Craniosynostosis Testing Panel

Test Description:
Craniosynostosis is the early fusion of bones or premature ossification of sutures (the tissues between bones) of the skull. This developmental anomaly often leads to an abnormal head shape. It is common and occurs in approximately 1 per 2500 live births. There is considerable variability in physical appearance between patients with craniosynostosis. A common finding is brachycephaly (a shortened distance between the front and back of the head) due to early closure of one or both coronal sutures. Other sutures can be involved as well, and the most dramatic appearance would be that of a cloverleaf (kleeblattschadel) skull deformity when multiple sutures are affected. Some individuals have isolated craniosynostosis and are mildly affected with only abnormal head shape. Others are clinically diagnosed with one of the more than 100 inherited conditions with craniosynostosis as a feature. Among those with coronal synostosis is Crouzon syndrome which is associated with only craniofacial abnormalities. One major feature is prominent eyes or ocular proptosis. Other findings include flat midface, prominent mandible, strabismus, dental abnormalities, cleft palate, hearing loss, and cervical spine problems. Jackson-Weiss syndrome also has large great toes or other bony foot deformities. Pfeiffer syndrome has hand and feet abnormalities with broad thumbs and great toes, brachydactyly (short phalanges) and syndactyly (webbing), and more severe cases have upper arm (radioulnar) synostosis and other organ system abnormalities. Muenke syndrome is highly variable and can have features of the previously described disorders and carpal and tarsal bony fusion. Antley-Bixler-like syndrome resembles severe cases of Pfeiffer syndrome with bowing of femoral bones, fractures, and Antley-Bixler syndrome (POR syndrome) has ambiguous genitalia. Apert syndrome has severe craniofacial features, symmetric hand and feet syndactyly, and more than half have learning problems. Crouzonodermoskeletal and Beare-Stevenson syndromes are associated with dermatologic findings of acanthosis nigricans; the former also has choanal atresia and hydrocephalus, and the latter has cutis gyrata. Saethre-Chotzen syndrome presents with facial asymmetry, eyelid ptosis (drooping), and mild hand and foot brachydactyly and syndactyly. Baller-Gerold syndrome has radial ray defects and visceral organ abnormalities. Craniosynostosis, Boston type is associated with forehead retrusion, recession of the superorbital region and digital abnormalities. Craniofrontonasal dysplasia is distinct with midline problems including hypertelorism and broad nasal tip. Carpenter syndrome is associated with polydacyty (extra digits). All but two of these syndromes mentioned above display autosomal dominant inheritance; however a significant percentage of mutations are de novo. Antley-Bixler and Carpenter syndromes are the exceptions and are autosomal recessive conditions. Testing can be ordered for the entire panel or for select disorders. It is performed via DNA sequencing of the appropriate exon(s) (see table below). For three syndromes (CFNS, CRS2 and SCS), deletions or duplications of the target genes are also determined by MLPA. See detection rates in table below. This testing may be ordered for confirmation of a clinical diagnosis, to facilitate genetic counseling of an affected individual or family member, or for prenatal diagnosis.

