A rare CTSC mutation in Papillon-Lefèvre Syndrome results in abolished serine protease activity and reduced NET formation but otherwise normal neutrophil function

Papillon-Lefèvre Syndrome (PLS) is an autosomal recessive monogenic disease caused by loss-of-function mutations in the CTSC gene, thus preventing the synthesis of the protease Cathepsin C (CTSC) in a proteolytically active form. CTSC is responsible for the activation of the pro-forms of the neutrophil serine proteases (NSPs; Elastase, Proteinase 3 and Cathepsin G), suggesting its involvement in a variety of neutrophil functions. In PLS neutrophils, the lack of CTSC protease activity leads to inactivity of the NSPs. Clinically, PLS is characterized by an early, typically pre-pubertal, onset of severe periodontal pathology and palmoplantar hyperkeratosis. However, PLS is not considered an immune deficiency as patients do not typically suffer from recurrent and severe (bacterial and fungal) infections. In this study we investigated an unusual CTSC mutation in two siblings with PLS, a 503A>G substitution in exon 4 of the CTSC gene, expected to result in an amino acid replacement from tyrosine to cysteine at position 168 of the CTSC protein. Both patients bearing this mutation presented with pronounced periodontal pathology. The characteristics and functions of neutrophils from patients homozygous for the 503A>G CTSC mutation were compared to another previously described PLS mutation (755A>T), and a small cohort of healthy volunteers. Neutrophil lysates from patients with the 503A>G substitution lacked CTSC protein and did not display any CTSC or NSP activity, yet neutrophil counts, morphology, priming, chemotaxis, radical production, and regulation of apoptosis were without any overt signs of alteration. However, NET formation upon PMA-stimulation was found to be severely depressed, but not abolished, in PLS neutrophils.

Punctate Palmoplantar Keratoderma

A 5-year-old caucasian boy, born of non-consanguineous parents, was referred to the dermatology department due to palmar hiperlinearity and multiple 2-3 mm hyperkeratotic circular lesions in the soles (Fig. 1). The remaining physical examination was unremarkable. There was a family history of palmoplantar hyperkeratosis in the mother and maternal grandfather. To spare the child, a punch skin biopsy was taken from his mother. Pathology revealed an epidermis with irregular acanthosis and orthokeratotic hyperkeratosis, without other morphologic alterations (Fig. 2). Clinical aspect of the lesions associated with a positive family history and histologic findings allowed the diagnosis of punctate palmoplantar keratoderma. Satisfactory results were achieved with urea 20% cream and emollient applied to the soles. [...]

Papillon-lefevere syndrome-Consanguity as a risk factor in siblings (Case series)

Papillon-Lefevere syndrome is a very rare autosomal recessive trait characterized by palmoplantar hyperkeratosis and severe generalized early-onset periodontitis leading to premature loss of primary and permanent dentitions. Various etiopathogenesis factors are associated with syndrome. The palmoplantar keratoderma typically has its onset between the ages of 1 and 4 years and severe periodontitis starts at age of 3-4 years. A dentist plays an important role in early diagnosing and preserving remaining teeth in oral cavity. This case series describes three cases of PLS in siblings with consanguineously married parents. All siblings in the family were affected which makes this a rare case.

Oral Phenotype and Salivary Microbiome of Individuals With Papillon–Lefèvre Syndrome

