Table 2.
Syndromic craniosynostoses associated with FGFR mutations.
| Syndrome | Mutationa,b | Mechanism | Key features | Inheritance |
|---|---|---|---|---|
| Pfeiffer112, 161, 162, 163 | P252R (FGFR1); several sequence variants (FGFR2) | P252R gain-of-function mutation results in increased receptor affinity for ligand binding; FGFR2-related gain-of-function mutations result in ligand-independent receptor activation | Proptosis, hypertelorism, maxillary hypoplasia, beaked nose, developmental delay (types II and III), cloverleaf skull (type II), turribrachycephaly (type III) | Autosomal dominant; sporadic |
| Apert160, 165, 169 | S252W and P253R (FGFR2) | Gain-of-function mutations result in increased receptor affinity for ligand binding | Turribrachycephaly, midface hypoplasia, syndactyly of fingers and toes, varying degrees of developmental delay | Autosomal dominant; sporadic |
| Crouzon112, 161, 165 | Several missense mutations (FGFR2) | Gain-of-function mutations result in disulfide bond that stabilizes the D3 loop to allow for ligand-independent receptor activation | Proptosis, external strabismus, mandibular prognathism, normal extremities, normal intelligence | Autosomal dominant; sporadic |
| Beare-Stevenson cutis gyrata112, 161, 174, 175 | Y394C (FGFR2) | Gain-of-function mutation results in ligand-independent receptor activation | Midface hypoplasia, abnormal ears, natal teeth, widespread cutis gyrata, acanthosis nigricans, skin tags, developmental delay, pyloric stenosis, anterior anus | Autosomal dominant; sporadic |
| Jackson-Weiss161, 176 | C342S, C342R, Q289P, A344G (FGFR2) | Gain-of-function mutations result in ligand-dependent receptor overactivation | Mandibular prognathism, broad and medially deviated great toes, short first metatarsal, calcaneocuboid fusion, normal intellect | Autosomal dominant; sporadic |
| Muenke112, 170 | P250R (FGFR3) | Gain-of-function mutation results in increased receptor affinity for ligand binding | Uni- or bicoronal synostosis, megalencephaly, midface hypoplasia, hypertelorism, variable sensorineural hearing loss, osteochondroma | Autosomal dominant; sporadic |
FGFR, fibroblast growth factor receptor.
a
Commonest mutation(s) is noted. Others may be documented.
b
Type I Pfeiffer syndrome is associated with a P252R mutation in FGFR1 in 5% of cases. The majority of type I and all of types II and III Pfeiffer syndrome cases are associated with sequence variant mutations in FGFR2.