Buciek, Hanne Hove

Darvann, Tron A.

Hermann, Nuno Vibe

Jeppesen, Bolette F.

Jørgensen, Finn Stener

Kreiborg, Sven

English

Copenhagen University Research Information System

u n i ve r s i t y  o f  co pe n h ag e n  Københavns UniversitetPrenatal diagnosis of autosomal recessive Robinow syndrome using 3D ultrasound.Jeppesen, Bolette F.; Buciek, Hanne Hove; Kreiborg, Sven; Hermann, Nuno Vibe; Darvann,Tron A.; Jørgensen, Finn StenerPublished in:Clinical Case ReportsDOI:10.1002/ccr3.784Publication date:2017Document versionPublisher's PDF, also known as Version of recordDocument license:CC BY-NC-NDCitation for published version (APA):Jeppesen, B. F., Buciek, H. H., Kreiborg, S., Hermann, N. V., Darvann, T. A., & Jørgensen, F. S. (2017).Prenatal diagnosis of autosomal recessive Robinow syndrome using 3D ultrasound. Clinical Case Reports, 5(7),1072-1076. https://doi.org/10.1002/ccr3.784Download date: 03. Feb. 2020CASE REPORTPrenatal diagnosis of autosomal recessive Robinowsyndrome using 3D ultrasoundBolette F. Jeppesen1,2, Hanne B. Hove1,3, Sven Kreiborg4,5, Nuno V. Hermann4,5,Tron A. Darvann5,6 & Finn Stener Jørgensen2,71Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark2Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark3Department of Clinical Genetics, The RAREDIS Database, Section of Rare Diseases, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark4Department of Pediatric Dentistry and Clinical Genetics, School of Dentistry, Faculty of Health and Medical Sciences, University of Copenhagen,Copenhagen, Denmark53D Craniofacial Image Research Laboratory (School of Dentistry, University of Copenhagen; Centre of Head and Orthopaedics, CopenhagenUniversity Hospital Rigshospitalet; and Department of Applied Mathematics and Computer Science, Technical University of Denmark),Copenhagen, Denmark6Department of Oral and Maxillofacial Surgery, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark7Fetal Medicine Unit, Department of Obstetrics and Gynecology, Copenhagen University Hospital Hvidovre, Hvidovre, DenmarkCorrespondenceBolette F. Jeppesen, Department of ClinicalGenetics 4062, Copenhagen UniversityHospital Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.Tel: +45 35455018; Fax: + 45 35454072;E-mail: xwq151@alumni.ku.dkFunding InformationNo sources of funding were declared for thisstudy.Received: 1 April 2016; Revised: 11 August2016; Accepted: 25 October 2016Clinical Case Reports 2017; 5(7): 1072–1076doi: 10.1002/ccr3.784Bulleted statements: Robinow syndrome isa genetic disorder with symptoms such asfacial abnormalities, dwarfism, genitalhypoplasia, and vertebral malformations. Thiscase report finds that the syndrome can bediagnosed prenatally using ultrasound byfocusing on the characteristic phenotypicaltrades, especially the facial morphology alongwith mesomelia.Key Clinical MessageThis article hypothesizes that it is possible to detect and diagnose both theautosomal recessive and dominant forms prenatally using ultrasound. By focus-ing on the characteristic phenotypical presentation, the examinator is able todiagnose the syndrome prenatally, which is of clinical importance to the parentsand counseling for the consideration of terminating the pregnancy.Keywords3D ultrasound, autosomal recessive Robinow syndrome, genital hypoplasia, hy-pertelorism, prenatal diagnose, wide nose.IntroductionRobinow syndrome is a rare, genetic disorder with symp-toms such as short stature, characteristic facial features,and genital hypoplasia [1].The syndrome was first described in 1969 by Robinowet al. [2]. Both autosomal dominant and recessive typeshave been identified [1]. Robinow syndrome has a rela-tively higher incidence in families with Turkish back-ground than in other nationalities [3].The autosomal recessive form of Robinow syndrome(OMIM #268310) has dwarfism caused by a geneticmutation in the ROR2 gene, a tyrosine kinase receptorthat is linked to the development of the skeleton [4]. The1072 ª 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use anddistribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.autosomal dominant form