FaCD Online Syndrome Fact Sheet

Last updated: 06 Nov 2009

Name: Saethre-Chotzen syndrome

Synonym: Acrocephalosyndactyly type III

Mode of Inheritance: AD

Genes

FGFR2, mapped to 10q26
FGFR3, mapped to 4p16.3
TWIST/TWIST1, mapped to 7p21

Tumor features (possible)

breast cancer
Hodgkin disease (Hodgkin's lymphoma)
nasopharyngeal cancer
pituitary adenoma
renal cell cancer
testicular teratoma

Non-tumor features

brachiocephaly
brachydactyly, of feet
brachydactyly, of hands
cleft palate
clinodactyly
craniosynostosis
developmental delay/mental deficiency/mental retardation
ears, low-set
ears, malformed
facies, asymmetric
facies, flat
forehead, broad
hallux valgus
hearing loss, neurosensory
hypertelorism
nose, beaked
occiput, flat
orbits, shallow
palate, high arched
strabismus
syndactyly of fingers
syndactyly of toes

Non-tumor features (possible)

immunodeficiency

Comment

This disorder is characterized by craniosynostosis, asymmetric facies and other craniofacial dysmorphisms, soft tissue syndactyly, mild brachydactyly and broad halluces. Mental retardation may be present.

McKeen et al.[1] reported on a family with Saethre-Chotzen syndrome, in which a female with the disorder was diagnosed at the age of 30-31 years with nasopharyngeal carcinoma. Three of her brothers, reported not to have the syndrome, developed Hodgkin disease at the ages of 28, 22 and testicular teratocarcinoma at the age of 18 years, respectively. In addition, cancer was diagnosed in 4 of 34 second- and third-degree paternal relatives. The Saethre-Chotzen gene was inherited from the father. A decreased in vitro T-lymphocyte response was observed in the father, the affected daughter, one of the sons with Hodgkin disease, a son with a known past EBV infection, without the syndrome, and a daughter with neither Saethre-Chotzen syndrome nor tumor. Whether decreased immune response, the neoplasia and Saethre-Chotzen syndrome in this family had a common etiology remained unclear.

Renal cell cancer (no histological subtype given) in a 6-year-old girl with Saethre-Chotzen syndrome was reported by Seifert al.[2].

In 15 Swedish Saethre-Chotzen families with TWIST muations, breast cancer was observed 15 of 29 (52%) female carriers over the age of 25 . At least four of them patients had developed breast cancer before 40 years of age, and five between 40 and 50 years of age.[3]. An Australian study on patients with confirmed TWIST mutations did not show an increased breast cancer risk[6]. In a Saethre-Chotzen family with a FGFR3 germline mutation, an affected male was diagnosed with a nonfunctioning pituitary adenoma at age 29 years and his affected mother was diagnosed with breast cancer at age 55 years[7]

The TWIST gene has been implicated in cancer development and metastasis[4], including that of breast cancer[5]. FGFR3 plays a role in cancer development as well[7]. The chance of finding a TWIST1 or FGFR3 germline mutation in BRCA1/2 negative breast cancer families appears to be very small[8].

Links

World Craniofacial Foundation 24 1 08

References

[1] McKeen EA, Mulvihill JJ, Levine PH, Dean JH, Howley PM. The concurrence of Saethre-Chotzen syndrome and malignancy in a family with in vitro immune dysfunction. Cancer 1984; 54(12):2946-2951.
[2] Seifert G, Kress W, Meisel C, Henze G, Seeger K. Genetic investigations of Saethre-Chotzen syndrome presenting with renal cell carcinoma. Cancer genetics and cytogenetics 2006; 171(1):76-8.
[3] Sahlin P, Windh P, Lauritzen C, Emanuelsson M, Grönberg H, Stenman G. Women with Saethre-Chotzen syndrome are at increased risk of breast cancer. Genes, chromosomes & cancer 2007; 46(7):656-60.
[4] Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004; 117(7):927-39.
[5] Mani SA, Yang J, Brooks M, Schwaninger G, Zhou A, Miura N, Kutok JL, Hartwell K, Richardson AL, Weinberg RA. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proceedings of the National Academy of Sciences of the United States of America 2007; 104(24):10069-74.
[6] James PA, Culling B, Mullan G, Jenkins M, Elakis G, Turner AM, Mowat DM, Wilson M, Anderson P, Savarirayan R, Cliffe ST, Caramins M, Buckley MF, Tucker K, Roscioli T. Breast cancer risk is not increased in individuals with TWIST1 mutation confirmed Saethre-Chotzen syndrome: An Australian multicenter study. Genes Chromosomes Cancer. 2009 Apr 16. [Epub ahead of print]
[7] Sahlin P, Tarnow P, Martinsson T, Stenman G. Germline mutation in the FGFR3 gene in a TWIST1-negative family with saethre-chotzen syndrome and breast cancer. Genes Chromosomes Cancer. 2009 Mar;48(3):285-8.
[8] Bergman A, Sahlin P, Emanuelsson M, Carén H, Tarnow P, Martinsson T, Grönberg H, Stenman G. Germline mutation screening of the Saethre-Chotzen-associated genes TWIST1 and FGFR3 in families with BRCA1/2-negative breast cancer.Scand J Plast Reconstr Surg Hand Surg. 2009;43(5):251-5.