Syndromes associated
with cleft lip and/or palate |
Chromosome 22q11.2 deletion syndrome (Velocardiofacial syndrome, VCFS,
DiGeorge syndrome) | Robin sequence, cleft palate, small mouth, myopathic facies, retrognathia,
prominent nose with squared-off nasal tip, hypoplastic nasal alae,
cardiac anomalies, learning disability, behavioral/psychiatric
disorders, short stature, slender tapering digits, immunodeficiencies | AD | 192430 | Microdeletion of chromosomal region containing multiple genes |
Robin sequence | Micrognathia, cleft palate, glossoptosis, airway obstruction,
feeding difficulties | Sporadic; Mendelian inheritance in some families | 261800 | |
Stickler syndrome (type I, II, & III) | Cleft palate, micrognathia, glossoptosis, severe myopia, risk
of retinal detachment, midfacial hypoplasia, hearing impairment,
arthropathy, pectus, short 4thand 5th metacarpals | AD | 180300; 604841; 184840 | Collagen gene mutations (COL2A1, COL11A1, COL11A2) |
IRF6-related disorders (Includes Van der Woude and Popiteal
Pterygium syndromes) | Cleft lip and/or palate, lower lip pits/cysts,
ankyloglossia. PPS includes cleft lip and/or palate, fistulae
of the lower lip, popliteal pterygia, bifid scrotum/cryptorchidism, syndactyly
of fingers and/or toes, and abnormalities of the skin around
the nails, syngnathia or ankyloblepharon | AD | 119300; 119500; 607199 | Interferon regulatory factor 6 (IRF6) |
Smith-Lemli-Opitz syndrome (See Chap. 164) | Cleft palate, micrognathia, short nose, ptosis, high square forehead,
microcephaly, hypospadias, cryptorchidism, VSD, TOF, hypotonia,
mental retardation, postaxial polydactyly, 2-3 toe syndactyly, defect
in cholesterol biosynthesis | AR | 270400 | Delta-7-reductase (DHCR7) |
CHARGE syndrome | Coloboma of the eye, heart malformations, atresia
(choanal), retardation, genital anomalies, ear
abnormalities and/or deafness, facial palsy, cleft palate,
dysphagia | AD | 214800 | Chromodomain helicase DNA-binding protein (CHD7), semaphorin-3E (SEMA3E) |
Ectrodactyly ectodermal dysplasia and clefting syndrome (EEC1;
EEC2) | Cleft lip and/or palate, split-hand/split-foot,
ectodermal dysplasia (sparse hair, dysplastic nails, hypohidrosis, anodontia),
GU anomalies | AD | 129900; p63 602077; 603273 | |
Ankyloblepharon ectodermal dysplasia and clefting syndrome
(AEC) | Cleft lip and palate, intraoral alveolar bands, maxillary hypoplasia,
filiform eyelid fusion (ankyloblepharon), ectodermal dysplasia (sparse
hair, dysplastic nails, hypohidrosis, anodontia) | AD | 106260 | |
Kabuki (Niikawa-Kuroki) syndrome | Cleft palate, arched eyebrows with sparse lateral hair, long
palpebral fissures, eversion of lateral third of lower eyelid, brachydactyly,
short fifth metacarpal, cardiac anomalies, postnatal growth deficiency/dwarfism,
mental retardation | Sporadic | 147920 | |
Oral-facial-digital syndrome (types 1-9) | Paramedian cleft of upper lip, asymmetric cleft palate, accessory
oral frena, lobulate tongue with hamartomas, broad nasal root, small
nostrils, syndactyly, brachydactyly, postaxial polydactyly, polycystic
renal disease, agenesis of the corpus callosum, OFD1 is X-linked
dominant lethal in males | X-linked dominant | 311200 | Oral-facial-digital syndrome 1 protein (OFD1) |
Pallister-Hall syndrome | Cleft palate, flat nasal bridge, short nose, multiple buccal frenula,
microglossia, micrognathia, malformed ears, hypothalamic hamartoblastoma,
hypopituitarism, postaxial polydactyly with short arms, imperforate anus,
GU anomalies, IUGR | AD | 146510 | Zinc finger protein (GLI3) |
Early amnion rupture sequence | Cleft lip and palate, oblique facial clefts, focal areas
of scalp aplasia, constriction bands with terminal limb amputations
and syndactylies, occasional anencephaly, encephalocele, and ectopia
cordis | Sporadic | 217100 | |
Syndrome associated
with branchial arch derivative anomalies |
