Cystic fibrosis (CF) is a multisystem disease affecting epithelia of the respiratory tract, exocrine pancreas, intestine, hepatobiliary system, and exocrine sweat glands. Morbidities include recurrent sinusitis and bronchitis, progressive obstructive pulmonary disease with bronchiectasis, exocrine pancreatic deficiency and malnutrition, pancreatitis, gastrointestinal manifestations (meconium ileus, rectal prolapse, distal intestinal obstructive syndrome), liver disease, diabetes, male infertility due to hypoplasia or aplasia of the vas deferens, and reduced fertility or infertility in some women. Pulmonary disease is the major cause of morbidity and mortality in CF.

Individuals with 22q11.2 deletion syndrome (22q11.2DS) can present with a wide range of features that are highly variable, even within families. The major clinical manifestations of 22q11.2DS include congenital heart disease, particularly conotruncal malformations (ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus), palatal abnormalities (velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate), immune deficiency, characteristic facial features, and learning difficulties. Hearing loss can be sensorineural and/or conductive. Laryngotracheoesophageal, gastrointestinal, ophthalmologic, central nervous system, skeletal, and genitourinary anomalies also occur. Psychiatric illness and autoimmune disorders are more common in individuals with 22q11.2DS.

Hallermann-Streiff syndrome is characterized by a typical skull shape (brachycephaly with frontal bossing), hypotrichosis, microphthalmia, cataracts, beaked nose, micrognathia, skin atrophy, dental anomalies, and proportionate short stature (Hallermann, 1948; Streiff, 1950; Francois, 1958). Mental retardation is present in a minority of cases (Gorlin et al., 1990).

Trichorhinophalangeal syndrome (TRPS) comprises TRPS I (caused by a heterozygous pathogenic variant in TRPS1) and TRPS II (caused by contiguous gene deletion of TRPS1, RAD21, and EXT1). Both types of TRPS are characterized by distinctive facial features; ectodermal features (fine, sparse, depigmented, and slow growing hair; dystrophic nails; and small breasts); and skeletal findings (short stature; short feet; brachydactyly with ulnar or radial deviation of the fingers; and early, marked hip dysplasia). TRPS II is characterized by multiple osteochondromas (typically first observed clinically on the scapulae and around the elbows and knees between ages 1 month and 6 years) and an increased risk of mild-to-moderate intellectual disability.

Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) is an X-linked multisystem disorder characterized by glycosaminoglycan (GAG) accumulation. The vast majority of affected individuals are male; on rare occasion heterozygous females manifest findings. Age of onset, disease severity, and rate of progression vary significantly among affected males. In those with early progressive disease, CNS involvement (manifest primarily by progressive cognitive deterioration), progressive airway disease, and cardiac disease usually result in death in the first or second decade of life. In those with slowly progressive disease, the CNS is not (or is minimally) affected, although the effect of GAG accumulation on other organ systems may be early progressive to the same degree as in those who have progressive cognitive decline. Survival into the early adult years with normal intelligence is common in the slowly progressing form of the disease. Additional findings in both forms of MPS II include: short stature; macrocephaly with or without communicating hydrocephalus; macroglossia; hoarse voice; conductive and sensorineural hearing loss; hepatosplenomegaly; dysostosis multiplex; spinal stenosis; and carpal tunnel syndrome.

The WAS-related disorders, which include Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN), are a spectrum of disorders of hematopoietic cells, with predominant defects of platelets and lymphocytes caused by pathogenic variants in WAS. WAS-related disorders usually present in infancy. Affected males have thrombocytopenia with intermittent mucosal bleeding, bloody diarrhea, and intermittent or chronic petechiae and purpura; eczema; and recurrent bacterial and viral infections, particularly of the ear. At least 40% of those who survive the early complications develop one or more autoimmune conditions including hemolytic anemia, immune thrombocytopenic purpura, immune-mediated neutropenia, rheumatoid arthritis, vasculitis, and immune-mediated damage to the kidneys and liver. Individuals with a WAS-related disorder, particularly those who have been exposed to Epstein-Barr virus (EBV), are at increased risk of developing lymphomas, which often occur in unusual, extranodal locations including the brain, lung, or gastrointestinal tract. Males with XLT have thrombocytopenia with small platelets; other complications of Wiskott-Aldrich syndrome, including eczema and immune dysfunction, are usually mild or absent. Males with XLN have congenital neutropenia, myeloid dysplasia, and lymphoid cell abnormalities.

The phenotypic spectrum of mucopolysaccharidosis IVA (MPS IVA) is a continuum that ranges from a severe and rapidly progressive early-onset form to a slowly progressive later-onset form. Children with MPS IVA typically have no distinctive clinical findings at birth. The severe form is usually apparent between ages one and three years, often first manifesting as kyphoscoliosis, genu valgum (knock-knee), and pectus carinatum; the slowly progressive form may not become evident until late childhood or adolescence, often first manifesting as hip problems (pain, stiffness, and Legg Perthes disease). Progressive bone and joint involvement leads to short stature, and eventually to disabling pain and arthritis. Involvement of other organ systems can lead to significant morbidity, including respiratory compromise, obstructive sleep apnea, valvular heart disease, hearing impairment, visual impairment from corneal clouding, dental abnormalities, and hepatomegaly. Compression of the spinal cord is a common complication that results in neurologic impairment. Children with MPS IVA have normal intellectual abilities at the outset of the disease.

T-cell immunodeficiency with thymic aplasia (TIDTA) is an autosomal recessive disorder that is often detected at birth through newborn SCID screening with the finding of decreased T-cell receptor excision circles (TRECs). Affected individuals have selective hypo- or aplasia of the thymus, which results in T-cell immunodeficiency due to impaired T-cell development and increased susceptibility to viral infections. The phenotype is similar to T-/B+/NK+ SCID. Some patients may die in childhood; thymus transplantation may be curative (summary by Du et al., 2019).

Aicardi syndrome is a neurodevelopmental disorder that affects primarily females. Initially it was characterized by a typical triad of agenesis of the corpus callosum, central chorioretinal lacunae, and infantile spasms. As more affected individuals have been ascertained, it has become clear that not all affected girls have all three features of the classic triad and that other neurologic and systemic defects are common, including other brain malformations, optic nerve abnormalities, other seizure types, intellectual disability of varying severity, and scoliosis.

An autosomal recessive subtype of cerebrooculofacioskeletal syndrome caused by mutation(s) in the ERCC6 gene, encoding DNA excision repair protein ERCC-6.

X-linked agammaglobulinemia (XLA) is characterized by recurrent bacterial infections in affected males in the first two years of life. Recurrent otitis is the most common infection prior to diagnosis. Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are also frequently seen. Approximately 60% of individuals with XLA are recognized as having immunodeficiency when they develop a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis. S pneumoniae and H influenzae are the most common organisms found prior to diagnosis and may continue to cause sinusitis and otitis after diagnosis and the initiation of gammaglobulin substitution therapy. Severe, difficult-to-treat enteroviral infections (often manifest as dermatomyositis or chronic meningoencephalitis) can be prevented by this treatment. The prognosis for individuals with XLA has improved markedly in the last 25 years as a result of earlier diagnosis, the development of preparations of gammaglobulin that allow normal concentrations of serum IgG to be achieved, and more liberal use of antibiotics.

PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is an autosomal recessive generalized connective tissue disorder characterized by hypotonia, early-onset kyphoscoliosis, and generalized joint hypermobility in association with skin fragility and ocular abnormality. Intelligence is normal. Life span may be normal, but affected individuals are at risk for rupture of medium-sized arteries. Adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease, recurrent pneumonia, and cardiac failure.

Alström syndrome is characterized by cone-rod dystrophy, obesity, progressive bilateral sensorineural hearing impairment, acute infantile-onset cardiomyopathy and/or adolescent- or adult-onset restrictive cardiomyopathy, insulin resistance / type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), and chronic progressive kidney disease. Cone-rod dystrophy presents as progressive visual impairment, photophobia, and nystagmus usually starting between birth and age 15 months. Many individuals lose all perception of light by the end of the second decade, but a minority retain the ability to read large print into the third decade. Children usually have normal birth weight but develop truncal obesity during their first year. Sensorineural hearing loss presents in the first decade in as many as 70% of individuals and may progress to the severe or moderately severe range (40-70 db) by the end of the first to second decade. Insulin resistance is typically accompanied by the skin changes of acanthosis nigricans, and proceeds to T2DM in the majority by the third decade. Nearly all demonstrate hypertriglyceridemia. Other findings can include endocrine abnormalities (hypothyroidism, hypogonadotropic hypogonadism in males, and hyperandrogenism in females), urologic dysfunction / detrusor instability, progressive decrease in renal function, and hepatic disease (ranging from elevated transaminases to steatohepatitis/NAFLD). Approximately 20% of affected individuals have delay in early developmental milestones, most commonly in gross and fine motor skills. About 30% have a learning disability. Cognitive impairment (IQ <70) is very rare. Wide clinical variability is observed among affected individuals, even within the same family.

Prolidase deficiency is characterized by skin lesions (typically severe, chronic, recalcitrant, and painful skin ulcers of the lower extremities and telangiectasias of the face and hands), recurrent infections (particularly of the skin and respiratory tract), dysmorphic facial features, variable intellectual disability, and organomegaly (typically splenomegaly but occasionally associated with hepatomegaly) with elevated liver enzymes. Skeletal anomalies, chronic pulmonary disease, anemia, thrombocytopenia, hypergammaglobulinemia, and hypocomplementemia are observed in a minority of affected individuals. An association between prolidase deficiency and autoimmune conditions – particularly systemic lupus erythematosus (SLE) – has been described.

Periodic fever, immunodeficiency, and thrombocytopenia syndrome (PFITS) is an autosomal recessive immunologic disorder with variable manifestations. Common features include early-onset recurrent respiratory infections, stomatitis, and cutaneous infections. Organisms usually include bacteria such as pneumococcus, Staphylococcus, and H. influenzae, but severe viral infections, including varicella, may also occur. Laboratory investigations may show neutropenia, neutrophilia, leukocytosis, or lymphopenia, although levels of immune cells may also be normal. Detailed studies often show impaired neutrophil chemotaxis associated with increased or abnormal F-actin levels, and impaired, normal, or even increased oxidative burst, depending on the stimulus. B- and T-cell abnormalities have also been observed. Some patients develop autoimmune manifestations, including chronic thrombocytopenia, anemia, and periodic fevers, associated with activation of the inflammasome. Early death may occur; however, hematopoietic stem cell transplantation may be curative (summary by Kuhns et al., 2016, Standing et al., 2017, and Pfajfer et al., 2018).

Primary trimethylaminuria is characterized by a fishy odor resembling that of rotten or decaying fish that results from excess excretion of trimethylamine in the urine, breath, sweat, and reproductive fluids. No physical symptoms are associated with trimethylaminuria. Affected individuals appear normal and healthy; however, the unpleasant odor often results in social and psychological problems. Symptoms are usually present from birth and may worsen during puberty. In females, symptoms are more severe just before and during menstruation, after taking oral contraceptives, and around the time of menopause.

Nijmegen breakage syndrome (NBS) is characterized by progressive microcephaly, early growth deficiency that improves with age, recurrent respiratory infections, an increased risk for malignancy (primarily lymphoma), and premature ovarian failure in females. Developmental milestones are attained at the usual time during the first year; however, borderline delays in development and hyperactivity may be observed in early childhood. Intellectual abilities tend to decline over time. Recurrent pneumonia and bronchitis may result in respiratory failure and early death. Other reported malignancies include solid tumors (e.g., medulloblastoma, glioma, rhabdomyosarcoma).

Hereditary mucoepithelial dysplasia (HMD) is a rare autosomal dominant genodermatosis characterized by onset in infancy of a panepithelial defect involving the oral, nasal, conjunctival, vaginal, cervical, perineal, urethral, and bladder mucosa. Patients develop cataracts, blindness, nonscarring alopecia, perineal psoriasiform lesions, and follicular keratoses (Witkop et al., 1982). Although 1 family was reported to have progressive severe interstitial lung disease (Witkop et al., 1979), this feature has not been reported in other families and is not considered a criterion for diagnosis. However, the clinical triad of nonscarring alopecia, well-demarcated fiery red mucosa, and psoriasiform perineal involvement has been consistently observed (review by Boralevi et al., 2005).

The phenotypic spectrum of X-linked severe combined immunodeficiency (X-SCID) ranges from typical X-SCID (early-onset disease in males that is fatal if not treated with hematopoietic stem cell transplantation [HSCT] or gene therapy) to atypical X-SCID (later-onset disease comprising phenotypes caused by variable immunodeficiency, immune dysregulation, and/or autoimmunity). Typical X-SCID. Prior to universal newborn screening (NBS) for SCID most males with typical X-SCID came to medical attention between ages three and six months because of recurrent infections, persistent infections, and infections with opportunistic organisms. With universal NBS for SCID, the common presentation for typical X-SCID is now an asymptomatic, healthy-appearing male infant. Atypical X-SCID, which usually is not detected by NBS, can manifest in the first years of life or later with one of the following: recurrent upper and lower respiratory tract infections with bronchiectasis; Omenn syndrome, a clinical phenotype caused by immune dysregulation; X-SCID combined immunodeficiency (often with recurrent infections, warts, and dermatitis); immune dysregulation and autoimmunity; or Epstein-Barr virus-related lymphoproliferative complications.

Al-Gazali syndrome (ALGAZ) is characterized by prenatal growth retardation, skeletal anomalies including joint contractures, camptodactyly, and bilateral talipes equinovarus, small mouth, anterior segment eye anomalies, and early lethality (summary by Ben-Mahmoud et al., 2018).

Primary ciliary dyskinesia-5 (CILD5) is an autosomal recessive disorder characterized by early onset of a progressive decline in lung function due to an inability to clear mucus and particles from the airways. Affected individuals have recurrent infections of the sinuses, ears, airways, and lungs. Sperm motility is also decreased. Individuals with CILD5 do not have situs inversus (summary by Olbrich et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).

