State of art: a narrative review on navigating pathogenesis and therapies for genetic oral disorders

Introduction

The oral cavity plays a vital role in everyday functions such as speech, swallowing, and breathing, and abnormalities in the structures involved can significantly impact these essential activities. This includes conditions such as cleft lip and palate and tongue and pharynx abnormalities, which have a genetic basis beyond tooth development and periodontal health. Patients with genetic disorders, whether common or rare, and with or without other birth defects, require special care from healthcare providers (1). Understanding the genetic factors contributing to these conditions is crucial to improving diagnosis, treatment, and prevention strategies. It is important to note that oral genetic conditions can significantly impact physical health and mental development, and in infants, they can even be life threatening. The oral cavity structures of the lip/palate, tongue, and pharynx develop in a remarkable way during embryonic development. The lip/palate form by merging multiple structures, while the tongue and pharynx arise from the arches and pouches. The proper fusion of these structures is vital for their normal function. The lip/palate are crucial for feeding and communication, whereas the tongue is indispensable for taste, speech, and swallowing. The pharynx acts as a channel for food and air to pass through. Understanding the development of these structures is critical for identifying and treating genetic disorders that affect the oral cavity. Consuming food is one of the most basic activities in an organism’s life, and a normal swallowing function in humans is required for nutritional function. While the swallowing function in humans progresses through several phases beginning at birth, this process occurs rather effortlessly and naturally in infants with regular growth (2). Dysphagia, a clinical synonym for swallowing difficulty, is a significant symptom, particularly in neurodegenerative or developmental conditions. Instead of being considered a standalone disease, dysphagia is recognized as a serious symptom that can negatively affect a person’s quality of life (3). The swallowing system is intricate, consisting of many different anatomical structures; these structures include striated muscles, intraoral structures, peripheral nerves, and various components of the central nervous system (4). Understanding the proper development and function of these structures is critical for identifying and treating dysphagia and other genetic disorders that affect the oral cavity and swallowing function. This knowledge is fundamental for the survival of an organism, as consuming food is a necessary process for life. Thus, continued research in this field is vital to improving our understanding and management of dysphagia and associated disorders. The factors linked to this illness are listed below; however, they do not conclusively lead to its occurrence.

• Family history and genetics: having a family member with geographic tongue (GT) raises the likelihood of developing the condition (5).
• Allergies and inflammatory conditions such as asthma, eczema, and psoriasis GT is more prevalent in individuals with these conditions (5).
• Fissured tongue: GT often coexists with fissured tongue, characterized by grooves on the tongue’s surface (6).
• Emotional stress: stress can trigger or worsen GT in some individuals (5).
• Nutrient deficiencies and hormonal fluctuations: inadequate levels of essential vitamins and minerals like vitamin B and zinc may be connected to GT, changes in hormones, particularly in women, might contribute to the onset of GT (6).
• Specific medical conditions: people with type 1 diabetes, down syndrome, and reactive arthritis are more likely to experience GT (5).

This research aims to shed light on the genetic causes and symptoms linked to specific genetic disorders impacting the lip/palate, tongue, and pharynx (refer to Table 1). This review was constructed by examining, analyzing, and deliberating on existing literature. Information was gathered without constraints on time or language, encompassing articles concerning the causes and genetic factors. Additionally, we investigate the diagnostic methods and treatment options accessible for these disorders. We present this article in accordance with the Narrative Review reporting checklist (available at https://fomm.amegroups.com/article/view/10.21037/fomm-24-13/rc).

Methods

In this narrative review, we employed a comprehensive and structured approach to literature search and analysis to explore the complex interplay of genetic factors in oral health and the therapeutic strategies for genetic oral disorders. The literature search spanned studies published from 1934 to 2023, using PubMed and Google Scholar as primary data sources. Search terms included specific genetic conditions such as “Genetic Oral Disorders”, “Cleft Lip”, “Cleft Palate”, “Ankyloglossia”, “Geographic Tongue”, and “Oculopharyngeal Muscular Dystrophy”. Studies that were not written in English were excluded from consideration to maintain consistency in data interpretation.

The selection process was meticulously conducted by a team consisting of Abdullah Ayad, Y.H., N.A.R.M., and J.M. Each member reviewed the literature independently to ensure a comprehensive capture of relevant studies. The selection was based on a consensus method, where discrepancies were discussed and resolved through collaborative review sessions. This approach ensured a balanced representation of the available evidence and minimized bias.

