3.2Syndromes and Rare Diseases with Asymmetry in the Craniofacial and Dental Regions
Hans Gjørup and Dorte Haubek
Syndromes and Rare Diseases
Syndromes and rare diseases might be associated with facial asymmetry and/or asymmetry of the oral cavity, the dental arches, or the dentition. The present chapter demonstrates examples of syndromes and rare diseases, which in different ways may cause asymmetry. The presentation is mainly restricted to inherited conditions, and it is not the intention to cover all syndromes with asymmetry.
In the medical world, a syndrome is defined as a recognizable complex of symptoms and physical findings, which indicate a specific condition deviating from normal, and for which a direct cause is not necessarily understood (Spranger et al. 1982). However, nowadays the genetic background for many syndromes has been discovered, e.g. Apert syndrome, which is associated with a pathologic variant of a specific gene, FGFR2 (Hamm and Robins 2014). Other syndromes are characterized by a diversity of genetic associations, e.g. Cornelia de Lange syndrome, which is associated with pathologic variants of one out of six different genes (Goldenberg and Vera 2021).
The definition of a rare disease varies according to national or regional criteria. According to EU regulations, a disease is rare, if the prevalence is equal to or less than 5 in 10,000 inhabitants (European Commission 1999). In the present context, we use the Danish/Scandinavian definition (Danish Health Authority 2014). According to this, a rare disease is defined as a congenital, complex, and serious disease or condition, which requires access to professionals with special knowledge and expertise. In addition, the rare disease needs well‐coordinated and highly specialized diagnostic setting, where relevant procedures, treatments, follow‐ups, and controls are carried out. Furthermore, the prevalence of a rare disease has to be equal to or less than 1–2/10,000 inhabitants.
Table 3.2.1 Overview of conditions included in the chapter.
| Unilateral overgrowth of craniofacial and/or oro‐dental structures | Unilateral underdevelopment of craniofacial and/or oro‐dental structures | |||||
|---|---|---|---|---|---|---|
| Overgrowth syndromes | Hamartoneoplastic syndromes | Branchial arch and oral‐acral disorders | Syndromic cranio‐dysostosis | Syndromes affecting skin and mucosa | Syndromes with unusual facies | Rare dental anomalies |
| Primary condylar hyperplasia | Klippel–Trenauneau syndrome (KTS) | Oculo‐auriculo‐vertebral spectrum | Saethre–Chotzen syndrome (SCS) | Focal dermal hypoplasia (Goltz syndrome) | Progressive hemifacial atrophy | Regional odontodys‐plasia |
| Congenital infiltrating lipomatosis of the face (CIL‐F) | Proteus syndrome | Hypoglossia‐hypodactyly syndrome | Incontinentia pigmenti | Oligodontia | ||
| Segmental odonto‐maxillary dysplasia (SOD) | Hypohidrotic ectodermal dysplasia | |||||
Basically, the craniofacial and dental asymmetries, which may develop in syndromes and rare diseases, are associated with either unilateral overgrowth or unilateral underdevelopment of the structures (Table 3.2.1). Thus, the following description of syndromes is divided into these two main categories, and each of them is subdivided according to a modification of Gorlin’s classification of syndromes with impact on head and neck (Gorlin et al. 2001). The diseases and syndromes are defined according to definitions by Orphanet® (“Orphanet: an online database of rare diseases and orphan drugs” 1997).
Unilateral Overgrowth of Craniofacial or Dental Structures
Syndromes with unilateral overgrowth can be divided into overgrowth and hamartoneoplastic syndromes. Selected conditions within these two main groups will be addressed in the following text and illustrations (Table 3.2.1).
Primary Condylar Hyperplasia
Primary condylar hyperplasia is a rare temporomandibular joint anomaly characterized by progressive, nonneoplastic overgrowth of a mandibular condyle. Normally, it is unilateral and leads to progressive facial asymmetry with the chin of the mandible deviating to the nonaffected side. It is hard to delineate bilateral condylar overgrowth from the development of mandibular prognathism, and bilateral cases are seldom reported (Obwegeser 2001). In the present context, only unilateral occurrence is of relevance. Previously, the condition was suggested to be divided into two types: hemimandibular hyperplasia affecting the whole ramal and corporal part of the mandible in the affected side and hemimandibular elongation with an extended vertical dimension of the condyle only (Obwegeser and Makek 1986). The etiology of the condition remains unclear, but it has been associated with excessive formation of articular cartilage or an extended zone of the proliferation zone of the condyle (de Bont et al. 1985; Pirttiniemi et al. 2009).
