If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.

X-linked lymphoproliferative disease (XLP) has two recognizable subtypes, XLP1 and XLP2. XLP1 is characterized predominantly by one of three commonly recognized phenotypes: Inappropriate immune response to Epstein-Barr virus (EBV) infection leading to hemophagocytic lymphohistiocytosis (HLH) or severe mononucleosis. Dysgammaglobulinemia. Lymphoproliferative disease (malignant lymphoma). XLP2 is most often characterized by HLH (often associated with EBV), dysgammaglobulinemia, and inflammatory bowel disease. HLH resulting from EBV infection is associated with an unregulated and exaggerated immune response with widespread proliferation of cytotoxic T cells, EBV-infected B cells, and macrophages. Dysgammaglobulinemia is typically hypogammaglobulinemia of one or more immunoglobulin subclasses. The malignant lymphomas are typically B-cell lymphomas, non-Hodgkin type, often extranodal, and in particular involving the intestine.

Immunodeficiency-59 is an autosomal recessive primary immunologic disorder characterized by combined immunodeficiency and recurrent septic infections of the respiratory tract, skin, and mucous membranes, as well as disturbed glucose metabolism. Granulocytopenia and B-cell and dentritic cell deficiency are present (Haapaniemi et al., 2017).

The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility (Beighton et al., 1998). The major characteristics of the musculocontractural form of EDS include distinctive craniofacial dysmorphism, congenital contractures of thumbs and fingers, clubfeet, severe kyphoscoliosis, muscular hypotonia, hyperextensible thin skin with easy bruisability and atrophic scarring, wrinkled palms, joint hypermobility, and ocular involvement (summary by Malfait et al., 2010). Janecke et al. (2015) reviewed the clinical findings in 34 reported EDSMC patients, 31 with CHST14 mutations and 3 with DSE (605942) mutations (see 615539), and stated that the disorder can be recognized based on the presence of distal arthrogryposis, including adducted thumbs or clenched fists and talipes equinovarus, as well as hands with atypically shallow palmar creases and tapering fingers, and neonatal muscular hypotonia. Characteristic craniofacial features include brachycephaly, large fontanel, hypertelorism, downslanting palpebral fissures, microcorneae, strabismus, prominent nasolabial folds, short philtrum, thin upper lip, small mouth, high palate, microretrognathia, and prominent and often low-set and posteriorly rotated ears. In addition, EDSMC patients show muscular hypoplasia and weakness, which has been confirmed by ultrasound and electromyography, and intellectual development appears to be normal. Genetic Heterogeneity of Musculocontractural Ehlers-Danlos Syndrome Ehlers-Danlos syndrome musculocontractural type 2 (EDSMC2; 615539) is caused by mutation in the DSE gene (605942) on chromosome 6q22.

Immunodeficiency-68 (IMD68) is an autosomal recessive primary immunodeficiency characterized by severe systemic and invasive bacterial infections beginning in infancy or early childhood. The most common organisms implicated are Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas, although other organisms may be observed. IMD68 is life-threatening in infancy and early childhood. The first invasive infection typically occurs before 2 years of age, with meningitis and upper respiratory infections being common manifestations. The mortality rate in early childhood is high, with most deaths occurring before 8 years of age. Affected individuals have an impaired inflammatory response to infection, including lack of fever and neutropenia, although erythrocyte sedimentation rate (ESR) and C-reactive protein may be elevated. General immunologic workup tends to be normal, with normal levels of B cells, T cells, and NK cells. However, more detailed studies indicate impaired cytokine response to lipopolysaccharide (LPS) and IL1B (147720) stimulation; response to TNFA (191160) is usually normal. Patients have good antibody responses to most vaccinations. Viral, fungal, and parasitic infections are generally not observed. Early detection is critical in early childhood because prophylactic treatment with IVIg or certain antibiotics is effective; the disorder tends to improve naturally around adolescence. At the molecular level, IMD68 results from impaired function of selective Toll receptor (see TLR4, 603030)/IL1R (see IL1R1; 147810) signaling pathways that ultimately activate NFKB (164011) to produce cytokines (summary by Picard et al., 2010). See also IMD67 (607676), caused by mutation in the IRAK4 gene (602170), which shows a similar phenotype to IMD68. As the MYD88 and IRAK4 genes interact in the same intracellular signaling pathway, the clinical and cellular features are almost indistinguishable (summary by Picard et al., 2010).

