B-Cell and T-Cell Combined Disorders Clinical Presentation

Clinical manifestations of many combined B-cell and T-cell deficiencies derive from associated organ involvement, thus eliciting variable onsets for the different symptoms. Neurologic and cutaneous symptoms predominate in ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS). Autoimmune endocrinopathies and cutaneous manifestations are seen in patients with chronic mucocutaneous candidiasis (CMC) and immune dysregulation with polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. In other combined B-cell and T-cell deficiencies, the presence of unusual organisms in certain infections, the chronic nature of infectious processes, and autoimmune phenomena may indicate the presence of an underlying immunodeficiency. ^[14]

AT is an obvious diagnosis when both ataxia and telangiectasia are present. A diagnosis of AT can also be made upon onset of ataxia and before telangiectasia appears, if confirmed by laboratory test results. In most patients, a misdiagnosis of cerebral palsy is usually made because ataxia most often occurs during infancy. Telangiectasia usually does not appear until patients are aged 5 years.

In a review of 48 patients with AT, mean age of ataxia onset was 15 months; mean age of telangiectasia onset was 72 months. ^[15] This study by confirmed that a misdiagnosis of cerebral palsy was made in most patients (29 of 48). To alleviate this problem, the study recommends routine serum alpha-fetoprotein (AFP) testing for all children with persistent ataxia.

Ataxia is initially cerebellar, with associated posture and gait problems. Speech may become slurred. Movement disorders also occur and may be choreoathetoid or ticlike. Oculomotor apraxia is usually present, and, less often, a dysconjugate gaze is noted. Muscle weakness may appear late in the course, with subsequent muscle atrophy. Mental function can be affected.

AT has increased alpha fetoprotein levels, whereas NBS has microcephaly and mental retardation.

Telangiectasia usually occurs on the bulbar conjunctivae in patients younger than 5-6 years and becomes more prominent in other areas, especially the pinna. Other cutaneous manifestations include progressive cutaneous atrophy, areas of hypopigmentation or hyperpigmentation, hypertrichosis, atopic dermatitis, and cutaneous malignancies. See the images below.

Bloom syndrome may also have telangiectasias, especially sun-exposed areas. However, patients have short stature and birdlike facies.

All patients have a deficiency of cell-mediated immunity. However, deficiency in humoral immunity is more variable. Therefore, the resulting predisposition to infection can vary. Recurrent sinopulmonary infections may be a complaint before ataxia or telangiectasia develops. An increase in lower respiratory tract infections is observed with age with subsequent chronic lung disease. Impaired oropharyngeal swallowing mechanisms may contribute with chronic aspiration. Infections can be caused by viral and bacterial pathogens, although typically not by opportunistic agents.

In a review of 100 patients with AT, recurrent upper and lower tract infections were common, including otitis media in 46%, sinusitis in 27%, bronchitis in 19%, and pneumonia in 15%. Systemic bacterial and severe viral or opportunistic infections were uncommon.

Although endocrine abnormalities are uncommon, they may include failure to develop secondary sex characteristics. Stiehm states that no offspring of AT homozygotes are known. ^[16] Patients may also have growth failure.

Patients with CMC have persistent or recurrent candidal infections of the skin, nails, and mucous membranes. The extent and location of infections, genetic factors, and associated autoimmune disorders delineate 6 clinical syndromes.

Candidiasis is almost always observed in patients with CMC. Infants with CMC type 3 usually present with persistent diaper rash or other localized lesions involving the extremities. Extreme hyperkeratosis may occur. Persistent or recurrent thrush is also common. Consider CMC in patients when chronic oral candidiasis (CMC type 1) continues after cessation of antibiotics or inhaled corticosteroid therapy and when T-cell deficiency has been excluded. Esophageal or tracheal candidiasis is uncommon and may simply represent colonization of mucous membranes after a course of systemic antibiotic therapy. See the image below.

More extensive cutaneous infections with skin, nail, and mucous membrane involvement may develop in late childhood or during adolescence (CMC type 4). These patients apparently are less likely to develop endocrinopathies.

According to Stiehm, "It is important to appreciate that the endocrinopathies may develop any time from childhood through adulthood and that patients may have sequential loss of functions of various endocrine organs..." ^[16] According to one study, the most commonly affected organs are the parathyroid glands (54 of 68 patients), adrenal glands (49 of 68 patients), and thyroid gland (2 of 68 patients). Gonadal failure commonly causes infertility. Insulin-dependent diabetes occurs in approximately 10% of patients. Overall, CMC is associated with autoimmune endocrinopathies in about 40% of patients.

An association of CMC with thymomas (CMC type 5) has been described, usually in adult or middle-aged patients. These patients may also have other autoimmune disorders, such as myasthenia gravis, aplastic anemia, and hypogammaglobulinemia.

An association of chronic keratitis with CMC has been noted and appears to be an autosomal dominant trait.

Patients with CMC are susceptible to frequent infections by viruses and bacteria in the skin and in the upper and lower respiratory tracts.

Other autoimmune disorders are common and include various autoimmune hematologic disorders (eg, red blood cell [RBC], white blood cell [WBC], platelets), chronic active hepatitis, and juvenile rheumatoid arthritis for CMC.

The combination of dermatitis and thrombocytopenia (as an autoimmune process) in males may confuse IPEX with patients with Wiskott-Aldrich syndrome. Indeed, IPEX was originally thought to be a Wiskott-Aldrich syndrome variant because the gene that encodes WASP also lies in the same region as FOXP3 gene. The dermatitis in IPEX is also eczematous in nature.

Enteropathy with failure to thrive is almost always present in IPEX. It usually presents with watery diarrhea and villous atrophy is commonly found on intestinal biopsy.

