Birgitta Bergendal

Mutations in the gene encoding fibroblast growth factor 10 are associated with aplasia of lacrimal and salivary glands

Autosomal dominant aplasia of lacrimal and salivary glands (ALSG; OMIM 180920 and OMIM 103420) is a rare condition characterized by irritable eyes and dryness of the mouth. We mapped ALSG to 5p13.2–5q13.1, which coincides with the gene fibroblast growth factor 10 (FGF10). In two extended pedigrees, we identified heterozygous mutations in FGF10 in all individuals with ALSG. Fgf10+/− mice have a phenotype similar to ALSG, providing a model for this disorder. We suggest that haploinsufficiency for FGF10 during a crucial stage of development results in ALSG.

Isolated oligodontia associated with mutations in EDARADD, AXIN2, MSX1, and PAX9 genes

Oligodontia is defined as the congenital lack of six or more permanent teeth, excluding third molars. Oligodontia as well as hypodontia (lack of one or more permanent teeth) are highly heritable conditions associated with mutations in the AXIN2, MSX1, PAX9, EDA, and EDAR genes. Here we define the prevalence of mutations in the AXIN2, MSX1, PAX9, EDA, and EDAR genes, and the novel candidate gene EDARADD in a cohort of 93 Swedish probands with non‐syndromic, isolated oligodontia. Mutation screening was performed using denaturing gradient gel electrophoresis and DNA sequence analysis. Analyses of the coding sequences of the six genes showed sequence alterations predicted to be damaging or potentially damaging in ten of 93 probands (10.8%). Mutations were identified in the EDARADD (n = 1), AXIN2 (n = 3), MSX1 (n = 2), and PAX9 (n = 4) genes, respectively. None of the 10 probands with mutations had other self‐reported symptoms from ectodermal tissues. The oral parameters were similar when comparing individuals with and without mutations but a family history of oligodontia was three times more frequent for probands with mutations. EDARADD mutations have previously been reported in a few families segregating hypohidrotic ectodermal dysplasia and this is, to our knowledge, the first report of an EDARADD mutation associated with isolated oligodontia.

WNT10A mutations account for ¼ of population‐based isolated oligodontia and show phenotypic correlations

A large proportion (>50%) of patients with isolated oligodontia were recently reported with WNT10A mutations. We have analyzed a population‐based cohort of 102 individuals diagnosed with non‐syndromic oligodontia and a mean of 8.2 missing teeth. The cohort included 94 families and screening of WNT10A identified that 26 probands (27.7%) had at least one WNT10A variant. When we included the MSX1, PAX9, AXIN2, EDA, EDAR, and EDARADD genes, 38.3% of probands were positive for a mutation. Biallelic WNT10A mutations were strongly associated with a larger number of missing teeth (11.09) when compared to both monoallelic WNT10 mutations (6.82) and the group without mutations in WNT10A, MSX1, PAX9, AXIN2, EDA, EDAR, or EDARADD (7.77). Genotype–phenotype analysis of individuals with WNT10A mutations showed that premolars were the most common missing teeth. Furthermore, biallelic WNT10A mutations were associated with absence of maxillary and mandibular molars as well as mandibular central incisors. Maxillary central incisors were always present. Thus, our study indicates that WNT10A mutations are associated with both the type and numbers of missing teeth. Furthermore, we show that this population‐based cohort of isolated oligodontia had a considerably lower frequency of mutated WNT10A alleles and a lower mean number of missing teeth when compared to patients recruited from dental specialist centers.

Orofacial dysfunction in ectodermal dysplasias measured using the Nordic Orofacial Test-Screening protocol

Objective. To screen orofacial function in people with various ectodermal dysplasia (ED) syndromes and compare with a healthy reference sample. Material and methods. The ED group comprised 46 individuals (30 M and 16 F; mean age 14.5 years, range 3–55). Thirty-two had hypohidrotic ED, while 14 had other ED syndromes. The reference sample comprised 52 healthy individuals (22 M and 30 F; mean age 24.9 years, range 3–55). Orofacial function was screened using the Nordic Orofacial Test-Screening (NOT-S) protocol containing 12 orofacial function domains (maximum score 12 points). Results. The total NOT-S score was higher in the ED group than in the healthy group (mean 3.5 vs. 0.4; p<0.001). The dysfunctions most frequently recorded in the subjects with ED occurred in the domains chewing and swallowing (82.6%), dryness of the mouth (45.7%), and speech (43.5%). Those with other ED syndromes scored non-significantly higher than those with hypohidrotic ED (mean 4.6 vs. 3.0; p>0.05). Conclusions. Individuals with ED scored higher than a healthy reference sample in all NOT-S domains, especially in the chewing and swallowing, dryness of the mouth, and speech domains. Orofacial function areas and treatment and training outcomes need to be more closely evaluated and monitored.

