Clinical heterogeneity of Papillon-Lefèvre syndrome: beyond periodontology

Papillon-Lefèvre syndrome (PLS) is classically defined by the association of palmoplantar keratoderma and early-onset aggressive periodontology. However, this binary view masks significant phenotypic variability. Linked to mutations in the cathepsin C (CTSC) gene, this enzymatic deficiency impairs neutrophil function, predisposing patients to manifestations extending beyond the usual oral and dermatological scope. The challenge for the practitioner lies in identifying atypical or paucisymptomatic forms that delay multidisciplinary management.

This study reports four molecularly confirmed cases from two distinct families to illustrate the breadth of the LPS clinical spectrum. The objective is to document unusual presentations, such as inaugural deep infections or fruste forms identified solely through family screening. The authors examine how the diagnosis can be obscured by manifestations mimicking other pathologies or by highly variable clinical severity between members of the same sibling group.

The study is based on the hypothesis that a systematic evaluation, including molecular screening and multifocal imaging, is essential to overcome diagnostic errors. By highlighting this intrafamilial variability, the authors emphasize the need to integrate PLS into the differential diagnosis when faced with recurrent infections or unexplained early dental loss, even in the absence of major cutaneous signs.

Study design and population

This study is a series of clinical case reports involving four patients from two unrelated families, presenting with Papillon-Lefèvre syndrome (PLS) confirmed by molecular diagnosis.

• Family 1 (non-consanguineous): Monozygotic twins. The index case was evaluated at 2 years and 9 months, her twin sister at 2 years and 11 months.
• Family 2 (consanguineous): Two brothers aged 13 and 12 at the time of diagnosis.

Diagnostic protocol and examinations

The methodology is based on a multidisciplinary approach combining clinical evaluation, imaging and biological analyses:

• Imaging and microbiology: For the index case, a contrast-enhanced abdominal CT scan identified an 81x50 mm collection. Culture following surgical drainage isolated a methicillin-sensitive Staphylococcus aureus (MSSA).
• Immunological assessment: A DHR (dihydrorhodamine) test by flow cytometry was performed to evaluate the oxidative burst. The assessment also included the measurement of immunoglobulins (IgG, IgA, IgM, IgE) and the analysis of lymphocyte subpopulations (CD3, CD4, CD8, CD19).
• Genetic analysis: Whole exome sequencing (WES) was performed for the index cases, supplemented by Sanger sequencing for family cascade screening.

Analysis and target variants

Molecular confirmation focused on the identification of pathogenic homozygous variants of the CTSC gene: the c.815G>C (p.Arg272Pro) variant for Family 1 and the c.415G>A (p.G139R) variant for Family 2.

Results: Marked phenotypic heterogeneity

Analysis of these two families highlights considerable clinical variability for identical mutations of the CTSC gene, ranging from life-threatening deep infection to discrete cutaneous forms.

Clinical manifestations and imaging

The index case of Family 1 (Case 1) presented a major purulent collection of 81x50 mm, localized by CT scan in the right iliac fossa and the iliopsoas muscle. Cultures revealed a methicillin-susceptible Staphylococcus aureus (MSSA) infection. In contrast, her monozygotic twin (Case 2), although carrying the same mutation, had no history of deep infection at the time of diagnosis at 2 years and 11 months.

In Family 2, Case 3 illustrated the diagnostic difficulties of LPS: its initial presentation as erythematous squamous plaques led to a misdiagnosis of psoriasis for 13 years, despite recurrent soft tissue abscesses.

Biological and molecular data

Genetic sequencing identified two distinct homozygous variants depending on the families. The hematological assessment revealed marked disparities, notably a massive acute inflammatory response in Case 1.

Periodontal and immunological observations

• Oral and dental involvement: Case 2 already presented gingival recession and premature loss of temporary teeth, inconsistent with his age (2 years 11 months).
• Immune exploration: For Case 1, the DHR (dihydrorhodamine) test showed a normal oxidative burst, allowing to exclude chronic granulomatous disease (CGD) despite the severity of the MSSA abscess.
• Dermatology: Palmoplantar keratoderma ranged from severe forms with lamellar desquamation (Case 1) to simple hyperhidrosis of the feet with mild hyperkeratosis (Case 2).

