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. 2010 Jul;152A(7):1641-53.
doi: 10.1002/ajmg.a.33441.

Facial diagnosis of mild and variant CdLS: Insights from a dysmorphologist survey

Sarika Rohatgi  1 , Dinah Clark, Antonie D Kline, Laird G Jackson, Juan Pie, Victoria Siu, Feliciano J Ramos, Ian D Krantz, Matthew A Deardorff
Affiliations

Facial diagnosis of mild and variant CdLS: Insights from a dysmorphologist survey

Sarika Rohatgi et al. Am J Med Genet A. 2010 Jul.

Abstract

Cornelia de Lange syndrome (CdLS) is a dominant disorder with classic severe forms and milder atypical variants. Central to making the diagnosis is identification of diagnostic facial features. With the recognition that patients with SMC1A and SMC3 mutations have milder, atypical features, we surveyed 65 dysmorphologists using facial photographs from 32 CdLS patients with the goals of (1) Illustrating examples of milder patients with SMC1A mutations and (2) Obtaining objective data to determine which facial features were useful and misleading in making a diagnosis of CdLS. Clinicians were surveyed whether the patient had CdLS or another diagnosis, the certainty of response and the clinical features used to support each response. Using only facial photographs, an average of 24 cases (75%) were accurately diagnosed per clinician. Correct diagnoses were made in 90% of classic CdLS and 87% of non-CdLS cases, however, only 54% of mild or variant CdLS were correctly diagnosed by respondents. We confirmed that CdLS is most accurately diagnosed in childhood and the diagnosis becomes increasingly difficult with age. This survey demonstrated that emphasis is placed on the eyebrows, nasal features, prominent upper lip and micrognathia. In addition, the presence of fuller, atypical eyebrows, a prominent nasal bridge and significant prognathism with age dissuaded survey takers from arriving at a diagnosis of CdLS in individuals with mild NIPBL and SMC1A mutations. This work underscores the difficulty in diagnosing patients with mild and variant CdLS and serves to objectively classify both useful and misleading features in the diagnosis of CdLS.

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Figures

FIG. 1
FIG. 1
Facies of patients used in this study. The number circled in white overlaps the frontal and profile image for each patient. [Color figure can be viewed in the online issue, available at www.interscience.wiley.com.]
FIG. 2
FIG. 2
Overall results from CdLS facial feature survey. A: Distribution of number of accurate diagnoses of CdLS by respondents. Number of correct answers per respondent are indicated on the x-axis. The number of respondents with each number correct are plotted on the y-axis. A non-linear Gaussian curve fit to the results is overlayed. B: Differences in ability to diagnose classic versus mild CdLS. Unpaired t-test P values calculated using the total number of responses for the number (n) patients in each category indicated the statistical difficulty in diagnosing mild CdLS.
FIG. 3
FIG. 3
Distribution and accuracy of CdLS diagnoses. Patient numbers correlate with Figure 1. Percent correct for each patient is indicated by a horizontal bar graph, with the scale from 0% to 100% indicated above. The dashed line indicates the 10% incorrect threshold, below which, individuals were analyzed by further analysis. The average certainty of diagnosis for each patient is indicated as a horizontal bar graph, with below the scale of 0 (least certain) to 10 (most certain). Horizontal black bars at the right side of the column indicate the standard deviation for the diagnosis certainty of each patient. Diagnosis of each patient and/ or CdLS molecular confirmation is indicated at the right. Solid black columns indicate patients with “classical” CdLS, solid gray bars indicate those with “mild CdLS” and open columns indicate patients with other diagnoses. Fine horizontal lines divide the age groups as indicated in the text.
FIG. 4
FIG. 4
Representative facies in mild NIPBL and SMC1A-mutated CdLS patients. Facial images are illustrated indicating if an NIBPL or SMC1A mutation was identified. Ages are indicated using (d)ays, (m)onths and (y)ears. A: NIPBL c. 6893G>A, p. R2298H, (B) SMC1A c.3364T>C, p. F1122L (patient #26 in survey), (C) SMC1A c. 2077C>G, p.R693G, and (D) SMC1A c.802_804del, p.K268del. Note in (A) and (B) the increased ease of diagnosis in early childhood. Note in (C) and (D) the flatter fuller eyebrows, the more prominent and bulbous nasal tip and the overall less distinctive facial features. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
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