Papillon–Lefèvre syndrome (PLS) is an autosomal recessive rare disease, main characteristics of which include palmoplantar hyperkeratosis and premature edentulism due to advanced periodontitis (formerly aggressive periodontitis). This study aimed to characterize the oral phenotype, including salivary parameters, and the salivary microbiome of three PLS sisters, comparatively. Two sisters were toothless (PLSTL1 and PLSTL2), and one sister had most of the teeth in the oral cavity (PLST). Total DNA was extracted from the unstimulated saliva, and the amplicon sequencing of the 16S rRNA gene fragment was performed in an Ion PGM platform. The amplicon sequence variants (ASVs) were obtained using the DADA2 pipeline, and the taxonomy was assigned using the SILVA v.138. The main phenotypic characteristics of PLS were bone loss and premature loss of primary and permanent dentition. The PLST sister presented advanced periodontitis with gingival bleeding and suppuration, corresponding to the advanced periodontitis as a manifestation of systemic disease, stage IV, grade C. All three PLS sisters presented hyposalivation as a possible secondary outcome of the syndrome. Interestingly, PLST salivary microbiota was dominated by the uncultured bacteria Bacterioidales (F0058), Fusobacterium, Treponema, and Sulfophobococcus (Archaea domain). Streptococcus, Haemophilus, and Caldivirga (Archaea) dominated the microbiome of the PLSTL1 sister, while the PLSTL2 had higher abundances of Lactobacillus and Porphyromonas. This study was the first to show a high abundance of organisms belonging to the Archaea domain comprising a core microbiome in human saliva. In conclusion, a PLST individual does have a microbiota different from that of the periodontitis’ aggressiveness previously recognized. Due to an ineffective cathepsin C, the impairment of neutrophils probably provided a favorable environment for the PLS microbiome. The interactions of Bacteroidales F0058, Caldivirga, and Sulfophobococcus with the microbial consortium of PLS deserves future investigation. Traditional periodontal therapy is not efficient in PLS patients. Unraveling the PLS microbiome is essential in searching for appropriate treatment and avoiding early tooth loss.

Rare Genetic Disorders Affecting the Periodontal Supporting Tissues in Adolescence

In adolescents periodontal destruction may be the primary manifestation of an as yet unrecognized rare systemic disease, and it may be up to the periodontist to make the correct tentative diagnosis. Many genetic diseases that present with primary periodontal manifestations in adolescence affect immune function, sometimes with only mild or absent systemic features. They include periodontal Ehlers-Danlos syndrome (lack of attached gingiva, various connective tissue abnormalities), Papillon-Lefèvre syndrome (palmoplantar hyperkeratosis), and plasminogen deficiency (fibrin deposition within mucous membranes). Other immune disorders with severe periodontitis manifesting in adolescence are usually diagnosed in early childhood due to unmistakeable systemic features. They include Cohen syndrome (developmental disorder, truncal obesity, and microcephaly), Hermansky-Pudlak Syndrome (oculocutaneous albinism, bleeding diathesis, and other systemic manifestations), glycogen storage disease type 1b, and Chediak-Higashi syndrome (pyogenic infections, albinism, and neuropathy). The structural integrity of periodontal tissue is affected in genodermatoses such as Kindler syndrome, a type of epidermolysis bullosa. In primary hyperoxaluria, inflammatory periodontal destruction is associated with renal calculi. Breakdown of periodontal tissues independent of dental plaque biofilm-induced periodontitis is found in hypophosphatasia (highly variable skeletal hypomineralization) or isolated odontohypophosphatasia, hypophosphatemic rickets and primary hyperparathyroidism. Finally, alveolar osteolysis mimicking localized periodontitis may be due to neoplastic processes, e.g., in neurofibromatosis type 1 (typical skin features including café au lait macules and neurofibromas), Langerhans cell histiocytosis (locally destructive proliferation of bone marrow-derived immature myeloid dendritic cells), and Gorham-Stout disease (diffuse cystic angiomatosis of bone).

Palmo-plantar hyperkeratosis associated with HTLV-1 infection: a case report

Background Palmoplantar hyperkeratosis is a cutaneous manifestation that had not been clearly associated with infection by the human T-cell lymphotropic virus, which is a retrovirus that in most cases does not develop clinical pathologies and its symptoms may be undetected. The skin is one of the most affected organs, however until now only seborrheic dermatitis, xerosis/ichthyosis and infective dermatitis associated with HTLV-1 have been described as cutaneous clinical manifestations of this disease. Case presentation We present the case of a 36-year-old male patient with serologically documented HTLV-1 infection, who presented symptoms of diarrhea, malabsorption due to Strongyloides stercoralis, and in whom a physical examination revealed an association with generalized xerosis and palmoplantar keratoderma confirmed by skin biopsy. Other infectious etiologies and malignancy were ruled out. This clinical manifestation was managed with dermal hydration, and skin care which improved the thickened skin and make it less noticeable. Conclusions According to our experience, this is the first reported case of palmoplantar keratoderma associated with a human lymphotropic virus infection. This is a skin manifestation that has not been confirmed in conjunction with HTLV-I before. This implies that palmoplantar keratoderma is a new clinical manifestation of this infection, that should be considered in the initial approach of patients in endemic areas with these dermatological characteristics.

