Klinische FragestellungLippen-Kiefer-Gaumen-[Gesichts-]Spalten, Differentialdiagnose

NGS +

[Sanger]

Orofaziale Spalten (Lippen-Kiefer-Gaumenspalte, Lippenspalte, Gaumenspalte) gehören weltweit zu denhäufigsten Fehlbildungen. Die Prävalenz orofazialer Spalten beträgt abhängig von der Bevölkerungsgruppe zwischen 1/500 (Asien) und 1/2500 (afrikanische Bevölkerung). Isolierte und syndromale Formen sind bekannt.

Orofaziale Spalten treten familiär gehäuft auf. In den meisten Fällen sind orofaziale Spaltbildungen multifaktoriell bedingt, das bedeutet, dass sowohl Umweltfaktoren (in der Schwangerschaft z.B. Folsäuremangel, Alkohol) als auch genetische Faktoren eine Rolle spielen. Seltener werden monogene Ursachen (Einzelgenveränderungen, die unterschiedlichen Erbgängen folgen) oder (submikroskopische)Chromosomenstörungen ursächlich nachgewiesen.

Die Wiederholungs¬wahrscheinlichkeit der Fehlbildung bei Verwandten von Betroffenen ist in der Regel gegenüber dem Bevölkerungsdurchschnitt erhöht, abhängig von der Ursache und der Ausprägung der orofazialen Spalte.

Eine relativ häufige chromosomale Ursache für Gaumenspalten ist das velokardiofaziale (Shprintzen) Syndrom in Folge einer Mikrodeletion 22q11.2. Die häufigste monogen bedingte, nicht-syndromale Ursache für orofaziale Spaltbildung ist das van-der-Woude-Syndrom (IRF6-Gen) (ca 2% aller Fälle von Lippen-Kiefer-Gaumenspalten). Weitere häufigere monogene Formen treten z.B. in Folge pathogener Veränderungen der Gene GRHL3 und COL11A2 (Stickler Syndrom) auf.

Referenz:

Pädiatrie, Hoffman et al. 2020: S.1543-1546

Babai et al., Genes. 2023; 4(8):1603

Kini, Br Dent J. 2023; 234(12):947-952)

