Fgfr Craniosynostosis Syndromes Overview
Summary
The purpose of this overview is to increase the awareness of clinicians regarding the FGFR craniosynostosis syndromes and their management.
Goal 1
Describe the clinical characteristics of FGFR craniosynostosis syndromes.
Goal 2
Review the genetic causes of FGFR craniosynostosis syndromes.
Goal 3
Provide an evaluation strategy to identify the genetic cause of an FGFR craniosynostosis syndrome in a proband.
Goal 4
Inform risk assessment and surveillance of at-risk relatives for early detection and treatment of FGFR craniosynostosis syndromes.
Goal 5
Summarize current management recommendations for individuals with an FGFR craniosynostosis syndrome.
Diagnosis
Clinical Characteristics
Differential Diagnosis
Craniosynostosis can be primary or secondary. In primary craniosynostosis, abnormal biology of the suture causes premature suture closure, as in FGFR craniosynostosis syndromes. Primary craniosynostosis can be isolated or part of a syndrome.
In secondary craniosynostosis, the suture biology is normal, but abnormal external forces result in premature suture closure.
Isolated Primary Craniosynostosis
Single-suture craniosynostosis results in recognizable head shapes: metopic (trigonocephaly), sagittal (scaphocephaly), lambdoid (posterior asymmetric flattening with vertical displacement of one ear and tilt of skull base), unicoronal (asymmetric forehead with nasal twist and harlequin eye deformity), and bicoronal (turribrachycephaly).
Among 204 individuals with apparently nonsyndromic and nonfamilial single-suture craniosynostosis, the likelihood of finding an underlying genetic difference varied by suture involvement [Wilkie et al 2010, Mathijssen 2015].
- Isolated unicoronal craniosynostosis. Among individuals with apparently nonsyndromic unicoronal craniosynostosis the prevalence of any syndrome was 17%; Muenke syndrome was identified in 10%.
- Isolated bicoronal craniosynostosis. Among individuals with apparently isolated bicoronal craniosynostosis, Muenke syndrome was diagnosed in 38%; no other syndromes were identified.
Note: (1) Those with apparently isolated synostosis of the lambdoid, sagittal, or metopic sutures had no pathogenic variants identified [Wilkie et al 2010, Mathijssen 2015]. (2) A study in individuals with either syndromic or nonsyndromic metopic craniosynostosis found no pathogenic variants in FGFR1, CER1, or CDON, suggesting that analysis of these genes is not warranted in persons with metopic craniosynostosis [Jehee et al 2006].
Syndromic Primary Craniosynostosis
Craniosynostosis is a finding in more than 150 genetic disorders. Additional syndromes that should be considered are included in Table 2.
Table 2.
Syndromes of Interest in the Differential Diagnosis of FGFR Craniosynostosis Syndromes
| Gene(s) | Disorder | MOI | Clinical Features of Differential Disorder | ||
|---|---|---|---|---|---|
| Craniosynostosis | Facial features | Hand & foot findings | |||
| CD96 | Opitz trigonocephaly syndrome (C syndrome) (OMIM 211750) | AD | Trigonocephaly | Micrognathia, epicanthal folds, upslanted palpebral fissures, strabismus, anteverted nares, broad nasal bridge, short nose, macrostomia | Postaxial polydactyly, clinodactyly, ulnar deviation of fingers, terminal transverse limb reduction, metacarpal hypoplasia, syndactyly |
| EFNB1 | Craniofrontonasal syndrome (OMIM 304110) | XL | Coronal | Asymmetric frontal bossing, low posterior hairline, widow's peak, hypertelorism, broad bifid nose, ± cleft lip & palate | Hands/feet: splitting nails, fingers & toes deviated distally or hypoplastic |
| FLNA | X-linked otopalatodigital spectrum disorders | XL | Variable | Variable | Variable, hypoplasia of 1st digit of hands & feet |
| GLI3 | Greig cephalopolysyndactyly syndrome | AD | Macrocephaly | Frontal bossing, hypertelorism, wide nasal bridge | Polydactyly of the hands (often postaxial), & feet w/syndactyly of toes 1-3 & often a duplicated hallux |
| IHH 1 | Philadelphia-type craniosynostosis 2 | AD | Sagittal | Prominent forehead | Hands/feet: cutaneous syndactyly |
| MSX2 | Boston-type craniosynostosis (OMIM 604757) | AD | Coronal; cloverleaf skull | Fronto-orbital recession or frontal bossing | Feet: short 1st metatarsals |
| POR | Antley-Bixler syndrome (See Cytochrome P450 Oxidoreductase Deficiency.) | AR | Brachycephaly or turricephaly | Midface retrusion | Hands: arachnodactyly, clinodactyly, camptodactyly, metacarpal synostoses, wrist deviation Feet: rocker-bottom, metatarsal synostoses, talipes |
| RAB23 | Carpenter syndrome (OMIM 201000) | AR | Variable sagittal, lambdoid & coronal; acrocephaly | Midface retrusion, flat nasal bridge, epicanthal folds, corneal opacity | Hands: brachydactyly, syndactyly, aplasia/hypoplasia of middle phalanges Feet: preaxial polydactyly |
| RECQL4 | Baller-Gerold syndrome | AR | Coronal or lambdoid; brachycephaly | Proptosis, prominent forehead | Hands: radial ray defect (thumb aplasia/hypoplasia, radius aplasia/hypoplasia) |
| SKI | Shprintzen-Goldberg syndrome | AD | Coronal, sagittal, or lambdoid | Tall or prominent forehead, proptosis, hypertelorism, downslanted palpebral fissures, malar flattening | Hands: arachnodactyly; camptodactyly Feet: malposition, pes planus |
| SOX9 | Campomelic dysplasia | AD | Not observed | Micrognathia, midface hypoplasia, macrocephaly, Robin sequence | Shortening of phalanges in hands & feet, talipes equinovarus |
| TGFBR1 TGFBR2 | Loeys-Dietz Syndrome | AD | Sagittal; dolichocephaly | Hypertelorism, bifid uvula ± cleft palate | Pes planus |
| TWIST1 | Saethre-Chotzen syndrome | AD | Coronal (uni- or bilateral) | Low frontal hairline, ptosis, strabismus, facial asymmetry | Hands: ± 2/3 syndactyly |
AD = autosomal dominant; AR = autosomal recessive; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
- 1.
Klopocki et al [2011]
- 2.
Robin et al [1996]
See Craniosynostosis: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.
Secondary craniosynostosis. In children with deficient brain growth, all cranial sutures fuse prematurely and the head is symmetric and microcephalic. Abnormal head positioning in utero or in infancy may also produce an abnormal head shape (plagiocephaly); the abnormality often resolves with appropriate head positioning but occasionally results in craniosynostosis [Hunt & Puczynski 1996, Kane et al 1996].