Craniofacial and skeletal disorders

Since 1993 Ute Hehr (born Schell) has been working on Mendelial disorders affecting craniofacial structures. As a DAAD postdoc in Max Muenkes lab at CHOP, University of Pennsylvania/USA she described for the first time FGFR1 and FGFR2 mutations in Pfeiffer syndrome and related craniosynostosis syndromes and substantially contributed to the identification of mutations in the SIX3 gene resulting in the combined craniofacial and brain malformations in patients with SIX3-associated Holoprosencephaly.

Currently the Hehr laboratory offers genetic testing for a wide spectrum of Mendelian craniofacial disorders with a special focus on Treacher-Collins-Franceschetti syndrome as the most frequent form of mandibulo-facial dysostosis. Genetic testing for this syndrome is done in close collaboration with the group of Dagmar Wieczorek in Essen.
The longstanding interest of the Hehr group in FGFR associated skeletal disorders naturally led to further work on FGFR associated skeletal disorders like Achondroplasia or Thanatophoric dysplasia. More recently other severe monogenic skeletal disorders such as Ellis van Creveld syndrome were included into our diagnostic spectrum in order to support the rapid prenatal genetic differential diagnosis of fetal skeletal dysplasias.

We offer in our accredited laboratory:

  • pretest evaluation of your patients clinical information in order to develop an individual genetic testing strategy
  • diagnostic prenatal and postnatal genetic testing by Sanger sequencing as well as MLPA analysis
  • carrier testing
  • prenatal carrier testing in subsequent pregnancies  for disorders with clinical manifestation prior to adolescence.

All identified sequence alterations, relevant or potentially relevant for the clinical findings of your patient, are

  • confirmed by Sanger sequencing,
  • carefully assessed using our in house evaluation workflow including comparison with the human reference genome hg19, publically available and our own extensive mutation database as well as in silico prediction of functional consequences applying different algorithms,
  • rated and summarized in an individual medical report considering provided clinical data.

We offer genetic testing by Sanger sequencing and MLPA(+MLPA) for:

Disease Disease
Gene Gene

Craniofacial disorders and skeletal dysplasias

Craniosynostosis, syndromic

Apert syndrome 101200 176943 10q26.13
Beare-Stevenson cutis gyrata syndrome 123790 176943 10q26.13
Craniofrontonasal syndrome 304110 300035 Xq13.1
Crouzon syndrome (Craniofacial Dysostosis, Type I) 123500 176943 10q26.13
Crouzon syndrome with acanthosis nigricans 612247 134934 4p16.3
Jackson-Weiss syndrome 123150 FGFR2
Muenke syndrome 602849 134934 4p16.3
Pfeiffer syndrome (Acrocephalosyndaktyly Typ V) 101600 FGFR1
Saethre-Chotzen syndrome 101400 601622 7p21.1