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.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder of phagocytes (neutrophils, monocytes, macrophages, and eosinophils) resulting from impaired killing of bacteria and fungi. CGD is characterized by severe recurrent bacterial and fungal infections and dysregulated inflammatory responses resulting in granuloma formation and other inflammatory disorders such as colitis. Infections typically involve the lung (pneumonia), lymph nodes (lymphadenitis), liver (abscess), bone (osteomyelitis), and skin (abscesses or cellulitis). Granulomas typically involve the genitourinary system (bladder) and gastrointestinal tract (often the pylorus initially, and later the esophagus, jejunum, ileum, cecum, rectum, and perirectal area). Some males with X-linked CGD have McLeod neuroacanthocytosis syndrome as the result of a contiguous gene deletion. While CGD may present anytime from infancy to late adulthood, the vast majority of affected individuals are diagnosed before age five years. Use of antimicrobial prophylaxis and therapy has greatly improved overall survival.

X-linked reticulate pigmentary disorder shows more severe manifestations in hemizygous males compared to heterozygous females. Affected males have early onset of recurrent respiratory infections and failure to thrive resulting from inflammatory gastroenteritis or colitis. Patients also show reticular pigmentation abnormalities of the skin and may develop corneal scarring. Carrier females may be unaffected or have only pigmentary abnormalities along the lines of Blaschko (summary by Starokadomskyy et al., 2016).

Corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome is a developmental anomalies syndrome characterized by coloboma of the iris and optic nerve, facial dysmorphism (high forehead, microretrognathia, low-set ears), intellectual deficit, agenesis of the corpus callosum (ACC), sensorineural hearing loss, skeletal anomalies and short stature.

Roifman syndrome is a multisystem disorder characterized by growth retardation, spondyloepiphyseal dysplasia, retinal dystrophy, distinctive facial dysmorphism, and immunodeficiency (summary by de Vries et al., 2006).

Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome is a rare, genetic primary bone dysplasia disorder characterized by disproportionate short stature with shortening of upper and lower limbs, short and broad fingers with short hands, narrowed chest with rib abnormalities and pectus excavatum, abnormal chondral calcifications (incl. larynx, trachea and costal cartilages) and facial dysmorphism (frontal bossing, hypertelorism, prominent eyes, short flat nose, wide nostrils, high-arched palate, long philtrum). Platyspondyly (esp. of cervical spine) and abnormal epiphyses and metaphyses are observed on radiography. Atlantoaxial instability causing spinal compression and recurrent respiratory disease are potential complications that may result lethal.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder of phagocytes (neutrophils, monocytes, macrophages, and eosinophils) resulting from impaired killing of bacteria and fungi. CGD is characterized by severe recurrent bacterial and fungal infections and dysregulated inflammatory responses resulting in granuloma formation and other inflammatory disorders such as colitis. Infections typically involve the lung (pneumonia), lymph nodes (lymphadenitis), liver (abscess), bone (osteomyelitis), and skin (abscesses or cellulitis). Granulomas typically involve the genitourinary system (bladder) and gastrointestinal tract (often the pylorus initially, and later the esophagus, jejunum, ileum, cecum, rectum, and perirectal area). Some males with X-linked CGD have McLeod neuroacanthocytosis syndrome as the result of a contiguous gene deletion. While CGD may present anytime from infancy to late adulthood, the vast majority of affected individuals are diagnosed before age five years. Use of antimicrobial prophylaxis and therapy has greatly improved overall survival.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder of phagocytes (neutrophils, monocytes, macrophages, and eosinophils) resulting from impaired killing of bacteria and fungi. CGD is characterized by severe recurrent bacterial and fungal infections and dysregulated inflammatory responses resulting in granuloma formation and other inflammatory disorders such as colitis. Infections typically involve the lung (pneumonia), lymph nodes (lymphadenitis), liver (abscess), bone (osteomyelitis), and skin (abscesses or cellulitis). Granulomas typically involve the genitourinary system (bladder) and gastrointestinal tract (often the pylorus initially, and later the esophagus, jejunum, ileum, cecum, rectum, and perirectal area). Some males with X-linked CGD have McLeod neuroacanthocytosis syndrome as the result of a contiguous gene deletion. While CGD may present anytime from infancy to late adulthood, the vast majority of affected individuals are diagnosed before age five years. Use of antimicrobial prophylaxis and therapy has greatly improved overall survival.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder of phagocytes (neutrophils, monocytes, macrophages, and eosinophils) resulting from impaired killing of bacteria and fungi. CGD is characterized by severe recurrent bacterial and fungal infections and dysregulated inflammatory responses resulting in granuloma formation and other inflammatory disorders such as colitis. Infections typically involve the lung (pneumonia), lymph nodes (lymphadenitis), liver (abscess), bone (osteomyelitis), and skin (abscesses or cellulitis). Granulomas typically involve the genitourinary system (bladder) and gastrointestinal tract (often the pylorus initially, and later the esophagus, jejunum, ileum, cecum, rectum, and perirectal area). Some males with X-linked CGD have McLeod neuroacanthocytosis syndrome as the result of a contiguous gene deletion. While CGD may present anytime from infancy to late adulthood, the vast majority of affected individuals are diagnosed before age five years. Use of antimicrobial prophylaxis and therapy has greatly improved overall survival.

Any severe combined immunodeficiency in which the cause of the disease is a mutation in the CD247 gene.

Poikiloderma with neutropenia (PN) is characterized by an inflammatory eczematous rash (ages 6-12 months) followed by post-inflammatory poikiloderma (age >2 years) and chronic noncyclic neutropenia typically associated with recurrent sinopulmonary infections in the first two years of life and (often) bronchiectasis. There is increased risk for myelodysplastic syndrome and, rarely, acute myelogenous leukemia. Other ectodermal findings include nail dystrophy and palmar/plantar hyperkeratosis. Most affected individuals also have reactive airway disease and some have short stature, hypogonadotropic hypogonadism, midfacial retrusion, calcinosis cutis, and non-healing skin ulcers.

Adenosine deaminase (ADA) deficiency is a systemic purine metabolic disorder that primarily affects lymphocyte development, viability, and function. The clinical phenotypic spectrum includes: Severe combined immunodeficiency disease (SCID), often diagnosed by age six months and usually by age 12 months; Less severe "delayed" onset combined immune deficiency (CID), usually diagnosed between age one and ten years; "Late/adult onset" CID, diagnosed in the second to fourth decades; Benign "partial ADA deficiency" (very low or absent ADA activity in erythrocytes but greater ADA activity in nucleated cells), which is compatible with normal immune function. Infants with typical early-onset ADA-deficient SCID have failure to thrive and opportunistic infections associated with marked depletion of T, B, and NK lymphocytes, and an absence of both humoral and cellular immune function. If immune function is not restored, children with ADA-deficient SCID rarely survive beyond age one to two years. Infections in delayed- and late-onset types (commonly, recurrent otitis, sinusitis, and upper respiratory) may initially be less severe than those in individuals with ADA-deficient SCID; however, by the time of diagnosis these individuals often have chronic pulmonary insufficiency and may have autoimmune phenomena (cytopenias, anti-thyroid antibodies), allergies, and elevated serum concentration of IgE. The longer the disorder goes unrecognized, the more immune function deteriorates and the more likely are chronic sequelae of recurrent infection.

Axial spondylometaphyseal dysplasia (SMDAX) is characterized by postnatal growth failure, including rhizomelic short stature in early childhood that evolves into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection. Impaired visual acuity comes to medical attention in early life and vision rapidly deteriorates. Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on funduscopic examination and as cone-rod dystrophy on electroretinogram. Radiologic hallmarks include short ribs with flared and cupped anterior ends, mild spondylar dysplasia, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora (summary by Suzuki et al., 2011).