Craniofacial and Dental Characteristics
The maxilla adapts to the asymmetric development of the mandible and becomes asymmetric as well. A severe canting of the occlusal plane evolves in addition to malocclusion with midline‐shift to the unaffected side and a tendency for lateral open bite in the affected side (Arora et al. 2019). In addition to facial disfigurement, the patients may experience severe attrition of the teeth in the nonaffected side because of the unbalanced occlusion. The recommended treatment in the active phase of the condition is high condylectomy, articular repositioning, and orthognathic surgery as alternatives to orthognathic surgery alone (Wolford et al. 2002, 2009). Recontouring of the mandibular inferior border by osteotomy is a treatment option in cases with moderate facial asymmetry and minor or no malocclusion.
Congenital Infiltrating Lipomatosis of the Face (CIL‐F)
Congenital infiltrating lipomatosis of the face (CIL‐F) is a very rare disorder in which mature unencapsulated lipocytes invade muscle and soft tissues of the facial region (Slavin et al. 1983). It is a unilateral facial condition, characterized by hypertrophy of both soft and hard structures on the affected side and the absence of malignancy. The hypertrophy of the affected side evolves gradually, and the resulting facial asymmetry becomes clearly visible during childhood (Frimpong et al. 2018; Li et al. 2018). The etiology of CIL‐F is unknown. However, it has been suggested that the condition might share its pathogenesis with other overgrowth syndromes, i.e. pathologic variants of gene PIK3CA (Couto et al. 2017; Maclellan et al. 2014; Sun et al. 2019).
Craniofacial and Dental Characteristics
In addition to the marked facial asymmetry, macrodontism, early eruption of teeth, maxillary and mandibular hypertrophy, macroglossia, and the proliferation of parotid gland on the affected side have been described. Furthermore, some case reports mention agenesis of permanent teeth (MacMillan et al. 1990; Padwa and Mulliken 2001; Sun et al. 2013). The unilateral overgrowth may be extreme and the dental midline of affected jaws can move dramatically to the contralateral side in addition to an obvious vertical effect with canting of the occlusal plane and rima oris (Figure 3.2.1).
Surgical treatment of the soft tissue is controversial because of the infiltrating nature of the condition, and recurrence of facial hypertrophy is common. Surgical treatment might include excision and liposuction (Kamal et al. 2010; Padwa and Mulliken 2001). Extraction of macrodontic teeth, orthodontic treatment, and orthognathic surgery might be indicated to solve the dental problems. Reports on outcome of dental treatment are, however, absent in the scientific literature.
Figure 3.2.1 Boy 9, 3 years of age with congenital infiltrating lipomatosis of the face (CIL‐F). (a) Facial asymmetry because of infiltration of lipocytes into soft tissues of the face in left side; (b–d) occlusion with canting of occlusal plane; (e) upper dental arch demonstrating hypertrophic left side processus alveolaris; (f) panoramic radiograph showing asymmetric in dental maturation and eruption, the left side being advanced compared to right side.
Segmental Odontomaxillary Dysplasia
Segmental odontomaxillary dysplasia (SOD) is a rare disorder characterized by unilateral enlargement of the right or left maxillary alveolar bone and gingiva in the region from the back of the canines to the maxillary tuberosity, including dental abnormalities (Danforth et al. 1990). The term SOD was introduced in 1990 as a specification of the term “hemi‐maxillofacial dysplasia” (HMFD), which previously was the denomination (Miles et al. 1987).
Craniofacial and Dental Characteristics
In the enlarged region, dental abnormalities, such as missing premolars, abnormal spacing, and delayed dental eruption, occur. Deciduous as well as the permanent molars of the affected region have an abnormal morphology: An enlarged crown, enamel hypoplasia, and widely spread roots of the deciduous molars, which typically present with primary or secondary retention; irregular outer contours and enamel hypoplasia of the permanent molars, which also may be retained or erupted very late. The bone of the affected area appears dense and sclerotic on radiographs. Histologically, the bone is irregular and immature. SOD has been reported in a limited number of case reports, some of them with reviews of cases (Alakeel 2020; Becktor et al. 2002b; González‐Arriagada et al. 2012; Prusack et al. 2000; Whitt et al. 2011) (Figure 3.2.2).
Figure 3.2.2 A boy, 10.5 years of age with segmental odontodysplasia (SOD). (a and b) Two en face pictures; (c) frontal view of dentition in occlusion; (d) dentition in upper jaw; (e) dentition in lower jaw; (f) occlusion left side; (g) panoramic radiograph showing enlarged left decidious maxillary molars, aplasia of 34,35, dysplastic permanent molars 26,27, and impacted permanent maxillary canines. Note asymmetric upper lip and hypertrophic processus alveolaris in left side of the maxilla.
In addition to the symptoms in bone, teeth, and mucosa, facial asymmetry and symptoms of the skin may also be present. Often, the facial asymmetry is moderate, and the facial appearance cannot be characterized as syndromic. The skin symptoms have been reported as unilateral erythema, hypertrichosis, hairy nevus, or Becker nevus. Thus, the condition has by some authors been denominated HATS (Hemifacial enlargement, Asymmetry of the face, Tooth abnormalities) (Alakeel 2020; Welsch and Stein 2004).