Leukocyte adhesion deficiency-3 (LAD3), also known as LAD1 variant (LAD1V), is an autosomal recessive disorder characterized by LAD1 (116920)-like immune deficiency and Glanzmann thrombasthenia (GT; 273800)-like bleeding problems. LAD3 results from mutations in FERMT3, or KINDLIN3, which encodes an intracellular protein that interacts with beta-integrins in hematopoietic cells. In LAD3, the adhesive functions of integrins on both leukocytes and platelets are disrupted, most likely due to defects in activation-dependent alterations of surface integrins that enable high-avidity binding to ligands on target cells, a process termed 'inside-out signaling' (Svensson et al., 2009; Zimmerman, 2009). For a discussion of genetic heterogeneity of leukocyte adhesion deficiency, see 116920.

Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1.

Mannose-binding lectin (MBL) deficiency, defined as MBL protein level of less than 100 ng/ml, is present in about 5% of people of European descent and in about 10% of sub-Saharan Africans. Most MBL-deficient adults appear healthy, but low levels of MBL are associated with increased risk of infection in toddlers, in cancer patients undergoing chemotherapy, and in organ-transplant patients receiving immunosuppressive drugs, particularly recipients of liver transplants (review by Degn et al., 2011). MBL is a soluble molecule that can activate the lectin pathway of the complement system; deficiency may thus lead to defects in the complement system (summary by Garcia-Laorden et al., 2008). Genetic Heterogeneity of Lectin Complement Activation Pathway Defects See also LCAPD2 (613791), caused by variation in the MASP2 gene (605102) on chromosome 1p36, and LCAPD3 (613860), caused by variation in the FCN3 gene (604973) on chromosome 1p36.

C3 glomerulopathy (C3G) is a complex ultra-rare complement-mediated renal disease caused by uncontrolled activation of the complement alternative pathway (AP) in the fluid phase (as opposed to cell surface) that is rarely inherited in a simple mendelian fashion. C3G affects individuals of all ages, with a median age at diagnosis of 23 years. Individuals with C3G typically present with hematuria, proteinuria, hematuria and proteinuria, acute nephritic syndrome or nephrotic syndrome, and low levels of the complement component C3. Spontaneous remission of C3G is uncommon, and about half of affected individuals develop end-stage renal disease (ESRD) within ten years of diagnosis, occasionally developing the late comorbidity of impaired visual acuity.

A rare genetic epidermal disorder with characteristics of congenital erythroderma with severe psoriasiform dermatitis, ichthyosis, severe palmoplantar keratoderma, yellow keratosis on the hands and feet, elevated immunoglobulin E, multiple food allergies, and metabolic wasting. Other variable features may include hypotrichosis, nail dystrophy, recurrent infections, mild global developmental delay, eosinophilia, nystagmus, growth impairment and cardiac defects.

Common variable immunodeficiency-12 with autoimmunity (CVID12) is an autosomal dominant complex immunologic disorder with multisystem involvement. CVID12 is mainly a primary immunodeficiency characterized by recurrent infections and associated with hypogammaglobulinemia. Notably, about half of patients develop autoimmune features, including cytopenia, as well as generalized inflammation and lymphoproliferation manifest as lymphadenopathy or hepatosplenomegaly. A smaller percentage of affected individuals (less than 20%) develop cancer, most commonly solid tumors, including lymphoma. Age at onset and disease severity are highly variable, even within the same family. There is also incomplete penetrance, such that mutation carriers may be asymptomatic, even if they have hypogammaglobulinemia. The gene involved, NFKB1, encodes a transcription factor that regulates the expression of target genes involved in the immune system, thus defining the phenotype as a disorder of immune dysregulation (summary by Fliegauf et al., 2015; Lorenzini et al., 2020). For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (607594).

