The Coffin-Siris syndrome: a proposed diagnostic approach and assessment of 15 overlapping cases

Abstract

Coffin-Siris syndrome (CSS) is a rare, clinically heterogeneous disorder often considered in the setting of cognitive/developmental delay and 5th finger/nail hypoplasia. Due to the clinical variability of facial and other features, this diagnosis is often difficult to confirm clinically and the existence of this disorder as a specific diagnosis has been at times an issue of debate. In an effort to further delineate the spectrum and key phenotypic features, we reviewed 80 previously reported cases to define features in patients that most closely correlated with a convincing diagnosis. There appear to be two subtypes of CSS, one which displays the "classic" coarse facial features previously described; another displays "variant" facial features which are less striking. Using these features, we defined an algorithm to rank the confidence of diagnosis and applied it to 15 additional patients who had been previously characterized by chromosome microarray. This approach will also facilitate uniform categorization for whole-exome analysis.

Figure 1

Photos of individuals. Illustrated are the varied facial features and hypoplastic fifth digits of the hands and/or feet. Radiographs of two probands are also shown, demonstrating the hypoplastic distal fifth phalanges of the hands. Individual patients photographs are outlined in a bold black line. Numbers in the photo correlate with those in the text and in Table I. P=proband, AS=affected sibling. Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.

Figure 2

Coffin-Siris diagnostic algorithm. DD = developmental delay; CD = cognitive delay; CSS = Coffin-Siris syndrome; BOD = brachymorphism-onychodysplasia-dysphalangism; DOOR = deafness, onychodystrophy, osteoodystrophy, and mental retardation; NCBRS = Nicolaides-Baraitser syndrome; CdLS = Cornelia de Lange syndrome