Distinct craniofacial‐skeletal‐dermatological dysplasia in a patient with W290C mutation in FGFR2

Abstract

Mutations in the fibroblast growth factor receptor genes (FGFR) have been known to be associated with many craniosynostosis syndromes with overlapping phenotypes. We studied a 15-year-old Thai boy with an unspecified craniosynostosis syndrome characterized by multiple suture craniosynostoses, a persistent anterior fontanel, corneal scleralization, choanal stenosis, atresia of the auditory meatus, broad thumbs and great toes, severe scoliosis, acanthosis nigricans, hydrocephalus, and mental retardation. Radiography revealed bony ankyloses of vertebral bodies of T9-12, humero-radio-ulnar joints, intercarpal joints, distal interphalangeal joints of fifth fingers, fibulo-tibial joints, intertarsal joints, and distal interphalangeal joints of the first toes. The patient was a heterozygous for a 870G --> T change resulting in a W290C amino acid substitution in the extracellular domain of the fibroblast growth factor receptor 2 gene (FGFR2). This mutation has previously been reported in a patient with severe Pfeiffer syndrome type 2 that is distinct from the craniosynostosis in our patient. These findings emphasize locus, allelic, and phenotypic heterogeneity of craniofacial-skeletal-dermatological syndrome due to FGFR2 mutations.

A case report of a patient with Pfeiffer syndrome, an FGRF 2 mutation (Trp290Cys) and unique ocular anterior segment findings

“…This demonstrates the importance FGFRs have in directing cellular development throughout the body. 3,6 Our patient confirms that FGFR2 mutations can lead to significant abnormalities in the development of the anterior segment of the eye, in this case severe enough to cause glaucoma.…”

“…A case report from Thailand described a 15 year old boy with a mutation of the FGFR 2 gene (Trp290Cys), craniosynostoses and corneal (limbal) scleralization. 3 Two additional cases were reported of children with Pfeiffer syndrome, one who had superior iris colobomas of both eyes and the other corectorpia and superior limbal scleralization of both eyes. Both of these were reported without genetic data.…”

“…2 Less commonly, anterior segment anomalies have been described in patients with Pfeiffer syndrome, including limbal scleralization, corectopia, iris colobomas. [3][4][5][6] Some of these cases have been linked to mutations in the FGFR2 gene. We describe a patient with Pfeiffer syndrome with a unique constellation of ocular anterior segment anomalies which include microcornea, limbal scleralization, corectopia and glaucoma and a mutation in the FGFR2 gene (Trp290Cys).…”

Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome

“…13,15,24 -26 An additional patient presented a severe nonclassifiable craniosynostosis syndrome with limb and joint anomalies and mental retardation. 27 Tyrosine 340 when converted into histidine gave rise to CS in 8/8 patients (Table 4). By contrast conversion into cysteine reproducibly led to very severe forms of PS 15,20,28 with cloverleaf skull, severe ocular proptosis, hydrocephalus, and early demise in some cases (Table 3).…”

The best-laid plans go oft awry: synaptogenic growth factor signaling in neuropsychiatric disease

“…Alterations in FGF expression in humans have also been associated with depression (Evans et al, 2004), substance abuse (Turner et al, 2012), and schizophrenia (Terwisscha Van Scheltinga et al, 2010). Mutations in FGFR2 are causative for Pfeiffer Syndrome, some severe forms of which manifest intellectual disability (Priolo et al, 2000; Shotelersuk et al, 2002). There are multiple other examples of FGFs and FGFRs linked to neuropsychiatric disease, which are detailed in Table 1.…”