A number sign (#) is used with this entry because of evidence that immunodeficiency-133 with ectodermal dysplasia with or without peripheral neuropathy (IMD133) is caused by heterozygous mutation in the ITPR3 gene (147267) on chromosome 6p21.

Immunodeficiency-133 with ectodermal dysplasia with or without peripheral neuropathy (IMD133) is a multisystem disorder characterized primarily by immunodeficiency manifest as combined immunodeficiency (CID) or common variable immunodeficiency (CVID) and features of ectodermal dysplasia, notably dysmorphic conical incisors and sparse hair. Additional features may include motor and speech developmental delay, poor growth, and demyelinating or axonal peripheral neuropathy. Affected individuals present in the first months or years of life with recurrent bacterial, viral, and fungal infections associated with T-cell lymphopenia and T-cell dysfunction. B-cell abnormalities and hypogammaglobulinemia may also be present. Some patients have features of immune dysregulation, such as immune thrombocytopenia, autoimmune hemolytic anemia, and lymphoproliferation. Hematopoietic stem cell transplant can resolve the immunologic deficits (Neumann et al., 2023; Molitor et al., 2024; Blanco et al., 2025).

Neumann et al. (2023) reported 2 unrelated male patients, each born of nonconsanguineous Caucasian parents, with primary immunodeficiency. P1, who had a more severe phenotype, was a 12-year-old boy who presented at 3 months of age with bronchitis and bacterial superinfection with subsequent recurrent viral respiratory tract infections and severe postnatal growth delay (-4 SD). Additional features included oral candidiasis, diaper dermatitis, molluscum contagiosum, thin brittle hair, delayed deciduous eruption of conical teeth, low muscle mass, frontal bossing, and hepatosplenomegaly. He showed mild developmental delay with walking at 16 months. Laboratory studies showed B- and T-cell lymphopenia and hypergammaglobulinemia. There were normal numbers of naive T cells and normal T-cell proliferative responses. Bone marrow biopsy at 2 years of age showed normocytic anemia and leukopenia with absolute lymphopenia. P1 was diagnosed with combined immunodeficiency (CID) and started on subcutaneous immunoglobulin replacement therapy; he later underwent allogenic hematopoietic stem cell transplant at age 6 years. Complications included immune hemolysis and endobronchial EBV-induced leiomyomas; he also had bilateral avascular necrosis of the hip at age 10. At age 11, he presented with a sensorimotor peripheral neuropathy consistent with axonal Charcot-Marie-Tooth disease. At 6 years post-transplant, he had full donor chimerism and good immune reconstitution, but severely impaired lung function. P2 was a 36-year-old man who presented at 18 years of age with idiopathic immune thrombocytopenia necessitating splenectomy. At age 24 years, he had weight loss, fatigue, and jaundice due to Coombs-positive autoimmune hemolytic anemia (AIHA). Prior to the onset of AIHA, he had gastrointestinal infection with Blastocystis hominis and respiratory infection with Mycoplasma pneumonia, and later had recurrent episodes of sinusitis treated with antibiotics. Additional features included invasive pulmonary Aspergillosis, granulomatous and lymphocytic interstitial lung disease, enteropathy with lymphocytic infiltrate, and CMV infection. Immunophenotyping showed low IgG and decreased switched memory B cells, He was diagnosed with common variable immunodeficiency (CVID) and treated with IV Ig.

Molitor et al. (2024) reported 4 unrelated patients with a complex immunodeficiency syndrome with variable multisystem manifestations associated in each case with the same de novo heterozygous recurrent missense mutation in the ITPR3 gene (R2524C; 147267.0003). The patients, who ranged from 3 to 19 years of age, presented in the first months or years of life with recurrent bacterial and viral infections, including upper respiratory tract infections, pneumonia, pneumococcal meningitis, stomatitis, mononucleosis, CMV, EBV, and mastoiditis. P4 had low TRECs identified through a neonatal screening program. Two patients had severe varicella infections, including 1 that occurred post-vaccination. Laboratory studies showed profound CD4+ T-cell lymphopenia and moderate CD8+ T-cell lymphopenia, with decreased numbers of naive CD4+ and CD8+ T cells, elevated levels of effector memory T cells, and decreased numbers of CD4+ recent thymus emigrants. There was variably impaired T-cell proliferation upon stimulation with anti-CD3 or PHA. B and NK cell numbers were decreased or at the lower end of normal. Most Ig levels were normal, although some had decreased IgM and there was a poor response to polysaccharide vaccination. A cytokine panel in P2 showed increased levels of IL1B (147720), IL2R (147730), TNFA (191160), and gamma-interferon (IFNG; 147570). Autoantibodies were not detected. Of note, P4 had pancytopenia, hepatosplenomegaly, and generalized lymphadenopathy. Lymph node and bone marrow biopsies showed atypical lymphohistiocytic proliferation suggestive of Rosai-Dorfman syndrome. The patients also had an ectodermal phenotype, with variable features such as sparse and thin scalp hair and eyelashes, light eyebrows, dry skin, abnormal nail beds, and dysmorphic conical primary incisors. Variable motor and speech developmental delay was also observed, and 2 had poor growth with short stature. The oldest patient (P3) developed a demyelinating polyneuropathy consistent with CMT. Three patients underwent successful hematopoietic stem cell transplant (HCT).

