Biomedicines, Vol. 11, Pages 81: Gingival Overgrowths Revealing PTEN Hamartoma Tumor Syndrome: Report of Novel PTEN Pathogenic Variants

3.1.1. Patients 1 and 2, Related Patients, Son, and Mother

A 25-year-old man (Patient 1) had been referred to our clinic to rule out a potential diagnosis of Acanthosis Nigricans.

The past medical history was unremarkable, just reporting folliculitis and the patient denied any oncological disorders. The main reason for the medical consultation was the onset of warty lesions involving multiple oral mucosal subsites and the vermilion.

Clinical examination Patient 1

At oral examination, small multiple whitish and pink oral lumps involving gingiva, vermilion, hard palate, and buccal mucosa were observed. The tongue had a fissured aspect with, on the lateral borders, papillomatous lesions in a cobblestone pattern. The lesions were asymptomatic. In addition, the patient had poor oral hygiene and multiple decays (Figure 1).Even in the presence of poor oral hygiene, lacking massive signs of gingivitis and lacking drug assumption, the oral lesions were evocative of PHTS. Therefore, extra-oral diagnostic criteria for PHTS were investigated. The head circumference was consistent with macrocephaly (61.5 cm; >99th percentile; +4.46 SD). In the presence of at least 2 major criteria, including macrocephaly, the CS/PHTS genetic testing criteria were met, even if clinical diagnostic criteria for CS/PHTS were not [3].

The patient had come to consultation accompanied by his mother. During conversation, lesions involving the mother’s tongue were occasionally detected and she was offered a visit. A potential link between mother and son for inherited disorders had never before been suspected.

Clinical examination Patient 2

At oral examination multiple oral lumps involved the alveolar ridge, buccal mucosa and tongue and oral melanosis was additionally observed. The lesions had a smooth surface, white-pink color and showed a cobblestone pattern. She also had poor oral hygiene.

Extraoral examination showed multiple skin keratotic pits and acral hyperkeratotic papules. The assessment of the head circumference was consistent with macrocephaly (61 cm; >99th percentile; +6.04 SD) (Figure 2).

The 55-year-old woman (Patient 2, mother of Patient 1) outlined her mouth lesions as being long lasting, not responsible for any symptoms and concluded that she had never cared about them.

The remote medical history of Patient 2 revealed appendectomy, uterus malignancy, cerebral ischemia, benign thyroid nodules (leading to partial thyroidectomy), hepatic angioma and four lipomas. Her current medical history was unremarkable.

The family history revealed that Patient 2′s sister had sudden cardiac death and two other siblings were healthy. Their mother was deceased for a not clarified central nervous system malignancy. Their father (smoker) died from larynx cancer and a sister of his had a cervical tumor, another had breast cancer, and a niece too. No other tumors were referred to on the maternal or paternal sides, nor in the older generations.

Patient 2 met the current diagnostic criteria for CS/PHTS. Even when not considering the uterus malignancy, the precise nature of which was undefined, she had two major criteria: macrocephaly and multiple mucocutaneous lesions (oral lumps ≥ 3) and three minor criteria: more than two lipomas, thyroid structural lesions, and vascular anomalies.

Based on this unexpected diagnosis, also Patient 1 fitted the diagnostic criteria for CS/PHTS as a lower number of diagnostic criteria are required for operational diagnosis in a family where at least one individual meets CS/PHTS diagnostic criteria (Table 2, Table 3 and Table 4). In the light of the confirmed CS/PHTS diagnosis for Patient 2, the two major criteria observed in Patient 1 (macrocephaly and oral lumps) led to CS/PHTS diagnosis.

Genetic analyses

The sequencing analysis did not identify any pathogenic mutation in the PTEN gene in Patient 1. An intronic heterozygous substitution in intron 6, c.635-245G>C was detected but no evidence supported its role in the splicing process. Nevertheless, this variant was not reported in the GnomAD database [19] and the segregation analysis confirmed that it was inherited from the mother (Patient 2).The MLPA analysis found the heterozygous deletion of the whole exon 6 c.(492+1_493-1)_(634+1_635-1)del, p.(Gly165Ilefs*9), similar to that reported by Nizialek EA and referred to in the LOVD database [20]. The same deletion was identified in both patients, pointing to a hereditary mutation (Figure 3).