of the syndrome (OMIM#180700) with mutations in WNT5A is phenotypicallymilder with normal stature [5].We present a case with prenatal diagnosis of autosomalrecessive Robinow syndrome, detected at gestational age21 weeks from 3D ultrasound. In the literature, only tworecessive cases have been detected prenatally (Percin et al.2001 [6] and Guven et al. 2006 [7]).The aim of the present case report was to describe the pre-natal characteristics of a fetus with Robinow syndrome usingprenatal ultrasound, as we find that recessive Robinow syn-drome belongs to the prenatally detectable skeletal dysplasias.An early clinical recognition is important to parents,who can receive relevant information concerning theprognosis of this syndrome at an early stage of pregnancyincluding the possibility of terminating the pregnancy.Case ReportThis case concerns a 25-year-old primigravida. Approvalto publish this article was provided by the parents of theproband.The parents and the grandparents of the proband areconsanguineous cousins from Iraq. Both parents arehealthy, but the father has two siblings and one cousinaffected by Robinow syndrome.The combined first-trimester screening examination,which is offered at gestational age 11–14 weeks accordingto the Danish national screening program, was not per-formed. The mother of the proband had an ultrasoundscan performed at a private clinic at gestational age15 weeks and was told that the fetus was a female.A routine ultrasound malformation scan performed bya sonographer at gestational age 21 weeks revealed afetus with severe short limbs why the patient wasreferred for a fetal medicine expert examination a fewdays later. The prenatal examination was performedusing a GE Voluson E8 Expert 3D ultrasound scanner,and later in the pregnancy, more examinations weremade using a GE Voluson E10 Expert 3D ultrasoundscanner. The scan revealed several dysmorphic facial fea-tures; for example, an abnormal short and wide nose,shortening of the long bones (Z-score 5 to 6), espe-cially ulnae and radius bilaterally (Z-score 8 to 9),(A) (B)(C)(D)Figure 1. (A) The 3D reconstruction shows an abnormal flat profile and a triangular mouth with gingival hyperplasia. (B) The 3D reconstructionshows an upper lip with a characteristic eversion, hypertelorism, and a wide nasal root. (C, D) Photography of the male infant at the age of7 weeks: an abnormal short and flat nose, a wide nasal root, hypertelorism, and prominent eyes.ª 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd. 1073B. F. Jeppesen et al. Prenatal diagnosis of Robinow syndromeand hemivertebrae. The shortening of the bones indi-cated mesomelia. The vertebral column was slightlycrooked due to several hemivertebrae. A scrotum wasseen but no penis. Combining the clinical and ultrasoundfindings, the case was found compatible with the reces-sive form of Robinow syndrome.The parents were offered a cytogenetic analysis andkaryotyping. However, they declined the offer on accountof the small procedure-related risk of abortion. They wereinformed about the possibility of applying for permissionfor termination. However, the parents decided to proceedwith the pregnancy to term.Due to reduced growth of the fetus in the last trimesterof the pregnancy, labor was induced at gestational age37 + 5 weeks. The proband, a male infant, was deliveredat gestational age 38 + 2 weeks; birthweight 2275 g; andbirth length 42 cm. After 2 weeks at the neonatal unit, hewas discharged with his parents to their home.Postnatally, we elucidated the dysmorphic prenatalfindings of the face even further, by transferring the ultra-sound data to a computer running GE 4DView Softwarefor 3D visualization and analysis of the specific facial fea-tures see Figure 1A and B. The 3D reconstruction in Fig-ure 1A shows an abnormal profile, hypertelorism, a widenasal root, and a triangular mouth with gingival hyper-plasia. Figure 1B shows a characteristic eversion of theupper lip.Postnatal examination and screening showed character-istic features similar to the prenatal ultrasound findings: awide nasal root, an abnormal short and flat