To provide clarity and a detailed understanding of our search methodology, two tables were created (Tables 2,3) to illustrate a more detailed search strategy using PubMed as an example. Table 3 highlights the use of both MeSH terms and free text to optimize the retrieval of pertinent articles. Our review adheres to rigorous standards to synthesize existing knowledge on the genetic underpinnings of oral health conditions and their management, setting the stage for future research directions.

Cleft lip and cleft palate (CL/P)

History

A cleft lip is a condition that occurs when the frontonasal and maxillary processes do not fuse properly during fetal development. This results in a separation or gap in the lip, alveolus (the bony ridge that contains the teeth), and nasal floor. The severity of the cleft can vary depending on the extent of the separation. A complete cleft lip has a complete separation of the lip and nasal sill, whereas an incomplete cleft lip has an opening that does not extend into the nose (Figure 1) (7). Certainly! When the tissues responsible for the formation of the upper mouth fail to fully merge during prenatal development, a condition known as a cleft palate arises. In certain instances, infants may present with an opening extending across both the front and back portions of the palate, while in other cases, the palate may exhibit only a partial opening (8). Orofacial clefts are the most common head and neck congenital malformation, encompassing a variety of congenital deformities. A diverse range of disorders impacting the lips and oral cavity is encompassed by clefts of the lip and palate. These conditions are commonly categorized into two groups: isolated cleft palate and cleft lip, whether with or without accompanying cleft palate. Orofacial clefting occurs in approximately 220,000 new cases annually, with wide variations across geographic regions, ethnic groups, and the type of cleft itself. The overall incidence is estimated to be 1.5 per one thousand live births (7). Across all ethnic groups, males are more likely to have a cleft lip with or without a cleft palate than females. The sex ratio varies according to the severity of the cleft (9), the presence of additional malformations, the number of affected siblings in a family, ethnicity, and perhaps paternal age (10), as well as other factors. The male-to-female sex ratio for cleft lip with or without cleft palate in white populations is roughly 2:1 (9). The first documented case of cleft lip surgery was performed in China in 390 BC on an 18-year-old individual named Wey Young-Chi (11). There are 154 known syndromes that are associated with cleft lip and palate (12). Numerous proposals have emerged regarding the classification of diverse cleft lip and cleft palate deformities. A detailed examination reveals Veau’s categorization into four groups: Group 1, encompassing clefts of the soft palate; Group 2, involving clefts of the hard palate; Group 3, covering complete unilateral clefts of the lip, alveolus, and palate; and Group 4, comprising bilateral clefts of the lip, alveolus, and palate. It is noteworthy that Veau did not assign a specific category for isolated lip clefts (13).

Figure 1 The figure shows a deficiency inside the mouth, affecting both the soft and hard palates, and extending to the alveolar process on the left side of the premaxillary region. Reuse with permission. Goswami M, Jangra B, Bhushan U. Management of feeding problem in a patient with cleft lip/palate. International Journal of Clinical Pediatric Dentistry 2016;9:143. https://doi.org/10.5005%2Fjp-journals-10005-1351.

Genetic causes

The etiology is polygenic and multifactorial, with multiple genetic and environmental factors involved (7). Numerous genetic techniques have been employed to pinpoint the genes and loci responsible for CL/P. Various genes and loci linked to CL/P have been identified, including IRF6, MSX1, TGFA, BMP4, PAX7, RUNX2, SUMO1, VAX1, FOXE1, CRISPLD2, MTHFR, WNT9B, MYH9, TGFB3, SPRY2, PDGFC, FGFR2, NOG, ARHGAP29, CDH1, THADA, GSTM1, JAG2, KIF7, NAT2, PAX3, PHF8, RARA, MMP3, TIMP2 (14), and many other genes that are associated with CL/P.

Given the complex genetic nature of CL/P, genetic counseling is essential for affected individuals and their families. It provides crucial information on the likelihood of recurrence in future pregnancies, helps distinguish between syndromic and nonsyndromic cases, and explains the implications of various genetic findings. Through understanding inheritance patterns and associated risk factors, families can make informed decisions about family planning and access early interventions when needed. By offering support and education, genetic counseling helps families navigate the emotional and practical challenges of cleft conditions, ultimately improving the overall management and outcomes for patients (15).

