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Beyond Gmezlpezhernndez Syndrome: Recurring Phenotypic

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Beyond Gmezlpezhernndez Syndrome: Recurring Phenotypic RESEARCH ARTICLE Beyond Gomez-Lopez-Hernandez Syndrome: Recurring Phenotypic Themes in Rhombencephalosynapsis Hannah M. Tully,1,2* Jennifer C. Dempsey,3 Gisele E. Ishak,4 Margaret P. Adam,3 Cynthia J.R. Curry,5 Pedro Sanchez-Lara,6,7 Alasdair Hunter,8 Karen W. Gripp,9 Judith Allanson,8 Christopher Cunniff,10 Ian Glass,3 Kathleen J. Millen,2,3 Daniel Doherty,2,3 and William B. Dobyns2,3 1Division of Pediatric Neurology, Department of Neurology, University of Washington, Seattle, Washington 2Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington 3Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington 4Department of Radiology, University of Washington, Seattle, Washington 5Genetic Medicine of Central California, UCSF/Fresno, California 6Department of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles 7Children’s Hospital Los Angeles, Los Angeles 8Medical Genetics PSU, Children’s Hospital of Eastern Ontario, Ottawa, Canada 9Division of Medical Genetics, Alfred I duPont Hospital for Children, Wilmington, Delaware 10Department of Pediatrics, University of Arizona College of Medicine, Tucson, Arizona Manuscript Received: 25 April 2012; Manuscript Accepted: 20 June 2012 Rhombencephalosynapsis (RES) is an uncommon cerebellar malformation characterized by fusion of the hemispheres with- How to Cite this Article: out an intervening vermis. Frequently described in association Tully HM, Dempsey JC, Ishak GE, Adam MP, with Gomez-L opez-Hern andez syndrome, RES also occurs in Curry CJR, Sanchez-Lara P, Hunter A, Gripp conjunction with VACTERL features and with holoprosence- KW, Allanson J, Cunniff C, Glass I, Millen KJ, phaly (HPE). We sought to determine the full phenotypic spec- Doherty D, Dobyns WB. 2012. Beyond trum of RES in a large cohort of patients. Information was Gomez-L opez-Hern andez syndrome: obtained through database review, patient questionnaire, radio- Recurring phenotypic themes in graphic, and morphologic assessment, and statistical analysis. Rhombencephalosynapsis. We assessed 53 patients. Thirty-three had alopecia, 3 had tri- Am J Med Genet Part A 9999:1–14. geminal anesthesia, 14 had VACTERL features, and 2 had HPE with aventriculy. Specific craniofacial features were seen throughout the cohort, but were more common in patients with alopecia. We noted substantial overlap between groups. We conclude that although some distinct subgroups can be delineated, the overlapping features seen in our cohort suggest an underlying spectrum of RES-associated malformations rather Additional supporting information may be found in the online version of than a collection of discrete syndromes. Ó 2012 Wiley Periodicals, Inc. this article. Grant sponsor: National Institute of Neurological Disorders and Stroke; Key words: rhombencephalosynapsis; Gomez-L opez-Hern andez Grant numbers: 5T32NS051171-05, 2R01-NS050375, KL2-RR025015; syndrome; congenital triangular alopecia; holoprosencephaly; Grant sponsor: Robert Wood Johnson Foundation; Grant sponsor: aventriculy; VACTERL; developmental field defect NIH; Grant number: K12-HD05954. *Correspondence to: Hannah M. Tully, Center for Integrative Brain Research, Mailstop: C9S-10, Dobyns Lab, 1900 9th Avenue, Seattle, WA 98101. INTRODUCTION E-mail: [email protected] Article first published online in Wiley Online Library Rhombencephalosynapsis (RES) is an uncommon but likely under- (wileyonlinelibrary.com): 00 Month 2012 recognized cerebellar malformation characterized by continuity of DOI 10.1002/ajmg.a.35561 Ó 2012 Wiley Periodicals, Inc. 1 2 AMERICAN JOURNAL OF MEDICAL GENETICS PART A the cerebellar hemispheres across the midline without an interven- features. Sporadic reports have also linked RES with holoprosen- ing vermis. This condition usually occurs sporadically but is cephaly (HPE) [Siebert et al., 2005; Pasquier et al., 2009; presumed to have genetic underpinnings (Table I), though no Ramocki et al., 2011] and features of the VACTERL association consistent genetic causes have been identified and no animal [Aydingoz et al., 1997; de Jong and Kirby, 2000; Toelle et al., 2002; models exist. Disruption of dorsal-ventral patterning has been Pasquier et al., 2009]. Seeking to better define the full clinical proposed as the cause of RES [Sarnat, 2000; Yachnis, 2002], but spectrum of RES, we assessed a large cohort of patients with RES the mechanisms involved have yet to be elucidated. The prevalence for associated anomalies. of RES is unknown, but Ishak et al. [2012] recently reported that 5 of 56 patients with aqueductal stenosis had unrecognized RES, METHODS suggesting that RES may be considerably more common than previously