Hereditary sensory and autonomic neuropathy type VIII is an autosomal recessive neurologic disorder characterized by congenital insensitivity to pain resulting in ulceration to the fingers, tongue, lips, and other distal appendages. Affected individuals may also have decreased sweating and tear production (summary by Chen et al., 2015). For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1A (162400).

Immunodeficiency-51 (IMD51) is an autosomal recessive primary immune deficiency that is usually characterized by onset of chronic mucocutaneous candidiasis in the first years of life. Most patients also show recurrent Staphylococcal skin infections, and may show increased susceptibility to chronic bacterial respiratory infections. Patient cells show a lack of cellular responses to stimulation with certain IL17 isoforms, including IL17A (603149), IL17F (606496), IL17A/F, and IL17E (IL25; 605658) (summary by Levy et al., 2016).

IMDDHH is a multisystem disorder characterized by immunodeficiency, mildly delayed psychomotor development, poor overall growth from infancy, and hypohomocysteinemia. Additional features, such as congenital heart defects and liver involvement, are more variable (summary by Huppke et al., 2017).

Hereditary primary lymphedema is caused by anatomic or functional defects in the lymphatic system, resulting in chronic swelling of body parts. There may be accompanying nail and skin changes, such as nail dysplasia or papillomatosis. Onset is usually at birth or in early childhood but can occur later, and the severity is variable (summary by Gordon et al., 2013 and Balboa-Beltran et al., 2014). For a discussion of genetic heterogeneity of lymphatic malformation, see 153100.

Hyper-IgE recurrent infection syndrome-3 is an autosomal recessive immunologic disorder characterized by childhood onset of atopic dermatitis, skin infections particularly with Staphylococcus aureus, recurrent sinopulmonary infections, and increased serum IgE and IgG. Patients are susceptible to bacterial and fungal infections, including chronic mucocutaneous candidiasis. Immunologic work-up shows impaired differentiation of CD4+ T cells into T-helper 17 cells, decreased memory B cells, and often decreased NK cells (summary by Beziat et al., 2018). For a discussion of genetic heterogeneity of hyper-IgE recurrent infection syndrome, see HIES1 (147060).

Immunodeficiency-66 (IMD66) is an autosomal recessive primary immune disorder caused by defective immune cell migration and chemotaxis resulting from defects in cytoskeletal actin dynamics. Neutrophils are primarily affected, although there may be defects in dendritic cells and T and B cells. The phenotype is characterized by onset of recurrent bacterial infections in infancy. Laboratory studies show normal levels of myeloid and lymphoid cells, but there may be mild thrombocytopenia (summary by Record et al., 2015).

Autosomal recessive hyper-IgE recurrent infection syndrome-5 (HEIS5) is an immunologic disorder characterized by onset of recurrent sinopulmonary and deep skin infections in early childhood. The infections are mostly caused by bacteria, including H. influenza and Staphylococcus aureus. Additional features include atopic dermatitis, impaired inflammatory responses during infection, increased serum IgE, and increased IL6 (147620) (summary by Spencer et al., 2019). For a discussion of genetic heterogeneity of hyper-IgE recurrent infection syndrome, see HIES1 (147060).

The IFAP/BRESHECK syndrome is an X-linked multiple congenital anomaly disorder with variable severity. The classic triad, which defines IFAP, is ichthyosis follicularis, atrichia, and photophobia. Some patients have additional features, including mental retardation, brain anomalies, Hirschsprung disease, corneal opacifications, kidney dysplasia, cryptorchidism, cleft palate, and skeletal malformations, particularly of the vertebrae, which constitutes BRESHECK syndrome (summary by Naiki et al., 2012). Genetic Heterogeneity of IFAP Syndrome IFAP syndrome-2 (IFAP2; 619016) is caused by heterozygous mutation in the SREBF1 gene (184756) on chromosome 17p11.

