Genetics of Crouzon Syndrome Differential Diagnoses

Updated: May 06, 2015
  • Author: Harold Chen, MD, MS, FAAP, FACMG; Chief Editor: Maria Descartes, MD  more...
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DDx

Diagnostic Considerations

Beare-Stevenson syndrome (OMIM 123790)

This is associated with cutaneous disorders (ie, cutis gyrata and acanthosis nigricans) and FGFR2 mutations.

Carpenter syndrome (OMIM 201000)

Characteristics are autosomal recessive linked, peculiar face, absence of osseous fusion of hand bones, and presence of preaxial polydactyly of hands and/or feet.

Crouzon syndrome with acanthosis nigricans (Crouzonodermoskeletal syndrome)

Craniofacial features are similar to those observed in patients with classic Crouzon syndrome (craniosynostosis with Crouzonoid facies), in addition to acanthosis nigricans and other severe physical manifestations, such as Chiari malformation, hydrocephalus, and atresia or stenosis of the choanas. [13]

Unlike classic Crouzon syndrome, which lacks any specific cutaneous features, the presence of acanthosis nigricans is essential for the clinical diagnosis of Crouzon syndrome with acanthosis nigricans. Affected individuals develop early-onset, severe, and widespread rugose thickening and hyperpigmentation of the skin. In addition to the most common locations on the neck and axillae, patients with Crouzon syndrome with acanthosis nigricans are affected periorally and periorbitally, on the chest, around the umbilicus, and on the breasts. [14]

Notably, the endocrine abnormality typical of patients with acanthosis nigricans is lacking. Genetically, the diagnosis is confirmed by the detection of the specific heterozygous missense Ala391Glu mutation in the transmembrane domain of the FGFR3 (C-to-A transition at nucleotide 1172). Whereas in classic Crouzon syndrome, in which several mutations in the FGFR2 gene have been documented, only this mutation has been associated to Crouzon syndrome with acanthosis nigricans. [10]

FGFR3 - associated coronal synostosis syndrome

Variable clinical presentation overlaps with Pfeiffer, Jackson-Weiss, or Saethre-Chotzen syndrome phenotypes. Some individuals with a disease-causing mutation may have no clinical problems.

Jackson-Weiss syndrome (OMIM 123150)

Broad great toes with varus deviation and tarsal/metatarsal fusions, lack of thumb abnormalities, craniofacial features suggestive of Pfeiffer syndrome, and FGFR2 mutations are characteristics.

Pfeiffer syndrome (OMIM 101600)

Both hand and foot abnormalities are characterized by broad thumbs and halluces with occasional cutaneous syndactyly, mild cranial deformities, lack of osseous fusion of the phalanges, and FGFR1 and FGFR2 mutations

Saethre-Chotzen syndrome (OMIM 101400)

Characteristic facies, relatively mild cranial deformity, normal thumbs, and lack of osseous fusion of the hand bones are features. Approximately 75% of patients have identifiable mutations in the TWIST gene.

Differential Diagnoses