Achondroplasia 100800 FGFR3 134934 4p16.3
Achondrogenesis, type IA 200600 TRIP11 604505 14q32.12
Achondrogenesis, type IB 600972 SLC26A2 606718 5q32
Acrofacial dysostosis 1, Nager type 154400 SF3B4 605593 1q21.2
Antley-Bixler syndrome 207410
Atelosteogenesis, type I 108720 FLNB 603381 3p14.3
Atelosteogenesis, type II 256050 SLC26A2 606718 5q32
Atelosteogenesis, type III 108721 FLNB 603381 3p14.3
Basal cell nevus syndrome/Gorlin-Goltz syndrome (+MLPA) 109400
Boomerang dysplasia 112310 FLNB 603381 3p14.3
Branchiooculofacial syndrome 113620 TFAP2A 107580 6p24.3
Branchiootorenal syndrome (+MLPA) 113650
Diastrophic dysplasia (DTD) 222600 SLC26A2 606718 5q32
EEC3 syndrome 604292 p63 603273 3q28
Ellis-van Creveld syndrome (+Linkage) 225500 EVC
Epiphyseal dysplasia, multiple, 4 (EDM4) 226900 SLC26A2 606718 5q32
Frontometaphyseal dysplasia 305620 FLNA NM 300017 Xq28
Greig Cephalopolysyndaktyly syndrome (+MLPA) 603543 p63 603273 3q28
Hay-Wells syndrome 175700 GLI3 HPE 165240 7p14.1
Hypochondroplasia 106260 p63 603273 3q28
Lacrimoauriculodentodigital syndrome (LADD) (+MLPA) 146000 FGFR3 134934 4p16.3
Larsen syndrome, autosomal-dominant 149730 FGFR3
Limb-mammary syndrome 150250 FLNB 603381 3p14.3
Mandibulofacial dysostosis with microcephaly 610536 EFTUD2 603892 17q21.31
Melnick-Needles syndrome 309350 FLNA NM 300017 Xq28
Microtia, hearing impairment and cleft palate 612290 HOXA2 604685 7p15.2
Osteoglophonic dysplasia 166250 FGFR1 136350 8p11.23-p11.22
Otofaciocervical syndrome (+MLPA) 166780 EYA1 601653 8q13.3
Otopalatodigital syndrome, type I 311300 FLNA NM 300017 Xq28
Otopalatodigital syndrome, type II 304120 FLNA NM 300017 Xq28
Pallister-Hall syndrome (+MLPA) 146510 GLI3 HPE 165240 7p14.1
Popliteal pterygium syndrome 1 (+MLPA) 119500 IRF6 607199 1q32.2
Rapp-Hodgkin syndrome 129400 p63 603273 3q28
Simpson-Golabi-Behmel syndrome (+MLPA) 312870 GPC3 NM
GPC4 (nur MLPA)
Split-hand/foot malformation 4 605289 p63 603273 3q28
Spondylocarpotarsal synostosis syndrome 272460 FLNB 603381 3p14.3
Terminal osseous dysplasia (TOD) 300244 FLNA NM 300017 Xq28
Thanatophoric dysplasia, type I 187600 FGFR3 NM 134934 4p16.3
Thanatophoric dysplasia, type II 187601 FGFR3 NM 134934 4p16.3
Treacher Collins Franceschetti syndrome (+MLPA) 154500
van der Woude syndrome (+MLPA) 119300 IRF6 607199 1q32.2
Weyers acrofacial dysostosis (+Linkage) 193530 EVC

Related Publications of our group


Czeschik JC, Hehr U, Hartmann B, Lüdecke HJ, Rosenbaum Th, Schweiger B, Wieczorek D 160 kb deletion in ISPD unmasking a recessive mutation in a patient with Walker-Warburg syndrome.  European journal of medical genetics 10/2013

Voigt C, Mégarbané A, Neveling K, Czeschik JC, Albrecht B, Callewaert B, von Deimling F, Hehr A, Falkenberg Smeland M, König R, Kuechler A, Marcelis C, Puiu M, Reardon W, Riise Stensland HM, Schweiger B, Steehouwer M, Teller C, Martin M, Rahmann S, Hehr U, Brunner HG, Lüdecke HJ, Wieczorek D. Oto-facial syndrome and esophageal atresia, intellectual disability and zygomatic anomalies - expanding the phenotypes associated with EFTUD2 mutations. Orphanet J Rare Dis. 2013 Jul 24;8:110.

Evers C, Jungwirth M, Morgenthaler J, Hinderhofer K, Maas B, Janssen J, Jauch A, Hehr U, Steinbeisser H, Moog U. Craniofrontonasal syndrome in a male due to chromosomal mosaicism involving EFNB1: further insights into a genetic paradox. Clin Genet. 2013 Apr 24. doi: 10.1111/cge.12171. [Epub ahead of print]

Czeschik JC, Voigt C, Alanay Y, Albrecht B, Avci S, Fitzpatrick D, Goudie DR, Hehr U, Hoogeboom AJ, Kayserili H, Simsek-Kiper PO, Klein-Hitpass L, Kuechler A, López-González V, Martin M, Rahmann S, Schweiger B, Splitt M, Wollnik B, Lüdecke HJ, Zeschnigk M, Wieczorek D. Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome. Hum Genet. 2013 Aug;132(8):885-98.

Schlump JU, Stein A, Hehr U, Karen T, Möller-Hartmann C, Elcioglu NH, Bogdanova N, Woike HF, Lohmann DR, Felderhoff-Mueser U, Linz A, Wieczorek D. Treacher Collins syndrome: clinical implications for the paediatrician--a new mutation in a severely affected newborn and comparison with three further patients with the same mutation, and review of the literature. Eur J Pediatr. 2012 Nov;171(11):1611-8.