Immunodeficiency-82 with systemic inflammation (IMD82) is a complex autosomal dominant immunologic disorder characterized by recurrent infections with various organisms, as well as noninfectious inflammation manifest as lymphocytic organ infiltration with gastritis, colitis, and lung, liver, CNS, or skin disease. One of the more common features is inflammation of the stomach and bowel. Most patients develop symptoms in infancy or early childhood; the severity is variable. There may be accompanying fever, elevated white blood cell count, decreased B cells, hypogammaglobulinemia, increased C-reactive protein (CRP; 123260), and a generalized hyperinflammatory state. Immunologic workup shows variable B- and T-cell abnormalities such as skewed subgroups. Patients have a propensity for the development of lymphoma, usually in adulthood. At the molecular level, the disorder results from a gain-of-function mutation that leads to constitutive and enhanced activation of the intracellular inflammatory signaling pathway. Treatment with SYK inhibitors rescued human cell abnormalities and resulted in clinical improvement in mice (Wang et al., 2021).

Immunodeficiency-55 is an autosomal recessive primary immunodeficiency characterized by intrauterine growth retardation, natural killer (NK) cell deficiency, and chronic neutropenia. Most patients also have postnatal growth retardation. Other clinical manifestations include mild facial dysmorphism, dry or eczematous skin, and recurrent infections with both viruses and bacteria. The disorder appears to result from a defect in DNA replication causing blockade of immune cell differentiation in the bone marrow, particularly affecting NK cells (summary by Cottineau et al., 2017).

Immunodeficiency-102 (IMD102) is an X-linked recessive immunologic disorder characterized by the onset of recurrent sinopulmonary, mucosal, and other infections in early childhood, usually accompanied by refractory autoimmune cytopenias. Affected individuals have bacterial, viral, and fungal infections, as well as hemolytic anemia, thrombocytopenia, lymphopenia, and decreased NK cells. Laboratory studies show defective T-cell proliferation and function, likely due to signaling abnormalities. The disorder may also manifest as a hyperinflammatory state with immune dysregulation (Delmonte et al., 2021).

Autosomal dominant hyper-IgE recurrent infection syndrome-4A (HIES4A) is an immunologic disorder characterized by recurrent mainly sinopulmonary infections associated with increased serum IgE. The phenotype is variable, even within families. Some patients have onset of symptoms in early childhood and develop complications, including bronchiectasis or hemoptysis, whereas others have later onset of less severe infections. Immunologic workup usually shows normal leukocyte levels, although some patients may demonstrate alterations in lymphocyte subsets, including T cells. Affected individuals also have variable skeletal abnormalities, including high-arched palate, hyperextensible joints, scoliosis, and bone fractures. The IL6ST mutations are loss-of-function, although the truncated mutant proteins are expressed and interfere with the wildtype protein in a dominant-negative manner by disrupting IL6 (147620) and IL11 (147681) signaling (summary by Beziat et al., 2020). For a discussion of genetic heterogeneity of hyper-IgE recurrent infection syndrome, see HIES1 (147060).

Immunodeficiency-97 with autoinflammation (IMD97) is an autosomal recessive complex immunologic disorder with variable features. Affected individuals present in the first decade of life with inflammatory interstitial lung disease or colitis due to abnormal tissue infiltration by activated T cells. Patients develop autoimmune cytopenias and may have lymphadenopathy; 1 reported patient had features of hemophagocytic lymphohistiocytosis (HLH; see FHL1, 267700). Some patients may have recurrent infections associated with mild lymphopenia, hypogammaglobulinemia, and NK cell dysfunction. Immunologic workup indicates signs of significant immune dysregulation with elevation of inflammatory serum markers, variable immune cell defects involving neutrophils, NK cells, and myeloid cells, and disrupted levels of T regulatory cells (Tregs). Two unrelated patients have been reported (summary by Takeda et al., 2019 and Thian et al., 2020).