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

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.

Wolf-Hirschhorn Syndrome: Clinical and Genetic Study of 7 New Cases, and Mini Review

“…However, in the cases 1, 2, and 4 presented by us, we have noted dysmorphic face, cardiac defects, multiple congenital anomalies and severe postnatal development which hints towards the involvement of genes other than the ones in the critical region. However, we have identified oral issues alongside psychomotor delays in case 1, 2, and 6(anodontia) similar to the findings of Limeres et al [ 23 ].…”

A practical approach to dental care for patients with Wolf‐Hirschhorn syndrome

“…Epilepsy is present in almost all patients with WHS 7,10 and tends to debut at very early ages, 14 although the frequency of seizures tends to decrease with age. In a series of patients who belonged to the AESWH whose mean age was 8.8 ± 7.3 years, 38.7% of the patients had not had a seizure in more than 2 years 4 .…”

“…Approximately 70% of seizures in WHS are generalized tonic‐clonic but can present as absences or atypical absences 4 . In approximately 40% of cases, these seizures are triggered by fever, occasionally becoming status epilepticus in almost half of those affected, requiring admission to an intensive care unit in 1 of every 3 episodes 14,15 . Accordingly, approximately 80% of the drugs that are prescribed for this group are antiepileptic agents, especially valproic acid and levetiracetam, 4 which are generally administered in combination with each other or with neuroleptics 7,14 …”

“…These problems can result in the onset of gastroesophageal reflux, aspirations and respiratory infections 1,17 . Therefore, approximately 10%–50% of such patients are carriers of nasogastric or endoscopic percutaneous gastrostomy tubes 1,14 …”

“…Table 2 details the most prevalent oral findings in WHS. The most common dental abnormality is tooth agenesis, with a prevalence approaching 60%, 14 which especially affects the definitive second premolars and the temporary second molars, followed by the lateral incisors and the definitive second molars 14,18 . A high percentage of these cases of agenesis (40%–70%) involve oligodontia, 14,18 with the verified absence of at least six teeth without counting the third molars 19 .…”