Oral Manifestations of Wolf-Hirschhorn Syndrome: Genotype-Phenotype Correlation Analysis.

Jacobo Limeres,Raquel Blanco-Lago,Julian Nevado,Isabel Maura,Marcio Diniz-Freitas,Candela Serrano,Pedro Diz,Guillermo Machuca,Jose Cruz Ruiz-Villandiego,Javier Silvestre-Rangil,Joaquin Manuel De Nova

doi:10.3390/jcm9113556

Abstract

Background: Wolf-Hirschhorn syndrome (WHS) is a rare disease caused by deletion in the distal moiety of the short arm of chromosome 4. The objectives of this study were to report the most representative oral findings of WHS, relate them with other clinical characteristics of the disease, and establish possible phenotype-genotype correlation. Methods: The study was conducted at 6 reference centers distributed throughout Spain during 2018–2019. The study group consisted of 31 patients with WHS who underwent a standardized oral examination. Due to behavioral reasons, imaging studies were performed on only 11 of the children 6 years of age or older. All participants had previously undergone a specific medical examination for WHS, during which anatomical, functional, epilepsy-related, and genetic variables were recorded. Results: The most prevalent oral manifestations were delayed tooth eruption (74.1%), bruxism (64.5%), dental agenesis (63.6%), micrognathia (60.0%), oligodontia (45.5%), and downturned corners of the mouth (32.3%). We detected strong correlation between psychomotor delay and oligodontia (p = 0.008; Cramér’s V coefficient, 0.75). The size of the deletion was correlated in a statistically significant manner with the presence of oligodontia (p = 0.009; point-biserial correlation coefficient, 0.75). Conclusion: Certain oral manifestations prevalent in WHS can form part of the syndrome’s phenotypic variability. A number of the characteristics of WHS, such as psychomotor delay and epilepsy, are correlated with oral findings such as oligodontia and bruxism. Although most genotype-phenotype correlations are currently unknown, most of them seem to be associated with larger deletions, suggesting that some oral-facial candidate genes might be outside the critical WHS region, indicating that WHS is a contiguous gene syndrome.

Highlights

Wolf-Hirschhorn syndrome (WHS) is a developmental disorder caused by subtelomeric deletion in the distal region of the short arm of chromosome 4 (4p16.3) [1]
We considered statistically significant only those correlations in which the null hypothesis was rejected in the independence test (p value < 0.05) and with a strong degree of association (CVC or CC > 0.70)
After analyzing the relationship between clinical findings/comorbidities and oral manifestations, we found no statistically significant correlations; we detected a tendency toward correlation between cardiac defects and micrognathia/Angle’s Class II (p = 0.035; Cramér’s V coefficient (CVC) = 0.69; Table S4)

Summary

Introduction

Wolf-Hirschhorn syndrome (WHS) is a developmental disorder caused by subtelomeric deletion in the distal region of the short arm of chromosome 4 (4p16.3) [1]. An almost pathognomonic finding in these patients is the characteristic “Greek warrior helmet” facies, which consists of a prominent glabella, wide forehead, arched eyebrows, hypertelorism, exophthalmos, epicanthal folds, wide nasal bridge, large nose, short philtrum, micrognathia, and a large mouth with downturned corners (Figure 1) [8]. In addition to this unique facial phenotype, the fundamental manifestations of this polymalformative syndrome in its “classical” presentation include developmental delay, intellectual disability, and epilepsy [9]. Most genotype-phenotype correlations are currently unknown, most of them seem to be associated with larger deletions, suggesting that some oral-facial candidate genes might be outside the critical WHS region, indicating that WHS is a contiguous gene syndrome

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