• (Syndromic) clefting
• Familial non-syndromic cleft lip and/or familial cleft palate
• Familial non-syndromic clefting
• Syndromic cleft lip and/or cleft palate
• Allelic: Triatrial heart [MONDO:0015450] (HYAL2)
• 3MC syndrome 1 (MASP1)
• 3MC syndrome 3 (COLEC10)
• ADULT syndrome (TP63)
• Aarskog-Scott syndrome (FGD1)
• Abruzzo-Erickson syndrome (TBX22)
• Acampomelic campomelic dysplasia (SOX9)
• Achondrogenesis Ib (SLC26A2)
• Achondrogenesis, type II or hypochondrogenesis (COL2A1)
• Acrocallosal syndrome (KIF7)
• Acrofacial dysostosis 1, Nager type (SF3B4)
• Acromelic frontonasal dysostosis (ZSWIM6)
• Adams-Oliver syndrome 1 (ARHGAP31)
• Adams-Oliver syndrome 2 (DOCK6)
• Adams-Oliver syndrome 4 (EOGT)
• Adams-Oliver syndrome 5 (NOTCH1)/Aortic valve disease 1 (NOTCH1)
• Adams-Oliver syndrome 6 (DLL4)
• Al-Gazali-Bakalinova syndrome (KIF7)
• Andersen syndrome (KCNJ2)
• Anterior segment anomalies with/-out cataract (EYA1)
• Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis (FGFR2)
• Aortic valve disease 1 (NOTCH1)
• Apert syndrome (FGFR2)
• Arboleda-Tham syndrome (KAT6A)
• Arrhythmogenic right ventricular dysplasia 1 (TGFB3)
• Arthrogryposis, distal, type 3 (PIEZO2)
• Arthrogryposis, distal, type 5 (PIEZO2)
• Arthrogryposis, distal, with impaired proprioception + touch (PIEZO2)
• Atelosteogenesis, type I (FLNB)
• Atelosteogenesis, type II (SLC26A2)
• Atelosteogenesis, type III (FLNB)
• Atrial fibrillation, familial, 9 (KCNJ2)
• Avascular necrosis of the femoral head (COL2A1)
• Baraitser-Winter syndrome 1 (ACTB)
• Baraitser-Winter syndrome 2 (ACTG)
• Bardet-Biedl syndrome 13 (MKS1)
• Bardet-Biedl syndrome 20 (IFT172)
• Basal cell nevus syndrome (PTCH1)
• Basel-Vanagait-Smirin-Yosef syndrome (MED25)
• Beare-Stevenson cutis gyrata syndrome (FGFR2)
• Beckwith-Wiedemann syndrome (CDKN1C)
• Bent bone dysplasia syndrome (FGFR2)
• Blepharocheilodontic syndrome 1 (CDH1)
• Blepharocheilodontic syndrome 2 (CTNND1)
• Bohring-Opitz syndrome (ASXL1)
• Boomerang dysplasia (FLNB)
• Brachydactyly, type A2 (BMP2)
• Brachydactyly, type B1(ROR2)
• Branchiooculofacial syndrome (TFAP2A)
• Branchiootic syndrome 1 (EYA1)
• Branchiootic syndrome 3 (SIX1)
• Branchiootorenal syndrome 1, with/-out cataracts (EYA1)
• Branchiootorenal syndrome 2 (SIX5)
• Burn-McKeown syndrome (TXNL4A)
• CHARGE syndrome (CHD7)
• COACH syndrome 2 (CC2D2A)
• Campomelic dysplasia (SOX9)
• Campomelic dysplasia with autosomal sex reversal (SOX9)
• Cardiac valvular dysplasia, XL (FLNA)
• Cardiospondylocarpofacial syndrome (MAP3K7)
• Carey-Fineman-Ziter syndrome (MYMK)
• Catel-Manzke syndrome (TGDS)
• Cerebrocostomandibular syndrome (SNRPB)
• Chondrodysplasia punctata, XLD (EBP)
• Chondrodysplasia with joint dislocations, GPAPP type (IMPAD1)
• Cleft lip with/-out cleft palate [panelapp] (ARHGAP29)
• Cleft lip/palate [MONDO:0016044] (HYAL2)
• Cleft lip/palate-ectodermal dysplasia syndrome (NECTIN1)
• Cleft palate with ankyloglossia (TBX22)