Endocrinopathy is commonly present but may not appear initially. The most common endocrine dysfunction is early onset insulin-dependent diabetes mellitus. Thyroid disease (either hypothyroidism or hyperthyroidism) is also common.

Examples of autoimmune phenomena include immune hemolytic anemia, immune thrombocytopenia, autoimmune neutropenia, lymphadenopathy, splenomegaly, tubular nephropathy, or alopecia.

Patients with IPEX usually present in early infancy and may die within the first 2 years of life due to either metabolic derangements or sepsis. The most common pathogens were Staphylococcus, cytomegalovirus (CMV), and Candida.

Neoplastic diseases other than thymomas can occur, which emphasizes the importance of T cells in immune surveillance. However, a greater incidence of malignancy is observed in AT, especially lymphoid tumors, which has been attributed to their increased sensitivity to radiation. Occasionally, leukemia has been a presenting finding of AT. On the other hand, CMC with squamous cell carcinoma of the oral cavity or esophagus has also been described. ^[13]

Depending on the specific combined immunodeficiency syndromes, physical examination may yield varying signs, as follows:

In patients with AT, gait abnormalities occur at a median age of 15 months. Deterioration of the newly acquired developmental milestone of walking signals a problem.

All patients manifest progressive cerebellar ataxia. However, the classic form has onset in infancy, and steady progression to milder forms in which the progression may be slower or the onset may be later have been noted. Other neurologic signs include dystonia and oculomotor apraxia. Drooling, strabismus, and a masklike facies may be seen. In addition to cerebellar signs, extrapyramidal and posterior column signs may be present. Reflexes are decreased, and muscle weakness may be present. Sensory involvement is uncommon.

Telangiectasia is commonly observed on the bulbar conjunctivae and may occur in children aged 1-6 years. Other areas, such as the lateral aspect of the nose, the ears, the antecubital and popliteal areas, and the dorsa of the hands and feet, may be affected later.

In CMC, almost all patients have skin or nail findings. ^[17] Mucous membranes in the oral cavity may be covered with a patchy pseudomembrane composed of mycelial Candida albicans (ie, thrush). Infants may have a persistent diaper rash with fungal infection. In more extensive forms, nails and extremities may develop severe hyperkeratosis with nail deformities.

In IPEX, the typical rash is eczematoid.

The gene responsible for AT, designated ATM (ie, AT, mutated), encodes for a protein that belongs to a family of phosphatidylinositol 3-kinase (PI3-K)–related kinases (PIKK). Members of this family are involved in mitogenic signal transduction, intracellular protein transport, and control of the cell cycle. In biologic terms, cells have an extreme sensitivity to radiation and an increased predisposition to become cancerous.

ATM is located on the long arm of chromosome 11 at subband q22.3. ATM is a large gene, with over 300 mutations described in 66 exons and no common, predominant mutation.

In contrast, the NBS1 gene involved in NBS is located on chromosomal band 8q21. Seven mutations are reported worldwide, with a high predominance of the founder mutation 567del5 in the Slavonic population.

Most patients with the classic AT phenotype are homozygous or compound heterozygous for ATM mutations that result in a truncated or unstable protein with total loss of ATM function. Some patients have mild forms of the disease, termed AT variants, and are either homozygous for mild mutations or compound heterozygotes for mild mutations. These mutations are leaky splice or missense mutations. Preservation of neurologic function is correlated with the degree of ATM protein kinase activity. About 10% of normal ATM kinase activity is apparently adequate to moderate the phenotype but not to prevent it.

The additional recognition of many ATM substrates involved in the recognition and repair of DNA double-strand breaks may also allow for the heterologous symptoms among patients with AT, some of whom may not have symptoms until adulthood.

Mutations in the ATM gene are probably not a common cause for cerebellar ataxia other than AT.

With the aid of molecular testing, AT can be distinguished from other autosomal recessive cerebellar ataxias, such as Friedrich ataxia, Mre11 deficiency (AT-like disease), and the oculomotor apraxias 1 (aprataxin deficiency) and 2 (senataxin deficiency). In addition, NBS1 deficiency defines NBS syndrome, and helicase gene defect defines Bloom syndrome.

Heterogeneous manifestations of CMC may indicate numerous causes and a heterogeneous pattern of inheritance.

Immunological studies indicate that dendritic maturation may be impaired in both CMC and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Subsequent altered regulation of pattern recognition receptors may be responsible for the disease manifestations. ^[18]

Other studies show that these patients have an inability to clear Candida. This may be due to a defect in the immune response of interleukin (IL)-17-producing T cells. ^[19]

CMC is included as part of the APECED disorder, which is also known as autoimmune polyglandular syndrome type I (APS I). This disease has been mapped to chromosome 21q22.3, and the gene is identified as the autoimmune regulator (AIRE) gene. It appears to be involved in DNA binding. At least 60 different disease-causing mutations in AIRE have been discovered, and the role in various manifestations of CMC and APECED/APS I are under investigation. AIRE may be involved in thymocyte negative selection, which may partially account for autoimmunity.

CMC can be broadly classified into familial (inherited) or nonfamilial (noninherited) forms. Familial forms are inherited as autosomal dominant or autosomal recessive and are associated with or without varying degrees of autoimmune endocrinopathy. Therefore, determining whether the AIRE gene markers (and autoantibodies) segregate with disease in a family in whom the diagnosis of CMC is possible is important.

Two other familial subtypes include an autosomal dominant form with nail candidiasis and intercellular adhesion molecule-1 (ICAM-1) deficiency and an autosomal recessive form with hyperimmunoglobulinemia E. Chronic localized CMC has no apparent genetic component.