Pulmonary surfactant metabolism dysfunction-2 (SMDP2) is a rare autosomal dominant disease associated with progressive respiratory insufficiency and lung disease with a variable clinical course. The pathophysiology of the disorder is postulated to involve intracellular accumulation of a structurally defective SPC protein (Thomas et al., 2002). For a general phenotypic description and a discussion of genetic heterogeneity of pulmonary surfactant metabolism dysfunction, see SMDP1 (265120).

GNPTAB-related disorders comprise the phenotypes mucolipidosis II (ML II) and mucolipidosis IIIa/ß (ML IIIa/ß), and phenotypes intermediate between ML II and ML IIIa/ß. ML II is evident at birth and slowly progressive; death most often occurs in early childhood. Orthopedic abnormalities present at birth may include thoracic deformity, kyphosis, clubfeet, deformed long bones, and/or dislocation of the hip(s). Growth often ceases in the second year of life; contractures develop in all large joints. The skin is thickened, facial features are coarse, and gingiva are hypertrophic. All children have cardiac involvement, most commonly thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Progressive mucosal thickening narrows the airways, and gradual stiffening of the thoracic cage contributes to respiratory insufficiency, the most common cause of death. ML IIIa/ß becomes evident at about age three years with slow growth rate and short stature; joint stiffness and pain initially in the shoulders, hips, and fingers; gradual mild coarsening of facial features; and normal to mildly impaired cognitive development. Pain from osteoporosis becomes more severe during adolescence. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left and/or right ventricular hypertrophy) are common causes of death, typically in early to middle adulthood. Phenotypes intermediate between ML II and ML IIIa/ß are characterized by physical growth in infancy that resembles that of ML II and neuromotor and speech development that resemble that of ML IIIa/ß.

A few individuals have been diagnosed with intermediate autosomal osteopetrosis (IAO), a form of the disorder that can have either an autosomal dominant or an autosomal recessive pattern of inheritance. The signs and symptoms of this condition become noticeable in childhood and include an increased risk of bone fracture and anemia. People with this form of the disorder typically do not have life-threatening bone marrow abnormalities. However, some affected individuals have had abnormal calcium deposits (calcifications) in the brain, intellectual disability, and a form of kidney disease called renal tubular acidosis.\n\nOther features of autosomal recessive osteopetrosis can include slow growth and short stature, dental abnormalities, and an enlarged liver and spleen (hepatosplenomegaly). Depending on the genetic changes involved, people with severe osteopetrosis can also have brain abnormalities, intellectual disability, or recurrent seizures (epilepsy).\n\nAutosomal recessive osteopetrosis (ARO) is a more severe form of the disorder that becomes apparent in early infancy. Affected individuals have a high risk of bone fracture resulting from seemingly minor bumps and falls. Their abnormally dense skull bones pinch nerves in the head and face (cranial nerves), often resulting in vision loss, hearing loss, and paralysis of facial muscles. Dense bones can also impair the function of bone marrow, preventing it from producing new blood cells and immune system cells. As a result, people with severe osteopetrosis are at risk of abnormal bleeding, a shortage of red blood cells (anemia), and recurrent infections. In the most severe cases, these bone marrow abnormalities can be life-threatening in infancy or early childhood.\n\nIn individuals with ADO who develop signs and symptoms, the major features of the condition include multiple bone fractures after minor injury, abnormal side-to-side curvature of the spine (scoliosis) or other spinal abnormalities, arthritis in the hips, and a bone infection called osteomyelitis. These problems usually become apparent in late childhood or adolescence.\n\nAutosomal dominant osteopetrosis (ADO), which is also called Albers-Schönberg disease, is typically the mildest type of the disorder. Some affected individuals have no symptoms. In affected people with no symptoms, the unusually dense bones may be discovered by accident when an x-ray is done for another reason. \n\nOsteopetrosis is a bone disease that makes bone tissue abnormally compact and dense and also prone to breakage (fracture). Researchers have described several major types of osteopetrosis, which are usually distinguished by their pattern of inheritance: autosomal dominant or autosomal recessive. The different types of the disorder can also be distinguished by the severity of their signs and symptoms.

Primary ciliary dyskinesia is an autosomal recessive disorder resulting from loss of normal ciliary function. Kartagener (pronounced KART-agayner) syndrome is characterized by the combination of primary ciliary dyskinesia and situs inversus, and occurs in approximately half of patients with ciliary dyskinesia. Since normal nodal ciliary movement in the embryo is required for normal visceral asymmetry, absence of normal ciliary movement results in a lack of definitive patterning; thus, random chance alone appears to determine whether the viscera take up the normal or reversed left-right position during embryogenesis. This explains why approximately 50% of patients, even within the same family, have situs inversus (Afzelius, 1976; El Zein et al., 2003). For a general phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia and the Kartagener syndrome, see CILD1 (244400).

Immunodeficiency-10 (IMD10) is an autosomal recessive primary immunodeficiency characterized by onset of recurrent infections in childhood due to defective T- and NK-cell function, although the severity is variable. Affected individuals may also have hypotonia, hypohidrosis, or dental enamel hypoplasia consistent with amelogenesis imperfecta (summary by Parry et al., 2016).

Congenital generalized lipodystrophy type 4 (CGL4) combines the phenotype of classic Berardinelli-Seip lipodystrophy (608594) with muscular dystrophy and cardiac conduction anomalies (Hayashi et al., 2009). For a general description and a discussion of genetic heterogeneity of congenital generalized lipodystrophy, see CGL1 (608594).

LTBP4-related cutis laxa is characterized by cutis laxa, early childhood-onset pulmonary emphysema, peripheral pulmonary artery stenosis, and other evidence of a generalized connective tissue disorder such as inguinal hernias and hollow visceral diverticula (e.g., intestine, bladder). Other manifestations can include pyloric stenosis, diaphragmatic hernia, rectal prolapse, gastrointestinal elongation/tortuosity, cardiovascular abnormality, pulmonary hypertension, hypotonia and frequent pulmonary infections. Bladder diverticula and hydronephrosis are common. Early demise has been associated with pulmonary emphysema.

Congenital disorders of glycosylation (CDG), previously called carbohydrate-deficient glycoprotein syndromes (CDGSs), are a group of hereditary multisystem disorders first recognized by Jaeken et al. (1980). The characteristic biochemical abnormality of CDGs is the hypoglycosylation of glycoproteins, which is routinely determined by isoelectric focusing (IEF) of serum transferrin. Type I CDG comprises those disorders in which there is a defect in the assembly of lipid-linked oligosaccharides or their transfer onto nascent glycoproteins, whereas type II CDG comprises defects of trimming, elongation, and processing of protein-bound glycans. CDG1G is a multisystem disorder characterized by impaired psychomotor development, dysmorphic features, failure to thrive, male genital hypoplasia, coagulation abnormalities, and immune deficiency. More variable features include skeletal dysplasia, cardiac anomalies, ocular abnormalities, and sensorineural hearing loss. Some patients die in the early neonatal or infantile period, whereas others are mildly affected and live to adulthood (summary by Tahata et al., 2019). For a general discussion of CDGs, see CDG1A (212065).

