported in the literature. We report on a 23-year-old girl, with features of microform holoprosencephaly and bilateral congenital elbow dislocation in association with hypoplastic radial heads. She was identified to have a variant in the CDON gene inherited from her father who had ocular hypotelorism, but no other clinical features. We discuss the clinical features of Steinfeld syndrome, and broaden the phenotypic spectrum of this condition. Struc- tural analysis suggests that this variant could lead to destabili- sation of binding of CDON with hedgehog proteins. Further work needs to be done to confirm whether mutations in the CDON gene are the cause of Steinfeld syndrome. Ó 2016 Wiley Periodicals, Inc. Key words: holoprosencephaly; Steinfeld syndrome; CDON; radial ray defects INTRODUCTION Holoprosencephaly (HPE) is a common structural malformation resulting from failure of midline cleavage of the developing brain. HPE occurs in up to 1 in 250 conceptions although, the estimated prevalence in liveborn children is less than 1 in 10,000 [Orioli and Castilla, 2010]. HPE is typically classified into three types with increasing severity: lobar, semi-lobar, and alobar. However, milder forms are well documented and include middle interhemispheric variants, in which the posterior, frontal, and parietal lobes are incompletely separated and the corpus callosum may be hypoplas- tic [Simon et al., 2002], and microforms characterised by midline defects (e.g., single maxillary central incisor or hypotelorism) without the brain malformations typical of HPE [Nanni et al., 1999]. HPE is associated with environmental (e.g., teratogens) and genetic factors, including cytogenetic abnormalities and single gene defects coding various components of the Sonic hedgehog (SHH) signalling pathway [Roessler and Muenke, 2010]. Recently muta- tions in the cell adhesion associated, oncogene regulated gene (CDON), which encodes a hedgehog receptor, have been found to cause HPE [Bae et al., 2011]. In 1982, Steinfeld reported a female child with HPE, bilateral reduction defects of the upper limbs with dislocated shoulders. She also had cardiac and renal anomalies, and midline cleft lip, and palate. Other individuals within the family had variable limb Conflict of interest: The authors declare no conflicts of interest. Ã Correspondence to: Dr. Gabriela Jones, Leicester Clinical Genetics Service, University Hospitals Leicester NHS Trust, Leicester Royal Infirmary, LE1 5WW, Leicester. Email: gabriela.jones@uhl-tr.nhs.uk Article first published online in Wiley Online Library (wileyonlinelibrary.com): 5 January 2016 DOI 10.1002/ajmg.a.37511 How to Cite this Article: Jones GE, Robertson L, Maniyar A, Shammas C, Phelan MM, Vasudevan PC, Tanteles GA. 2016. Microform holoprosencephaly with bilateral congenital elbow dislocation; increasing the phenotypic spectrum of Steinfeld syndrome. Am J Med Genet Part A 170A:754–759. Ó 2016 Wiley Periodicals, Inc. 754