• Cleft palate, cardiac defects + mental retardation (MEIS2)
• Colorectal cancer, hereditary nonpolyposis, type 6 (TGFBR2)
• Congenital heart defects, nonsyndromic, 1, XL (ZIC3)
• Congenital short bowel syndrome (FLNA)
• Cornelia de Lange syndrome 1 (NIPBL)
• Cornelia de Lange syndrome 2 (SMC1A)
• Cornelia de Lange syndrome 3 (SMC3)
• Cornelia de Lange syndrome 5 (HDAC8)
• Cortical dysplasia, complex, with other brain malformations 6 (TUBB)
• Craniofacial dysmorphism, skeletal anomalies + mental retardation syndrome (TMCO1)
• Craniofacial-deafness-hand syndrome PAX3)
• Craniofacial-skeletal-dermatologic dysplasia (FGFR2)
• Craniofrontonasal dysplasia (EFNB1)
• Craniosynostosis, nonspecific (FGFR2)
• Crouzon syndrome (FGFR2)
• Czech dysplasia (COL2A1)
• De la Chapelle dysplasia (SLC26A2)
• Deafness, AD 13 (COL11A2)
• Deafness, AD 20/26 (ACTG)
• Deafness, AD 23 (SIX1)
• Deafness, AD 37 (COL11A1)
• Deafness, AR 53 (COL11A2)
• Desbuquois dysplasia 2 (XYLT1)
• Developmental + epileptic encephalopathy 85, with/-out midline brain defects (SMC1A)
• Diamond-Blackfan anemia 10 (RPS26)
• Diamond-Blackfan anemia 6 (RPL5)
• Diastrophic dysplasia (SLC26A2)
• Diastrophic dysplasia, broad bone-platyspondylic variant (SLC26A2)
• Duane-radial ray syndrome (SALL4)
• Dystonia, juvenile-onset (ACTB)
• Ectodermal dysplasia 3, Witkop type (MSX1)
• Ectrodactyly, ectodermal dysplasia + cleft lip
• Ehlers-Danlos syndrome, musculocontractural type 1 (CHST14)
• Endocrine-cerebroosteodysplasia (CILK1)
• Epiphyseal dysplasia, multiple, 4 (SLC26A2)
• Epiphyseal dysplasia, multiple, 6 (COL9A1)
• Epiphyseal dysplasia, multiple, with myopia and deafness (COL2A1)
• Escobar syndrome (CRNG)
• FG syndrome 2 (FLNA)
• Facial clefting, oblique, 1 (SPECC1L)
• Fibrochondrogenesis 1 (COL11A1)
• Fibrochondrogenesis 2 (COL11A2)
• Focal dermal hypoplasia (PORCN)
• Fraser syndrome 1 (FRAS1)
• Frontometaphyseal dysplasia (MAP3K7)
• Frontometaphyseal dysplasia 1 (FLNA)
• Gastric cancer, hereditary diffuse, with/-out cleft lip and/or palate (CDH1)
• Glass syndrome (SATB2)
• Goldberg-Shprintzen megacolon syndrome (KIFBP)
• Greig cephalopolysyndactyly syndrome (GLI3)
• Hartsfield syndrome (FGFR1)
• Hay-Wells syndrome (TP63)
• Heterotaxy, visceral, 1, XL (ZIC3)
• Heterotopia, periventricular, 1 (FLNA)
• Holoprosencephaly 2 SIX3)
• Holoprosencephaly 3 (SHH)
• Holoprosencephaly 5 (ZIC2)
• Holoprosencephaly 7 (PTCH1)
• Hydrolethalus syndrome (HYLS1)
• Hydrolethalus syndrome 2 (KIF7)
• Hyperphosphatasia with mental retardation syndrome 1 (PIGV)
• Hypogonadotropic hypogonadism 2 with/-out anosmia (FGFR1)
• Hypogonadotropic hypogonadism 5 with/-out anosmia (CHD7)
• IFAP syndrome with/-out BRESHECK syndrome (MBTPS2)
• IMAGE syndrome (CDKN1C)
• IVIC syndrome (SALL4)
• Intellectual developmental disorder, XL 99 (USP9X)
• Intellectual developmental disorder, XL 99, syndromic, female-restricted (USP9X)
• Intellectual developmental disorder, XL syndromic, Snyder-Robinson type (SMS)