nose, hyper-telorism, and prominent eyes see Figure 1C and D. Therewas a shortening of the upper and lower extremitiesincluding digits and toes, representative of dwarfism, mal-formations of the vertebrae, and a micropenis with nor-mal scrotum see Figure 2. X-rays of the columndemonstrated several malformations including dysplasticcorpora with multiple hemivertebrae and spina bifidafrom L2 and distally.MRI column showed several malformations includingsyrinx from Th8 to Th10, diastematomyelia from Th10 toThL1, and a dermal sinus from L3 to L4. The child hadno neurological signs or symptoms from the findings. Allclinical findings indicated the diagnosis of autosomalrecessive Robinow syndrome as proposed prenatally. Thefacial dysmorphology alone can be seen as a strong mar-ker of the diagnosis when it comes to prenatal ultrasoundscans, because it has a characteristic and explicit appear-ance.The diagnosis was genetically confirmed at the age of4 months with the finding of a novel homozygous frame-shift mutation in the ROR2 gene: c.139del p.Asp48 fs(OMIM 268310) corresponding to autosomal recessiveRobinow syndrome [4].Discussion and ConclusionBy focusing on the characteristic phenotypical features inRobinow syndrome, among these especially the short dis-proportionate stature, the facial dysmorphology, and gen-ital hypoplasia, we hypothesize that it is possible to detectand diagnose both the autosomal recessive and dominantforms prenatally. To the best of our knowledge, only twoprevious cases of prenatally diagnosed autosomal recessiveRobinow syndrome (Percin et al. 2001 [6] and Guvenet al. 2006 [7]) and two cases of prenatally diagnosedautosomal dominant Robinow syndrome (Loverro et al.1990 [8] and Castro et al. 2013 [9]) have been reportedin the literature.In the dominant cases, Loverro et al. [8] found short-ening of the forearms and an abnormal ulna/humeruslength ratio. Castro et al. [9] found shortening of theforearms, an abnormal profile with flattening of thefrontal bone, a broad nasal bridge, hypertelorism withprominent eyes, cleft palate, micrognathia, and low-setears. Furthermore, the thorax was observed to be nar-rower in comparison with the abdomen. In the recessivecases, Percin et al. [6] found shortening of the humerusand femur, and Guven et al. [7] found decreased femurand humerus lengths and shortening of the long bonesof the forearms. Only in the dominant case of Castroet al. [9], the facial dysmorphology was recognized pre-natally.Figure 2. Photography of the male infant at the age of 7 weeks:Shortening of the upper and lower extremities including digits andtoes and a micropenis with normal scrotum.1074 ª 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.Prenatal diagnosis of Robinow syndrome B. F. Jeppesen et al.This case report showed the prenatal findings of afetus with autosomal recessive Robinow syndrome using3D ultrasound. The findings included shortening of thelong bones, especially radius and ulnae, bilaterally, sev-eral hemivertebrae, an abnormal facial profile, a widenasal root, hypertelorism, and a triangular formedmouth with gingival hyperplasia. Furthermore, wefound a normal scrotum, but no penis could be visual-ized. No previous studies have to our knowledge notedthis genital malformation prenatally in Robinow syn-drome, which also is an important diagnostic indicatorof the syndrome.Based on previous publications and the findings inthe present case, we suggest that Robinow syndromeshould be considered in the fetus with mesomelicgrowth retardation, facial characteristics, and micropenisin male fetuses. Prenatally, the examiner should beaware of differential diagnoses as discussed by Castroet al. [9]. With knowledge of the well-known character-istic features of Robinow syndrome outlined in thisstudy, the examiner will be able to recognize and diag-nose an affected fetus when performing prenatal ultra-sound. According to Castro et al., 80% of the affectedindividuals have a normal IQ, but among the rest somemay have some degree of mental retardation, primarilyin the autosomal recessive form of Robinow syndrome[9]. In relation