Craniofacial microsomia (CFM, hemifacial microsomia, oculo-auriculo-vertebral
spectrum, Goldenhar syndrome) | Unilateral/bilateral microtia/anotia/atresia,
preauricular tags, conductive hearing loss, microphthalmia, mandibular
hypoplasia, maxillary hypoplasia, macrostomia, vertebral anomalies
(hemivertebra and fusions), structural renal malformations/agenesis | Sporadic; AD, AR in some families | 164210 | |
Branchiootorenal syndrome (BOR syndrome) | Branchial cleft fistulas, preauricular pits, cochlear and stapes
malformation, mixed sensory and conductive hearing loss, renal dysplasia/aplasia | AD | 113650 | Eyes absent-1 gene (EYA1) |
Treacher Collins syndrome (mandibulofacial dysostosis) | Cleft palate, malar hypoplasia, micrognathia with prominent
antigonial notch, downslanting palpebral fissures, lower eyelid
coloboma (missing medial lower lid lashes), microtia/atresia,
conductive hearing loss | AD | 154500 | Treacle (TCOF1) |
Nager syndrome (preaxial acrofacial dysostosis) | Cleft palate, malar hypoplasia, downslanting palpebral fissures,
lower eyelid coloboma (missing medial lower lid lashes), mandibular
hypoplasia, microtia/atresia, conductive hearing loss,
radial ray hypoplasia, hypoplastic/absent thumbs, paternal
age effect (dominant and recessive inheritance suggested) | AR | 154400 | |
Miller syndrome (postaxial acrofacial dysostosis) | Cleft palate (occasional cleft lip), malar hypoplasia, downslanting
palpebral fissures, lower eyelids coloboma (missing medial lower
lid lashes), mandibular hypoplasia, microtia/atresia, conductive
hearing loss, postaxial limb deficiency, absent fifth digital rays,
short forearms, gastric and midgut volvulus | AR | 263750 | |
Syndromes associated
with craniosynostosis |
Crouzon syndrome | Craniosynostosis, (coronal > lambdoid > sagittal), proptosis,
hypertelorism, strabismus, maxillary hypoplasia | AD | 123500 | Fibroblast growth factor receptor-2 (FGFR2) |
Saethre-Chotzen syndrome | Unilateral/bilateral coronal craniosynostosis, acrocephaly,
brachycephaly, hypertelorism, strabismus, maxillary hypoplasia,
ptosis, small ears, cutaneous 2-3 syndactyly of hands (variable) | AD | 101400 | Twist (TWIST) |
Muenke syndrome | Unilateral coronal > bicoronal craniosynostosis, occasionally
with limb anomalies similar to Jackson-Weiss syndrome, overlap with
the Saethre-Chotzen phenotype has been suggested | AD | 602849 | Fibroblast growth factor receptor-3 (FGFR3) |
Apert syndrome | Craniosynostosis (coronal > lambdoid > sagittal), brachycephaly,
acrocephaly, hypertelorism, proptosis, strabismus, maxillary hypoplasia,
narrow palate (cathedral ceiling palate), invariable syndactyly
(cutaneous and boney), “single nails” | AD | 101200 | Fibroblast growth factor receptor-2 (FGFR2) |
Pfeiffer syndrome (types I, II, III) | Craniosynostosis (coronal > sagittal > lambdoid), acrocephaly,
hypertelorism, proptosis, maxillary hypoplasia, broad first digits
with radial deviation | AD | 101600 | Fibroblast growth factor receptor-1, 2 (FGFR1, FGFR2) |
Jackson-Weiss syndrome | Craniosynostosis (usually coronal), midfacial hypoplasia,
enlarged great toes, 2-3 syndactyly, tarsonavicular and calcaneonavicular fusions
in the feet, widely variable expression (e.g. foot anomalies without
synostosis) | AD | 123150 | Fibroblast growth factor receptor-2 (FGFR2) |
Crouzon syndrome with acanthosis nigricans | Coronal craniosynostosis with craniofacial appearance of
Crouzon syndrome associated with acanthosis nigricans | AD | 134934.001 | Fibroblast growth factor receptor-3 (FGFR3) |
Craniosynostosis, type 2 (Boston-type craniosynostosis) | Coronal craniosynostosis, forehead retrusion, frontal bossing,
turribrachycephaly, occasional Kleeblattschaedel-deformity (clover-leaf
skull), short first metatarsals | AD | 123101 | Msh homeobox homolog 2 (MSX2) |
Carpenter syndrome (Acrocephalopolysyndactyly type II) | Craniosynostosis (coronal > lambdoid > sagittal) hypertelorism,