Symptoms

Clefts are classified into two types: syndromic and nonsyndromic (7). Cleft palate only (CPO) is more likely to be associated with a syndrome or genetic defect than a cleft lip or cleft lip and palate. However, most instances of cleft lip and palate occur independently without other congenital anomalies. However, certain syndromes, such as Van der Woude syndrome, Stickler syndrome, and velocardiofacial syndrome, are commonly associated with cleft palate. Stickler and Van der Woude syndromes are both inherited as autosomal dominant disorders. Individuals with Stickler syndrome often exhibit features like cleft palate, a petite jaw, and collagen-related issues. On the other hand, children with Van der Woude syndrome commonly present with lower lip pits, cleft lips, and genitourinary anomalies. Van der Woude syndrome is the most commonly associated with cleft lip and palate (16,17). Velocardiofacial syndrome is a genetic disorder frequently associated with the occurrence of a cleft palate. While manifestations may vary among affected individuals, many exhibit congenital heart disease, speech difficulties, and immune-related issues (18). Newborns with CPO may encounter challenges in feeding and are prone to experiencing speech issues during childhood. Additionally, they may contend with recurring otitis media and various dental issues, including natal and neonatal teeth, microdontia, taurodontism, ectopic eruption, enamel hypoplasia, and delayed tooth maturation. Children affected by any cleft anomalies often grapple with societal biases, leading to potential impacts on self-esteem (8,16). A study found that infants with CL/P have an elevated risk of sleep-disordered breathing (SDB) symptoms and obstructive respiratory events prior to palate surgery (19).

Diagnosis and treatment

To achieve functional and aesthetic well-being, patients with orofacial cleft deformities must be treated at the appropriate time and age. Coordination of care from a variety of specialties is required for the successful management of a child born with a cleft lip and palate. including otolaryngology, speech-language pathology, genetics and dysmorphology, oral and maxillofacial surgery, orthodontics, prosthodontics, and others.

This surgical intervention aims to achieve a facial appearance that does not draw undue attention, a vocal apparatus conducive to clear speech, and a set of teeth that is both functional and aesthetically pleasing (20). The position of the cleft alveolar segments has been improved through a variety of documented methods over the years. Hoffman explained the use of a head cap with arms extended to the face to retract the premaxilla and narrow the cleft in 1686 (21). This technique of using the head as an extraoral anchorage has been greatly improved (22), and it is now used to retract the premaxilla (23). To generate an orthopedic effect, many techniques or approaches are suggested, including alveolar molding, lip straps, nasoalveolar molding (NAM), and lip adhesion. The operator’s preference and the kind of cleft that needs to be corrected typically dictate which technique is used. Prior to surgical repair, alveolar molding, which is a key component of presurgical cleft lip and palate orthopedics (PSO) treatment, is used to actively move the maxillary fragments with passive or active alveolar plates. Molding the infant’s perioral structures with a CLP is a clinical technique that has been used since before the 1950s (24). In the realm of surgical treatment strategies for lip cleft correction, the foundational principle involves addressing the margins of the non-tensioned wound. The labial cleft is then closed using a variety of methods, including local flaps, to achieve the desired outcome (7). Cheiloplasty and palatoplasty are two surgical procedures for the treatment of cleft lip and cleft palate, respectively. The clefts can be displayed in a variety of ways. As a result, surgical planning must be tailored to each patient. Surgery for lip cleft, be it unilateral or bilateral, is recommended to commence by the 10^th week of life, adhering to the “rule of 10”, which considers factors such as hemoglobin levels (10 mg/dL), the age of the infant (10 weeks), and weight (approximately 10 pounds or 4.5–5 kg) (25,26). One of the techniques most frequently employed today is Millard’s, which has the major benefit of allowing the natural contours of the lip and nose to be positioned when tissue advancements are performed (19). Palatoplasty, a surgical intervention integral to the primary correction of clefts affecting the hard and/or soft palate, is aimed at the comprehensive reconstruction of this anatomical structure, addressing aspects of functionality and aesthetics. Typically, cleft palate surgery is performed between 9 and 12 months after birth. Currently, a significant challenge lies in achieving an intervention that mitigates alterations in speech while simultaneously preserving optimal maxillofacial development (27).

