The Oral Health of Patients with DiGeorge Syndrome (22q11) Microdeletion: A Case Report

Background

DiGeorge syndrome (OMIM: 188,400) is a congenital disorder, all the clinical manifestations of which are related to the genes surrounding the 22q11.2 region.¹ It is one of the most frequent rare disorders, resulting in an embryological defect involving the third and fourth branchial arches.^1,2 The approximate frequency is around 1 per 4000 newborns, reaching up to 1 in 1000 in certain populations.^3–6 The majority of cases result from heterozygous chromosomal deletion in the above-mentioned region. The size of the deleted chromosomal region has been reported in different series to be around 0.7–3 million base pairs⁷ As a result of this deletion, several genes are lost, including HIRA protein (HIRA), T-box 1 protein (TBX1), Catechol-O-methyltransferase (COMT), and Recombinant Human Crkl (CRKL).^8–10 These genes are related to the formation and development of the pharyngeal arches (PA) and the migration of neural crest cells; for that reason, the genetic disruption of these genes alters various structures, resulting in conditions such as conotruncal cardiac anomalies, thymus hypoplasia, hypocalcemia resulting from lack of development of the parathyroid glands, cognitive deficits, frequent infections, and autoimmune disorders.¹

This syndrome presents a variable and broad phenotype, which can include craniofacial abnormalities (CA), congenital heart diseases, endocrine dysfunction, cognitive deficits, and psychiatric disorders.¹⁰ The CA in DiGeorge Syndrome (DG) include micrognathia or abnormal mandible, broad nasal base, bulbous nasal tip, upslanting palpebral fissure, midface hypoplasia, low-set, and posteriorly rotated ears, ocular hypertelorism, vertical maxillary excess, overt cleft palate, and submucosal cleft palate.^11–13 Although the majority of the clinical spectrum of this syndrome has been described, little is known about the oral status of these patients and the relationship between the genotype and phenotype, apart from the presence of a high frequency of dental aberrations, enamel hypoplasia, and hypomineralization, as well as a high prevalence of caries, in patients with 22q11 microdeletion.^14–16

22q11.2 DS has also been shown to be associated with developmental disturbance in dental enamel development and increased prevalence of tooth agenesis and hypodontia.^14,16 These issues have traditionally been considered to be secondary effects of conditions affecting organ systems, such as CA, hypoparathyroidism, and premature birth.^14,16 Moreover, other studies have shown that the disturbances of enamel are independent alterations associated with the genetic disruption itself, playing an important role in the pathogenesis of the microdeletion syndrome.^17,18 The aim of this case presentation was to determine the state of gingival health and oral hygiene in patients with 22q11.2, as well as to perform a literature review of the dental and oral features of 22q11 DS because of a lack of knowledge of this issue.

Case Presentation

The patients were visited at Fundación Valle de Lili Hospital to the Genetic Department in a period of time between 2016 and 2018. The oral examination was performed in the Dentistry School (UNICOC) in Cali, Colombia by an ondotopediatric expert and two periodontic trainees. This paper describes a series of nine DG patients (four males and five females), with an average age of 9.44 Interquartile Range (IR) (IR 5–17). Medical records of 9 patients were examined and the data are extrapolated in Table 1. The extrapolated data describes the clinical characteristics of these patients including height and weight at birth Table 1. Other clinical features such as head and neck, oral cavity and other systems' involvement found in the medical records are shown in Table 2. The findings reveal the variability of the clinical spectrum of DG and highlight the high frequency of malocclusion and high susceptibility to oral infection in the patients. Additionally, hypomineralization was also observed. Of these patients, two patients with DG underwent oral examination exhibited mixed dentition. Multiple intraoral features were observed in this series, including high palate (22%), cleft palate (22%), bifid uvula (11%), enamel hypomineralization and hypoplasia (22%), dental wear (22%), caries (22%), and also malocclusion as the most prevalent feature (44%). In total, seven of the nine cases showed at least one intraoral anomaly Table 2.

Table 1 Age, and Weight and Height at Birth

Table 2 Clinical Variables of the Patients with DS

Case 1

Case 1 was a female patient aged 9 years old, who at 4 months after birth was diagnosed with tetralogy of Fallot and at 8 months underwent surgical correction for it. A second procedure was performed at 15 months, with the aim of correcting pulmonary stenoses. At 4 years old, the patient presented acute heart insufficiency and a clinical episode of seizures and infection. Additionally, from the age of 5 years old, the patient undertook speech therapy due to dyslexia, with special difficulty pronouncing the letters r, j, g, and s because of velopharyngeal insufficiency.