Solomon BD, Bear KA, Wyllie A, Keaton AA, Dubourg C, David V, Mercier S, Odent S, Hehr U, Paulussen A, Clegg NJ, Delgado MR, Bale SJ, Lacbawan F, Ardinger HH, Aylsworth AS, Bhengu NL, Braddock S, Brookhyser K, Burton B, Gaspar H, Grix A, Horovitz D, Kanetzke E, Kayserili H, Lev D, Nikkel SM, Norton M, Roberts R, Saal H, Schaefer GB, Schneider A, Smith EK, Sowry E, Spence MA, Shalev SA, Steiner CE, Thompson EM, Winder TL, Balog JZ, Hadley DW, Zhou N, Pineda-Alvarez DE, Roessler E, Muenke M. Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog. J Med Genet. 2012 Jul;49(7):473-9.

Beygo J, Buiting K, Seland S, Lüdecke HJ, Hehr U, Lich C, Prager B, Lohmann DR, Wieczorek D. First Report of a Single Exon Deletion in TCOF1 Causing Treacher Collins Syndrome. Mol Syndromol. 2012 Jan;2(2):53-59.

Lines MA, Huang L, Schwartzentruber J, Douglas SL, Lynch DC, Beaulieu C, Guion-Almeida ML, Zechi-Ceide RM, Gener B, Gillessen-Kaesbach G, Nava C, Baujat G, Horn D, Kini U, Caliebe A, Alanay Y, Utine GE, Lev D, Kohlhase J, Grix AW, Lohmann DR, Hehr U, Böhm D; FORGE Canada Consortium, Majewski J, Bulman DE, Wieczorek D, Boycott KM. Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly. Am J Hum Genet. 2012 Feb 10;90(2):369-77.

Hehr U Molecular Genetic Testing of Patients with Craniosynostosis 01/2011: pages 177-183; , ISBN: 978-3-8055-9594-0

Rudnik-Schöneborn S, Zerres K, Graul-Neumann L, Wiegand S, Mellerowicz H, Hehr U. Two Adult Patients with Ellis-van Creveld Syndrome Extending the Clinical Spectrum. Mol Syndromol. 2011 Sep;1(6):301-306.

Dauwerse JG, Dixon J, Seland S, Ruivenkamp CA, van Haeringen A, Hoefsloot LH, Peters DJ, Boers AC, Daumer-Haas C, Maiwald R, Zweier C, Kerr B, Cobo AM, Toral JF, Hoogeboom AJ, Lohmann DR, Hehr U, Dixon MJ, Breuning MH, Wieczorek D. Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome. Nat Genet. 2011 Jan;43(1):20-2.

Solomon BD, Lacbawan F, Mercier S, Clegg NJ, Delgado MR, Rosenbaum K, Dubourg C, David V, Olney AH, Wehner LE, Hehr U, Bale S, Paulussen A, Smeets HJ, Hardisty E, Tylki-Szymanska A, Pronicka E, Clemens M, McPherson E, Hennekam RC, Hahn J, Stashinko E, Levey E, Wieczorek D, Roeder E, Schell-Apacik CC, Booth CW, Thomas RL, Kenwrick S, Cummings DA, Bous SM, Keaton A, Balog JZ, Hadley D, Zhou N, Long R, Vélez JI, Pineda-Alvarez DE, Odent S, Roessler E, Muenke M. Mutations in ZIC2 in human holoprosencephaly: description of a novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals. J Med Genet. 2010 Aug;47(8):513-24.

Lacbawan F, Solomon BD, Roessler E, El-Jaick K, Domené S, Vélez JI, Zhou N, Hadley D, Balog JZ, Long R, Fryer A, Smith W, Omar S, McLean SD, Clarkson K, Lichty A, Clegg NJ, Delgado MR, Levey E, Stashinko E, Potocki L, Vanallen MI, Clayton-Smith J, Donnai D, Bianchi DW, Juliusson PB, Njølstad PR, Brunner HG, Carey JC, Hehr U, Müsebeck J, Wieacker PF, Postra A, Hennekam RC, van den Boogaard MJ, van Haeringen A, Paulussen A, Herbergs J, Schrander-Stumpel CT, Janecke AR, Chitayat D, Hahn J, McDonald-McGinn DM, Zackai EH, Dobyns WB, Muenke M. Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function. J Med Genet. 2009 Jun;46(6):389-98.