Ankyloglossia

History

Ankyloglossia, commonly referred to as tongue-tie, is a congenital abnormality characterized by the presence of a short and/or thick lingual frenulum, which limits the movement of the tongue in a child from birth (Figure 2) (28). The term “ankyloglossia” is derived from the Greek words “agkilos” (curved) and “glossa” (tongue). Ankyloglossia was first used in medical literature in the 1960s when Wallace defined tongue-tie as “a condition in which the tip of the tongue cannot be protruded beyond the lower incisor teeth due to a short frenulum lingua, often containing scar tissue” (29). This condition impacts the process of latch and sucking during breastfeeding in infancy. Subsequently, throughout childhood and into adulthood, it often leads to challenges in children’s psychological well-being and cognitive behavior. Ankyloglossia poses difficulties in pronouncing specific sounds, contributing to speech impediments and hindering overall development (28). A study revealed that ankyloglossia can be inherited in an autosomal dominant or recessive mode of inheritance (29). There are two types of tongue tie, anterior ankyloglossia as a prominent lingual frenulum and restricted tongue protrusion with tongue tip tethering, and posterior ankyloglossia the lingual frenulum is typically excessively short, thick, or fibrous cord-like, and the base of the tongue’s back is where it is attached. Tongue ties are generally agreed to affect 3–4% of infants, although some sources indicate a higher prevalence of 10.7%. It is also commonly stated that males are more frequently affected than females, with ratios ranging from 1.5:1 to 2.6:1 (30,31). certain research reported that ankyloglossia affects males more than females, but a reasonably recent study shows the posterior type of tongue tie can be more difficult to diagnose because the frenulum is not as visible as in the anterior tongue tie. Consequently, confirm males are more likely to have anterior ankyloglossia, while females are more likely to have posterior ankyloglossia (31). Kotlow categorized ankyloglossia into four classes, considering the tongue’s lifting ability (with the typical range of free tongue being greater than 16 mm): class IV signifies complete ankyloglossia (less than 3 mm); class III indicates severe ankyloglossia (3–7 mm); class II denotes moderate ankyloglossia (8–10 mm); and class I represents mild ankyloglossia (12–16 mm) (29). When a baby had difficulty breastfeeding as far back as the 16^th century, the prime suspect was tongue-tie (ankyloglossia). Midwives kept a long and sharp fingernail on hand to perform a rudimentary procedure to slice the tissue anchoring the tongue to the bottom of the infant’s mouth and restricting movement (32). Tongue-tie typically manifests as an isolated anomaly; however, it may also serve as a clinical feature in specific syndromes, such as X-linked Van Der Woude syndrome or cleft palate, Opitz syndrome, and orodigitofacial syndrome, and very rarely may be associated with Pierre-Robin syndrome (29,33).

Figure 2 Depictions of ankyloglossia (tongue-tie) in children, showing the restricted movement of the tongue caused by a tight lingual frenulum. Reuse with permission. (I) Becker S, Brizuela M, Mendez MD. Ankyloglossia (Tongue-Tie). StatPearls - NCBI Bookshelf. 2023, June 9. https://www.ncbi.nlm.nih.gov/books/NBK482295/. (II) Hall DMB. Tongue tie. Archives of Disease in Childhood 2005;90:1211-5. https://doi.org/10.1136/adc.2005.077065.

Genetic causes

Ankyloglossia has been linked to several genes. One of these genes is TBX22, known as “T-box transcription factor 22”, situated on human chromosome Xq21.1. Mutations in this gene have been identified as the cause of non-syndromic ankyloglossia, which may lead to X-linked cleft palate and ankyloglossia. Another gene associated with this condition is LGR5, “leucine rich repeat containing G protein-coupled receptor 5”, located on human chromosome 12q21.1. In mouse studies, the LGR5 gene has been linked to lethality (29,34). Additionally, various investigations have unveiled an association between ankyloglossia and the methylenetetrahydrofolate reductase (MTHFR) genetic mutation. Furthermore, tongue ties have frequently been observed alongside lip ties, cheek ties, and other midline defects (29).

