**2. Methodology**

This chapter used a review approach aim to summarize the current literature concerning periodontal disease associated with genetic disorders, meanwhile, the chapter also provided some clinical cases including hereditary gingival fibromatosis, Papillon-Lefèvre syndrome, cyclic neutropenia, Ehlers-Danlos syndrome, and hypophosphatasia.

#### **2.1 Literature search strategies**

A review of the literature concerning periodontal disease associated with genetic disorders was conducted using PubMed, Embase, Web of Science, Google Scholar, and the Cochrane Library with no restrictions placed on country or publication date. The search involved the genetic disorders listed in the 2017 Classification System for Periodontal Diseases and Conditions [6]. The keywords used in the online searches were (the name of disorder) AND (periodontal disease OR periodontitis OR attachment loss). Additional relevant articles were also found by scanning the references of included articles as well as those citing the papers concerned.

#### **2.2 Screening and selection criteria of studies**

The identified study titles were first screened to exclude studies not relevant to periodontal disease associated with genetic disorders. For studies with apparent relevant title, the abstract would be reviewed to check and confirm potential eligibility, normally followed by careful study of the full text involved. Once eligibility is confirmed, the reference list of the included paper as well as those articles cited the latter would be reviewed for additional relevant reports. Different types of studies were included and evaluated, including case series/reports. Etiology, gene(s) involved, inheritance pattern, clinical signs and proposed therapeutic approach(es) for these periodontal diseases associated with genetic disorders were noted (**Table 1**).

In particular, five genetic disorders were given special attention: hereditary gingival fibromatosis, Papillon-Lefèvre syndrome, cyclic neutropenia, Ehlers-Danlos syndrome, and hypophosphatasia. Information regarding etiology, prevalence and incidence, clinical oral manifestations and the possible therapeutic approaches concerning these five disorders would be noted and summarized.

### **3. Genetic disorders that affect the periodontal tissue**

According to the International Workshop in 2017, periodontal disease as a manifestation of systemic diseases is a separate disease category, systemic diseases are divided into hematological and genetic disorders [6]. Genetic disorders are caused by gene mutations or chromosome disorders that cause a change in the number or structure of chromosomes [7]. **Table 1** shows some well described genetic disorders that have a major impact on the periodontal tissue, including some disorders affecting gingival tissue (hereditary gingival fibromatosis), connective tissues (vascular Ehlers-Danlos syndrome, periodontal Ehlers-Danlos syndrome), some




*AD, autosomal dominant;* ALPL, *alkaline phosphatase, biomineralization associated gene; AR, autosomal recessive;* C1R*, complement 1 subunit r gene;* C1S, *complement 1 subunit s gene;* COL1A1, *collagen type I alpha 1 chain gene;* COL3A1*, c*ollagen type III alpha 1 chain gene; CTS*C, cathepsin C gene; ELANE, elastase, neutrophil expressed gene; FERMT3, fermitin family member 3 gene; HAX1, HCLS1-associated protein X-1 gene; HCLS1, hematopoietic cell-specific lyn substrate 1; IP, inheritance pattern; ITGB2, integrin subunit beta 2 gene; LYST, lysosomal trafficking regulator gene; OMIM,* online Mendelian Inheritance in man*; RE1, transcriptional repressor element-1,* REST, *RE1 silencing transcription factor gene;* SLC35C1, *solute carrier family 35 member C1 gene;* SLC37A4, *solute carrier family 37 member 4 gene;* SOS*, son of sevenless genes;* SOS1, SOS *Ras/Rac guanine nucleotide exchange factor 1 gene;* VPS13B, *vacuolar protein sorting 13 homolog B gene;* ZNF862, *Zinc finger protein 862 gene.*

#### **Table 1.**

*Periodontal disease associated with genetic disorders.*

*Periodontal Disease Associated with Genetic Disorders DOI: http://dx.doi.org/10.5772/intechopen.97497*

diseases associated with immunologic disorders (Down syndrome, leukocyte adhesion deficiency, Papillon-Lefèvre syndrome, Haim-Munk syndrome, Chediak-Higashi syndrome, Severe congenital neutropenia, cyclic neutropenia, Cohen syndrome) and metabolic disorders (glycogen storage disease 1b, hypophosphatasia) [6, 8–12].

#### **3.1 Hereditary gingival fibromatosis**

Hereditary gingival fibromatosis (HGF) is a rare, hereditary disorder characterized by a benign, non-hemorrhagic, localized or generalized fibrous enlargement of free and attached gingivae with slow progression, and was initially reported by Goddard and Gross in 1856 [13, 14]. It has been designated by such terms as gingivostomatosis, elephantiasis, idiopathic fibromatosis, hereditary gingival hyperplasia, idiopathic gingival enlargement, and congenital familial fibromatosis. The prevalence is unknown, the incidence is 1:175,000 according to phenotype and 1:350,000 according to genotype, and equal between males and females. HGF is commonly described as an isolated disorder (non-syndromic), or it can develop as a part of a syndrome (syndromic) like Cowden's syndrome, Zimmermann-laband syndrome, Cross syndrome, Rutherford syndrome, Ramon syndrome, Jones syndrome, Costello syndrome, Ectro-amelia syndrome, and hyaline fibromatosis syndrome [15]. In this part, we mainly discuss non-syndromic HGF.

