Table 1.
Core Genes for which Specific Types of Mutation Are Associated with Craniosynostosis in More than Half of Affected Individuals
| Gene (MIM#)a | Inheritance Pattern | Clinical Disorder (MIM#) | Prevalence (%)b | Typical Suture Fusion | Major Phenotypic Features | Ref(s) |
|---|---|---|---|---|---|---|
| ASXL1 (612990) | AD (n) | Bohring-Opitz syndrome (605039) | – | metopic | forehead nevus flammeus, ulnar deviation and flexion of wrists and metacarpalophalangeal joints, severe intellectual disability | 22 |
| CDC45 (603465) | AR | – | – | coronal | thin eyebrows, small ears, variable short stature | 23 |
| COLEC11 (612502) | AR | 3MC syndrome 2 (265050) | – | metopic | hypertelorism, blepharoptosis, arched eyebrows, cleft lip/palate, hearing loss, radio-ulnar synostosis, genital and vesicorenal anomalies | 24 |
| EFNB1 (300035) | XLD (male sparing) | craniofrontonasal syndrome (304110) | 0.8 | coronal | hypertelorism, notched nasal tip, chest anomalies, longitudinal splitting of nails; heterozygous females more severely affected than hemizygous males | 15,25 |
| ERF (611888) | AD | ERF-related craniosynostosis (600775) | 1.1 | multisuture | exorbitism, midface hypoplasia, Chiari type I malformation, postnatal onset of craniosynostosis | 26 |
| FGFR1 (136350) | AD | Pfeiffer syndrome (101600) | – | coronal | mild craniofacial features, broad medially deviated thumbs and halluces, cutaneous syndactyly, specific amino acid substitution p.Pro252Arg | 27 |
| FGFR1 | AD (n) | osteoglophonic dysplasia (166250) | – | multisuture | prominent brow ridges, depressed nasal bridge, rhizomelic dwarfism, localized lytic lesions of metaphyses | 28 |
| FGFR2 (176943) | AD (n) | Apert syndrome (101200) | 3.6 | coronal, multisuture | midface hypoplasia, dilated cerebral ventricles, complex syndactyly of the hands and feet | 29 |
| FGFR2 | AD (n) | Beare-Stevenson syndrome (123790) | ∗ | multisuture | choanal atresia, prominent umbilical stump, furrowed scalp/neck skin, acanthosis nigricans in survivors | 30 |
| FGFR2 | AD | Crouzon syndrome (123500) | 2.4 | multisuture, coronal, sagittal | exorbitism, midface hypoplasia, beaked nose (“crouzonoid” facies), clinically normal hands and feet | 31,32 |
| FGFR2 | AD (n) | Pfeiffer syndrome (101600) | 0.8 | multisuture | broad thumbs and halluces; in severe cases, cloverleaf skull, brain anomalies, tracheal sleeve, fused elbows | 33–35 |
| FGFR2 | AD (n) | bent bone dysplasia (614592) | ∗ | coronal | osteopenia, reduced mineralization of the calvaria, bent long bones; perinatal lethal | 36 |
| FGFR3 (134934) | AD | Muenke syndrome (602849) | 4.0 | coronal | defined by specific amino acid substitution p.Pro250Arg; may include sensorineural hearing loss, mild brachydactyly, cone-shaped epiphyses | 37 |
| AD (n) | Crouzon/acanthosis nigricans (612247) | 0.4 | multisuture | crouzonoid facies, choanal stenosis, hydrocephalus, acanthosis nigricans; specific amino acid substitution p.Ala391Glu | 38 | |
| AD (n) | thanatophoric dysplasia II (187601) | ∗ | multisuture | lethal skeletal dysplasia, micromelic limb shortening, straight femora; specific amino acid substitution p.Lys650Glu | 39 | |
| IHH (600726) | AD | Philadelphia craniosynostosis (185900) | – | sagittal | cutaneous and osseous syndactyly | 40 |
| IL11RA (600939) | AR | craniosynostosis and dental anomalies (614188) | – | multisuture | maxillary hypoplasia, delayed tooth eruption, supernumerary teeth, minor digit abnormalities, conductive hearing loss | 41 |
| MEGF8 (604267) | AR | Carpenter syndrome 2 (614796) | – | metopic | hypertelorism, arched eyebrows, lateralization defects, brachydactyly, syndactyly, preaxial polydactyly | 42 |
| MSX2 (123101) | AD | Boston craniosynostosis (604757) | – | sagittal, coronal, multisuture | none diagnostic; syndrome defined by specific amino acid substitutions p.Pro148His, p.Pro148Leu | 21 |
| POR (124015) | AR | Antley-Bixler syndrome (201750) | – | bicoronal, multisuture | choanal stenosis, radio-humeral synostosis, bowed femora, multiple joint contractures, genital abnormalities; abnormal steroidogenesis | 43 |
| RAB23 (606144) | AR | Carpenter syndrome 1 (201000) | – | multisuture | obesity, cardiac defects, polysyndactyly, brachydactyly, genu valgum, hypogenitalism, umbilical hernia, learning disability | 44 |
| RUNX2 (600211) | AD (n) | – | – | multisuture | none diagnostic; syndrome defined by specific gene duplication | 45,46 |
| SKI (164780) | AD (n) | Shprintzen-Goldberg syndrome (182212) | – | sagittal, multisuture | hypertelorism, micrognathia, high arched palate, arachnodactyly, joint contractures, pectus deformity, aortic root aneurysm, mitral valve prolapse, learning disability | 47 |
| TCF12 (600480) | AD | TCF12-related craniosynostosis (615314) | 1.3 | coronal | resembles mild Saethre-Chotzen syndrome; diagnosis defined by presence of mutations in the gene, ∼50% non-penetrance | 48 |
| TWIST1 (601622) | AD | Saethre-Chotzen syndrome (101400) | 3.6 | coronal | low frontal hairline, hypertelorism, eyelid ptosis, downslanting palpebral fissures, blocked tear ducts, small ears with prominent crus helicis | 49,50 |
| WDR35 (613602) | AR | cranioectodermal dysplasia 2 (613610) | – | sagittal | facial dysmorphism, narrow thorax, short long bones, brachydactyly, sparse hair, hypoplastic teeth, cystic kidneys, hepatic fibrosis | 51 |
| ZIC1 (600470) | AD (n) | ZIC1- craniosynostosis | 0.2 | coronal | severe learning disability | 52 |
Abbreviations are as follows: AD, autosomal dominant; AR, autosomal recessive; XLD, X-linked dominant; (n), usually arises by new mutation; ∗ usually lethal at birth.
a
Information has been extracted from Table S1, which contains further details on mutational category and phenotype and additional references.
b
The prevalence figures are for percent total craniosynostosis cases with specified mutation, from the cohort attending the Craniofacial Unit, Oxford, born between 1998 and 2008 (n = 531), and surgically treated before end of 2013 (updated from Wilkie et al.17).