Symptoms

The severity of tongue-tie symptoms can vary. The tongue may exhibit a notch or a heart-shaped appearance. In newborns, this condition can result in challenges during breastfeeding, including issues with latching, prolonged feeding sessions, persistent hunger, difficulty in weight gain, and the occurrence of a clicking sound during feeding. Breastfeeding may additionally give rise to symptoms like cracked and sore nipples, discomfort during nursing, and inadequate milk production (35,36). Children in their early years who have tongue-tie may encounter difficulties in articulating speech that is not easily comprehensible and difficulties with sounds that necessitate a child’s tongue touching the upper front teeth. In addition to swallowing, licking, and blowing difficulties. Additional indications involve challenges in moving the tongue towards the roof of the mouth, sideways, or protruding it upward (35). In adults, tongue-tie can cause mouth breathing, difficulty speaking clearly, jaw pain, and tongue thrust (35). A short frenulum can also play a role in the development of abnormalities, an open bite, periodontal diseases, and shortness of breath due to epiglottis displacement forward. A short lingual frenulum can make it difficult to lift the tongue. This leads to the constriction of the upper jaw as transverse growth is hindered. An enlarged and shortened lingual frenulum can also contribute to the development of a gap between the central incisors of the lower jaw. In later stages of life, the stability of a removable prosthesis diminishes due to the firmly attached frenulum of the tongue on an edentulous jaw (37).

Diagnosis and treatment

Diagnosis of ankyloglossia involves subjective clinical inspections, and its identification in infants may prove challenging, as the condition is not always visually apparent. The Hazelbaker Assessment Tool for Lingual Frenulum Function (HATLFF) serves as a valuable screening tool specifically designed to assess the severity of tongue ties in newborns, as recommended by the Academy of Breastfeeding Medicine. In older children and adults, diagnosis is commonly based on clinical evaluations conducted by pediatricians, lactation consultants, and dentists, considering a combination of observation, physical examination, and assessment of functional difficulties like feeding problems or speech impairments. This process may rely on evaluating the range of motion permitted by the genioglossus muscles to confirm the presence of ankyloglossia. Furthermore, diagnosis in some instances seems to prioritize the assessment of functional limitations. To ensure effective management and therapy in clinical practice, a comprehensive understanding of the diagnostic procedures and age-specific considerations for ankyloglossia is essential (38,39). Management of this condition can take two distinct routes: non-surgical approaches, which encompass speech therapy and lactation interventions, and a period of observation to assess the need for intervention (40), such as myofunctional therapy, which is a physical therapy that is exclusive to the face and oral structures. It involves exercises that train the orofacial muscles to work harmoniously together. It thereby promotes a proper bite, easy breathing, and correct facial posture. It offers both health benefits and aesthetic advantages (41). And surgical approaches such as a frenectomy, and tongue tie release surgery are surgical modalities. In a standard lingual frenotomy, the practitioner employs their fingers, a grooved tongue director, or a combination of both to clip or cut the lingual frenulum (42). A frenectomy can be carried out using a laser, scalpel, or surgical scissors. However, some experts argue that laser radiation excision of the lingual frenulum is particularly effective. Over the past few decades, laser surgery has gained extensive usage in dentistry for treating ankyloglossia in both adults and children. Laser surgery surpasses the effectiveness of traditional methods like scalpel or scissors in tongue frenectomy, offering numerous intraoperative and postoperative advantages. The concept of laser application in surgery is founded on photothermal interaction with biological tissues. Several studies have explored the successful application of dental lasers like CO₂, Er:YAG, Nd:YAG, and diode lasers in performing tongue frenectomy. Laser surgery offers multiple advantages compared to traditional methods, including enhanced precision, minimal intraoperative bleeding, shorter procedure times, elimination of the need for sutures, reduced postoperative pain and swelling, and minimized scarring. Additionally, laser radiation exhibits bactericidal properties, ensuring a sterile environment during the operation (37).

GT

History

GT is a benign and recurring condition whose underlying cause remains unknown. that affects the tongue and is characterized by loss of epithelium, particularly filiform papillae, which gives the tongue a distinctive appearance (Figure 3) (43). GT has been examined under various terms, including lingua geographica, Benign migratory glossitis, erythema migrans, exfoliatio areata linguae, superficial migratory glossitis, lingual dystrophy, pityriasis linguae, transitory benign plaques of the tongue, marginal exfoliative glossitis, and glossitis areata migrans (44). Rayer coined the term “geographic tongue” in 1831 (43). GT is estimated to affect approximately 1% to 2.5% of the general population (45). According to studies, children aged 4 and 5 years and adults under the age of 30 years have a higher incidence of GT. Prevalence is higher in women than in men, with a ratio of 1.5 to 1 (46,47). Redman et al. observed an increased occurrence of GT among individuals with mental health disorders. It has been documented by Ebrahimi et al. that management of stress can aid in the healing of GT lesions, demonstrating yet another link between stress and GT. Hume put forward a thorough clinical classification for GT in 1982, considering both the appearance of lesions and their specific anatomical locations. This classification system categorizes GT into four distinct types. Type 1 represents the classic form characterized by exclusive involvement of the tongue with circinate migratory lesions. Type 2 entails the presence of lingual lesions as seen in Type 1, along with additional lesions elsewhere in the oral cavity. Type 3 includes lingual lesions that lack distinct characteristics and may or may not be accompanied by other oral lesions. Within Type 3, there are two distinct variations: a fixed form characterized by non-migrating and recurrent lesions in the same location, and an abortive form where lesions initially appear as white patches and vanish before acquiring the typical appearance of GT. Finally, Type 4, also known as geographic stomatitis or migratory stomatitis, is characterized by lesions occurring exclusively outside the tongue without the presence of GT (48).

