A number sign (#) is used with this entry because of evidence that immunodeficiency-104 (IMD104), usually manifest as T cell-negative (T-), B cell-positive (B+), natural killer cell-positive (NK+) severe combined immunodeficiency (SCID), is caused by homozygous or compound heterozygous mutation in the interleukin-7 receptor gene (IL7R; 146661) on chromosome 5p13.

Immunodeficiency-104 (IMD104) is an autosomal recessive disorder characterized by the onset of recurrent infections in early infancy. Manifestations may include oral thrush, fever, and failure to thrive. Some patients have lymphadenopathy and hepatosplenomegaly, whereas others have absence of lymph nodes and lack a thymic shadow. Laboratory studies show decreased or absent numbers of nonfunctional T cells, normal or increased levels of B cells, variable hypogammaglobulinemia, and normal NK cells. The disorder is caused by a defect in IL7 (146660) signaling due to a mutant IL7 receptor. Hematopoietic stem cell transplantation may be curative (Roifman et al., 2000 and Giliani et al., 2005).

Giliani et al. (2005) provided a detailed review of IL7R deficiency, including discussion of the IL7R gene and its function in the immune system, clinical features of the disorder, and experiences with hematopoietic stem cell transplant as treatment.

For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive SCID, see 601457.

Puel et al. (1998) reported a patient (P1) who presented at age 2 months with gastroesophageal reflux. Despite a Nissen fundoplication and pylorotomy, he continued to cough and had poor weight gain. He also had recurrent otitis, thrush, and a monilial diaper dermatitis. Immunologic evaluation showed elevated IgG and IgA, both of which contained paraproteins. A second unrelated patient (P2) presented at age 1 month with recurrent otitis media resistant to treatment, persistent oral moniliasis, diarrhea, fevers, and poor growth. At the age of 13 months, he developed parainfluenza type 3. Both patients had normal or elevated numbers of CD20+ B cells, greatly diminished CD3+ T cells, and normal or elevated CD16+ NK cells. Proliferation to mitogen and allogeneic cells was defective, but NK-cell killing of K562 target cells was normal. Both patients received a haploidentical bone marrow transplant with which full immunologic reconstitution was achieved; they were clinically well more than 4 years posttransplantation.

Roifman et al. (2000) reported 3 patients from a consanguineous Sicilian family with a primary immunodeficiency. The proband presented at 4 months of age with persistent oral thrush, oral ulcers, and failure to thrive. He had no palpable lymph nodes and no thymic shadow on chest radiograph. His younger brother was diagnosed with a similar condition soon after birth. Both died, presumably in infancy. Their unaffected mother had 5 first cousins, 3 of whom died in infancy from failure to thrive, diarrhea, and fungal and bacterial infections. One of the mother's first cousins presented in infancy with features of the disease, including no lymph nodes, no thymic shadow, and persistent lymphopenia. This patient underwent successful bone marrow transplant and was alive 25 years later. Laboratory studies of the 3 patients (the 2 sibs and their older cousin) showed markedly reduced circulating T cells, an absence of serum Ig in spite of normal B-cell numbers, and preserved NK cell numbers and function.

Giliani et al. (2005) identified 16 patients from 11 unrelated families of various ethnic origins, including European, Israeli, Algerian, and Turkish, with IMD104 due to biallelic mutations in the IL7R gene. Seven of the families were consanguineous; some of the patients and families had previously been reported. The mean age at diagnosis was 4.2 months (range prenatal to 11 months); those diagnosed prenatally were identified through a positive family history. Affected individuals presented with typical features of an immunodeficiency, including fever, recurrent infections, pneumonia, prolonged diarrhea, and failure to thrive. Lymphopenia was a common finding, with markedly decreased numbers of T cells that showed proliferative defects, normal or increased B cells, and normal NK cells. Serum immunoglobulins were often low, although there was variability. All patients were treated with hematopoietic stem cell transplant (HSCT) with mostly successful results and engraftment of donor T cells. However, 3 patients died of complications, including CMV infection.

Lev et al. (2019) identified 5 unrelated infants, all born of consanguineous Muslim parents, who were diagnosed with a primary immunodeficiency though newborn screening due to undetectable T-cell receptor excision circles (TRECs) on dried blood spots. All had lymphopenia with low T-cell numbers, normal B and NK cells numbers, and poor T-cell proliferative responses. Genetic analysis in all infants identified the same homozygous missense variant in the IL7R gene (F40L; see MOLECULAR GENETICS), which was demonstrated to result from a founder effect in this population. Despite the common mutation, the 5 probands showed a heterogeneous clinical course. The most severely affected individuals were P5, who died of sepsis at 47 days of age, and P1, who had significant recurrent infections and underwent successful hematopoietic bone marrow transplant at 8 months of age. The other 3 patients had minimal (P2 and P4) or no (P3) clinical symptoms and were alive and well between 11 and 39 months of age. These 3 patients had normal antibody production to vaccines, including to live vaccines in 2 of the patients. Of note, an unaffected sib of P1 and the unaffected father of P3 were both homozygous carriers of the F40L variant.

