Cardiovascular malformations in Fryns syndrome: is there a pathogenic role for neural crest cells?

Am J Med Genet A. 2005 Dec 15;139(3):186-93. doi: 10.1002/ajmg.a.31023.


We performed a comprehensive literature and case report review to characterize the cardiovascular malformations (CVMs) associated with Fryns syndrome (OMIM #229850), a multiple congenital anomaly/mental retardation syndrome consisting of diaphragmatic defects, significant pulmonary hypoplasia, distinctive facial appearance, distal digital hypoplasia, and numerous other external and internal anomalies. A total of 112 patients meeting diagnostic guidelines for Fryns syndrome were identified, of whom 82 met narrowly defined criteria (Group I) and 30 met broader diagnostic criteria (Group II). Twelve patients reported as having Fryns syndrome with atypical features (Group III) were also analyzed. A CVM was reported in 51% (42 of 82) of Group I patients, most commonly an atrial or ventricular septal defect (VSD) (23 of 42, 55%). Conotruncal and aortic arch CVMs were common (11 of 42, 26%), but not significantly so compared to the general population of infants to age 1 year [Ferencz et al., 1997]. Recognizing that minor septal defects associated with congenital diaphragmatic hernia (CDH) may occur in response to altered hemodynamics (instead of being a bonafide CVM), we excluded four patients reported as having hemodynamically insignificant VSDs. Following these exclusions, conotruncal CVMs were found more commonly than in the general population (11 of 38, 29%, P < or = 0.025). In Group II, 9 of 30 (30%) had a CVM with no predominant type among the small number of cases reviewed. Among the atypical Fryns syndrome patients in Group III, half (6 of 12, 50%) had a CVM; most (4 of 6, 67%) were conotruncal, in particular, type B interrupted aortic arch (3 of 4). Patients with Fryns syndrome have a high rate of CVMs, warranting thorough cardiac evaluation including echocardiogram (fetal and/or postnatal) in all patients, similar to the evaluation for other patients with diaphragmatic hernia. The possible association between conotruncal CVMs and Fryns syndrome may provide additional support for an etiologic role of genes related to neural crest cell development in the pathogenesis of Fryns syndrome and hence, congenital diaphragmatic hernia.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Abnormalities, Multiple / classification
  • Abnormalities, Multiple / diagnosis
  • Abnormalities, Multiple / pathology*
  • Cytogenetic Analysis
  • Heart Defects, Congenital / pathology*
  • Hernia, Diaphragmatic / pathology*
  • Humans
  • Intellectual Disability / pathology*
  • Neural Crest / growth & development*
  • Syndrome