Figure 3 Showcases the categorization of GT based on its clinical appearance. Health professionals evaluated and selected nine GT cases for assessment. These cases are further divided into three groups: (A-C) representing mild GT category cases; (D-F) representing moderate GT category cases; and (G-I) representing severe GT category cases. Reuse with permission. Picciani BLS, Santos LR, Amin TN, et al. Applicability of the geographic tongue area and severity index among healthcare professionals: a cross-sectional clinical validation of a newly developed geographic tongue scoring system. Journal of Clinical Medicine 2021;10:5493. https://doi.org/10.3390/jcm10235493. GT, geographic tongue.

Interestingly, there is a strong association between GT and psoriasis, with about 10% of psoriasis patients exhibiting GT as the most common oral manifestation of the disease (49). This association suggests that GT may serve as an early indicator of psoriasis, possibly evolving into a fissured tongue variant. Histological and genetic similarities further support this link, with the HLA-Cw6 genetic marker found in a significant percentage of both psoriasis and GT patients, indicating a common genetic basis (45). Meta-analysis results show psoriasis patients are 3.53 times more likely to have a GT than non-psoriatic individuals, correlating with more severe psoriasis and poorer treatment response based on Psoriasis Area and Severity Index (PASI) scores (50). However, conflicting findings exist, as some studies suggest GT may not be a definitive oral manifestation of psoriasis, with a notable percentage of healthy individuals also exhibiting it. This raises the possibility that while some cases of GT indicate oral psoriasis, others may be unrelated.

Genetic causes

GT, a benign inflammatory disorder of the tongue, has recently been the subject of a genetic investigation to uncover its underlying causes. A study revealed that mutations in the IL36RN gene, responsible for encoding the interleukin-36 receptor antagonist (IL-36Ra) protein, are associated with the development of the GT. The IL-36Ra protein functions as a regulator of the immune system by inhibiting the activity of interleukin-36 (IL-36) cytokines. Disrupting the balance between IL-36Ra and IL-36γ proteins within the tongue tissue leads to an inflammatory response and visible changes in the tongue’s appearance. Additionally, the study proposed that GT could be considered a localized manifestation of generalized pustular psoriasis (GPP) or a distinct phenotype known as deficiency of IL-36 receptor antagonist (DITRA). These findings shed light on the genetic basis of GT and could potentially contribute to improving its diagnosis and treatment approaches (51).

Symptoms

The way that GT presents clinically varies. The asymptomatic condition of GT typically manifests on the lateral and dorsal regions of the tongue. It presents as erythematous migratory atrophic circinate patches, characterized by the loss of filiform papillae and distinct white circinate borders. The GT exhibits a map-like pattern, migrating during periods of remission and exacerbation, displaying highly variable sizes and shapes. The term “ectopic geographic tongue” is utilized when the lesions develop in areas other than the tongue (48), these extra-lingual lesions are rare, they may appear on various oral structures such as the lips, hard palate, uvula, labial and buccal mucosa, and oral floor (45,48). Lesions may be devoid of symptoms or may present with indications such as pain, burning sensations, discomfort, dysgeusia, sensitivity to hot, sour, and spicy foods, ear pain, or the presence of lymphadenopathy in the ipsilateral submandibular region (45,47). The majority of patients will not have any symptoms. According to Sigal et al., there have been two cases of environmental allergies in children who have shown symptoms such as oral discomfort, increased salivation, altered taste, and pain when eating and drinking (43).

