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. 2021 Feb 3;16(1):63.
doi: 10.1186/s13023-021-01686-8.

Diagnostic and severity scores for Cockayne syndrome

M A Spitz  1 , F Severac  2   3 , C Obringer  4 , S Baer  1 , N Le May  4 , N Calmels  5 , V Laugel  6   7
Affiliations

Diagnostic and severity scores for Cockayne syndrome

M A Spitz et al. Orphanet J Rare Dis. .

Abstract

Background: Cockayne syndrome is a progressive multisystem genetic disorder linked to defective DNA repair and transcription. This rare condition encompasses a very wide spectrum of clinical severity levels ranging from severe prenatal onset to mild adult-onset subtypes. The rarity, complexity and variability of the disease make early diagnosis and severity assessment difficult. Based on similar approaches in other neurodegenerative disorders, we propose to validate diagnostic and severity scores for Cockayne syndrome.

Methods: Clinical, imaging and genetic data were retrospectively collected from 69 molecularly confirmed CS patients. A clinical diagnostic score and a clinical-radiological diagnostic score for CS were built using a multivariable logistic regression model with a stepwise variable selection procedure. A severity score for CS was designed on five items (head circumference, growth failure, neurosensorial signs, motor autonomy, communication skills) and validated by comparison with classical predefined severity subtypes of CS.

Results: Short stature, enophtalmos, hearing loss, cataracts, cutaneous photosensitivity, frequent dental caries, enamel hypoplasia, morphological abnormalities of the teeth, areflexia and spasticity were included in the clinical diagnostic score as being the most statistically relevant criteria. Appropriate weights and thresholds were assigned to obtain optimal sensitivity and specificity (95.7% and 86.4% respectively). The severity score was shown to be able to quantitatively differentiate classical predefined subtypes of CS and confirmed the continuous distribution of the clinical presentations in CS. Longitudinal follow-up of the severity score was able to reflect the natural course of the disease.

Conclusion: The diagnostic and severity scores for CS will facilitate early diagnosis and longitudinal evaluation of future therapeutic interventions. Prospective studies will be needed to confirm these findings.

Keywords: Clinical severity; Cockayne syndrome; Diagnosis; Score.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flowchart of the patient cohort
Fig. 2
Fig. 2
Optimal ROC curve for the clinical diagnostic score showing the maximal area under the curve (AUC) obtained for the score defined in Table 2. Optimal sensitivity and specificity on this curve are 95.7% and 86.4% respectively (a), corresponding to a threshold of 8.5 for the diagnostic score (b). Solid lines draw the thresholds of 7 and 10 that were chosen to distinguish low/moderate/high likelihood for CS diagnosis based on positive predictive value (not shown)
Fig. 3
Fig. 3
Optimal ROC curve for the clinical-radiological diagnostic score showing the maximal area under the curve (AUC) obtained for the score defined in Table 2 Optimal sensitivity and specificity on this curve are 96.2% and 96.8% respectively (a), corresponding to a threshold of 15.5 for the clinical-radiological diagnostic score (b). Solid lines draw the thresholds of 14 and 16 that were chosen to distinguish low/moderate/high likelihood for CS diagnosis based on positive predictive value (not shown)
Fig. 4
Fig. 4
Box plots expressing severity score at the time of the diagnosis as a function of clinical subgroups (a) or mutated genes (b). Type II CS patients have a significantly lower score (more severe) at the time of the diagnosis than type I CS patients and type III CS patients. Due to the small number of type III patients available the difference between type I and type III does not reach statistical significance. CSA patients have a significantly higher (less severe) score than CSB patients at the time of the diagnosis
Fig. 5
Fig. 5
Correlation between age at first symptom and severity score at the time of the diagnosis for type I (red triangles), type II (blue squares) and type III (green circles) CS patients
Fig. 6
Fig. 6
Natural course of the severity score over time in 19 CS patients. Each curve represents a different patient. Dotted curves correspond to type III CS patients, solid curves correspond to type I CS patients, dashed curves correspond to type II CS patients
See this image and copyright information in PMC

References

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