to the prognosis and the psychologicaland mental challenges, it is of clinical importance tothe parents, that they can receive counseling when con-sidering the possibility of terminating the pregnancy(Table 1).AuthorshipBFJ: collected the clinical data and prepared the manu-script. HBH: presented the genetical confirmation of thediagnosis as well as the genetical counseling of the fam-ily. SK, NVH, and TAD: contributed with 3D data han-dling, reconstruction, and quantitative and qualitativecomparison of the patient’s prenatal morphologyobtained by 3D ultrasound to postnatal obtained 3Dfacial surface scanning (in the 3D laboratory’s 3dMDsurface scanner, specially designed for infants and youngchildren). FSJ: performed the prenatal diagnosis of thefetus. All authors contributed in both discussion andanalysis of the patient data and commented on themanuscript at all stages.Conflict of InterestThere are no conflict of interests for any of the co-authors of this manuscript.References1. Hosalkar, H. S., and G. J. Shaw. 2002. Robinow syndrome.J. Postgrad. Med. 48:50–51.2. Robinow, M., F. N. Silverman, and H. D. Smith. 1969. Anewly recognized dwarfing syndrome. Am. J. Dis. Child.117:645–651.3. Aksit, S., H. Aydinlioglu, G. Dizdarer, S. Caglayan, D.Bektaslar, and A. Cin. 1997. Is the frequency of Robinowsyndrome relatively high in Turkey? Four more casereports. Clin. Genet. 52:226–230.Table 1. Ultrasound findings in prenatal diagnosis of Robinow syndrome.PhenotypicaltraitsDominant RecessiveLoverro et al. (1990) Castro et al. (2014) Guven et al. (2006) Percin et al. (2001) Present studyGender Female Female Male Male MaleAge of diagnosis GA 19 weeks GA 23 + 1 weeks GA 33 weeks GA 12 + 4 weeks GA 21 weeksShortening ofthe bonesForearms,ulna/humeruslength ratioRadius, ulna Humerus, femur,and forearmHumerus and femur All long bones,especially ulnaand radiusLow-set ears  +   +Hypertelorism  +   +Prominent eyes  +   +Nose Short upturned Wide nasal bridge   Short upturnedWide nasal bridgeMouth Cleft palate Triangular mouthGingival hyperplasiaFacial bones Abnormal flat profile withflattening of the frontal boneMicrognathiaAbnormal flat profileHemivertebra   +  +Genital abnormalities Micropenisª 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd. 1075B. F. Jeppesen et al. Prenatal diagnosis of Robinow syndrome4. Bokhoven, V. H., J. Celli, H. Kayserili, E. V. Beusekom, S.Balsi, W. Brussel, et al. 2000. Mutation of the geneencoding the ROR2 tyrosine kinase causes autosomalrecessive Robinow syndrome. Nat. Genet. 25:423–426.5. Masseu, J. F., E. Pardoro, A. M. Vianna-Morgante, A.Richieri-Costa, C. A. Kim, and D. Brunoni. 2007. ClinicalCharacterization of autosomal dominant and recessiveRobinow syndrome. Am. J. Med. Genet. A 143:320–325.6. Percin, E. F., T. Guvenal, A. Cetin, S. Percin, F. Goze, andS. Arici. 2000. First trimester diagnosis of Robinowsyndrome. Fetal Diagn. Ther. 16:308–311.7. Guven, M. A., C. Batukan, S. Ceylaner, M. Uzel, A. Ozbek,and G. Demirpolat. 2006. Prenatal and postnatal findings ina case with the autosomal recessive type of Robonowsyndrome. Fetal Diagn. Ther. 21:386–389.8. Loverro, G., G. Guanti, G. Caruso, and L. Selvaggi. 1990.Robinow’s syndrome: prenetal diagnosis. Prenat. Diagn.10:121–126.9. Castro, S., E. Peraza, A. Barraza, and M. Zapata. 2014.Prenatal diagnosis of Robinow syndrome: a case report.J. Clin. Ultrasound 42:297–300.Supporting InformationAdditional Supporting Information may be found onlinein the supporting information tab for this article:Video S1. GA 34+6: 3D ultrasound video shows the char-acteristic facial morphology of the fetus compatible withRobinow syndrome: an upper lip with a characteristiceversion, a wide nasal root and hypertelorism.1076 ª 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.Prenatal diagnosis of Robinow syndrome B. F. Jeppesen et al.

Prenatal diagnosis of autosomal recessive Robinow syndrome using 3D ultrasound.

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Prenatal diagnosis of autosomal recessive Robinow syndrome using 3D ultrasound.

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