Diagnosis and treatment

If it is the patient’s first visit or when the history is unclear, periodic follow-up is required to confirm the diagnosis. Assure the patient that the lesion is harmless and self-limiting (43). GT varies from other skin rashes in humans (52). Patients with GT commonly do not undergo treatment, as the condition is benign in nature and generally follows a primarily asymptomatic course (47). Since there is no definitive treatment for GT, current therapies focus on symptom relief. Although they have been included in suggested treatment plans (53). The clinical manifestation can vary from being without symptoms to presenting with painful and burning ulceration (43). Considering mouthwashes that contain local anesthetics, topical corticosteroids, or sucralfate might be an option for addressing symptoms such as discomfort and/or a burning sensation (48). There are case reports of people with symptomatic glossitis who responded well to topical tacrolimus treatment, even when it was administered to them over a brief period of time and to children (54). Oral cyclosporine, however, has been identified as the primary effective treatment in cases that are severe and persistent (48). Avoiding irritating substances that aggravate injuries, such as spicy and acidic foods, and practicing proper mouth hygiene using toothpaste devoid of colors and preservatives are advised. In cases of intense pain and discomfort, medications such as analgesics (e.g., acetaminophen), anti-inflammatory drugs, antihistamines like diphenhydramine hydrochloride, mouth rinse containing topical anesthetics like lidocaine gel, topical corticosteroids like betamethasone, cyclosporine, vitamin A therapy with tretinoin, zinc supplements, and vitamin K₂ supplements may be recommended. Notably, a complete resolution of the condition has been observed after a few weeks of supplementation (43).

Oculopharyngeal muscular dystrophy (OPMD)

History

OPMD is one of several rare genetic muscle disorders known as muscular dystrophy. These disorders are distinguished by the weakness and atrophy of various voluntary muscles throughout the body (55). OPMD is a genetic disorder inherited in an autosomal dominant pattern, this neuromuscular disorder is characterized by a slow and progressive onset. The disease is characterized by a range of symptoms, with progressive ptosis and dysphagia being the most common manifestations (Figure 4). Although OPMD is typically inherited in an autosomal dominant manner, there have been documented cases of autosomal recessive inheritance. However, such instances are exceedingly rare (56). onset in adulthood, most commonly between the ages of 40 and 60 years (57). OPMD had a higher impact on men than on women (58). The term “oculopharyngeal” refers to the eyes (oculo-) and a section of the throat called the pharynx (pharyngeal) (59). Taylor first identified OPMD in four members of a French-Canadian family in 1915. Taylor’s clinical report was largely ignored until the classic description by Victor et al. was published in 1962 (60,61).

Figure 4 A photograph of an elderly woman who is showing typical clinical features of OPMD. The woman has forehead wrinkling, which is a common symptom of OPMD. The absence of forehead wrinkling suggests the diagnosis of a different type of muscular dystrophy called oculopharyngodistal muscular dystrophy. The woman also appears cachectic, which means she has a severe loss of body weight and muscle mass, and her neck muscles appear atrophied, which is typical of advanced cases of OPMD. Reuse with permission. Brais B. Oculopharyngeal muscular dystrophy. Handbook of Clinical Neurology 2011;101:181-192. https://doi.org/10.1016/B978-0-08-045031-5.00014-1. OPMD, oculopharyngeal muscular dystrophy.

Genetic causes

OPMD is a result of mutations in the poly(adenylate)-binding protein nuclear1 (PABPN1) gene by a short expansion of the (GCN trinucleotide) in the PABPN1 gene localized on chromosome 14q11.2. The size of the expansion has been linked to the onset and severity of the disease (62,63). In addition to that, heterozygous frameshift variants in HNRNPA2B1 have been identified as causative factors in early-onset OPMD (64).

Symptoms

The main symptom is ptosis caused by levator palpebrae weakness. ptosis is always bilateral but can be asymmetrical, other extraocular muscles may become involved gradually (65). accompanied by ocular motor dysfunction (56). Dysphagia is caused by weakness of the throat muscles, which causes difficulty swallowing solid foods. Fluids may also become difficult to swallow later. The vast majority of patients have atrophy and weakness of the tongue (66), also include complications of choking, regurgitation, and deterioration of respiratory function such as aspiration and pneumonia (56,62). The leading causes of death in OPMD patients are aspiration pneumonia, malnutrition, or even starvation (66). The majority of patients were unable to perform daily activities, participate in social activities, or walk because of proximal limb weakness (56). Hyporeflexia or areflexia, pes cavus, fasciculations of the limbs or tongue muscles, amyotrophy distally in the limbs, and distal hypesthesia in the lower or upper limbs, frequently with poor vibration perception, are clinical characteristics that are consistent with denervation in OPMD (56).

