Oral Health Status of Children and Adolescents With Phenylketonuria: A Case‐Control Study

ABSTRACT

Background and Aims

Phenylketonuria (PKU) is a genetic metabolic disorder affecting phenylalanine metabolism. While its neurological and skeletal impacts are well‐documented, its influence on oral health is less understood. This study aimed to evaluate the oral health status of children and adolescents with PKU compared to healthy controls.

Methods

The case‐control study included 136 children and adolescents aged 6–18 years, with 68 PKU patients and 68 healthy controls from February to June 2024. Oral hygiene practice was assessed from both groups. Oral health was assessed using the ICDAS, gingival index (GI), and basic periodontal examination (BPE) indices. Sweet nutrition consumption was also analyzed, and the relationship between serum phenylalanine (Phe) levels and oral health indices was examined.

Results

Assessment of oral hygiene showed poorer oral hygiene in PKU patients, with 54.4% brushing less than once daily compared to 26.5% of controls (p < 0.001). PKU patients exhibited significantly higher ICDAS score compared to controls (median = 1.50 vs. 1.00, p = 0.045); however, the effect size was low (0.08). While the GI scores of the PKU patients was higher, the outcomes indicated insignificant results (median = 2.00 vs. 1.00, p = 0.487). The BPE scores exhibited significantly higher outcomes compared to controls (median = 2.00 vs. 1.00, p < 0.001) with a large effect size (0.53). The nutritional assessments indicated PKU patients consumed less sugary food overall. Moreover, serum Phe levels were not associated with ICDAS, GI, or BPE scores.

Conclusion

The findings underscore the importance of preventive oral care for PKU patients. A multidisciplinary approach involving dentists from the time of diagnosis of disease is recommended to ensure comprehensive dental and periodontal care, schedule regular appointments, and implementation of preventive strategies.

1. Introduction

Phenylketonuria (PKU) is a genetic disease recognized as impaired metabolism of phenylalanine amino acid (Phe) due to genetic mutations in both alleles of phenylalanine hydroxylase (PAH) gene [1, 2]. If left untreated, PKU can lead to severe neurological impairments, including intellectual disability, seizures, and behavioral disorders. The global prevalence of PKU is ~1:24,000 newborns with higher estimates observed in communities with high rate of consanguinity [3, 4, 5]. Studies suggest PKU is more prevalent in the societies with higher rate of intrafamilial marriage [1, 6].

The metabolic consequence of PKU arises from insufficient amounts of PAH, which converts Phe to tyrosine (Tyr). The resulting accumulation of serum Phe levels can have toxic effects, especially causing neurological function, severe mental disabilities, seizures, and psychological disorders [7]. To mitigate these effects [8], patients are prescribed low‐protein diets and avoid protein‐rich foods [7]. However, this dietary restriction often results in high reliance on high‐carbohydrate and high‐fat diets for energy compensation, increasing the risk of reduced bone density and fractures [7, 9].

While the impact of PKU on neurological and bone health is well‐documented, the oral health status is still unclear. Using a low‐protein and high‐carbohydrate diet from childhood raises concerns about the potential increased risk of dental caries [10, 11, 12, 13, 14]. However, conflicting evidence exists, with some studies suggesting that PKU may reduce the incidence of dental caries due to altered metabolic factors [10, 12, 13].

Oral health status is assessed by evaluating the frequency and severity of dental caries, gingival, and periodontal health status. Several indices are introduced to assess the health status of oral tissues. In this regard, International Caries Detection and Assessment System (ICDAS) and Decayed, Missing, and Filled Teeth (DMFT) are two commonly used indices [15, 16, 17, 18]. ICDAS is reported to have a high precision in detecting the different stages of dental caries [19, 20, 21] offering a comprehensive diagnostic tool supported by systematic reviews and clinical studies [22, 23, 24]. After the introduction of ICDAS I in 2002, ICDAS II was proposed in 2005 [25]. Both ICDAS I and II were based on the studies by Ekstrand and colleagues and Ismail [22, 23, 24].

In addition to dental caries assessment, gingival and periodontal health are crucial components in oral health evaluation, including PKU [13]. In order to assess the gingival and periodontal status of the patients the gingival index of Loe and Silness (GI) and the basic periodontal examination (BPE) method are used in some studies [26, 27]. Emerging evidence suggests patients affected by PKU are at high risk of developing periodontal diseases, especially pocket depth of more than 4 mm [13]. In another study [11], PKU patients had four times higher periodontal screening record values compared to healthy controls.