#### *3.1.1 Etiology and pathogenesis*

The mode of HGF inheritance is still controversial, while it is generally considered to be an autosomal dominant disease, there are a few studies demonstrating that it may also follow an autosomal recessive pattern [16]. **Figure 1** shows a Chinese pedigree with non-syndromic HGF in an autosomal dominant mode. As reported earlier, four loci (2p22.1 [MIM: 135300], 2p23.3-p22.3 [MIM: 609955], 5q13-q22 [MIM: 605544] and 11p15 [MIM: 611010]) were recognized to be related with HGF [17–20], while SOS Ras/Rac guanine nucleotide exchange factor 1 gene (SO*S1*) (MIM: 182530) heterozygous frameshift mutation was acknowledged causing autosomal dominant HGF in a Brazilian family [21]. From three independent families, two Turkish and one American, protein truncating mutations of RE1 silencing transcription factor or *REST* gene (MIM: 600571) were identified to cause autosomal dominant HGF [22]. In our department, we identified seventeen autosomal dominant non-syndromic HGF patients from a Chinese family (**Figure 1**). Across three generations, whole-exome sequencing then genetic co-segregation analysis were performed identifying an original Zinc finger protein 862 (*ZNF862*) gene heterozygous missense mutation to be the cause of the genetic problem [23].

## *Periodontology - Fundamentals and Clinical Features*

The pathophysiologic mechanisms underpinning HGF remain elusive. Nonetheless, extracellular matrix overproduction involving major component of collagen type I was believed to be a cause of the gingival fibroblast overgrowth phenotype; on the other hand, increased production of TIMP-1 appeared to be associated with excessive collagen I accumulation in HGF fibroblasts [24, 25]. Also, Martelli-Junior and coworkers claimed that TGF-β1, IL-6 and perhaps other specific growth factors overproduction in fibroblasts might play pivotal roles in unwarranted collagen I synthesis [26].

## *3.1.2 Clinical manifestations*

The onset of the gingival overgrowth usually coincides with the eruption of permanent incisors, while under rare circumstances, HGF can present at birth (**Figures 2**–**4**). The overgrowth affects the attached gingiva as well as the gingival margin and the interdental papillae. The facial and lingual surfaces of the permanent teeth are generally affected, the enlarged gingiva is usually firm, smooth and occasionally nodular, with minimal or no inflammation and normal or pale in color. The upper gingiva is more severely affected and may prevent the eruption of the teeth. In severe cases, the teeth are almost completely covered. The firm yet painless enlargement of the gingiva does not commonly affect the alveolar bone but can lead

**Figure 2.** *HGF in Chinese elderlies.*

**Figure 3.** *HGF in Chinese adults.*

**Figure 4.** *HGF in Chinese children.*

#### *Periodontal Disease Associated with Genetic Disorders DOI: http://dx.doi.org/10.5772/intechopen.97497*

to the development of pseudo-pockets, which facilitate plaque accumulation due to suboptimal daily oral hygiene [13–16].

Enlarged gingival tissues due to HGF cause functional and esthetic problems. The lesion partially and at times totally cover the crowns of teeth causing pseudopocketing. In extreme situations, HGF could delay or even impede tooth eruption, causing diastemas, mal-position/alignment of teeth, cross/open-bite, excessive lip support including vermillion eversion, and/or incompetence lips. Common clinical complications secondary to gingival enlargement including but not limited to difficulties in speech, mastication, and occlusion, as well as changes in facial features. Interestingly, the condition may disappear or regress with the loss of teeth, thus suggesting that the presence of teeth might serve as one condition for the development of HGF [13–16].

#### *3.1.3 Diagnosis*

Diagnosis of HGF is usually based on clinical findings, a generalized severe gingival overgrowth without medication history, and the familial aggregation of HGF can assist in early diagnosis [27, 28]. The differential diagnosis should include gingival hyperplasia due to phenytoin, nifedipine and cyclosporine and gingival fibromatosis, which may occur as part of other genetic syndromes.

HGF related gingival fibrous enlargement typically display marked increase in submucosal connective tissue histologically. The involved connective tissue looks densely collagenized, populated scantly with fibroblasts, avascular and with signs indicating minimal inflammatory infiltrate. The overlying dense epithelial layer appears hyperkeratotic with elongated rete pegs. In situation when abnormal thickening of the stratum spinosum or prickle cell layer, i.e. acanthosis of the HGF involved epithelium, areas with chronic inflammation within the epithelium can sometimes be detected [27, 29].