• Intellectual developmental disorder, XL, syndromic, Siderius type (PHF8)
• Intestinal pseudoobstruction, neuronal (FLNA)
• Jackson-Weiss syndrome (FGFR1)
• Jackson-Weiss syndrome (FGFR2)
• Joubert syndrome 10 (OFD1)
• Joubert syndrome 12 (KIF7)
• Joubert syndrome 17 (C5orf42)
• Joubert syndrome 18 (TCTN3)
• Joubert syndrome 23 (KIAA0586)
• Joubert syndrome 28 (MKS1)
• Joubert syndrome 9 (CC2D2A)
• Juberg-Hayward syndrome (ESCO2)
• Juvenile polyposis
• KBG syndrome (ANKRD11)
• Kabuki syndrome 1 (KMT2D)
• Kabuki syndrome 2 (KDM6A)
• Keratosis follicularis spinulosa decalvans, XL (MBTPS2)
• Kniest dysplasia (COL2A1)
• LADD syndrome (FGFR2)
• Larsen syndrome (FLNB)
• Legg-Calve-Perthes disease (COL2A1)
• Leukodystrophy, hypomyelinating, 11 (POLR1C
• Limb-mammary syndrome (TP63)
• Loeys-Dietz syndrome 1 (TGFBR1)
• Loeys-Dietz syndrome 2 (TGFBR2)
• Loeys-Dietz syndrome 3 (SMAD3)
• Loeys-Dietz syndrome 5 (TGFB3)
• Lymphedema-distichiasis syndrome (FOXC2)
• Lymphedema-distichiasis syndrome with renal disease + diabetes mellitus (FOXC2)
• MEHMO syndrome (EIF2S3)
• MEND syndrome (EBP)
• Mandibulofacial dysostosis with alopecia (EDNRA)
• Mandibulofacial dysostosis, Guion-Almeida type (EFTUD2)
• Marden-Walker syndrome (PIEZO2)
• Marshall syndrome (COL11A1)
• Meckel syndrome 1 (MKS1)
• Meckel syndrome 6 (CC2D2A)
• Melnick-Needles syndrome (FLNA)
• Mental retardation, AD 21 (CTCF(`)
• Mental retardation, AR 13 (TRAPPC9)
• Mental retardation, XL syndromic 16 (FGD1)
• Microcephaly-capillary malformation syndrome (STAMBP)
• Microphthalmia with coloboma 5 (SHH)
• Microphthalmia, syndromic 2 (BCOR)
• Miller syndrome (DHODH)
• Mowat-Wilson syndrome (ZEB2)
• Mulibrey nanism (TRIM37)
• Multiple congenital anomalies-hypotonia-seizures syndrome 1 (PIGN)
• Multiple pterygium syndrome, lethal type (CRNG)
• Multiple self-healing squamous epithelioma, susceptibility to (TGFBR1)
• Myhre syndrome (SMAD4) 3
• Neurodevelopmental disorder with movement abnormalities, abnormal gait, autistic features (ZSWIM6)
• Olmsted syndrome, XL (MBTPS2)
• Opitz GBBB syndrome, type I (MID1)
• Opitz GBBB syndrome, type II (SPECC1L)
• Orofacial cleft 5 (MSX1)
• Orofacial cleft 6 (IRF6)
• Orofacial cleft 7 (NECTIN1)
• Orofacial cleft 8 (TP63)
• Orofaciodigital syndrome I (OFD1)
• Orofaciodigital syndrome IV (TCTN3)
• Orofaciodigital syndrome VI (C5orf42)
• Orofaciodigital syndrome XIV (C2CD3)
• Osteoarthritis with mild chondrodysplasia (COL2A1)
• Osteogenesis imperfecta, type XIX (MBTPS2)
• Osteoglophonic dysplasia (FGFR1)
• Osteopathia striata with cranial sclerosis (AMER1)
• Otofaciocervical syndrome (EYA1)
• Otopalatodigital syndrome, type I (FLNA)
• Otopalatodigital syndrome, type II (FLNA)
• Otospondylomegaepiphyseal dysplasia, AD + AR (COL11A2)
• Pallister-Hall syndrome (GLI3)
• Periventricular nodular heterotopia 7 (NEDD4L)
• Peters-plus syndrome (B3GLCT)
• Pfeiffer syndrome (FGFR1)
• Pfeiffer syndrome (FGFR2)