Given the critical importance of oral health among children and adolescents with PKU, and the limited evidence regarding the specific effects of PKU on oral tissues, this study aimed to evaluate the oral health status (ICDAS, GI, BPE), its correlation with serum Phe levels, and the nutritional status of children and adolescents with PKU in comparison to healthy controls through clinical examination and questionaries.

2. Methods

This case‐control study was approved by the Human Ethics Committee, Shiraz University of Medical Sciences (IR.SUMS.DENTAL.REC.1402.078). This study was conducted on patients diagnosed with PKU and receiving treatment. Recruitment began in Feb 2024 and was completed within 5 months. The patients were enrolled by employees at special care clinic center (Ghotbeddin Center) for PKU patients. The participants were aged from 6 to 18 years old. Based on the number of enrolled patients, controls were included with consideration for matching by age and sex. All the participants were clearly informed concerning the process of conducting the oral health examinations.

The patients included in this study were patients diagnosed with PKU with an age range of 6–18. The included participants were under the prescribed nutritional regimen for PKU. Besides, the informed consent of at least one of the patient's guardians was considered mandatory for participation. The study included all the spectrum of the manifestations of PKU in terms of physiological or psychological severities except the ones who were unable to cooperate for oral and dental examination.

The patients with additional systemic disease that could affect the oral and dental health, including diabetes, cystic fibrosis, Down's syndrome, or consumption of medications, such as antibiotics, antifungals, and anti‐inflammatory medications in the last 3 months were excluded from the study. Also, the patients with history of recent trauma, oral surgery, or orthodontic treatment for the last 6 months were excluded from the study.

The diagnosis of the included patients was undertaken by a pediatric endocrinologist. The oral health assessment was performed by two professional dentists. Before the oral and dental examinations, the basic demographic data of the patients were recorded.

In order to assess the oral hygiene status of the patients, a questionnaire was designed addressing the demographic data, oral hygiene practices, recording the indices of oral health status, and sweet nutrition consumption of the studied populations. Oral hygiene practices and sweet nutrition consumption were assessed as potential behavioral factors known to influence dental caries and periodontal health. These variables were collected to aid the interpretation of oral health outcomes in relation to PKU rather than as independent predictors.

Concerning the oral hygiene practice, brushing frequency, brushing time, record of bleeding while brushing, parent's supervision while brushing, and the reason for dental check‐ups were evaluated. Furthermore, serum Phe was also recorded for each patient for the last 6 months.

Regarding the indices for oral health status, ICDAS, GI, and BPE were recorded. To assess the ICDAS score, the examiner asked the patient to brush before the examination. Then, visual examination was performed with a disposable mirror, explorer, and headlight (Table S1). Besides, GI and BPE were determined using the WHO periodontal probe and visual examination (Tables S2 and S3). To further assess the impact of PKU on dental and periodontal health status, the correlation of serum Phe with ICDAS, GI, and BPE scores was recorded.

Moreover, to evaluate nutritional status, the overall frequency and the most common type of the high‐carbohydrate food were recorded for each patient. For the studied children with poor oral hygiene at high risk of dental caries, fluoride varnish was applied as a prevention strategy.

2.1. Statistical Analysis

To assess statistical data, SPSS version 24 (IBM Corp., Armonk, NY, USA) was used. The statistical reporting style was adopted from the guidelines developed by Assel et al. [28]. Categorical data were summarized using frequency and percentage. Quantitative data were described using mean, standard deviation, or median with interquartile range. Categorical variables were compared between the two groups using Pearson's χ ² test. However, quantitative variables were compared between the groups using the Mann–Whitney U test. Also, the effect size was reported as well as the p value. The correlation analysis was conducted with Spearman's ρ test. p < 0.05 was considered statistically significant.

3. Results

This study included 136 participants with 68 children and adolescents with PKU and 68 age and sex‐matched healthy controls. The age of the participants in the study group and the control group were 9.92 ± 0.58 and 10.31 ± 0.47, respectively (p > 0.05). The study results demonstrate significant differences in oral hygiene and dental health status between patients with PKU and healthy controls, as outlined in Tables 1 and 2.

Table 1.

Comparison of oral hygiene practices and dietary habits between PKU patients and healthy controls.