Discussion: Beyond the classic "Skin-Teeth" phenotype

The results of this study illustrate a striking phenotypic variability within Papillon-Lefèvre syndrome (PLS), even between monozygotic twins sharing the same CTSC variant (c.815G>C). While case no. 1 began with a surgical emergency (an 81x50 mm iliopsoas abscess), his twin sister presented only minor cutaneous and dental signs. This clinical discordance highlights that PLS should no longer be perceived solely as a systematic association of keratoderma and periodontology, but as an immune deficiency with potentially systemic and severe manifestations from a very young age.

The 13-year diagnostic delay observed in the second family (case no. 3), due to a presentation simulating psoriasis, highlights the clinical pitfall represented by this syndrome. Although classic literature often reports hepatic abscesses, the occurrence of a deep iliopsoas abscess as an inaugural sign is remarkable here. These data confirm the IUIS classification, which ranks cathepsin C deficiency among congenital anomalies of phagocyte number or function. The lack of activation of neutrophil serine proteases (elastase, proteinase 3) compromises the intracellular elimination of pathogens, explaining the susceptibility to Staphylococcus aureus infections observed in these patients.

The study remains limited by its small sample size (n=4), inherent to the rarity of the pathology (1 to 4 cases per million). However, the strength of this work lies in the systematic molecular confirmation, which allowed for the identification of fruste or subclinical forms in siblings who would otherwise have escaped diagnosis.

Summary of results

This study demonstrates that Papillon-Lefèvre syndrome (PLS) can manifest as an inaugural deep infection, such as an 81x50 mm iliopsoas abscess identified in a 2-year-old child. The authors highlight a major diagnostic pitfall: a presentation simulating psoriasis led to a 13-year delay in management, reminding that this rare pathology (1 to 4 cases per million) linked to the CTSC gene affects the bactericidal capacity of neutrophils well beyond the oral sphere.

In concrete terms, for the practitioner:

• Think outside the oral cavity: In the presence of aggressive prepubertal periodontology, a dermatological examination is imperative; psoriasis-like lesions or simple plantar hyperhidrosis are frequent markers of PLS.
• Identify the immune status: Any history of recurrent abscesses (cutaneous or visceral) in a young periodontal patient should raise suspicion of a phagocytosis defect linked to cathepsin C.
• Mandatory family screening: Phenotypic variability within the same sibling group requires systematic molecular testing for brothers and sisters, in order to establish early periodontal prophylaxis, even in the absence of overt cutaneous signs.

Technical lexicon of the study

CTSC gene: Located on the 11q14.1–q14.3 locus, it encodes for cathepsin C (dipeptidyl peptidase I). This enzymatic deficiency inactivates neutrophil serine proteases (elastase, proteinase 3, cathepsin G), which compromises the intracellular destruction of pathogens.

DHR (Dihydrorhodamine) test: Flow cytometry assay evaluating the oxidative burst of phagocytes. Used here in an emergency setting to exclude chronic granulomatous disease (CGD) in the presence of a deep Staphylococcus aureus abscess.

Cascade screening: Systematic screening strategy for siblings or family members following the identification of an index case. Essential for identifying subclinical forms or minor phenotypes of the disease.

Palmoplantar keratoderma: Major dermatological manifestation of Papillon-Lefèvre syndrome. It manifests as progressive hyperkeratosis and lamellar desquamation of the palms and soles from early childhood.

Pre-pubertal periodontitis: Aggressive and rapid destruction of the dental supporting apparatus. It results in gingival inflammation, deep pockets and premature loss of primary and permanent teeth.

Iliopsoas abscess: Deep purulent infection affecting the iliopsoas muscle. In this report, it constitutes an atypical and severe inaugural manifestation of the syndrome in a subject under 3 years of age.

WES (Whole-Exome Sequencing): Genomic sequencing technique targeting coding regions. It has identified homozygous pathogenic variants of CTSC, confirming the diagnosis in cases with heterogeneous clinical presentations.

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