Craniosynostosis conditions Test (panel) genes and exons1 sequenced and MLPA if applicable Overall test sensitivity References
Antley-Bixler syndrome FGFR2; exons 7,8 28% Chun et al (1998) Am J Med Genet 77:219.
Apert syndrome FGFR2; exon 7 99-100% Wilkie et al. (1995) Nat Genet 9:101.
Beare-Stevenson syndrome FGFR2; exon 9 99% Przyelpa et al (1997) Nat Genet 13:492.
Crouzon syndrome FGFR2; exons 7, 8
(*FGFR3; exon 6)
90% Lewanda & Jabs (2002. 4th ed.) Craniosynostosis, In Principles and Practices of Medical Genetics,
Crouzon and acanthosis syndrome (Crouzonodermoskeletal syndrome) FGFR3; exon 8 99% Meyers et al (1995) Nat Genet 11:462.
Jackson-Weiss syndrome FGFR2; exons 7, 8
(*FGFR3; exon 6)
90% Jabs et al (1994) Nat Genet 8:275.
Muenke syndrome FGFR3; exon 6 100%
(syndrome is defined by mutation, not phenotype)
Lewanda & Jabs (2002) Craniosynostosis, In Principles and Practices of Medical Genetics, 4th edition
Non-syndromic coronal synostosis FGFR2; exons 7, 8 Familial 74% Lajeunie et al (1999) J Med Genet. 36:9.
Non-syndromic coronal synostosis (cont.) FGFR3; exon 6 Sporadic 15% Renier et al (2000) J Neurosurg. 92:631
Pfeiffer syndrome FGFR1; exon 7
FGFR2; exons 7, 8
(*FGFR3; exon 6)
85% Lewanda & Jabs (2002. 4th ed.) Craniosynostosis, In Principles and Practices of Medical Genetics
Carpenter syndrome RAB23 cds less than 100% Jenkins et al (2007) Am J Hum Genet 80:1162.
Craniofrontonasal syndrome (CFNS) EFNB1 cds 93% Wieland et al Hum Mutat 26:113.
Craniosynostosis, Boston Type (CRS2) MSX2 cds ~10% Jabs et al. (1993) Cell 75:443.
Craniosynostosis with radial defects (phenotypic overlap with Baller-Gerold syndrome) TWIST1 cds Some cases Gripp et al (1999) Am J Med Genet 82:170.
Saethre-Chotzen syndrome (SCS) TWIST1 cds
(*FGFR2; exon 7. FGFR3; exon 6)
79% Paznekas et al (1998) Am J Hum Genet 62: 1370.
POR deficiency POR coding sequence (cds) 47% Miller et al (2005) Ann N Y Acad Sci 061:100.

1. Exon numbering according to ENSEMBL database
(www.ensembl.org/Homo_sapiens/index.html)
* If preceding exons are negative for any mutations, then the following exon(s) will be sequenced.

Specimen Requirements:
Two 5-10 ml tubes of anticoagulated blood. The preferred anticoagulant is EDTA (lavendar top tubes), ACD (yellow top) tubes are also accepted.

Shipping: Send at room temperature.

Turnaround Time: 3-4 weeks

CPT Codes:
Craniosynostosis conditions CPT codes
Antley-Bixler syndrome 83891, 83898x3, 83904x6, 83912
Apert syndrome 83891, 83898x2, 83904x4, 83912
Beare-Stevenson syndrome 83891, 83898, 83904x2, 83912
Crouzon syndrome 83891, 83898x4, 83904x8, 83912
Crouzon & acanthosis syndrome (Crouzonodermoskeletal syndrome) 83891, 83898, 83904x2, 83912
Jackson-Weiss syndrome 83891, 83898x3, 83904x6, 83912 (83898, 83904x2)
Muenke syndrome 83891, 83898, 83904x2, 83912
Non-syndromic coronal synostosis 83891, 83898x4, 83904x8, 83912
Pfeiffer syndrome 83891, 83898x4, 83904x8, 83912 (83898, 83904x2)
Carpenter syndrome 83891, 83898x6, 83904x12, 83912
Craniofrontonasal syndrome (CFNS) 83891, 83898x6, 83904x12, 8900, 8901x3, 83909, 83914x5, 83912
Craniosynostosis, Boston Type (CRS2) 83891, 83898x2, 83904x4, 8900, 83909, 83914x2, 83912
Craniosynostosis w/ radial defects (phenotypic overlap w/ Baller-Gerold syndrome) 83891, 83898x2, 83904x4, 83912
Saethre-Chotzen syndrome (SCS) 83891, 83898x2, 83904x4, 8900, 8901x3, 83909, 83914x5, 83912 (83898x3, 83904x6)
POR deficiency 83891, 83898x17, 83904x34, 83912

Consent Form: Craniosynostosis Consent [PDF]

Requisition Form: General Test Requisition [PDF]