Blanco et al. (2025) reported 5 unrelated patients, all born of unrelated parents, who presented in early childhood with combined immunodeficiency (CID). They mainly had recurrent viral and bacterial respiratory infections, but also nonrespiratory viral infections, mainly with DNA viruses. Three patients had features of immune dysregulation, including immune thrombocytopenia, lymphoproliferation, and atopy. Immunologic work-up showed lymphopenia with extremely low T cells and moderately low B cells associated with mild hypogammaglobulinemia, although response to vaccination was preserved. TRECs and naive T cells were low, and memory and effector T cells were increased, consistent with cellular activation and exhaustion. Regulatory T cells were reduced, invariant NK T cells were absent, and there was a profound reduction in gamma/delta T cells. TCR V beta repertoires were restricted and T cells showed impaired intracellular signaling, decreased proliferation, and downregulation of metabolic and mitochondrial pathways. Two patients underwent hematopoietic stem cell transplantation at 9 and 3 years of age, and 2 others developed EBV-driven lymphomas at 22 and 12 years of age, requiring chemotherapy followed by hematopoietic stem cell transplant; the fifth patient was clinically well on conservative management with antibiotic prophylaxis at 18 years of age. Variable features of ectodermal dysplasia were observed in all but 1 patient, and included micro- and hypodontia with conical incisors, thin hair and nails, and hypohidrosis. Patients P2 had features of a chronic motor neuronopathy, and P5 of demyelinating motor and sensory neuropathy.

The heterozygous mutations in the ITPR3 gene that were identified in patients with IMD133 by Molitor et al. (2024) and Blanco et al. (2025) occurred de novo. Blanco et al. (2025) reported that ectodermal dysplasia and peripheral neuropathy in patients with IMD133 showed incomplete penetrance and variable expressivity.

In 2 unrelated patients (P1 and P2), each born of nonconsanguineous parents, with IMD32, Neumann et al. (2023) identified compound heterozygous missense variants in the ITPR3 gene: R2524C (147267.0003), F1628L (147267.0004), and R1850Q (147267.0005). The variants were found by whole-exome sequencing and confirmed by Sanger sequencing. The R2524C variant occurred de novo in P1. The heterozygous R1850Q polymorphic variant (frequency of 6% in public databases) was inherited from the unaffected fathers of both patients; the F1628L variant was inherited from the unaffected mother of P2. P2 had a much milder phenotype than P1. Patient fibroblasts and peripheral blood mononuclear cells (from P2) showed decreased ITPR3 protein levels compared to controls, as well as dysregulated intracellular calcium homeostasis and impaired calcium flux in response to TCR stimulation. The impaired TCR signaling in immune cells was associated with decreased NFAT1 (600490) translocation to the nucleus, decreased ERK phosphorylation, and reduced proliferation of both T and B cells.

In 4 unrelated patients (P1-P4) with IMD133, Molitor et al. (2024) identified a recurrent de novo heterozygous R2524C mutation in the ITPR3 gene. Fibroblasts and peripheral blood cells derived from 3 of the patients showed normal levels of mutant ITPR3 mRNA, whereas fibroblasts derived from one of the patients showed decreased ITPR3 protein levels. Functional studies in patient fibroblasts and T cells and Jurkat T cell lines engineered to express the R2524C mutation showed that the mutation caused defective calcium flux responses in a dominant-negative manner. Fibroblasts from P1 showed decreased ITPR3 subcellular localization to the endoplasmic reticulum (ER) and mitochondria. RNA-seq analysis on immune cells from P2 indicated altered calcium signaling and mitochondrial malfunction. P3, a 19-year-old man, was the only patient with peripheral neuropathy.

In 5 unrelated patients with IMD133, Blanco et al. (2025) identified de novo heterozygous missense mutations in the ITPR3 gene: A196T (147267.0006), I2506N (147267.0007), R2524C (147267.0003), and R2524H (147267.0008). The mutations, which were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, were not present in dbSNP(151), the 1000 Genomes Project, or gnomAD (v4.1.0) databases. Patient lymphoblastoid cells, patient skin fibroblasts, and HEK293 cells transfected with the mutations showed normal levels of mutant ITPR3 mRNA and stable expression of the mutant ITPR3 protein at levels similar to wildtype. Patient T cells showed altered calcium homeostasis, impaired calcium signaling after stimulation, and depleted intracellular ER calcium stores. No significant changes in cytosolic calcium dynamics were observed in patient fibroblasts compared to controls, suggesting cell-specific differences or compensatory mechanisms. Further studies in gene-edited Jurkat T cell lines showed that the A196T, I2506N, and R2524C mutations acted in a dominant-negative manner to impair ITPR3 channel function by causing leakiness and depletion of intracellular calcium stores, resulting in impaired store-operated Ca(2+) entry (SOCE) in T cells. Overall, the findings indicated that the de novo missense ITPR3 variants identified in the patients resulted in the expression of dominant-negative proteins that interfere with the function of IP3R heterotetramers by causing channel leakiness and impaired calcium dynamics in T cells.