proptosis, acrocephaly, preaxial polysyndactyly, mental retardation,
only well described recessive craniosynostosis syndrome | AR | 201000 | RAS-associated protein (RAB23) |
Kleeblattschadel (cloverleaf skull deformity) | Cloverleaf skull (trilobar) coronal, lambdoid, sagittal and metopic
craniosynostosis, proptosis to exophthalmos, hydrocephalus, presumed
dominant—all cases to date have been sporadic, can be seen
as part of thanatophoric dysplasia (OMIM#187600) and most
forms of syndromic craniosynostosis, this is a descriptive term
for the head shape seen in these cases of severe craniosynostosis | AD | 148800 | |
Antley-Bixler syndrome | Coronal and lambdoid craniosynostosis, brachycephaly, proptosis,
choanal stenosis/atresia, maxillary hypoplasia, humeroradial
synostosis, camptodactyly, multiple contractures | AR | 207410 | |
Syndromes associated
with calvarial size/shape anomalies |
Holoprosencephaly 3 (HPE3) | Microcephaly, ocular hypotelorism to cyclopia, single central
incisor, proboscis, midface hypoplasia, brain anomalies range from
holoprosencephalon to a structurally normal brain, mental retardation
to lethality, *several other loci have been identified
for this phenotype | AD | 142945 | Sonic Hedgehog |
Cleidocranial dysplasia | Brachycephaly, frontal and parietal bossing, wormian bones,
persistent open anterior fontanelle, maxillary hypoplasia, delayed
eruption of deciduous and permanent teeth, supernumerary and fused
teeth, hypoplastic to absent clavicles, brachydactyly, joint laxity | AD | 119600 | Runt-related transcription factor 2 (RUNX2, CBFA1) |
Neurofibromatosis, type I | Macrocephaly, neurofibroma, plexiform neurofibroma (occasionally
intraorbital), dysplasia of the sphenoid bone, hypertelorism, other
malignancies, learning disabilities to mental retardation | AD | 162200 | Neurofibromatosis, type 1 gene (NF1) |
Nevoid basal cell carcinoma syndrome (NBCCS, Gorlin syndrome) | Macrocephaly, broad facies, frontal and biparietal bossing,
hypertelorism, mandibular prognathism, odontogenic keratocysts of
jaws, cleft lip and palate, brachydactyly, rib anomalies, calcification
of falx cerebri, mental retardation, paternal age effect | AD | 109400 | Patched (PTCH) |
Syndromes associated
with hypertelorism or frontonasal malformation |
Aarskog (Faciodigitogenital) syndrome | Hypertelorism, widow’s peak, ptosis, down-slanting
palpebral fissures, strabismus, maxillary hypoplasia, broad nasal
bridge with anteverted nostrils, occasional cleft lip and/or
palate, floppy ears, brachydactyly, clinodactyly, joint laxity,
shawl scrotum, cryptorchidism, moderate short stature, females mildly
effected, *there is also thought to be an autosomal dominant
sex-influenced form | X-linked | 100050 | Faciogenital dysplasia 1 (FGD1) |
Waardenburg syndrome (type I, type IIa) | Partial albinism, white forelock, premature graying, heterochromic
iridis, wide nasal bridge, short philtrum, cleft lip and/or
palate, occasional cochlear deafness, spina bifida, lumbosacral
myelomeningocele, occasional Hirschsprung disease (dystopia canthorum
and absent vagina specific to Type I) | AD | 193500; 193510 | Paired box homeotic gene-3 (PAX3); Microphthalmia-associated
transcription factor (MITF) |
Craniofrontonasal Dysplasia | Coronal synostosis (unilateral > bilateral), frontonasal dysplasia with
marked hypertelorism, broad to bifid nose, brachycephaly, broad
great toe, syndactyly, hypermobile shoulders with pseudoarthrosis
of clavicle, female preponderance (more severe in females), males
may have shawl scrotum | X-linked | 304110 | Ligand for EPH-related RECEPTOR TYROSINE KINASE (EFNB1) |
Opitz Oculo-genital-laryngeal syndrome (Opitz BBB/G,
Hypertelorism with esophageal abnormality and hypospadias) | Hypertelorism, telecanthus, cleft lip and/or palate,
dysphagia, esophageal dysmotility, laryngotracheoesophageal cleft