Extraoral Clinical Examination

Soft tissues were evaluated in all patients; it was observed that the superior and inferior medial dental lines did not match the facial medial line because of deflection of around 1 mm to the left Figure 1A and B. Other findings were also noted, such as a bicommissural line parallel with the pupillary line, narrow mouth, hypotonic upper lip, increase inferior third of the lip, dolichofacial type, concave profile, biprochelia, upper and lower anterior dental crowding, high smile, and high smile not consonant.

Figure 1 Dysmorphic phenotype in patient with DS. (A) Frontal view. (B) Smile in a frontal view. (C) Lateral view.

Oral Findings

The patient had an abnormal dental formula, with panoramic radiography showing anodontia with absence of the dental follicle in the upper right second premolar related to overlap of the maxillary incisors Figures 2C and B. There was also a deep bite of the mandibular incisors, along with the right side of the jaw being offset from the left Figure 1B. Additionally, there were significant changes of the color and texture of the dental tissue. Some teeth showed a granular appearance with holes in the vestibular surface of the enamel, predominantly in canines and molars Figure 1A and B. Enamel hypoplasia was visualized with hypocalcification and wear of the lower incisal edges Figure 1B.

Figure 2 Dental photography. (A) Cross-bite. (B) The square in the medial incisors show enamel hypomineralization affecting both dentitions (C) superior maxillary (D) inferior maxillary, vertical overbite.

Intraoral examination showed normal oral mucosa (coral pink color) with orange flecks and appropriately keratinized gums, without signs of inflammation or bleeding. At the time of evaluation, the following teeth were found: upper and lower permanent incisors and first molars, as well as canines and molars. In addition, caries was identified at 74 and resin seals at 54 and 84 Figure 1A–C. The patient presented a deep bite with interdental spaces and malocclusion class II Figures 2A–D and 3.

Figure 3 Dental photography (A) centric occlusion, it is evident the hyperpigmentation in the medial incisors and the generalize enamel hypoplasia. (B) Opening centric occlusion also shown the amalgam restoration of the lower molars, dental crowding in lower incisor and twisted of the upper first and second premolars.

Case 2

Case 2 was a male patient aged 16 years old. At the first month of life, he had been diagnosed with tetralogy of Fallot, which was surgically corrected. Additionally, he presented developmental delay, cognitive deficits, and velopharyngeal insufficiency. Upon physical examination, dolichocephaly was evident, with pansystolic murmur in the pulmonary area. Upon intraoral examination, malocclusion was observed, with hyperpigmentation of 11 teeth, enamel hypoplasia, amalgam restoration of the lower molars, dental crowding in the lower incisors, and apparent twisting of the upper teeth Figure 4A and B.

Figure 4 Panoramic dental X-ray. (A) Lateral view. (B) Panoramic dental X-ray shows dental crowding especially from the first and second superior premolars until the superior molars.

Finally, the results of the survey Tables 3 and 4 provided evidence matching the clinical spectrum as reported in the literature, including immune dysfunction, frequent hospitalizations, and cognitive deficits. Regarding the oral hygiene, the patients reported appropriate oral hygiene habits. The information from the different medical records is summarized in Table 2. In the majority of cases, the syndrome was diagnosed at birth due to congenital heart defect or disturbance of calcium metabolism; in the other cases, diagnosis was achieved later in development in association with poor speech and/or psychomotor development by using multiplex ligation probe amplification; the 22q11 deletion was also confirmed by fluorescence in situ hybridization testing.

Table 3 Results of the Survey

Table 4 Summarizes the Current Literature About Di George Syndrome Dentistry Management and Craniofacial Characteristics

Discussion and Conclusion

Facial characteristics associated with 22q11 microdeletion are common, and they have been clearly described in the literature, such as the presence of a retrusive lower part and a prominent upper part of the face compared with those of healthy controls.^19,20 These findings were also evidenced in our cases. The facial phenotype characterized by prominent and slightly broad forehead, prominence of the midface, and retrognathia. In this series, we also show the typical features of the nose, namely, tubular nose, bulbous nasal tip, and philtrum defect associated with a narrow mouth, as also mentioned in other reports.^19,21–25