Fibroblast growth factor 10 haploinsufficiency causes chronic obstructive pulmonary disease

Background Genetic factors influencing lung function may predispose to chronic obstructive pulmonary disease (COPD). The fibroblast growth factor 10 (FGF10) signalling pathway is critical for lung development and lung epithelial renewal. The hypothesis behind this study was that constitutive FGF10 insufficiency may lead to pulmonary disorder. Therefore investigation of the pulmonary functions of patients heterozygous for loss of function mutations in the FGF10 gene was performed. Methods The spirometric measures of lung function from patients and non-carrier siblings were compared and both groups were related to matched reference data for normal human lung function. Results The patients show a significant decrease in lung function parameters when compared to control values. The average FEV1/IVC quota (FEV1%) for the patients is 0.65 (80% of predicted) and reversibility test using Terbutalin resulted in a 3.7% increase in FEV1. Patients with FGF10 haploinsufficiency have lung function parameters indicating COPD. A modest response to Terbutalin confirms an irreversible obstructive lung disease. Conclusion These findings support the idea that genetic variants affecting the FGF10 signalling pathway are important determinants of lung function that may ultimately contribute to COPD. Specifically, the results show that FGF10 haploinsufficiency affects lung function measures providing a model for a dosage sensitive effect of FGF10 in the development of COPD.

Orodental manifestations in ectodermal dysplasia—A review

Oral signs and symptoms are present in most ectodermal dysplasias (EDs). The aim of this article is to summarize some of the literature on current knowledge of oral manifestations and orofacial function in EDs. The review will focus on the most common forms where dental manifestations can be crucial for a differential diagnosis of ED among individuals with hypodontia and oligodontia, and preferably where the investigations included persons who had a genetically verified diagnosis. Disturbances in tooth development are common and can appear as tooth agenesis, variations in size and shape of teeth, defects in the mineralized tissues, and problems in tooth eruption. Abnormalities in number, size, and shape of teeth, and reduced salivary secretion, present in isolated oligodontia as well as in hypohidrotic ED and incontinentia pigmenti. In some more rare EDs these symptoms appear in combination with clefts of lip and/or palate in some affected individuals. Leukokeratosis in the oral mucosa presents in 70% of genetically confirmed cases of pachyonychia congenita. Also, orofacial function is often affected in ED, due to malformations, an incomplete dentition, and low salivary secretion which can compromise chewing, swallowing, and speech. In conclusion, there is a clinical overlap in oral signs and symptoms between isolated oligodontia and the most common EDs. Studies with genetically confirmed diagnoses and larger cohorts, as well as multicenter collaboration and the establishing of international registries, would create a basis for refined diagnostics, where oral examinations should be an integrated part of clinical assessment.

Further evidence for specific IFIH1 mutation as a cause of Singleton–Merten syndrome with phenotypic heterogeneity

Singleton–Merten syndrome (MIM 182250) is an autosomal dominant inherited disorder characterized by early onset periodontitis, root resorption, osteopenia, osteoporosis, and aortic valve or thoracic aorta calcification. The disorder can have significant intrafamilial phenotypic variability. Here, we present a mother and daughter with Singleton–Merten syndrome harboring a previously described pathogenic missense mutation, c.2465G>A p.(Arg822Gln), in IFIH1 (interferon induced with helicase C domain 1), encoding MDA5 (Melanoma Differentiation‐Associated protein 5). These data confirm the pathogenicity of IFIH1 c.2465G>A p.(Arg822Gln) for Singleton–Merten syndrome and affirm the striking phenotypic heterogeneity of this disorder. In addition, we expand the Singleton–Merten phenotype by adding severe systemic lupus erythematosus (SLE) to the clinical picture. Investigations of known SLE genes as well as a single nucleotide polymorphism suggested to be involved in development of SLE were normal.