Common variable immunodeficiency (CVID) is a clinically and genetically heterogeneous group of disorders characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections, and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B cells are usually in the normal range, but can be low. Most individuals with CVID have onset of infections after age 10 years. CVID represents the most common form of primary immunodeficiency disorders and is the most common form of primary antibody deficiency. Approximately 10 to 20% of patients with a diagnosis of CVID have a family history of the disorder (reviews by Chapel et al., 2008, Conley et al., 2009, and Yong et al., 2009). Genetic Heterogeneity of Common Variable Immunodeficiency Common variable immunodeficiency is a genetically heterogeneous disorder. See also CVID2 (240500), caused by mutation in the TACI gene (TNFRSF13B; 604907); CVID3 (613493), caused by mutation in the CD19 gene (107265); CVID4 (613494), caused by mutation in the BAFFR gene (TNFRSF13C; 606269); CVID5 (613495), caused by mutation in the CD20 gene (112210); CVID6 (613496), caused by mutation in the CD81 gene (186845); CVID7 (614699), caused by mutation in the CD21 gene (CR2; 120650); CVID8 (614700), caused by mutation in the LRBA gene (606453); CVID10 (615577), caused by mutation in the NFKB2 gene (164012); CVID11 (615767), caused by mutation in the IL21 gene (605384); CVID12 (616576), caused by mutation in the NFKB1 gene (164011); CVID13 (616873), caused by mutation in the IKZF1 gene (603023); CVID14 (617765), caused by mutation in the IRF2BP2 gene (615332); and CVID15 (620670), caused by heterozygous mutation in the SEC61A1 gene (609213). The disorder formerly designated CVID9 has been found to be a form of autoimmune lymphoproliferative disorder; see ALPS3 (615559).

Any autosomal agammaglobulinemia in which the cause of the disease is a mutation in the CD79B gene.

Any autosomal agammaglobulinemia in which the cause of the disease is a mutation in the IGLL1 gene.

Any autosomal agammaglobulinemia in which the cause of the disease is a mutation in the BLNK gene.

Cranioectodermal dysplasia (CED) is a ciliopathy with skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly, polydactyly, brachydactyly), ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth deficiency, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage kidney disease in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur.

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.

MASP2 deficiency, classically defined as MASP2 protein level of less than 100 ng/ml, occurs in about 4% of Caucasians and up to 18% of some African populations. Some MASP2-deficient individuals have increased risk of infection or autoimmune disease, but most are asymptomatic. MASP2 plays a role in activation of the lectin pathway of the complement system; deficiency may thus lead to defects in the complement system (summary by Thiel et al., 2007 and Sokolowska et al., 2015). For a discussion of genetic heterogeneity of lectin complement activation pathway defects, see LCAPD1 (614372).

Abnormalities in sexual development may also occur in Meier-Gorlin syndrome. In some males with this condition, the testes are small or undescended (cryptorchidism). Affected females may have unusually small external genital folds (hypoplasia of the labia majora) and small breasts. Both males and females with this condition can have sparse or absent underarm (axillary) hair.\n\nAdditional features of Meier-Gorlin syndrome can include difficulty feeding and a lung condition known as pulmonary emphysema or other breathing problems.\n\nMeier-Gorlin syndrome is a condition primarily characterized by short stature. It is considered a form of primordial dwarfism because the growth problems begin before birth (intrauterine growth retardation). After birth, affected individuals continue to grow at a slow rate. Other characteristic features of this condition are underdeveloped or missing kneecaps (patellae), small ears, and, often, an abnormally small head (microcephaly). Despite a small head size, most people with Meier-Gorlin syndrome have normal intellect.\n\nSome people with Meier-Gorlin syndrome have other skeletal abnormalities, such as unusually narrow long bones in the arms and legs, a deformity of the knee joint that allows the knee to bend backwards (genu recurvatum), and slowed mineralization of bones (delayed bone age).\n\nMost people with Meier-Gorlin syndrome have distinctive facial features. In addition to being abnormally small, the ears may be low-set or rotated backward. Additional features can include a small mouth (microstomia), an underdeveloped lower jaw (micrognathia), full lips, and a narrow nose with a high nasal bridge.

Primary ciliary dyskinesia-14 (CILD14) is an autosomal recessive disorder characterized by recurrent respiratory infections associated with defects in ciliary inner dynein arms and axonemal disorganization (Merveille et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).

Primary ciliary dyskinesia-15 (CILD15) is an autosomal recessive disorder characterized by recurrent respiratory infections associated with defects in ciliary inner dynein arms and axonemal disorganization (summary by Becker-Heck et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).

Osteogenesis imperfecta (OI) comprises a group of connective tissue disorders characterized by bone fragility and low bone mass. The disorder is clinically and genetically heterogeneous. OI type X is an autosomal recessive form characterized by multiple bone deformities and fractures, generalized osteopenia, dentinogenesis imperfecta, and blue sclera (Christiansen et al., 2010).

Agammaglobulinemia is a primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life. The most common form of agammaglobulinemia is X-linked agammaglobulinemia (AGMX1, XLA; 300755), also known as Bruton disease, which is caused by mutation in the BTK gene (300300). AGMX1 accounts for anywhere from 85 to 95% of males who have the characteristic findings (Lopez Granados et al., 2002; Ferrari et al., 2007). Autosomal recessive inheritance of agammaglobulinemia, which has a similar phenotype to that of the X-linked form, has been observed in a small number of families, and accounts for up to 15% of patients with agammaglobulinemia (Ferrari et al., 2007). Conley (1999) gave a comprehensive review of autosomal recessive agammaglobulinemia. Genetic Heterogeneity of Autosomal Agammaglobulinemia Autosomal agammaglobulinemia is a genetically heterogeneous disorder: see also AGM2 (613500), caused by mutation in the IGLL1 gene (146770); AGM3 (613501), caused by mutation in the CD79A gene (112205); AGM4 (613502), caused by mutation in the BLNK gene (604515); AGM5 (613506), caused by disruption of the LRRC8 gene (608360); AGM6 (612692), caused by mutation in the CD79B gene (147245); AGM7 (615214), caused by mutation in the PIK3R1 gene (171833); AGM8 (616941), caused by mutation in the TCF3 gene (147141); AGM9 (619693), caused by mutation in the SLC39A7 gene (601416); and AGM10 (619707), caused by mutation in the SPI1 gene (165170).

Keppen-Lubinsky syndrome (KPLBS) is a rare disorder characterized by severely delayed psychomotor development, hypertonia, hyperreflexia, generalized lipodystrophy giving an aged appearance, and distinctive dysmorphic features, including microcephaly, prominent eyes, narrow nasal bridge, and open mouth (summary by Masotti et al., 2015).

Cranioectodermal dysplasia (CED) is a ciliopathy with skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly, polydactyly, brachydactyly), ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth deficiency, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage kidney disease in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur.

Concentration of the complement component C4b in the blood circulation below the lower limit of normal.

CILD20 is an autosomal recessive ciliopathy characterized by infantile onset of chronic sinopulmonary infections resulting from immotile cilia and defective clearance. Patients may also have situs inversus or cardiac anomalies. Electron microscopy of respiratory epithelial cells shows absence of the outer dynein arms. Unlike other forms of CILD, patients with CILD20 do not appear to be infertile. For a phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see 244400.