Variable		Group		p a
		PKU	Control
Brushing frequency	< Once daily	37 (54.4%)	18 (26.5%)	< 0.001*
	Once daily	26 (38.2%)	26 (38.2%)
	> Once daily	5 (7.4%)	24 (35.3%)
Minimum brushing time	≤ 1 min	36 (52.9%)	23 (35.4%)	0.042*
	≥ 2 min	32 (47.1%)	42 (64.6%)
Bleeding in brushing	+	9 (13.2%)	14 (23.0%)	0.150
	−	59 (86.8%)	47 (77%)
Parents' supervision while brushing	+	25 (80.6%)	21 (61.8%)	0.095
	−	6 (19.4%)	13 (38.2%)
Dental examination	Plans on check‐ups	19 (27.9%)	19 (28.8%)	< 0.001*
	When painful	12 (17.6%)	36 (54.5%)
	Never	37 (54.4%)	11 (16.7%)
Sweet nutrition consumption	< Once daily	40 (60.6%)	27 (40.3%)	0.019*
	≥ Once daily	26 (39.4%)	40 (59.7%)

^a Pearson's χ ² test.

^*Statistically significant.

Table 2.

Comparative analysis of dental and periodontal health indicators (ICDAS, GI, BPE) between PKU patients and healthy controls.

Variable	Median (IQR)		p a	ES (category)
	Group
	PKU	Control
ICDAS	1.50 (2.58)	1.00 (2.25)	0.045*	0.08 (small)
GI	2.00 (1.00)	1.00 (1.00)	0.487	0.07 (small)
BPE	2.00 (0.58)	1.00 (0.98)	< 0.001*	0.53 (large)

Abbreviations: IQR, interquartile range; ES, effect size = |z|/√N.

^a Mann–Whitney U test.

^*Statistically significant.

3.1. Oral Hygiene Practices

Brushing frequency varied significantly between the groups (p < 0.001). A larger proportion of children and adolescents with PKU brushed less than once daily (54.4%, 37 individuals) compared to controls (26.5%, 18 individuals) (p < 0.001). Conversely, a higher percentage of controls brushed more than once daily (35.3%, 24 individuals) compared to PKU patients (7.4%, 5 individuals). Regarding brushing duration, children and adolescents with PKU were more likely to brush for 1 min or less (52.9%, 36 individuals) compared to controls (35.4%, 23 individuals) (p = 0.042). No significant differences were observed in bleeding during brushing (p > 0.05) or parental supervision while brushing (p > 0.05). The details are represented in Table 1.

Different trends in referring to the dentist were observed between the two groups. The majority of the control group referred to the dentist when pain was the chief complaint (54.5%, 36 individuals). Whereas most of the PKU patients have never gone to the dentist (54.4%, 37 individuals) (p < 0.001).

3.2. Dental Health Assessments

Significant differences were found in the ICDAS scores, with children and adolescents with PKU showing higher values (median = 1.50) compared to controls (median = 1.00) (p = 0.045). However, we did not see significant differences in GI scores between the groups (p = 0.487). Whereas BPE scores were significantly higher among children and adolescents with PKU (median = 2.00) compared to controls (median = 1.00) (p < 0.001) which indicates poorer periodontal health in the PKU group. The details are illustrated in Table 2.

3.3. Dietary Habits (Sweet Nutrition Consumption)

Sweet nutrition consumption was notably different between groups. Children and adolescents with PKU consume sweet nutrition less frequently than the controls (60.6% vs. 40.3% consuming sweets less than once daily; p = 0.019). The interview with the patients' guardians indicated that their awareness concerning the impact of sweet nutrition on dental caries was high enough to control their diet and the frequency of sweet consumption in these patients.

Moreover, the frequency of different common types of snacks or sweet nutrition was assessed between the two groups. The overall sweet nutrition consumption was less in these patients. However, we intended to find the patients' preferences for the type of sweet nutrition they are more likely to use. Concerning the tendencies to use biscuits, cake, chocolate, chips, and pastil we were unable to demonstrate a significant difference between the two groups (p > 0.05). However, the tendency toward ice cream (p = 0.032) and nuts (p < 0.001) was less in children and adolescents with PKU.

Worth mentioning, most of the nutritional products produced for the PKU patients were shown to be based on starch. The starch‐based products customized for the children and adolescents with PKU in the studied center are also phenylalanine free.

3.4. Correlation of Oral Indices With Serum Phe

The results of the Spearman's ρ correlation analysis of serum Phe with ICDAS, GI, and BPE scores indicated no significant correlation with either of the indices (p > 0.05). The last record of serum Phe and the Phe average in the last 6 months among patients were 12.85 ± 5.52 mg/dL and 13.43 ± 5.91 mg/dL.

