Diagnostic Considerations
Mutations of the human FGFR s have also been identified as the cause of other craniosynostosis syndromes, including Crouzon syndrome, Pfeiffer syndrome, Jackson-Weiss syndrome, Beare-Stevenson syndrome, cutis gyrata, Antley-Bixler syndrome, and Muenke syndrome, as well as skeletal dysplasias such as achondroplasia and thanatophoric dysplasia. These conditions are described as follows [18, 19, 20, 21, 22, 23, 24] :
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Beare-Stevenson syndrome (OMIM 123790): Patients present with mental retardation and associated cutaneous disorders, including cutis gyrata and acanthosis nigricans; patients with Beare-Stevenson syndrome may have FGFR2 mutations
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Carpenter syndrome (OMIM 201000): This condition is autosomal recessive; patients present with a peculiar face, absence of osseous fusion of hand bones, and preaxial polydactyly of hands, feet, or both
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FGFR3 -associated coronal synostosis syndrome: Patients present with variable clinical presentation overlapping with Pfeiffer, Jackson-Weiss, or Saethre-Chotzen syndrome phenotypes; some individuals with a disease-causing mutation may have no clinical problems
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Jackson-Weiss syndrome (OMIM 123150): Patients present with enlarged or broad great toes with varus deviation and tarsal or metatarsal fusion, lack of thumb abnormalities, and craniofacial features, suggesting Pfeiffer syndrome; patients may have FGFR2 mutations
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Pfeiffer syndrome (OMIM 101600): Patients present with hand and foot abnormalities characterized by broad thumbs and halluces with occasional cutaneous syndactyly; they also exhibit mild cranial deformities and lack of osseous fusion of the phalanges; approximately 67% of patients with Pfeiffer syndrome have identifiable mutations in FGFR1 and FGFR2
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Saethre-Chotzen syndrome (OMIM 101400): Patients exhibit characteristic facies, relatively mild cranial deformity, and lack of osseous fusion of the hand bones; approximately 75% of patients with Saethre-Chotzen syndrome have identifiable mutations in the TWIST gene
Differential Diagnoses
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An infant with Apert syndrome is shown. Note the characteristic ocular hypertelorism, down-slanting palpebral fissures, proptotic eyes, horizontal groove above the supraorbital ridge, break of the eyebrows' continuity, depressed nasal bridge, and short, wide nose with bulbous tip.
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Note the mitten appearance of the hands with syndactyly involving the second, third, fourth, and fifth fingers. This patient also has characteristic concave palms, hitchhiker posture (radial deviation) of the short broad thumbs, and contiguous nail beds (synonychia).
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Note the socklike appearance of the feet with syndactyly involving the second, third, fourth, and fifth toes. The patient also has contiguous nail beds (synonychia).
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In this profile photo, turribrachycephaly (high prominent forehead), proptosis, a depressed nasal bridge, a short nose, and low-set ears are prominent.
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This radiograph demonstrates turribrachycephaly, shallow orbits, ocular hypertelorism, and a hypoplastic maxilla.
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Note the osseous syndactyly involving the second, third, fourth, and fifth fingers; multiple synostosis involving the distal phalanges and proximal fourth and fifth metacarpals; symphalangism of the interphalangeal joints; shortening and radial deviation of the distal phalanx; and the delta-shaped deformity of proximal phalanx of the thumbs.
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Note the osseous syndactyly, fusion of the interphalangeal joints, synostosis involving the proximal first and second metatarsals, and the partially duplicated and delta-shaped proximal phalanx of the great toes.
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A 9-month-old girl was seen because of syndactyly of the hands and feet as well as associated with craniofacial anomalies. The family and pregnancy histories were noncontributory. The child had broad thumbs with 2-5 digits with cutaneous syndactyly (only the right hand is shown here). The feet were characterized by brachydactyly and syndactyly of 2-5 toes. Genomic DNA analysis showed a heterozygous C-to-G mutation at nucleotide 755 of the fibroblast growth factor receptor 2 (FGFR2) gene (c.755C>G) that changes a codon for serine (TCG) to that for tryptophan (TGG) at amino acid position 252 (p.Ser252Trp). This mutation is diagnostic for Apert syndrome.
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The right hand radiograph for the same patient in the previous image, at age 15 months (left image), showed soft-tissue fusion between the second through fourth digits as well as fusion of the proximal soft tissues between the fourth and fifth digits. Hypoplastic, deformed phalanges were present with fusion of the proximal and middle phalanges of the second through fourth digits. Bony fusion was also seen at the bases of the fourth and fifth metacarpals along with fusion of the capitate and hamate. The thumb pointed laterally with a sharp angulation at the first metacarpophalangeal joint. A right hand radiograph from the child at age 1 month (right image) is provided for comparison. Similar abnormalities were also seen in the left hand (not shown).
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Radiographs of both feet in the same child as in the previous images, at age 1 month, showed foreshortening of the bilateral second metatarsals, the right third proximal phalanx and left fourth phalanx, and the distal phalanges of the left second, third, fourth, and fifth digits. Both great toes are bulbous and foreshortened, with deformed phalanges and partially duplicated metatarsals. Soft-tissue fusion was present in the second through fifth digits of both feet.
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Magnetic resonance images of the brain obtained at in the same patient as in the previous images, at age 16 months, showed hypoplasia of the parieto-occipital white matter, with undulating bilateral lateral ventricle occipital horns (arrow; left image). Shallow orbits can be appreciated bilaterally with ocular hypertelorism (right image).
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A 17-month-old boy with Apert syndrome. Three-dimensional (3-D) CT imaging of the head showed craniosynostosis of the coronal suture and a hypoplastic midface.
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Axial facial CT scans in the same patient as in the previous image showed bilateral shallowed orbits with proptosis and mild hypertelorism. Crowding of the teeth was present.
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Radiograph of bilateral hands in the same patient as in the previous images, at age 18 months, showed bilateral syndactyly involving the second through fifth digits, with absent distal phalanges. Bilateral shortened hypoplastic middle phalanges are present, with bony fusion at the third and fourth middle phalanges, along with deformities of the proximal phalanges and shortened metacarpals.
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Radiograph of bilateral feet in the same patient as in the previous images, at age 7 years, showed syndactyly with diffuse deformities and multiple midfoot and hindfoot tarsal coalitions.
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Three-dimensional facial CT scans in the same child as in the previous images, at age 9 years, showed hypoplastic midfacial bones.