Congenital myopathy-10B (CMYP10B) is an autosomal recessive skeletal muscle disorder characterized by infantile- or childhood-onset myopathy, areflexia, dysphagia, and respiratory distress that usually requires nocturnal ventilation. Other common features include facial and neck muscle weakness, feeding difficulties, contractures, scoliosis, high-arched palate, hyporeflexia, and difficulties walking. The disorder is slowly progressive and most patients follow a chronic course. Muscle biopsy shows variable findings, including type 1 fiber predominance, minicore lesions, and myofibrillar disorganization (Boyden et al., 2012; Harris et al., 2018). Patients with missense mutations affecting conserved cysteine residues in the EGF-like domain show the mild variant phenotype (CMYP10B) with later onset of respiratory failure and minicores on muscle biopsy, whereas patients with more damaging mutations, including nonsense or frameshift null mutations, show the severe variant phenotype (CMYP10A) (Croci et al., 2022). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).

Common variable immunodeficiency-8 with autoimmunity is an autosomal recessive disorder of immune dysregulation. Affected individuals have early childhood onset of recurrent infections, particularly respiratory infections, and also develop variable autoimmune disorders, including idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and inflammatory bowel disease. The presentation and phenotype are highly variable, even within families (summary by Lopez-Herrera et al., 2012 and Alangari et al., 2012). Immunologic findings are also variable and may include decreased B cells, hypogammaglobulinemia, and deficiency of CD4+ T regulatory (Treg) cells (Charbonnier et al., 2015). For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (607594).

Immunodeficiency-110 (IMD110) is an autosomal recessive primary T-cell immunodeficiency syndrome characterized by progressive loss of naive T cells, recurrent bacterial, viral, and fungal infections, warts, and abscesses, and autoimmune manifestations. Patients are at risk for developing lymphoproliferative disorders or lymphoma, particularly associated with EBV. Some patients may show cardiac malformations, including atrial septal defect (Abdollahpour et al., 2012; Nehme et al., 2012).

Leptin deficiency or dysfunction (LEPD) is characterized by severe early-onset obesity, hyperphagia, hypogonadotropic hypogonadism, and neuroendocrine/metabolic dysfunction (Ozata et al., 1999).

Lymphoproliferative syndrome-2, also known as CD27 deficiency, is an autosomal recessive immunodeficiency disorder associated with persistent symptomatic EBV viremia, hypogammaglobulinemia, and impairment in specific antibody function resulting from impaired T cell-dependent B-cell responses and T-cell dysfunction (summary by van Montfrans et al., 2012). The phenotype can vary significantly, from asymptomatic borderline-low hypogammaglobulinemia, to a full-blown symptomatic systemic inflammatory response with life-threatening EBV-related complications, including hemophagocytic lymphohistiocytosis, a lymphoproliferative disorder, and malignant lymphoma requiring stem cell transplantation (summary by Salzer et al., 2013). For a discussion of genetic heterogeneity of lymphoproliferative syndrome, see XLP1 (308240).

Immunodeficiency-56 is an autosomal recessive primary immunodeficiency characterized by B- and T-cell defects and variable dysfunction of NK cells. Patients tend to have normal numbers of lymphocytes, but show defective class-switched B cells, low IgG, defective antibody response, and defective T-cell responses to certain antigens (summary by Kotlarz et al., 2013).

Primary ciliary dyskinesia-21 (CILD21) is an autosomal recessive ciliopathy characterized by infantile onset of chronic sinopulmonary infections resulting from abnormal ciliary function. Electron microscopy of respiratory epithelial cells shows normal outer and inner dynein arms, but absence of nexin links and defects in the nexin-dynein regulatory complex (N-DRC). Video microscopy of patient cilia shows an increased beat frequency with decreased bending amplitude (summary by Wirschell et al., 2013). For a phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).

Primary ciliary dyskinesia-23 is an autosomal recessive disorder resulting from defective ciliary motility. Affected individuals have respiratory distress and recurrent upper and lower airway infections, and they often develop bronchiectasis. About 50% of patients have situs inversus or laterality defects. Ultrastructural analysis of respiratory cilia shows defects in the outer dynein arm (summary by Hjeij et al., 2013). For a phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see 244400.

Primary ciliary dyskinesia-25 is an autosomal recessive disorder caused by defective ciliary movement. Affected individuals have recurrent upper and lower airway disease, bronchiectasis, and decreased fertility. About half of patients show laterality defects, including situs inversus totalis. Respiratory cilia from patients show defects in the inner and outer dynein arms (summary by Tarkar et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see 244400.

Idiopathic CD4 lymphopenia (ICL) is a rare and heterogeneous syndrome defined by a reproducible reduction in the CD4 T-lymphocyte count (less than 300 cells per microliter or less than 20% of total T cells) in the absence of HIV infection or other known causes of immunodeficiency. ICL predisposes to infections and malignancy (summary by Gorska and Alam, 2012).

Common variable immunodeficiency-10 (CVID10) is an autosomal dominant primary immunodeficiency characterized by childhood-onset of recurrent infections, hypogammaglobulinemia, and decreased numbers of memory and marginal zone B cells. Some patients may develop autoimmune features and have circulating autoantibodies. An unusual feature is central adrenal insufficiency (summary by Chen et al., 2013). For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (607594).

Immunodeficiency-18 is an autosomal recessive primary immunodeficiency characterized by onset in infancy or early childhood of recurrent infections. The severity is variable, encompassing both a mild immunodeficiency and severe combined immunodeficiency (SCID), resulting in early death without bone marrow transplantation in some patients. Immunologic work-up of the IMD18 SCID patients shows a T cell-negative, B cell-positive, natural killer (NK) cell-positive phenotype, whereas T-cell development is not impaired in the mild form of IMD18 (summary by de Saint Basile et al., 2004).

Autosomal recessive intellectual developmental disorder-41 (MRT41) is characterized by macrocephaly and global developmental delay. Some patients have seizures (Baple et al., 2014).

Any neonatal inflammatory skin and bowel disease in which the cause of the disease is a mutation in the EGFR gene.

Tenorio syndrome (TNORS) is characterized by overgrowth, macrocephaly, and impaired intellectual development. Some patients may have mild hydrocephaly, hypoglycemia, and inflammatory diseases resembling Sjogren syndrome (270150) (summary by Tenorio et al., 2014).

Familial glucocorticoid deficiency is an autosomal recessive disorder resulting from resistance to the action of adrenocorticotropin (ACTH) on the adrenal cortex, which stimulates glucocorticoid production. Affected individuals are deficient in cortisol and, if untreated, are likely to succumb to hypoglycemia or overwhelming infection in infancy or childhood (summary by Metherell et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of familial glucocorticoid deficiency, see GCCD1 (202200).

Primary ciliary dyskinesia-33 is an autosomal recessive disorder characterized by recurrent upper and lower respiratory infections due to defective ciliary clearance and resulting in chronic lung disease. Some patients may have recurrent ear infections resulting in conductive hearing impairment. Examination of respiratory cilia shows subtle movement defects. Laterality defects have not been reported (summary by Olbrich et al., 2015). For a phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).

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).

