PLS is an autosomal recessive disorder with palmoplantar hyperkeratosis, early-onset destructive periodontitis, and premature tooth loss, caused by mutations in CTSC leading to deficiency of cathepsin C. APDS1 is an autosomal dominant disorder due to heterozygous gain-of-function mutations in PIK3CD causing increased PI3K/mTOR/AKT intracellular signaling.
We present 2 siblings with an atypical presentation in which both disorders may be coexisting.
P1 is an 18-year-old male with palmoplantar erythema and hyperkeratosis since early childhood without periodontitis or dentition issues. At 16, he presented in ARDS and a CT chest showing multifocal consolidation, early cavitation, and a pattern suspicious for chronic hypersensitivity pneumonitis from the retinoid dermatological treatment. All infectious investigations were negative. He had lymphopenia and low IgG and IgM. He improved after methylprednisolone pulses and remained asymptomatic for 7 months when he had hypoxemia and a repeat CT showing multifocal nodular opacities and splenomegaly. EBV viral load was high. Despite a course of high-dose steroids, his symptoms and CT worsened with multifocal round opacities and nodules. An open lung biopsy showed histiocytes, CD4+ T cells, and B cells obliterating the normal lung architecture with areas of necrosis and positive EBER staining. Genetic testing showed compound heterozygosity for 2 CTSC variants (a pathogenic and a VUS), heterozygous pathogenic variant in FLG, and heterozygous VUS in PIK3CD. He was treated with rituximab clearing EBV and is on sirolimus. He is asymptomatic but with progressive T cell lymphopenia.
P2 is 19 years old and has palmoplantar erythema and hyperkeratosis but no history of severe infections or periodontic disease. He has normal IgGAME and normal T/B/NK cell subsets. Genetic testing revealed the same variants as P1. They are adopted and thus have no known family history and no possibility for variant segregation or verification of cis vs. trans for CTSC variants.
There are no reports of PLS without periodontitis. The skin manifestations in our patients are characteristic. The FLG variant may be contributing. Functional validation of the PIK3CD missense variant is pending. Tools predict a deleterious change in the protein; it is not in gnomAD and is located near the hotspot for mutations in APDS1.