Ebenrett I, Koerber F, Gabriel H, Hehr U, Heller R, Hoopmann MGezielte genetische Diagnostik nach Ersttrimester-Ultraschallscreening bei letaler fetaler Skelettdysplasie Geburtshilfe Und Frauenheilkunde - GEBURTSH FRAUENHEILK. 01/2009; 69(03):244-247.

Wieczorek D, Gener B, González MJ, Seland S, Fischer S, Hehr U, Kuechler A, Hoefsloot LH, de Leeuw N, Gillessen-Kaesbach G, Lohmann DR. Microcephaly, microtia, preauricular tags, choanal atresia and developmental delay in three unrelated patients: a mandibulofacial dysostosis distinct from Treacher Collins syndrome. Am J Med Genet A. 2009 May;149A(5):837-43.

de Lima RL, Hoper SA, Ghassibe M, Cooper ME, Rorick NK, Kondo S, Katz L, Marazita ML, Compton J, Bale S, Hehr U, Dixon MJ, Daack-Hirsch S, Boute O, Bayet B, Revencu N, Verellen-Dumoulin C, Vikkula M, Richieri-Costa A, Moretti-Ferreira D, Murray JC, Schutte BC. Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome. Genet Med. 2009 Apr;11(4):241-7.

Roessler E, Lacbawan F, Dubourg C, Paulussen A, Herbergs J, Hehr U, Bendavid C, Zhou N, Ouspenskaia M, Bale S, Odent S, David V, Muenke M. The full spectrum of holoprosencephaly-associated mutations within the ZIC2 gene in humans predicts loss-of-function as the predominant disease mechanism. Hum Mutat. 2009 Apr;30(4):E541-54.

Wieczorek D, Shaw-Smith C, Kohlhase J, Schmitt W, Buiting K, Coffey A, Howard E, Hehr U, Gillessen-Kaesbach G. Esophageal atresia, hypoplasia of zygomatic complex, microcephaly, cup-shaped ears, congenital heart defect, and mental retardation--new MCA/MR syndrome in two affected sibs and a mildly affected mother? Am J Med Genet A. 2007 Jun 1;143A(11):1135-42.

Hehr U, Muenke M. Craniosynostosis syndromes: from genes to premature fusion of skull bones. Mol Genet Metab. 1999 Oct;68(2):139-51. Review.

Wallis DE, Roessler E, Hehr U, Nanni L, Wiltshire T, Richieri-Costa A, Gillessen-Kaesbach G, Zackai EH, Rommens J, Muenke M. Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nat Genet. 1999 Jun;22(2):196-8.

Schell-Hehr U, Hehr A, Muenke M  Fibroblast growth factor receptors and their role in human dysmorphogenesis 01/1997: pages 145-162; , ISBN: 1 859960 36 7

Schell U, Wienberg J, Köhler A, Bray-Ward P, Ward DE, Wilson WG, Allen WP, Lebel RR, Sawyer JR, Campbell PL, Aughton DJ, Punnett HH, Lammer EJ, Kao FT, Ward DC, Muenke M. Molecular characterization of breakpoints in patients with holoprosencephaly and definition of the HPE2 critical region 2p21. Hum Mol Genet. 1996 Feb;5(2):223-9.

Muenke M, Schell U. Fibroblast-growth-factor receptor mutations in human skeletal disorders. Trends Genet. 1995 Aug;11(8):308-13. Review.

Schell U, Hehr A, Feldman GJ, Robin NH, Zackai EH, de Die-Smulders C, Viskochil DH, Stewart JM, Wolff G, Ohashi H, et al. Mutations in FGFR1 and FGFR2 cause familial and sporadic Pfeiffer syndrome. Hum Mol Genet. 1995 Mar;4(3):323-8.

Muenke M, Schell U, Hehr A, Robin NH, Losken HW, Schinzel A, Pulleyn LJ, Rutland P, Reardon W, Malcolm S, et al. A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nat Genet. 1994 Nov;8(3):269-74.