believed. Initially described as an isolated brain malfor- Patient Acquisition mation, RES is increasingly recognized in conjunction with other We performed a comprehensive search for patients with RES in our anomalies. database of more than 6,800 subjects with brain malformations or The first syndrome to be associated with RES was described by other developmental brain disorders maintained by the senior Gomez [1979] and Lopez-Hern andez [1982], though the nature of author (WBD). Most patients were referred by their families or the underlying brain malformation was not evident at the time. Key physicians for imaging review. In some, the diagnosis of RES had features of Gomez-L opez-Hern andez syndrome (GLH) include been made previously, while in others it was noted upon our review RES, parietal-occipital scalp alopecia and trigeminal anesthesia, of their imaging studies. Several patients in the database had the latter often leading to recurrent corneal and facial scarring. previously been ascertained by reviewing MRIs of children with Distinctive craniofacial features have been described in GLH, aqueductal stenosis in whom RES had not been recognized [Ishak including a towering skull with short anterior-posterior and et al., 2012]. Patients whose families elected to enroll in research side-to-side dimensions (turricephaly) [Gomez, 1979; Lopez- underwent a formal consent process, supplied DNA samples and Hernandez, 1982], a flat facial contour or midface retrusion, provided additional clinical information. hypertelorism, and low-set ears with increased posterior angulation [Lopez-Hern andez, 1982]. GLH has also been associated with variable degrees of motor developmental delay, intellectual disabil- Assessment of RES and Additional Structural ity, short stature, and behavioral difficulties [Brocks et al., 2000; Brain Abnormalities Gomy et al., 2008]. Imaging studies were reviewed by four authors (Dobyns, Doherty, Recently, some of the features once considered integral to a Ishak, and Tully) to confirm the diagnosis of RES. Scans were also diagnosis of GLH have been called into question [Sukhudyan et al., assessed for major additional malformations of the forebrain and 2010]; the term GLH is now often applied to RES with alopecia the ventricular system. Subtle abnormalities such as fusion of the but without trigeminal anesthesia or characteristic craniofacial colliculi and absent mammillary bodies, which are frequently seen in conjunction with RES but often not mentioned in routine radiology reports, are described in a related article by Ishak et al. TABLE I. Genetic Changes Described in Association With RES [2012]. Genetic changes described in Evaluation of GLH Features association with RES Recurrence in two Pasquier et al. [2009] Alopecia was assessed directly during clinic visits, through patient subsequent pictures and by parental questionnaire. Trigeminal anesthesia was pregnancies assessed directly when possible (corneal swab or saline drops to Consanguinity Chemli et al. [2007], elicit blink reflex), through review of medical records, or by parental Pasquier et al. [2009], questionnaire. In questionable situations, a history of repeated Romanengo et al. [1997], corneal injuries or facial scarring was considered indicative of Sandalcioglu et al. [2006], trigeminal anesthesia. Morphologic features were assessed by send- and Toelle et al. [2002] ing photographs of patients to nine authors (Adam, Allanson, Interstitial deletion of 2q Truwit et al. [1991] Cunniff, Curry, Dobyns, Glass, Gripp, Hunter, and Sanchez-Lara) Unbalanced subtelomeric Lespinasse et al. [2004] for subjective assessment of head shape (turricephaly and translocation: t(2p:10q) brachycephaly), forehead shape (high and wide), facial contour Tetrasomy 9p di Vera et al. [2008] Microduplication 1p Pasquier et al. [2009] (flat contour and midface retrusion), eye placement (subjectively Microduplication 7q Pasquier et al. [2009] wide-set and telecanthus), and ear placement (low set and increased Complex rearrangement Ramocki et al. [2011]a posterior angulation). Respondents could answer Yes, No, or of 22q13.3 Unable to Determine for each variable and were given the oppor- tunity to comment on other features. A patient was deemed to have aThe authors also reported partial RES in conjunction with HPE in two sisters with truncating mutations of ZIC2. However, the presence of RES was disputed by Guleria [2011] and could the feature in question if a majority of the nine evaluating geneticists not be confirmed by our review. agreed that it was present, with a minimum consensus of three when some respondents were unsure. When skull shape could not be TULLY ET AL. 3 reliably assessed because of hair, a neuroradiologist made the brachycephaly without turricephaly. Forehead shape was assessed
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