4. Discussion

This study highlights significant disparities in oral hygiene practices, oral health status, and dietary habits between patients with PKU and healthy controls. PKU patients displayed notably poorer oral hygiene practices, lower dental check‐up frequencies, and a higher risk of dental caries and periodontal indices. These results point to a critical need for targeted dental care interventions in this population. These findings align partially with previous studies [11, 13, 29], while also revealing unique insights into the oral health challenges faced by PKU patients. The patients included in this study were diagnosed with PKU through neonatal screening. All patients underwent treatment and adhered to dietary restrictions. The severity of neurological and psychological symptoms varied among them.

The significantly lower brushing frequency and shorter brushing duration among children and adolescents with PKU compared to the control group in our study (54.4% and 52.9% brushing less than once daily and brushing ≤ 1 min, respectively) are in line with findings by Abola et al. [13], who reported that only 60% of PKU patients brushed twice daily compared to 95.6% of controls. Similarly, Bingol et al. [11] highlighted that PKU patients exhibited higher Plaque Control Record scores, indicating more plaque accumulation due to inadequate oral hygiene. This highlights a consistent trend across studies of inadequate oral hygiene practices being prevalent among PKU populations. The suboptimal oral hygiene practice among these patients can be ascribed to the possible ignorance of the patient and guardians due to major medical issues in accompanied with PKU.

Concerning the insignificant difference between the groups in bleeding during brushing, given that 54.4% of children and adolescents with PKU do not brush their teeth once daily, the lack of significant findings regarding bleeding during brushing may not provide a reliable basis for assessing their overall periodontal health status.

While our study observed higher ICDAS and BPE scores in PKU patients, indicating worse caries and periodontal health, other studies have reported varying findings. In this regard, Abola et al. [29] have demonstrated higher median number of carious teeth and lower median number of filled teeth in PKU patients compared to the healthy individuals. On the other hand, Kilpatrick and colleagues found no significant differences in caries prevalence between PKU patients and controls, attributing this to the potential protective effect of Phe in limiting plaque formation [10]. Similarly, Ghasemi et al. [12] showed no significant difference in the DMFT index between groups but noted significant correlations between high salivary phenylalanine levels and increased caries risk.

It is speculated that highphenylalanine concentration of saliva could exert an antibacterial and anticaries impact in patients with PKU [12, 13, 30]. Among the studies reporting enhanced rate of dental caries among the patients with PKU, low salivary flow rate is also reported [13]. Worth mentioning, despite the significant correlation of DMFT levels with salivary Phe [12], serum Phe did not indicate any correlation with the risk of dental caries. Given the significant correlation between salivary phenylalanine levels with increased caries risk demonstrated by Ghasemi et al. [12], as well as potential cognitive and dexterity challenges among PKU patients, the variations in results may be attributed to these factors, which can differ across studied populations.

Regarding periodontal health, Abola et al. [13] and Bingol et al. [11] both reported significantly worse periodontal indices among PKU patients, including higher Community Periodontal Index of Treatment Needs scores, periodontal screening and recording index, and calculus removal necessity. This is in line with our findings of poorer BPE scores in the PKU group, suggesting consistent periodontal challenges across studies. Moreover, Bingol et al. [11] have indicated PKU patients and their siblings exhibit higher risk of dental caries and periodontal diseases compared to the healthy individuals. This can indicate that both the PKU disease and the lifestyle can possibly be the contributor factors in this regard.

The connection between the periodontal disease and PKU can be explained by the alterations in the microbiological population in the oral cavity. Evidence suggests microbiological changes in PKU patients affect oral health. Abola et al. [29] reported higher levels of Actinomyces, Porphyromonas (linked to periodontal diseases), and Prevotella nanceiensis (linked to tooth loss), along with reduced Lactobacillus levels. These alterations, likely influenced by diet, may increase oral health risks warranting further exploration.

Dietary habits play a critical role in oral health outcomes among PKU patients. Our study noted less frequent sweet consumption among PKU patients (60.6% consuming sweets less than once daily). However, Kilpatrick et al. [10] emphasized on the potential cariogenic and erosive nature of PKU‐specific amino acid supplements, particularly flavored varieties with low pH and high titratable acidity. Bingol et al. [11] also identified increased enamel defects in PKU patients, which they associated with high carbohydrate intake and potential nutritional imbalances.