None of the family members were available to extend the genetic examination.

Based on the clinical and genetic results, both patients entered a cancer surveillance program as indicated for PTEN mutation patients (Table 5). The surveillance program includes an annual oral cavity follow-up. So far, the gingival overgrowths had not caused discomfort to the patients and did not require any surgical treatment. Conversely, they entered a professional hygiene program. 3.1.2. Patient 3

A 50-year-old woman (Patient 3) was referred to our clinic by the dentist for the evaluation of multiple gingival warty lesions. The differential diagnosis included squamous papillomas and CS/PHTS manifestations.

Clinical examination

At oral examination, multiple warty lumps were observed involving mainly the gingiva. The most affected area was the lower gingiva at the anterior portion. Of note, the attached gingiva of the central incisors had the typical cobblestone appearance. While the other mucous were free from lesions at the time of the first visit (Figure 4).At the general medical history, macrocephaly (head circumference 59 cm; >99th percentile; +4.2 SD) and intellectual disability (IQ ≤ 65) were observed, and the patient reported previous surgical asportation of multiple cutaneous acral hyperkeratotic papules, and thyroidectomy for multinodular goiter. Of note, although the mother of the patient (dead at the time of our visit) never received a CS/PHTS diagnosis, the patient was able to report that she had multiple lipomas. In the presence of multifocal oral papillomatosis, associated with macrocephaly (i.e., two or more major criteria; one must be macrocephaly) genetic testing criteria for CS/PHTS were met [3].

Genetic analyses

The sequencing analysis identified a heterozygous deletion in exon 6, c.562del, p.(Tyr188fs).

The pathogenic variant had never been reported before, either in healthy individuals or in CS/PHTS-affected individuals. It causes the production of a truncated protein with a premature stop after 11 codons (p.Tyr188fs). The new protein was likely non-functional, and, according to the in-silico programs, it had a pathogenic effect. The mutation c.562del, p.(Tyr188fs), in conclusion, should be considered a novel pathogenic variant.

Based on this result, the patient entered a cancer surveillance program as indicated for patients with PTEN pathogenic variants (Table 5).

Gingival overgrowths never interfered with the patient’s daily habits, and she never had surgical treatments to remove them. The patient was provided with clinical monitoring for the gingival lumps as well as being provided with cancer surveillance.

3.1.3. Patient 4

A 46-year-old man (Patient 4) was referred to our clinic by the dentist for the evaluation and treatment of lumps of the right lateral margin of the tongue and of the mucosal side of the lower lip.

Clinical examination

At the oral examination, in addition to the lesions reported by the dental practitioner, a verrucous aspect and mild hypertrophy of the gingiva surface was also observed. The clinical aspect was of multiple and sessile papules, with smooth surfaces, white–pink color, and of different sizes (<5 mm), showing a cobblestone pattern.

The patient reported previous excisions with pathological reports consistent with papillomatosis.

The gingival hypertrophy was not consistent with plaque-related disease, although the oral hygiene was poor. Similarly, the drug history was negative, and the gingival hypertrophy could not be drug-related (Figure 5a–c).

The patient presented macrocephaly (head circumference 60.5 cm; >99th percentile; +3.8 SD), cutaneous lesions (crusted nevus at the back, schwannoma (1 cm) on the second toe of the left foot). In his medical history he had thyroidectomy for goiter, and several gastric and colon hyperplastic polyps.

The patient did not meet the revised clinical diagnostic criteria for CS/PHTS, but he already had been submitted to genetic analysis revealing a PTEN mutation.

Genetic analyses

Through the Single Strand Conformation Polymorphism (SSCP) and direct sequencing on peripheral blood of the patient, the c.179del mutation, with stop formation at codon 98, was identified p.(Lys60fs). The mutation should be considered pathogenic for PHTS, and tailored cancer surveillance had already been set.

During our clinical follow-up, 4 years after the first assessment, the patient complained about very large lumps of the gingiva, hindering proper oral hygiene, and quite a large overgrowth of the lateral margin of the tongue (Figure 5d–i). We performed surgical excisions, with the restoration of a physiological and hygienically maintainable gingival profile (Figure 5j–o). Due to previous genetic testing revealing the PTEN mutation at time of our first visit, the patient was already on a cancer surveillance program when he first came to our clinic.

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