Diagnosis and treatment

At present, there is no known cure for OPMD. Patients undergo surgical procedures to temporarily relieve symptoms, but recent clinical trials with myoblast transplantation and small molecule drug therapies have shown promise (67,68). Symptomatic relief through medical intervention is the primary approach; however, surgical techniques come into play for individuals with moderate to severe symptoms, aiming to enhance swallowing and address ptosis (66,69). One such surgical procedure is cricopharyngeal myotomy, performed to alleviate dysphagia symptoms (66,70). Additionally, surgeons employed two primary surgical techniques (the resection of the levator palpebrae aponeurosis, and frontal suspension of the eyelids) to correct ptosis (70), notwithstanding the implementation of myotomy as a remedial measure for dysphagia, it has been observed that the aforementioned ailment tends to recur gradually in a substantial proportion of patients, primarily due to the inadequacy of the aforementioned intervention in halting the progressive degradation of the pharyngeal musculature. Due to the disease’s late onset, many patients are either medically unsuitable for surgery or are unwilling to accept the risk involved (68). An alternative avenue demonstrating potential is gene therapy, an emerging strategy in the realm of muscular dystrophy, supported by both in vivo experiments and clinical trials. The pathological characteristics of the disease, such as muscle function loss and degeneration, are linked to soluble PABPN1 levels. In the gene therapy approach for OPMD, the strategy involves introducing a functional PABPN1 into the affected muscles to replenish the diminished soluble protein. However, for a comprehensive therapeutic effect, a successful gene-replacement strategy necessitates an approach that dismantles aggregates (71).

Discussion

Delving into the complexities of genetic influences on oral health, our investigation unravels a compelling exploration into the intricate relationship between genetic factors and oral health, as well as the diverse therapeutic interventions available for managing oral cavity disorders. A notable strength of this research lies in its comprehensive examination of various genetic variants influencing oral health, encompassing conditions such as cleft lip and palate, ankyloglossia, GT and OPMD. Through shedding light on the genetic underpinnings of these disorders, the study emphasizes the paramount importance of unraveling the molecular basis of oral health conditions. This insight lays the groundwork for personalized prevention and treatment strategies, signifying a significant stride towards more tailored and effective clinical practices.

The research review paper not only delves into the genetic landscape but also scrutinizes therapeutic interventions for oral cavity disorders. It discusses non-invasive approaches like orofacial myofunctional therapy and surgical modalities, including frenectomy and tongue tie release surgery. This thorough exploration equips healthcare practitioners with a nuanced understanding of the diverse treatment options available. Consequently, it stands to enhance patient care and contribute to improved clinical outcomes, reflecting the practical implications of the research on healthcare practices.

However, it is imperative to acknowledge certain limitations within the study. While providing a valuable overview of genetic variants and therapeutic interventions, the research could benefit from a more in-depth exploration of the long-term efficacy and potential complications associated with these interventions. Additionally, a more robust analysis of the socioeconomic and cultural factors influencing the prevalence and management of oral cavity disorders would add depth to the overall understanding of the subject matter.

Conclusions

After reviewing the research, it appears that oral disease can be caused by genetic factors in combination with environmental factors. There are various genetic causes for genetic oral disorders, which can affect the type and severity of the disease. Although there is still much to be understood about the causes of genetic oral disorders, genetic factors cannot be overlooked. Future advancements in gene manipulation may lead to gene therapies and the use of dental stem cells to develop dental tissues.

Acknowledgments

We hereby affirm that the utilization of AI-assisted tools in the refinement of the manuscript was strictly limited to enhancing its readability. At no point were AI technologies employed to supplant essential authorial responsibilities, including the generation of scientific, pedagogic, or medical insights, the formulation of scientific conclusions, or the issuance of clinical recommendations. The implementation of AI for readability enhancement was rigorously supervised under the discerning eye of human oversight and control.

Funding: This work was supported by the Iraqi Ministry of Higher Education and Scientific Research (MOHSER).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://fomm.amegroups.com/article/view/10.21037/fomm-24-13/rc

Peer Review File: Available at https://fomm.amegroups.com/article/view/10.21037/fomm-24-13/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://fomm.amegroups.com/article/view/10.21037/fomm-24-13/coif). Ali Alsuraifi is employed as an assistant professor at the University of Basra, College of Dentistry and receives his salary from there on a monthly basis. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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