These findings collectively indicate that while PKU patients may consume fewer direct cariogenic foods, their specialized diets and supplements may still pose risks for dental erosion and caries which should be further investigated. Besides, it can be concluded that the care center has been successful in advising the consumption of low‐carbohydrate diet for PKU patients.

Regarding the modified diet of the studied population, it was found that the patients received phenylalanine‐free dairy products. Despite the controlled sweet nutrition consumption, this factor should also be considered in assessing the impact of diet quality on dental caries in children and adolescents with PKU.

Our findings suggest while children and adolescents with PKU exhibit some favorable dietary habits in terms of frequency of sweet nutrition consumption, their oral hygiene practices and periodontal health are significantly poorer compared to their healthy counterparts.

Concerning the possible association of Phe with the oral health status, this study found no significant association between serum Phe levels and ICDAS, GI, or BPE scores, suggesting serum Phe may not directly impact oral health severity. However, Ghasemi et al. [12] reported salivary Phe, linked to serum Phe, is associated with dental caries risk in PKU patients. Therefore, it is possible that assessing salivary Phe instead of serum Phe may have a correlation with the studied oral health indices.

Several limitations inherent to the study design should be acknowledged. First, the case‐control nature of the study precludes causal inference regarding the relationship between PKU and oral health outcomes. Although due to the aim and scope of the study, oral hygiene practices and dietary habits were not systematically assessed. Besides, due to the distribution of variables, multivariable analytical models could not be incorporated to assess possible confounding factors. Nevertheless, their descriptive evaluation provided important clinical context, as poorer oral hygiene practices and higher caries and periodontal indices were observed among children and adolescents with PKU despite lower reported sweet consumption. This finding suggests that factors beyond simple sugar exposure, such as oral hygiene behavior, treatment burden, and disease‐related challenges, may contribute to oral disease susceptibility. Second, a detailed quantitative assessment of PKU‐specific dietary supplements was not performed. Although such products may influence dental caries and erosion risk, they were uniformly prescribed and phenylalanine‐free at the study center, resulting in limited interindividual variability and restricting comparative dietary analyses. This may affect the generalizability of the dietary findings to PKU populations managed under different nutritional protocols. Finally, reliance on caregiver‐reported oral hygiene and dietary behaviors may introduce reporting bias. Future longitudinal studies incorporating comprehensive dietary analyses, salivary biomarkers, and multivariable modeling are warranted to clarify causal pathways and to evaluate the effectiveness of tailored preventive and oral health education programs for individuals with PKU.

5. Conclusion

This study highlights significant disparities in oral health status between patients with PKU and healthy individuals. Despite consuming fewer sweets, PKU patients demonstrated poorer oral hygiene practices, including less frequent brushing and shorter brushing durations, contributing to higher rates of dental caries and periodontal disease. Elevated ICDAS and BPE scores among PKU patients underscore the need for enhanced oral care interventions in this population.

Reduced time of brushing and less frequency of daily brushing among children and adolescents with PKU can be attributed to patients' guardians being overly occupied by the patients' basic medical needs and controlling the PKU disease severity leaving insufficient time and motive for monitoring oral health status. Therefore, regular dental check‐ups, preventive care, and education tailored to PKU patients and their parents are essential to mitigate these risks and improve overall oral health outcomes. Future research should focus on longitudinal studies to establish causative relationships and develop comprehensive oral health care strategies for PKU patients.

Author Contributions

Homa Ilkhanipoor: conceptualization, methodology, validation, supervision, project administration, writing – original draft, writing – review and editing. Mahtab Memarpour: conceptualization, methodology, validation, supervision, project administration, finding acquisition, writing – original draft, writing – review and editing. Narges Ghorbani: investigation, data curation, writing – original draft, writing – review and editing. Mohammad Amin Amiri: investigation, data curation, writing – original draft, writing – review and editing. Azade Rafiee: supervision, project administration, writing – original draft, writing – review and editing. Mehrdad Vossoughi: formal analysis, software, validation, writing – original draft, writing – review and editing. All authors have read and approved the final version of the manuscript. Mahtab Memarpour had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.

Disclosure

The lead author Mahtab Memarpour affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Ethics Statement

This case‐control study was approved by the Human Ethics Committee, Shiraz University of Medical Sciences (IR.SUMS.DENTAL.REC.1402.078).

Consent

Informed consent of at least one of the patient's guardians was considered mandatory for participation.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Supporting File: hsr271983‐sup‐0001‐Supplementary_file.docx.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.