Basel-Vanagaite-Smirin-Yosef syndrome is an autosomal recessive multiple congenital anomaly disorder characterized by severely delayed psychomotor development resulting in mental retardation, as well as variable eye, brain, cardiac, and palatal abnormalities (summary by Basel-Vanagaite et al., 2015).

Immunodeficiency-40 is an autosomal recessive primary form of combined immunodeficiency mainly affecting T-cell number and function, with other more variable defects in B-cell and NK-cell function. Patients have onset of severe invasive bacterial and viral infections in early childhood and may die without bone marrow transplantation (summary by Dobbs et al., 2015).

MPSPS is an autosomal recessive inborn error of metabolism resulting in a multisystem disorder with features of the mucopolysaccharidosis lysosomal storage diseases (see, e.g., 607016). Patients present in infancy or early childhood with respiratory difficulties, cardiac problems, anemia, dysostosis multiplex, renal involvement, coarse facies, and delayed psychomotor development. Most patients die of cardiorespiratory failure in the first years of life (summary by Kondo et al., 2017).

Primary ciliary dyskinesia-35 (CILD35) is an autosomal recessive disorder characterized by recurrent upper and lower respiratory infections due to defective ciliary function. Examination of respiratory cilia shows lack of outer dynein arms (ODAs) and immotile cilia. Some patients may have laterality defects (summary by Wallmeier et al., 2016). For a phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).

Specific granule deficiency-2 (SGD2) is an autosomal recessive immunologic disorder characterized by recurrent infections due to defective neutrophil development. Bone marrow findings include paucity of neutrophil granulocytes, absence of granule proteins in neutrophils, abnormal megakaryocytes, and features of progressive myelofibrosis with blasts. The disorder is apparent from infancy, and patients may die in early childhood unless they undergo hematopoietic stem cell transplantation. Most patients have additional findings, including delayed development, mild dysmorphic features, tooth abnormalities, and distal skeletal defects (Witzel et al., 2017). For a discussion of genetic heterogeneity of SGD, see SGD1 (245480).

IMD52 is an autosomal recessive primary immunodeficiency with variable manifestations, including severe combined immunodeficiency, hematologic autoimmune disorders, progressive lymphopenia and hypogammaglobulinemia, and lymphoproliferation with splenomegaly. Patients develop severe recurrent infections from infancy, and most die without bone marrow transplantation. The variable clinical features result from a defect in T-cell receptor signaling (summary by Keller et al., 2016 and Bacchelli et al., 2017).

Immunodeficiency-71 with inflammatory disease and congenital thrombocytopenia (IMD71) is an autosomal recessive immunologic disorder characterized by the onset of recurrent infections and inflammatory features such as vasculitis and eczema in infancy or early childhood. Infectious agents include bacteria and viruses. Laboratory findings are variable, but usually show thrombocytopenia, sometimes with abnormal platelet morphology, increased serum IgE, IgA, or IgM, leukocytosis, decreased or increased T lymphocytes, and increased eosinophils. Detailed studies show impaired neutrophil and T-cell chemotaxis, as well as impaired T-cell activation due to defects in F-actin (see 102610) polymerization (summary by Brigida et al., 2018).

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay and moderate to severe intellectual disability, as well as variable other manifestations, such as macro- or microcephaly, epilepsy, hypotonia, behavioral problems, stereotypic movements, and facial dysmorphism (including arched eyebrows, long palpebral fissures, prominent nasal bridge, upturned nose, dysplastic ears, and broad mouth), among others. Brain imaging may show cerebellar anomalies, hypoplastic corpus callosum, enlarged ventricles, polymicrogyria, or white matter abnormalities.

Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia is an inborn error of folate metabolism due to deficiency of methylenetetrahydrofolate dehydrogenase-1. Manifestations may include hemolytic uremic syndrome, macrocytosis, epilepsy, hearing loss, retinopathy, mild mental retardation, lymphopenia involving all subsets, and low T-cell receptor excision circles. Folinic acid supplementation is an effective treatment (summary by Ramakrishnan et al., 2016).

Any specific granule deficiency in which the cause of the disease is a mutation in the CEBPE gene.

STAT3 hyper IgE syndrome (STAT3-HIES) is a primary immune deficiency syndrome characterized by elevated serum IgE, eczema, and recurrent skin and respiratory tract infections, together with several nonimmune features. This disorder typically manifests in the newborn period with a rash (often diagnosed as eosinophilic pustulosis) that subsequently evolves into an eczematoid dermatitis. Recurrent staphylococcal skin boils and bacterial pneumonias usually manifest in the first years of life. Pneumatoceles and bronchiectasis often result from aberrant healing of pneumonias. Mucocutaneous candidiasis is common. Nonimmune features may include retained primary teeth, scoliosis, bone fractures following minimal trauma, joint hyperextensibility, and characteristic facial appearance, which typically emerges in adolescence. Vascular abnormalities have been described and include middle-sized artery tortuosity and aneurysms, with infrequent clinical sequelae of myocardial infarction and subarachnoid hemorrhage. Gastrointestinal (GI) manifestations include gastroesophageal reflux disease, esophageal dysmotility, and spontaneous intestinal perforations (some of which are associated with diverticuli). Fungal infections of the GI tract (typically histoplasmosis, Cryptococcus, and Coccidioides) also occur infrequently. Survival is typically into adulthood, with most individuals now living into or past the sixth decade. Most deaths are associated with gram-negative (Pseudomonas) or filamentous fungal pneumonias resulting in hemoptysis. Lymphomas occur at an increased frequency.

Hyper-IgE syndrome-2 with recurrent infections (HIES2) is an autosomal recessive immunologic disorder characterized by recurrent staphylococcal infections of the skin and respiratory tract, eczema, elevated serum immunoglobulin E, and hypereosinophilia. It is distinguished from autosomal dominant HIES1 (147060) by the lack of connective tissue and skeletal involvement (Renner et al., 2004). For a discussion of genetic heterogeneity of hyper-IgE syndrome, see 147060. See also TYK2 deficiency (611521), a clinically distinct disease entity that includes characteristic features of both autosomal recessive HIES2 and mendelian susceptibility to mycobacterial disease (MSMD; 209950) (Minegishi et al., 2006).

Immunodeficiency-58 is an autosomal recessive primary immunologic disorder characterized by early-onset skin lesions, including eczematous dermatitis, infectious abscesses, and warts, recurrent respiratory infections or allergies, and chronic persistent infections with candida, Molluscum contagiosum, mycobacteria, EBV, bacteria, and viruses. Some patients may have gastrointestinal involvement, including inflammatory bowel disease, EBV+ smooth muscle tumors, and esophagitis. Immunologic analysis shows defective T-cell function with decreased Treg cells and deficient CD3/CD28 costimulation responses in both CD4+ and CD8+ T cells. B-cell function may also be impaired (summary by Wang et al., 2016 and Alazami et al., 2018).

Hyper-IgE syndrome-3 with recurrent infections (HIES3) 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 workup 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 syndrome, see HIES1 (147060).

Hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities (HIDEA) is an autosomal recessive neurodevelopmental syndrome characterized by global developmental delay, poor or absent speech, hypotonia, variable ocular movement and visual abnormalities, and respiratory difficulties, including hypoventilation, and sleep apnea. Patients may have significant breathing problems during respiratory infections that may lead to early death (summary by Rahikkala et al., 2019).