Regarding dental characteristics, dental agenesis was reported in previous studies in around 15–20% of cases.^14,19,26 In this series, we found a similar frequency of dental agenesis, in around 11% of cases. This is around double the level in the healthy population, in which dental agenesis has been reported to occur at a rate of around 5.5%.²⁷ TBX-1 is considered to play a major role in the phenotypic spectrum of the syndrome, being responsible for the dental and craniofacial features due to its role in the development of these structures.^17,28

Other oral manifestations that have been reported in the literature include a high frequency of enamel defects, including hypermineralization, more often in permanent rather than temporary dentition.^25,26 From our evaluation of the medical records, we found that 33% of the patients had hypomineralization and both patients who underwent oral/physical examination had hypomineralization and other dental defects. In the literature, enamel hypoplasia has been shown to be associated with heart abnormalities,²⁹ which are common in patients with DG, and premature delivery. On the other hand, enamel hypomineralization is associated with recurrent infection,¹⁴ which might be related to immune system deficits in DG due to the thymus agenesia and also related to the higher prevalence of dental agenesia, dental eruption delay, and changes in tooth size (hypodontia) compared with those in the general population.¹⁵ It has also been described that there is a high probability of caries due to the changes in enamel and recurrent infections.^14,30

Mineralization disturbances occurred in dental enamel, as well as affecting tooth shape and number of teeth; there were also eruption problems commonly associated with numerous carious lesions and gingivitis, which were also expected to be due to the underlying hypoparathyroidism and hypocalcemia.^14,16 However, analyses of the damaged enamel found at rates as high as 66% of cases, showed that the etiology differs from those in other conditions. The above-mentioned conditions are not clear causal factors of the enamel disturbances and no major correlations between the medical conditions and the changes in enamel were identified.²⁶ Enamel defect might be caused by changes in the expression of the deleted gene(s). The candidate gene for this is TBX, the expression of which in a murine model showed that this gene is involved in creating ameloblasts during tooth development. Furthermore, a mouse model lacking functional TBX-1 exhibited hypoplasia of maxillary incisors and arrested enamel formation.

The rate of occurrence of abnormalities of teeth and soft tissue in this series was 78%, similar to that reported in a previous study (76%).³¹ By performing a TBX-1 lineage tracing experiment, it was found that this gene is related to microdontia, which coincides with a decrease in stem cell proliferation in the labial cervical cell niche (LaCL). Mice with knockout of TBX-1 showed the 22q11.2 DG phenotype in terms of oral findings such as cleft palate and craniofacial/tooth defects.²⁸ These experiments confirmed the fundamental role of the proliferation of dental progenitors, correlating with the oral findings in different cases reported in the literature Table 4.

Malocclusion was also found in 36% of our cases, congruent with previous reports showing high frequencies of malocclusion type I (67%) and class type II (30% to 60%).^14,19 Another common orofunctional disturbance associated with 22q11.2 DG is velopharyngeal insufficiency (VPI).^32,33 However, in this study, VPI was not objectively evaluated. However, hypernasal speech was observed in both of the patients undergoing oral examination and submucous cleft and high palate were exhibited in 22% of the cases, at a frequency similar to that reported in other series.¹⁹

With respect to gingivitis and periodontitis, it is reported in the literature that patients with DG have a higher predisposition to these conditions because the deleted genes are involved in the process of T-lymphocyte maturation.³⁴ In the cases presented here, we did not find any evidence of periodontium inflammation. However, in DG cases, professionals have a responsibility to provide quality oral care, given the most frequent manifestations of this disease, in order to ensure a level of oral health equal to that of the rest of the population.³⁵

The orthopedic treatment, combined with orthodontic devices, allows the eruption of the impacted tooth and allows the appropriate alignment with this treatment. The crossbite correction can also be achieved, as seen in a 9 years old male with DG reported by Cazzolla et al.³⁶ In the case of severe hyperdivergency associated with III angle skeletal class, an orthognathic surgery should be proposed at the end of the growth.

Although DG patients were shown to be genetically predisposed to periodontium diseases in the present series, there was no evidence of any specific characteristics of DG. However, the most common dental features were agenesia, enamel defects, dental crowding, and malocclusion. It is important to diagnose DG in order to implement multidisciplinary management via a familiarity with 22q11 DS among those working in the field of pediatric dentistry, to overcome the frequent oral health issues found in these patients.