Profiles of orofacial dysfunction in different diagnostic groups using the Nordic Orofacial Test (NOT-S)—A review

Abstract Objective. The Nordic Orofacial Test-Screening (NOT-S) was developed as a comprehensive method to assess orofacial function. Results from the screening protocol have been presented in 11 international publications to date. This study reviewed these publications in order to compile NOT-S screening data and create profiles of orofacial dysfunction that characterize various age groups and disorders. Materials and methods. NOT-S results of nine reports meeting the inclusion criteria were reviewed. Seven of these studies not only provided data on the mean and range of total NOT-S scores, but also on the most common domains of orofacial dysfunction (highest rate of individuals with dysfunction scores), allowing the construction of orofacial dysfunction profiles based on the prevalence of dysfunction in each domain of NOT-S. Results. The compiled data comprised 669 individuals, which included healthy control subjects (n = 333) and various patient groups (n = 336). All studies reported differences between individuals with diagnosed disorders and healthy control subjects. The NOT-S data could measure treatment effects and provided dysfunction profiles characterizing the patterns of orofacial dysfunction in various diagnoses. Conclusions. This review corroborates previous results that the NOT-S differentiates well between patients and healthy controls and can also show changes in individuals after treatment. NOT-S could be used as a standard instrument to assess orofacial dysfunction, evaluate the outcomes of oral habilitation and rehabilitation and improve comparability in clinical practice and research.

Abnormal primary and permanent dentitions with ectodermal symptoms predict WNT10A deficiency

BackgroundThe WNT10A protein is critical for the development of ectodermal appendages. Variants in the WNT10A gene may be associated with a spectrum of ectodermal abnormalities including extensive tooth agenesis.MethodsIn seven patients with severe tooth agenesis we identified anomalies in primary dentition and additional ectodermal symptoms, and assessed WNT10A mutations by genetic analysis.ResultsInvestigation of primary dentition revealed peg-shaped crowns of primary mandibular incisors and three individuals had agenesis of at least two primary teeth. The permanent dentition was severely affected in all individuals with a mean of 21 missing teeth. Primary teeth were most often present in positions were succedaneous teeth were missing. Furthermore, most existing molars had taurodontism. Light, brittle or coarse hair was reported in all seven individuals, hyperhidrosis of palms and soles in six individuals and nail anomalies in two individuals. The anomalies in primary dentition preceded most of the additional ectodermal symptoms. Genetic analysis revealed that all seven individuals were homozygous or compound heterozygous for WNT10A mutations resulting in C107X, E222X and F228I.ConclusionsWe conclude that tooth agenesis and/or peg-shaped crowns of primary mandibular incisors, severe oligodontia of permanent dentition as well as ectodermal symptoms of varying severity may be predictors of bi-allelic WNT10A mutations of importance for diagnosis, counselling and follow-up.

Orofacial function and monitoring of oral care in amyotrophic lateral sclerosis

Abstract Objective: The aim was to assess orofacial function and monitor oral care in patients with amyotrophic lateral sclerosis (ALS) to maintain oral comfort and oral health. Materials and methods: A case series of 14 patients newly diagnosed with ALS accepted to participate in a quality improvement project. After initial examinations, baseline oral conditions were obtained and the patients were seen every 3 months. Nordic Orofacial Test-Screening (NOT-S) was used for evaluation of orofacial function. Results: Patients were grouped according to initial symptoms in a bulbar group and a spinal group with eight and six patients, respectively. The mean age at diagnosis was 62.8 years. All were dentate with a mean of 26.7 natural teeth. Most patients had very good oral and dental conditions. As expected, orofacial functions were differently affected in the two groups; at initial NOT-S registration, the mean total score was 5.6 (range 3–8 domains) in the bulbar group and 0.7 (0–2 domains) in the spinal group. At final registration, the corresponding figures were 6.1 and 3.2. Oral and dental aids were introduced according to need. Conclusions: In the bulbar group, several orofacial functions became impaired at an early stage of disease development, and at final registrations many vital orofacial functions were severely compromised. The spinal group was less severely affected orally. However, all individuals irrespective of type of initial symptoms needed assistance in performing oral hygiene measures in the latter part of the disease period. Good oral health and oral comfort could be maintained in all participants and no other dental treatment was needed.