patient is the only daughter of non-consanguineous parents of Italian origin. At the age of 5 years, she had repeated episodes of hematochezia, which progressively evolved into chronic bloody mucous diarrhea lasting for over 4 weeks (9). When the girl was firstly evaluated at 5.5 years of age, physical examination was normal, and growth was regular. Her family and personal history were unremarkable, without any opportunistic or severe infection. Stool culture for bacteria and stool tests for viruses and parasites were negative. Fecal calprotectin showed repeatedly elevated results (>2,100 μg/g, normal value < 50 μg/g), while C-reactive protein and erythrocyte sedimentation rate were normal. Anti-neutrophil cytoplasmic antibodies (ANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA) were negative. Sugar intestinal permeability was markedly altered (lactulose/mannitol ratio 0.09, normal value < 0.03). Upper and lower gastrointestinal digestive endoscopy showed numerous small nodules throughout the entire gastrointestinal tract from the stomach to the rectum (Figures 1A–F), whose histopathologic features were consistent with the diagnosis of NLH (Figures 1G–I). No signs of chronic intestinal inflammation or autoimmune enteropathy, such as enterocyte apoptosis, were observed in the multiple biopsies taken at endoscopy.

Whole-exome sequencing with phenotype-driven analysis was performed, focusing on genes primarily implicated in immunological diseases (11, 12), revealing the presence of the heterozygous variant p.Glu525Gly (c.1574A>G) in the PIK3CD gene. Sanger sequencing confirmed the presence of this variant, and segregation analysis demonstrated its de novo occurrence (Figures 2A,B). The variation affects the same codon of two previously reported PIK3CD variants causing APDS, namely, c.1573G>A, p.(Glu525Lys) and c.1573A>C, p.(Glu525Ala) (Figure 2C) (13, 14). It has not been identified previously, and it is absent from the largest allele frequency databases (gnomAD, EVS, and 1000 Genomes Project).

case of a girl with isolated diffuse NLH (extending from the stomach to the rectum) caused by activated PI3Kδ syndrome (APDS) due to the novel p.Glu525Gly variant in PIK3CD

The gain-of-function effect of the variant was confirmed by demonstration of over activation of the Akt/mTOR pathway in the patient's cells. APDS diagnosis led to treatment with sirolimus, which resulted in the complete remission of NLH and in the prevention of extra intestinal complications. In conclusion, we identify APDS as a novel cause of isolated NLH and suggest that patients with severe pan-enteric NLH should be screened for this disorder that may not be apparent on first-line immunological testing.