Mansour et al. (2022) reported a 1-year-old girl who had recurrent upper respiratory tract infections since birth, oral thrush, bronchiolitis, and a rotavirus infection. During hospitalization for the rotavirus infection, she had a high reticulocyte count, low hemoglobin, and positive direct Coombs test, and she was diagnosed with autoimmune hemolytic anemia. Immunophenotyping demonstrated decreased total lymphocytes with normal numbers of B cells and elevated numbers of natural killer cells. At 12 months of age, she had persistent anemia and severely low numbers of T cells. The patient underwent hematopoietic stem cell transplantation using an HLA-matched relative. Family history was notable for 4 cousins who died in infancy due to a suspected, but undiagnosed, immunodeficiency.

The transmission pattern of IMD104 in the family reported by Roifman et al. (2000) was consistent with autosomal recessive inheritance.

Lev et al. (2019) observed incomplete penetrance and variable expressivity of IMD104 in their families.

In a patient (patient 1) with IMD104 manifest as T-, B+, NK+ SCID originally reported by Puel et al. (1998), Puel and Leonard (2000) identified a homozygous splice site mutation in the IL7R gene (146661.0007). Each unaffected parent was heterozygous for the splice site mutation. Patient cells showed no detectable IL7R mRNA, consistent with complete IL7R deficiency. This patient had originally been reported to be homozygous for 2 missense variants in the IL7R gene (T66I; 146661.0001 and I138V; 146661.0002), but functional studies of these variants did not reveal significant defects and the variants were present in healthy controls, indicating that T66I and I138V represent polymorphisms and were not responsible for the disease.

Puel et al. (1998) reported a second patient with IMD104 who was compound heterozygous for a splice site mutation and a nonsense mutation in the IL7R gene (146661.0003 and 146661.0004). IL7R mRNA levels were greatly reduced in patient 2.

In 3 affected patients from a consanguineous Sicilian family with IMD104, Roifman et al. (2000) identified a homozygous missense mutation in the IL7R gene (P132S; 146661.0005). The mutation, which was confirmed by direct sequencing, segregated with the disorder in the family. The mutation did not affect mRNA or protein expression, but severely compromised affinity to IL7 (146660) and signal transduction. Stimulation with IL7 resulted in markedly reduced JAK3 (600173) phosphorylation in patient cells and in cells transfected with the mutant IL7R.

In 16 patients from 11 unrelated families with IMD104, Giliani et al. (2005) identified 13 different mutations in the IL7R gene. All patients were homozygous or compound heterozygous for the mutations, except 1 (patient 8) in whom a second mutation could not be found. There were missense, nonsense, frameshift, and splicing mutations; functional studies of the variants and studies of patient cells were not performed.

In a 1-year-old girl, born to consanguineous parents, with IMD104, Mansour et al. (2022) identified a homozygous splice site mutation in the IL7R gene (146661.0006). IL7R-alpha protein expression was reduced to 2.5% and 50% of control levels in patient and carrier parents' T cells, respectively.

Lev et al. (2019) identified a homozygous missense variant (F40L; 146661.0008) in the IL7R gene in 7 individuals from 5 unrelated consanguineous Muslim families. Two of the 7 (P1 and P5) had a severe form of IMD104. Three others (P2, P3, and P4) had mild early symptoms and showed spontaneous recovery in the first years of life. Two other homozygous carriers were clinically unaffected (the father of P3) or showed only mild laboratory abnormalities (the brother of P1). These findings were consistent with incomplete penetrance and variable expressivity. The 5 probands (P1-P5) were diagnosed with a primary immunodeficiency though newborn screening due to undetectable TRECs on dried blood spots. The IL7R mutation, which was subsequently found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Filtering of the variant against public databases did not reveal any homozygous carriers. Haplotype analysis indicated a founder effect. Patient T cells showed decreased expression of IL7R as well as decreased signaling response to IL7 compared to controls. In patient cells, genetic analysis of TRG showed profound restriction and clonal expansions of the T-cell receptor repertoire compared to controls, indicating an impact on V(D)J diversity. In addition, all patients except patient 3 (who had the most benign phenotype) showed skewing of the complementarity-determining region 3 (CDR3) length distribution of the TCR. Despite the common mutation, the 5 probands showed a heterogeneous clinical course. The authors suggested that the variant may be a 'leaky' allele, and that the phenotypic variability was likely influenced by a combination of additional genetic, epigenetic, and environmental factors.