(aspiration), hypospadias, bifid scrotum, cryptorchidism, agenesis
of the corpus callosum, congenital heart disease, mental retardation | X-linked, AD | 145410 | MIDI |
Craniometaphyseal Dysplasia | Craniofacial hyperostosis (leonine facies), hypertelorism,
wide nasal bridge, cranial nerve compression (facial palsy, deafness,
anosmia), characteristic diaphyseal sclerosis and metaphyseal dysplasia
of long bones | AD (CMDD); AR (CMDR) | 123000; 218400 | Human ankylosis gene (ANKH) in CMDD |
Acrocallosal syndrome | Macrocephaly, prominent forehead and occiput, hypertelorism,
absent corpus callosum, hypospadias and cryptorchidism, postaxial
polydactyly and hallux duplication, hypotonia and severe mental
retardation | AR | 200990 | |
Greig cephalopolysyndactyly syndrome | Macrocephaly without synostosis, high forehead and bregma,
frontal bossing, hypertelorism, bifid great toe and thumb, polysyndactyly,
advanced bone age | AD | 175700 | GLI-Kruppel family member 3 oncogene (GLI3) |
Maxillonasal dysplasia (Binder syndrome) | Maxillonasal dysplasia, maxillary hypoplasia, short nose with
flat nasal bridge and absent anterior nasal spine, convex upper
lip | Sporadic, AR/AD forms suggested | 155050 | |
Reiger syndrome, type 1 | Hypertelorism, telecanthus, iris dysplasia, microcornea, corneal
opacity, maxillary hypoplasia, broad nasal root, prognathism, protruding
lower lip, short philtrum, microdontia, hypodontia, cone-shaped
teeth, hypospadias, anal stenosis | AD | 180500 | Pituitary Homeobox 2 (PITX2) |
Other craniofacial
syndromes |
Sturge-Weber syndrome | Hemangiomata in the distribution of the trigeminal nerve,
can involve the choroid of the eye and the menigies, glaucoma, seizures,
those with seizures often have learning disability, no clear evidence
for mendelian inheritance | Sporadic | 185300 | |
Beckwith-Wiedemann syndrome | Coarse facial features, macroglossia (often with secondary
maxillary and mandibular deformity), ear lobe creases, posterior
auricular pits, mid face hypoplasia, omphalocele, generalized overgrowth
or hemihypertrophy, visceromegaly, Wilms tumor (and other malignancies),
cryptorchidism, cardiomyopathy | AD, imprinting | 130650 | Cyclin-dependent kinase inhibitor 1C (CDKN1C) |
Moebius sequence | Congenital facial palsy, cranial nerve VI and VII palsy, distal
limb deficiencies, occasional arthrogryposis and/or mental
retardation | Sporadic, AD | 157900 | |
Cornilia de Lange | Microbrachycephaly, micrognathia, low hairline, synophrys,
arched eyebrows, long eyelashes, thin upper lip, low-set ears, spade
like hands, 2-3 syndactyly of toes (more severe limb anomalies common), failure
to thrive, prenatal growth deficiency, short stature, *dominant
forms suggested | Sporadic, AD forms suggested | 122470 | CDLS1: Nipped-B-Like gene (NIPBL); CDLS2: Structural maintenance of
chromosomes 1 gene (SMC1A); CDLS3: Structural maintenance of chromosomes
3 gene (SMC3) |
Romberg syndrome (progressive hemifacial atrophy, Parry-Romberg syndrome) | Slowly progressive hemifacial atrophy, normal at birth, atrophy
of facial soft tissue and bone, always unilateral with well demarcated
median border, malocclusion, hemiatrophy of tongue, enophthalmos
on effected side, hyperpigmentation and vitiligo, can be associated
with trigeminal neuralgia, migraine-like headaches, and contralateral
Jacksonian epilepsy | Sporadic, AD | 141300 | |
Freeman-Sheldon syndrome (Distal arthrogryposis, type 2A) | Whistling facies (with small mouth and vertical skin folds
on chin), hypertelorism, “sunken” eyes, small nose,
adducted thumbs, ulnar deviation of hands, camptodactyly, clubfoot | AD | 193700 | Myosin, heavy chain 3(MYH3) |
Trichorhinophalangeal syndrome (type I) | Micrognathia, “pear-shaped” nose, short
stature, brachydactyly, with short metacarpals, normal intelligence | AD | 190350 | Zinc finger transcription factor (TRPS1) |