Orthodontic Treatments of Papillon-Lefevre Syndrome: Two Case Reports

Papillon-Lefevre syndrome (PLS) is a rare autosomal recessive disorder characterized by palmoplantar hyperkeratosis and early onset of severe destructive periodontitis causing premature loss of both deciduous and permanent dentitions at a young age. In this article two cases of patients with Papillon-Lefevre syndrome in late mixed dentition are presented. The objective of these case reports was to illustrate that under a controlled regime of periodontal treatment, orthodontic treatment is possible in patients with Papillon-Lefevre syndrome. In both cases, the deciduous dentition was lost prematurely shortly after eruption. The permanent teeth erupt without any guidance, and this can lead to loss of space, crowding, and collapse of the dental arch. The aim of the treatment was to expand the arch, create space to allow normal eruption of the permanent teeth, and stabilize the occlusion to help the patient achieve a normal facial appearance rather than the collapsed appearance caused by early extractions. KEYWORDS: Papillon-Lefevre Syndrome, Orthodontics, Mixed dentition, Case reports

Novel Pathogenic Mutations of FERMT1 in two Chinese Kindler Syndrome Families

Background: Kindler syndrome (KNDLRS) is a very rare autosomal recessive disorder characterized by bullous poikiloderma with photosensitivity. Loss-of-function mutations in FERMT1, which located on chromosome 20p12.3, were responsible for KNDLRS. Numerous mutations in FERMT1 have been reported to be associated with KNDLRS. Results: The present study reported two Chinese KNDLRS families, and affected individuals from both families presented with poikiloderma, palmoplantar hyperkeratosis, and diffuse cigarette paper like atrophy on hands. Skin biopsy of the proband from family 2 showed atrophy of epidermis, hyperkeratosis, dilated blood vessels in upper dermis, and microbubbles at the dermis and epidermis junction. Medical Whole Exome Sequencing V4 combined with Sanger sequencing revealed mutations in FERMT1 with affected individuals. Compound heterozygous nonsense mutations (c.193C>T, c.277C>T) were found with family 1, and a homozygous frameshift mutation (c.220delC) was observed in family 2. According to the clinical features and genetic analysis, KNDLRS was diagnosed in two Chinese families. Conclusions: This study revealed two novel pathogenic mutations in FERMT1 that caused KNDLRS and briefly summarized all pathogenic mutations in FERMT1 that have been documented via the PubMed.

Potential Role of the Mitochondria for the Dermatological Treatment of Papillon-Lefèvre

The Papillon–Lefèvre syndrome (PLS) is a rare autosomal recessive disorder caused by mutations in the Cathepsin C (CTSC) gene, characterized by periodontitis and palmoplantar hyperkeratosis. The main inflammatory deficiencies include oxidative stress and autophagic dysfunction. Mitochondria are the main source of reactive oxygen species; their impaired function is related to skin diseases and periodontitis. The mitochondrial function has been evaluated in PLS and mitochondria have been targeted as a possible treatment for PLS. We show for the first time an important mitochondrial dysfunction associated with increased oxidative damage of mtDNA, reduced CoQ10 and mitochondrial mass and aberrant morphologies of the mitochondria in PLS patients. Mitochondrial dysfunction, determined by oxygen consumption rate (OCR) in PLS fibroblasts, was treated with CoQ10 supplementation, which determined an improvement in OCR and a remission of skin damage in a patient receiving a topical administration of a cream enriched with CoQ10 0.1%. We provide the first evidence of the role of mitochondrial dysfunction and CoQ10 deficiency in the pathophysiology of PLS and a future therapeutic option for PLS.