## 2 Genetics of Pustular Psoriasis  
Although the first GPP case was reported a century ago, its etiology and detailed pathogenesis have only been discussed within the last ten years (Table 1). It was not until 2011 that IL36 RN was initially discovered as a gene responsible for causing GPP [12; 13]. Since then, a growing number of genetic mutations such as CARD14, AP1S3, MPO, and the SERPIN family have been identified as associated with GPP. However, not all GPP patients carry mutations of these genes, suggesting that there are still other genetic factors to be discovered. These disease-causing genes may participate in common or similar pathogenic molecular pathways [14].  
\begin{table}
\begin{tabular}{c c c c} \hline \hline
**Gene** & **Protein** & **Proposed Effect** & **Proposed GPP Mechanism** \\ \hline _IL36 RN_ & Interleukin-36 receptor antagonist & LOF & Loss of IL-36 antagonism \\ _CARD14_ & Caspase recruitment domain family & GOF & Enhanced NF-kB signaling \\ _AP1S3_ & Adaptor-related protein complex 1 & LOF & Enhanced NF-kB signaling \\ _AP1S3_ & subunit sigma 3 & LOF & Enhanced neutrophil protease activity; \\ _MPO_ & Myeloperoxidase & LOF & decreased neutrophil turnover \\ _SERPINA1_ & Serpin family A member 1 & LOF & Loss of protease inhibitor activity; \\ _SERPINA3_ & Serpin family A member 3 & LOF & Loss of protease inhibitor activity; \\ _STN3A3_ & Butyrophilin subfamily 3 member A3 & LOF & enhanced IL-36 activation \\ _TGFBR2_ & Transforming growth factor \(\beta\) receptor 2 & LOF & Stimulated keratinocytes to \\  & & & produce cytokines \\ \hline \hline \end{tabular}
\end{table}
Table 1: Genetic mutations associated with generalized pustular psoriasis and their proposed effects.  
Ethnic differences in GPP should also take into consideration. For example, pathogenic mutations of AP1S3 have been reported in individuals of European origin but not in Malaysian populations [15; 16], while MPO and SERPINA3 variants were identified in patients of European descent [17; 18]. Associations with other ethnic groups remain to be elucidated.  
The cases of pustular psoriasis are classified into GPP, PPP, and ACH according to the ERASPEN criteria [2]. [PERSON] et al. suggested that PPP and ACH might be separate diseases while still maintaining some overlap [19]. Accordingly, there are prospective phenotype-genotype and multi-omics studies to better recognize the mechanisms of each subgroup. Another study conducted in Italy in a real-life setting revealed the concomitant rate of plaque psoriasis, which was the greatest in GPP and the least in ACH [20]. To distinguish GPP alone from those with PV is quite important since the selection of treatment is based on the disease mechanism and the clinical phenotype, which can include GPP alone, ACH alone, predominate ACH, ACH evolving into GPP, and ACH with GPP.  
Adult-onset immunodeficiency syndrome (AOID) is known as an AIDS-like illness with abnormal interferon-\(\gamma\) (IFN-\(\gamma\))/IL12 signaling. It is associated with high-titer neutralizing antibodies to IFN-\(\gamma\), the controller of numerous pathogens [21]. The majority of cases exhibit skin-related symptoms, such as reactive skin conditions (82%) and infectious skin diseases (45%), with neutrophid dermatoses being the most common among them [21; 22]. A recent study conducted by [PERSON] et al. supports that both GPP and AOID involving pustular reactions are diseases caused by dysregulated proteolytic and apoptotic processes [23]. Clinically and genetically, GPP and AOID are likely to share some common pathogenic mechanisms. To date, there have been no reports of AOID and GPP occurring in the same individuals or within the same families. However, genetic research has found heterozygous variants in the SERPINA3 and SERPINA1 genes in patients with AOID and GPP, respectively [24; 25].