• Platyspondylic skeletal dysplasia, Torrance type (COL2A1)
• Polydactyly, postaxial, types A1 + B (GLI3)
• Polydactyly, preaxial, type IV (GLI3)
• Polyposis, juvenile intestinal (SMAD4)
• Popliteal pterygium syndrome 1 (IRF6)
• Raine syndrome (FAM20C)
• Rapp-Hodgkin syndrome (TP63)
• Retinitis pigmentosa 23 (OFD1)
• Retinitis pigmentosa 71 (IFT172)
• Retinitis pigmentosa 80 (IFT140)
• Rhabdomyosarcoma 2, alveolar (PAX3)
• Roberts-SC phocomelia syndrome (ESCO2)
• Robin sequence with cleft mandible + limb anomalies (EIF4A3)
• Robinow syndrome, AD 1 (WNT5A)
• Robinow syndrome, AD 2 (DVL1)
• Robinow syndrome, AD 3 (DVL3)
• Robinow syndrome, AR (ROR2)
• SED congenita (COL2A1)
• SMED Strudwick type (COL2A1)
• Saethre-Chotzen syndrome (FGFR2)
• Scaphocephaly + Axenfeld-Rieger anomaly (FGFR2)
• Scaphocephaly, maxillary retrusion + mental retardation (FGFR2)
• Schizencephaly (SHH)
• Schizencephaly (SIX3)
• Short QT syndrome 3 (KCNJ2)
• Short stature, facial dysmorphism + skeletal anomalies with/-out cardiac anomalies 1 (BMP2)
• Short-rib thoracic dysplasia 10 with/-out polydactyly (IFT172)
• Short-rib thoracic dysplasia 14 with polydactyly (KIAA0586)
• Short-rib thoracic dysplasia 15 with polydactyly (DYNC2LI1)
• Short-rib thoracic dysplasia 2 with/-out polydactyly (IFT80)
• Short-rib thoracic dysplasia 3 with/-out polydactyly (DYNC2H1)
• Short-rib thoracic dysplasia 6 with or without polydactyly (NEK1)
• Short-rib thoracic dysplasia 9 with/-out polydactyly (IFT140)
• Shprintzen-Goldberg syndrome (SKI)
• Simpson-Golabi-Behmel syndrome, type 1 (GPC3)
• Simpson-Golabi-Behmel syndrome, type 2 (OFD1)
• Single median maxillary central incisor (SHH)
• Smith-Lemli-Opitz syndrome (DHCR7)
• Spondylocarpotarsal synostosis syndrome (FLNB)
• Spondyloepiphyseal dysplasia, Stanescu type (COL2A1)
• Spondyloperipheral dysplasia (COL2A1)
• Stickler sydrome, type I, nonsyndromic ocular (COL2A1)
• Stickler syndrome, type I (COL2A1)
• Stickler syndrome, type II (COL11A1)
• Stickler syndrome, type IV (COL9A1)
• Symmetric circumferential skin creases, congenital, 1 (TUBB)
• Symmetric circumferential skin creases, congenital, 2 (MAPRE2)
• TARP syndrome (RBM10)
• Teebi hypertelorism syndrome (SPECC1L)
• Terminal osseous dysplasia (FLNA)
• Tooth agenesis, selective, 1, with/-out orofacial cleft (MSX1)
• Treacher Collins syndrome 1 (TCOF1)
• Treacher Collins syndrome 2 (POLR1D)
• Treacher Collins syndrome 3 (POLR1C)
• Treacher-Collins syndrome 4 (POLR1B)
• Trigonocephaly 1 (FGFR1)
• VACTERL association, XL (ZIC3)
• VICI syndrome (EPG5)
• Van den Ende-Gupta syndrome (SCARF2)
• Van der Woude syndrome (IRF6)
• Van der Woude syndrome 2 (GRHL3)
• Vitreoretinopathy with phalangeal epiphyseal dysplasia (COL2A1)
• Waardenburg syndrome, type 1 (PAX3)
• Waardenburg syndrome, type 3 (PAX3)
• You-Hoover-Fong syndrome (TELO2)
• ZTTK syndrome (SON)
• foot malformation 4 (TP63)
• hereditary hemorrhagic telangiectasia syndrome (SMAD4)
• palate syndrome 3 (TP63)