Abstract

Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes-NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37 years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide.

Highlights

  • Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome with an estimated incidence of 1:10,000 to 1:30,000 live births [Mannini et al, 2013]

  • Clinical information and photos were collected on 246 patients with confirmed molecular diagnoses of CdLS, coming from diverse ancestral categories from 15 countries

  • CdLS is a rare condition that has multisystemic phenotypic variability within the general population. It is most commonly the recognition of the classically reported facial and limb anomalies that leads to clinical suspicion of the diagnosis and subsequent testing of the multiple genes known to be implicated in CdLS

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Summary

Introduction

Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome with an estimated incidence of 1:10,000 to 1:30,000 live births [Mannini et al, 2013]. While wide phenotypic variability exists within the CdLS spectrum, ranging from mild to severe, most patients have growth deficiency, intellectual disability, and facial dysmorphism [Kline et al, 2007a; Mehta et al, 2016]. There are 5 identified genes known to cause CdLS when mutated – NIPBL, SMC1A, HDAC8, SMC3, and RAD21 [Krantz et al, 2004]. Because there is variability between clinical presentation based on causative gene and mutation type, evaluating the CdLS phenotype in patients of diverse descent or mixed-ancestry can make diagnosis difficult. Diagnosis of CdLS is imperative to address life threatening medical issues such as malrotation and seizures [Deardorff et al, 2016; Kline et al, 2007b]

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