#### *3.1.4 Treatment*

The maintenance of good oral hygiene and plaque control is fundamental. Treatments vary according to the degree of severity of gingival enlargement and different types of treatment modality could be employed for the excision, including conventional surgery, electrosurgery, apically positioned flap and laser ablation [14, 27, 30].

For HGF patients with mild gingival hyperplasia, supportive periodontal therapy is recommended every 3 months.

For HGF patients with modern-severe gingival hyperplasia, periodontal surgery is required (**Figures 5** and **6**), including gingivectomy, gingivoplasty, and flap surgery. Some literature indicated that laser can also be used to remove hyperplastic gingival, with higher patient comfort and less trauma. Recurrence after surgical treatment was observed within 3–10 years, and children and adolescents are more likely to recurrence than adults. Therefore, regular follow-up and good oral hygiene are very important.

For HGF patients with severe gingival hyperplasia deformation, surgical interventions that may be required include tooth extraction, osteoplasty and ostectomy.

A comprehensive medical and family history, along with clinical examination can aid early HGF diagnosis because the latter often associates with a few extra-oral features on top of familial aggregation. Gingivectomy is often the treatment of choice while long-term follow-up post-surgery is recommended for the relatively high probability of HGF recurrence.

#### **Figure 5.**

*Periodontal surgery (gingivectomy, gingivoplasty, and flap surgery) in a Chinese HGF patient (IV-1, Figures 1 and 3; pre-operation [left panels: Set of nine intra-oral photographs] and 6 months follow-up [right hand panels]).*

**Figure 6.**

*Periodontal surgery (gingivectomy, gingivoplasty, and flap surgery) in a Chinese HGF patient (IV-2, Figure 1; pre-operation [right hand panels] and 2 years follow-up [left hand panels]).*

#### **3.2 Papillon-Lefèvre syndrome**

Papillon-Lefèvre syndrome (PLS), first reported in a French family by physicians Papillon and Lefèvre in 1924, is an autosomal recessive disorder characterized by diffuse palmoplantar erythematous, fissured hyperkeratosis, and aggressive periodontal disease that starts in the early periods of childhood. It has been designated by such terms as "keratoris palmoplantaris" and "hyperkeratosis palmoplantaris" [31, 32]. Periodontitis occurs with the early loss of deciduous teeth at the age of 2 to 4 years, followed by the loss of permanent teeth during adolescence. The prevalence is unknown, more than 300 families worldwide have been reported in the medical literature [33]. In the general population, PLS occurs in approximately one to four individuals per million, and consanguinity is reported as a significant risk factor and has been demonstrated in 20–40% of PLS patients [34]. With reference to 124 PLS cases, Haneke raise the following generalizations: (1) females and males appeared equally affected; (2) no racial predominance of the condition, apparently, could be observable; (3) however, consanguinity was associated with a third of the cases; and (4) other than periodontitis, increased susceptibility to other infections was observed in a quarter of PLS patients [32].

#### *3.2.1 Etiology and pathogenesis*

PLS is caused by changes (alterations) in *CTSC* gene, which encodes cathepsin C, a lysosomal protease capable of removing dipeptides from the amino-terminus portion of its respective substrates [35]. The protein is expressed at high levels in

#### *Periodontal Disease Associated with Genetic Disorders DOI: http://dx.doi.org/10.5772/intechopen.97497*

various immune cells and certain bodily areas affected by PLS, including epithelial cells, that form the protective outer layer of the skin (epidermis), such as of the palms, soles, and knees, as well as certain cells of the gingiva. To date, more than 90 mutations in *CTSC* have been reported associate with PLS with the majority being located between Exons 5 and 7, the region encoding the heavy chain domain of cathepsin C that controls its enzymatic activity. Cathepsin C activity is proposed to play a key role in the epithelial differentiation and desquamation, while the inappropriate genetic alterations may result in nearly complete loss of cathepsin C enzymatic activity in homozygous individuals with the disease, or correspondently reduced activity of the enzyme in the family members who are heterozygous carriers [36, 37]. The present research group reported a PLS patient with a 110 kb deletion (Chr11: 88032292:88142997 [NC\_000011]) and a nonsense mutation exists (Gln182Ter, CAG > TAG) in the fourth exon of the *CTSC* gene [38].

Another important related periodontitis etiologic factor is an alteration of the host defense owing to decreased function of lymphocytes, polymorphonuclear leucocytes or monocytes. However, research into such factors has not led to consistent findings and more research is necessary to decipher the underlying mechanisms that lead to the development of clinical manifestation observed in PLS [39, 40]. The subgingival plaque sampled from periodontal pockets of PLS patients resembled typical periodontitis-associated microflora, i.e. predominant gramnegative anaerobic microbes, including *Porphyromonas gingivalis* and spirochetes. Recent microbiologic report indicated that *Aggregatibacter actinomycetemcomitans* was detectable in periodontal sites in PLS patients [41].
