Genetics of Crouzon Syndrome Differential Diagnoses

Updated: Dec 05, 2018
  • Author: Marie M Tolarova, MD, PhD, DSc; Chief Editor: Maria Descartes, MD  more...
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Diagnostic Considerations

A thorough clinical examination forms a basis for diagnostic considerations. The clinical examination should include medical history and pregnancy history of the mother; family history of parents, first-degree relatives, and other available relatives; and clinical examination of these relatives. It is very useful to construct a pedigree showing affected individuals. Objective measurements of the head, a thorough examination of the eyes and extremities, and a general examination of all organ systems to reveal even subtle malformations should be performed. Neurologic assessment, ophthalmologic and audiologic examinations, and a thorough radiologic examination of the head and extremities are necessary.

It is necessary to establish the diagnosis of a proband. Findings on the initial evaluation (complete medical history, physical examination, review of systems, family history) should help to direct a selection of the most appropriate molecular genetic study (see Table 1).

 Table 1. Skeletal features that help to distinguish craniosynostosis syndromes* (Open Table in a new window)

Disorder

Thumbs

Hands

Great Toes

Feet

Targets for genetic testing

Crouzon syndrome

Normal

Normal

Normal

Normal

FGFR2

Crouzon syndrome with acanthosis nigricans

Normal

Normal

Normal

Normal

FGFR3

Apert syndrome

Fusion of thumb to fingers is occasionally seen

Soft tissue with or without  bone syndactyly

Fusion of great toe to other toes is occasionally seen

Soft tissue with or without bone syndactyly

FGFR2

Pfeiffer syndrome

Broad, medially deviated

Variable brachydactyly

Broad, medially deviated

Variable

brachydactyly

FGFR1, FGFR2

Muenke

syndrome

 

Normal

With or without carpal fusion

May or may not be broad

Tarsal fusion may or may not be present

FGFR3

Jackson-Weiss syndrome

Normal

Variable

Broad, medially deviated

Abnormal tarsals

FGFR2

Beare-Stevenson syndrome

Normal

Normal

Normal

Normal

FGFR2

*Adapted from Robin et al (2011). [39]

Differential Diagnoses

  • Apert syndrome (OMIM: 101200)

    Craniosynostosis, midface hypoplasia, and hand and foot syndactyly, with bony structures tending to fuse. Inheritance is autosomal dominant, resulting from mutations in the Ig II-III linker region of the FGFR2 gene.

  • Beare-Stevenson cutis gyrata syndrome (OMIM 123790)

    Craniosynostosis is associated with cutaneous disorders (cutis gyrata, acanthosis nigricans). Inheritance is autosomal dominant, resulting from mutations of the FGFR2 gene.

  • Carpenter syndrome (OMIM 201000)

    Craniosynostosis (acrocephaly), brachydactyly of the hands with syndactyly, preaxial polydactyly and syndactyly of the feet, congenital heart defects, growth retardation,

    mental retardation, hypogenitalism. Inheritance is autosomal recessive.

  • Crouzon syndrome with acanthosis nigricans (Crouzonodermoskeletal syndrome; OMIM: 612247)

    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 choanae. 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 in axillae, patients with Crouzon syndrome with acanthosis nigricans are affected periorally and periorbitally,

    on the chest, around the umbilicus, and on the breasts.

    Notably, the endocrine abnormality typical of patients with acanthosis nigricans is lacking. Genetically, the diagnosis is confirmed by detection of the specific missense

    Ala391Glu mutation in the transmembrane domain of the FGFR3 gene. Inheritance is autosomal dominant.

  • Jackson-Weiss syndrome (OMIM 123150)

    Craniosynostosis, midfacial hypoplasia, and foot anomalies in an Amish kindred. Broad great toes with varus deviation and tarsal/metatarsal fusions, lack of

    thumb abnormalities, craniofacial features suggestive of Pfeiffer syndrome. Inheritance is autosomal dominant, caused by mutations in the Ig III domain of the FGFR2 gene.

  • Muenke syndrome (OMIM: 602849)

    Unicoronal or bicoronal synostosis, macrocephaly, midfacial hypoplasia, and developmental delay. Thimble-shaped middle phalanges, brachydactyly, carpal and tarsal fusions, and deafness are more variable characteristics of the disease. Exhibiting a variable phenotype, Muenke syndrome arises via autosomal dominant inheritance, resulting from a Pro250Arg mutation in the Ig II-III linker region of the FGFR3 gene.

  • Pfeiffer syndrome (OMIM 101600)

    Craniosynostosis, hand and foot abnormalities characterized by broad thumbs and halluces with occasional cutaneous syndactyly, mild cranial deformities,

    lack of osseous fusion of the phalanges. Inheritance is autosomal dominant, caused by mutation in the Ig II-III linker region of the FGFR1 gene or in the

    Ig III domain or tyrosine kinase domain of the FGFR2 gene.

  • Saethre-Chotzen syndrome (OMIM 101400)

    Craniosynostosis, characteristic facies, relatively mild cranial deformity, normal thumbs, and lack of osseous fusion of the hand bones are the main features. Inheritance is autosomal dominant, caused by TWIST1 loss-of-function mutation in 46-80% of patients. TWIST1 is a transcriptional regulator that inhibits expression of the RUNX2 gene, which is a master gene for ossification. TWIST1 decreased function leads to increased functioning of RUNX2 and accelerated ossification of cranial sutures. (Cunningham et al, 2007)

  • Solitary cases of Crouzon syndrome are caused by fresh mutations.