Activated phosphoinositide-3-kinase delta syndrome (APDS) is a rare primary immunodeficiency caused by gain-of-function mutations in the PIK3CD gene, resulting in the hyperactivation of the PI3K-Akt-mTOR pathway and subsequent immune dysregulation. Although recurrent sinopulmonary infections are typical, cutaneous manifestations remain poorly characterized. Nummular dermatitis is an uncommon presentation in this context and may reflect the underlying inflammatory imbalance. A 17-year-old female patient with genetically confirmed APDS (heterozygous PIK3CD c.3061G>A; p.Glu1021Lys) presented with erythematous papules that evolved into tense bullae on the lower limbs following an insect bite. Over subsequent weeks, multiple well-defined, coin-shaped eczematous plaques developed on the extremities and trunk, consistent with nummular dermatitis. The patient had a history of recurrent respiratory infections, chronic sinusitis, and otitis media, managed with intravenous immunoglobulin and prophylactic antibiotics. Topical betamethasone with fusidic acid and oral antihistamines produced partial improvement, though intermittent relapses occurred during follow-up. No systemic symptoms or new infectious complications were identified. This case represents an unusual dermatologic manifestation of APDS, where a minor external trigger led to persistent eczema-like lesions. Dysregulated PI3K-Akt-mTOR signaling may amplify local inflammation and impair epidermal barrier recovery. Recognition of atypical or chronic dermatitis in immunodeficient patients is crucial for early diagnosis, targeted treatment, and multidisciplinary management. Reporting such cases expands the clinical spectrum of APDS and underscores the importance of considering immune dysregulation in persistent cutaneous disorders.

Deficiency of dedicator of cytokinesis 8 (DOCK8) is a combined immunodeficiency characterized by severe atopic dermatitis, recurrent infections, and elevated serum immunoglobulin E (IgE) levels. Following genetic confirmation, early hematopoietic stem cell transplantation (HSCT) is the treatment of choice. We report a 7-year-old girl who presented with refractory atopic dermatitis and recurrent sinopulmonary infections. Laboratory evaluation revealed markedly elevated total IgE, lymphopenia, decreased memory B cells, and poor vaccine responses. Whole exome sequencing identified a previously unreported homozygous nonsense mutation in the DOCK8 gene (c.5382C>A; p.Tyr1794*). Functional validation was achieved through flow cytometry, which demonstrated significantly reduced DOCK8 protein expression. The patient underwent successful HSCT from a fully matched (10/10) HLA-compatible donor following conditioning with fludarabine and treosulfan. At 1 year follow-up, full donor chimerism was achieved, and the patient remained in remission. This case highlights a novel pathogenic variant in DOCK8 deficiency and demonstrates curative success following definitive diagnosis and timely HSCT.

Young syndrome, also named sinusitis-infertility syndrome, is named after urologist Dr. Donald Young who first observed this condition. It is a rare inherited syndrome similar to Kartagener syndrome and often presents in middle-aged men with chronic rhinosinusitis, reduced fertility due to azoospermia, and bronchiectasis. Its prevalence is comparable to Klinefelter syndrome and is one of the causes of both chronic sinopulmonary infections and azoospermia. Spermatogenesis is normal, and the reduced fertility is due to obstruction of sperm transport down the genital tract.[1] Individuals born with this disorder have normally functioning lungs but tend to produce thick, viscous mucus, which also traps sperms in epididymis affecting their movement. The azoospermia is due to functional obstruction of sperm transportation down the epididymis.[2]

Hyper-IgE syndrome (HIES) is a rare, primary immunodeficiency distinguished by the clinical triad of atopic dermatitis, recurrent skin staphylococcal infections, and recurrent pulmonary infections. Furthermore, there are elevated IgE levels of early-onset in primary childhood. David et al. first described reported "Job syndrome" in 1966 in two patients with eczema, recurrent pulmonary infections, and cold lung abscesses. Later, in 1972, Buckley et al. reported the association of this condition with increased serum immunoglobulin E (hyper-IgE) levels and a series of phenotypic features called HIES. The HIES is classified into 2 types.  Type I: Autosomal dominant hyper-IgE syndrome (AD-HIES), in which patients have abnormalities in different systems, including the immune system, connective tissue, skeletal and vascular among others. Type II: Autosomal recessive hyper-IgE syndrome (AR-HIES), which also affects the immune system, manifesting in high IgE, recurrent skin and lung infections, sensitivity to viral infections such as molluscum contagiosum, and central nervous system (CNS) involvement, but does not have musculoskeletal alterations. Most recently, the International Union of Immunology Societies describes primary immunodeficiencies (PID) with well-defined syndromes as AD-HIES (Job syndrome) and 3 subtypes of AR-HIES that do not present skeletal or pneumatoceles alterations. These are further subdivided into TYK2 deficiency, DOCK8 deficiency, according to a molecular abnormality, and one of unknown origin.[1][2][3]

Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome characterized by neutropenia and pancreatic insufficiency. The current understanding of immune function in SDS is limited. We performed a retrospective study of the US-based Shwachman-Diamond Syndrome Registry (SDSR) to characterize the immunological profile of patients with SDS. Data were obtained from chart review of patients with biallelic mutations in SBDS enrolled on the SDSR (n = 223) or followed clinically at participating institutions with local IRB approval (n = 6). Immunological data were available from 409 time points on 98 individuals with SDS at healthy time points. We identified limited immune deficits, largely quantitative changes in the B-cell compartment in a subset of patients with SDS including low absolute B cells in 31% of patients and low IgM in 30% of patients. Patients with SDS with low B cells may be at increased risk for sinopulmonary, skin or soft tissue infections particularly if they also have low IgG levels. These data support a baseline immunological evaluation, including a full blood count, lymphocyte subpopulations and immunoglobulin levels, for patients with SDS. However, it is reasonable to reserve more detailed assessments for patients with recurrent or severe infections.

Activated phosphoinositide 3-kinase δ syndrome 1 (APDS1) is a combined immunodeficiency caused by monoallelic gain-of-function mutations in the PIK3CD gene. Patients with APDS1 have significant sinopulmonary involvement, lymphoproliferation, and autoimmune manifestations. We analyzed the clinical profile, treatment, and outcomes of five patients with APDS1. A total of 556 patients were diagnosed with inborn errors of immunity at our center between February 2017 and October 2025. Five patients had APDS1, confirmed by next-generation sequencing. Their records were analyzed in detail. The male-to-female ratio was 4:1. The mean age at symptom onset and at diagnosis was 14.8 and 62 mo, respectively. The age at onset of infections (mean age: 26 mo) preceded lymphoproliferation (mean age: 36 mo). Sinopulmonary infections (n = 3), recurrent gastroenteritis (n = 2), oral candidiasis (n = 1), and meningoencephalitis (n = 1) were the most commonly noted infections. Lymphoproliferation was seen in four patients, the most common being cervical lymph node enlargement (n = 4), followed by adenotonsillar hypertrophy (n = 3) and chronic splenomegaly (n = 3). Three of these patients with lymphoproliferation had Epstein-Barr viremia. Inflammatory colitis (n = 1) was the sole autoimmune manifestation noted in our cohort. Lymphocyte subset analysis showed increased CD8 cells and a reversal of the CD4:CD8 ratio (n = 4). Therapy included antibiotic prophylaxis (n = 5), intravenous immunoglobulin replacement therapy (n = 3), steroids (n = 3), mycophenolate mofetil (n = 1), and sirolimus (n = 1). Presently, four patients are alive and doing well, while one child is lost to follow-up. To the best of our knowledge, this is the first case series of APDS1 from the Indian subcontinent. We observed a significant delay in the diagnosis of these patients highlighting the need for raising awareness regarding this entity among pediatricians and primary care physicians.

Stiff-person syndrome (SPS) is a rare autoimmune neurologic disorder characterized by progressive rigidity and spasms, while common variable immunodeficiency (CVID) features hypogammaglobulinemia and recurrent infections. Their coexistence complicates management by requiring autoimmune suppression without further compromising host defense. A 54-year-old man with CVID, diagnosed based on hypogammaglobulinemia (IgG 386 mg/dL) and recurrent sinopulmonary infections, subsequently developed SPS with progressive truncal and limb stiffness, causing gait impairment and dyspnea. He experienced a severe aspergillus pneumonia, and examination showed finger clubbing and resting hypoxemia. Pulmonary function testing demonstrated moderate airflow obstruction with distal airway involvement. Chest radiography later revealed an elevated left hemidiaphragm, consistent with respiratory muscle dysfunction in SPS. Combined therapy with intravenous immunoglobulin (IVIG) and rituximab was initiated, yielding meaningful improvement in stiffness and a reduction in respiratory infections. After a motor vehicle accident with spinal fusion, the patient reported worsening exertional dyspnea and variable IgG troughs; treatment was transitioned to subcutaneous immunoglobulin (SCIG) 10% with rHuPH20 to maintain steadier IgG levels. This case emphasizes the importance of immunologic evaluation in refractory SPS and demonstrates that combined IVIG and rituximab can provide functional benefit while addressing CVID. Transition to SCIG may stabilize IgG exposure and sustain clinical gains. A timeline of diagnoses and treatments highlights the interplay between autoimmunity and hypogammaglobulinemia and supports a tailored, multidisciplinary strategy.