The etiology of SOD is unknown. A vascular theory has been suggested. Recently, a genetic background to SOD has been suggested: Mosaicism with a pathologic variant of PIK3CA gene expressed in the affected region (Gibson et al. 2021).
The prognosis of the malformed teeth in the affected side is less favorable and implant‐supported prosthesis to replace missing teeth is a prevalent need in young adults with SOD. However, the number of reports on the outcome of implant treatment is very limited (Whitt et al. 2011). With lack of eruption and/or early loss of teeth in the affected side, there is a risk of over‐eruption of mandibular teeth and a succeeding canting of the mandibular occlusal plan. Reports on the outcome of orthodontic interventions are nonexistent.
Proteus Syndrome and Klippel–Trenauneau Syndrome
Proteus syndrome (PS) is a rare and complex hamartomatous overgrowth disorder, characterized by progressive overgrowth of the skeleton, skin, adipose, and central nervous systems. Normally, the onset of PS occurs from 6 to 18 months of age, and the disease is characterized by asymmetric overgrowth mainly of the hands or feet, but may in addition include unilateral overgrowth of other structures, e.g. facial structures. The skeletal overgrowth occurs rapidly and progressively resulting in the development of distorting and irregular calcified overgrowth in the tubular bones of the limbs, the skull, and vertebral bodies. PS has been reported to be associated with pathologic mutations in one of two components of the phosphatidylinositol 3‐kinase (PI3K)‐AKT signaling pathway: PTEN and AKT1. The gene deviations may occur as either a de novo mutation or a somatic mosaic mutation (Keppler‐Noreuil et al. 2016).
Klippel–Trenauneau syndrome (KTS) (Synonyms: Klippel–Trenaunay–Weber syndrome or Angio‐osteohypertrophic syndrome) is a congenital vascular bone syndrome (CVBS) characterized by the presence of an arteriovenous malformation in a limb, which results in overgrowth of the affected limb (You et al. 1983). The disease is associated with deviation in PIK3CA (John 2019). Craniofacial and oro‐dental involvement in terms of overgrowth and venous varicosities and skeletal and dental hypertrophy may occur (Auluck et al. 2005; Fakir et al. 2009).
Craniofacial and Dental Characteristics
PS, and in some cases also KTS, may be associated with a severely asymmetric development of both craniofacial and oro‐dental structures. The result is an obvious disfigurement of the face due to a unilateral overgrowth of skeletal structures and soft tissue. In addition, the maturation of the dentition in the affected side is accelerated, and the physical dimensions of the teeth increase in comparison to teeth of the unaffected side. Furthermore, the patients develop dental crowding and malocclusion with obvious midline‐shift toward unaffected side and a canting of the occlusal plane (Munhoz et al. 2021). Idiopathic root resorptions and dysfunction of the temporomandibular joint have also been described in cases with PS (Becktor et al. 2002a) (Figure 3.2.3).
Unilateral Underdevelopment of Craniofacial or Dental Structures
The second overall topic, being unilateral underdevelopment of craniofacial and/or dental structures, can be divided into many subgroups as illustrated in Table 3.2.1, where an overview of the conditions addressed in the present chapter is given.
Oculo‐Auriculo‐Vertebral Spectrum
Branchial arch disorders include oculo‐auriculo‐vertebral spectrum (OAV), previously denoted “hemifacial microsomia” (HFM) or Goldenhar syndrome. The phenotypic spectrum of OAV ranges from isolated mild facial asymmetry to severe bilateral craniofacial microsomia and additional multiple extracranial abnormalities. The craniofacial involvement is in most cases unilateral and includes auricular abnormalities, preauricular appendages and/or fistulas, hypoplasia of the mandible, the maxilla, the malar bone, and/or the zygomatic arch, and epibulbar dermoids. The extent of involvement varies from mild and hardly recognizable to severe with socially handicapping dysmorphic appearance (Rath 2017). Next to cleft lip and palate, OAV is the most common facial anomaly affecting one in 5000 births. Unilateral occurrence in terms of HFM is much more prevalent than bilateral occurrence, and it is a well‐known background for facial asymmetry. The etiology of OAV/HFM is debatable, but it is suggested to be associated with incidents occurring during the development and migration of neural crest cells, responsible for the mandibular arch formation (the first branchial arch). In the more severe cases, the second branchial arch is also affected (Gorlin et al. 2001). Embryonic vascular abnormality or hemorrhage might be another explanation to HFM (Hartsfield 2007).
Craniofacial and Dental Characteristics
The variation in severity is the background for a classification according to the degree of mandibular hypoplasia. In mildly affected cases, the contour of the mandibular ramus and condyle is fairly normal, but reduced in size, and the facial asymmetry is moderate. In the most severely affected cases, the condyle and most of the ramus are absent, and the facial asymmetry is severe (Kaban et al. 1988).
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