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder of phagocytes (neutrophils, monocytes, macrophages, and eosinophils) resulting from impaired killing of bacteria and fungi. CGD is characterized by severe recurrent bacterial and fungal infections and dysregulated inflammatory responses resulting in granuloma formation and other inflammatory disorders such as colitis. Infections typically involve the lung (pneumonia), lymph nodes (lymphadenitis), liver (abscess), bone (osteomyelitis), and skin (abscesses or cellulitis). Granulomas typically involve the genitourinary system (bladder) and gastrointestinal tract (often the pylorus initially, and later the esophagus, jejunum, ileum, cecum, rectum, and perirectal area). Some males with X-linked CGD have McLeod neuroacanthocytosis syndrome as the result of a contiguous gene deletion. While CGD may present anytime from infancy to late adulthood, the vast majority of affected individuals are diagnosed before age five years. Use of antimicrobial prophylaxis and therapy has greatly improved overall survival.

Immunodeficiency-73B with defective neutrophil chemotaxis (IMD73B) is an autosomal dominant immunologic disorder characterized by onset of recurrent infections in infancy or early childhood. Affected individuals develop respiratory infections, cellulitis, and severe invasive infections or sepsis; organisms include bacteria such as Staphylococcus, as well as viruses, fungi, and mycobacterial species. Laboratory studies show variable abnormalities, including B- and T-cell lymphopenia, decreased immunoglobulin subsets, decreased TRECs and dysfunctional T cells, decreased NK cells, neutropenia, and impaired neutrophil chemotaxis. Hematopoietic stem cell transplantation is curative (summary by Hsu et al., 2019; review by Lougaris et al., 2020). In a review of autosomal forms of chronic granulomatous disease (see 306400 for genetic heterogeneity of CGD), Roos et al. (2021) noted that patients with RAC2 mutations may manifest CGD-like symptoms due to defects in neutrophil NADPH oxidase activity.

Blepharophimosis-impaired intellectual development syndrome (BIS) is a congenital disorder characterized by a distinct facial appearance with blepharophimosis and global development delay. Affected individuals have delayed motor skills, sometimes with inability to walk, and impaired intellectual development with poor or absent speech; some patients show behavioral abnormalities. There are recognizable facial features, including epicanthal folds, sparse eyebrows, broad nasal bridge, short nose with downturned tip, and open mouth with thin upper lip. Other more variable features include distal skeletal anomalies, feeding difficulties with poor growth, respiratory infections, and hypotonia with peripheral spasticity (summary by Cappuccio et al., 2020).

Immunodeficiency-76 (IMD76) is an autosomal recessive primary immunologic disorder characterized by onset of recurrent bacterial, viral, and fungal infections in early childhood. Laboratory studies show T-cell lymphopenia and may show variable B-cell or immunoglobulin abnormalities. More variable features found in some patients include lymphoma and neurologic features. Although bone marrow transplantation may be curative, many patients die in childhood (summary by Lyszkiewicz et al., 2020).

Autosomal dominant primary microcephaly-26 (MCPH26) is characterized by progressive microcephaly beginning at birth and associated with global developmental delay with variably impaired intellectual development. Some patients may have only mild learning difficulties or speech delay, whereas other are more severely affected with the inability to walk or speak. Additional features may include short stature, spasticity, feeding difficulties requiring tube feeding, and nonspecific dysmorphic facial features. Brain imaging in some patients shows a simplified gyral pattern or dysgenesis of the corpus callosum, suggesting abnormal neuronal migration (summary by Cristofoli et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).

Autosomal recessive primary immunodeficiency-14B (IMD14B) is characterized by onset of recurrent infections in early childhood. Most patients have respiratory infections, but some may develop inflammatory bowel disease or osteomyelitis. Laboratory studies tend to show hypogammaglobulinemia and decreased levels of B cells. Although NK cell and T cell numbers are normal, there may be evidence of impaired immune-mediated cytotoxicity and defective T-cell function (summary by et al., 2018 and et al., 2019).

Buratti-Harel syndrome (BURHAS) is a neurodevelopmental disorder characterized by infantile hypotonia, global developmental delay, mild motor and speech delay, and mild to moderately impaired intellectual development. Some patients are able to attend special schools and show learning difficulties, whereas others are more severely affected. Patients have prominent dysmorphic facial features, including hypertelorism, downslanting palpebral fissures, strabismus, and small low-set ears. Additional features may include laryngomalacia with feeding difficulties and distal skeletal anomalies (summary by Buratti et al., 2021).

Primary ciliary dyskinesia-46 (CILD46) is characterized by recurrent sinus and respiratory infections, with reduced pulmonary function and uncoordinated beating of respiratory cilia. No situs abnormalities have been observed (Edelbusch et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).

Otospondylomegaepiphyseal dysplasia (OSMED) is characterized by sensorineural hearing loss, enlarged epiphyses, disproportionate shortness of the limbs, abnormalities in vertebral bodies, and typical facial features (summary by Harel et al., 2005).

Immunodeficiency-91 and hyperinflammation (IMD91) is an autosomal recessive complex immunologic disorder characterized by both immunodeficiency and recurrent infections, often to viruses or mycobacteria, as well as by hyperinflammation with systemic involvement. Affected individuals present in infancy with variable features, including fever, infection, thrombocytopenia, renal or hepatic dysfunction, recurrent infections, or seizures. Most patients eventually develop hepatic or renal failure, compromised neurologic function, lymphadenopathy or hepatosplenomegaly, and multiorgan failure resulting in death. More variable features may include intermittent monocytosis, features of hemophagocytic lymphohistiocytosis (HLH), and serologic evidence of hyperinflammation. The disorder is thought to result from dysregulation of the interferon response to viral stimulation in the innate immune system (summary by Le Voyer et al., 2021; Vavassori et al., 2021).

CLPB (caseinolytic peptidase B) deficiency is characterized by neurologic involvement and neutropenia, which can range from severe to mild. In severe CLPB deficiency, death usually occurs at a few months of age due to significant neonatal neurologic involvement (hyperekplexia or absence of voluntary movements, hypotonia or hypertonia, swallowing problems, respiratory insufficiency, and epilepsy) and severe neutropenia associated with life-threatening infections. Individuals with moderate CLPB deficiency present with neurologic abnormalities in infancy including hypotonia and feeding problems, and develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability. Neutropenia is variable, but not life threatening. In those with mild CLPB deficiency there is no neurologic involvement, intellect is normal, neutropenia is mild and intermittent, and life expectancy is normal.

Immunodeficiency-94 with autoinflammation and dysmorphic facies (IMD94) is a systemic immunologic disorder with onset in early infancy. Primary features include lymphadenopathy, autoinflammation, immunodeficiency with hypogammaglobulinemia, and dysmorphic facial features. Intellectual development is normal and serum IgE is not elevated. The disease results from constitutive activation of the IL6 signaling cascade, resulting in immune dysregulation and a hyperinflammatory state (summary by Materna-Kiryluk et al., 2021).

Hyper-IgE syndrome-4A with recurrent infections (HIES4A) is an autosomal dominant 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 syndrome, see HIES1 (147060).

Macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin (MNDLFH) is characterized by clinically significant pharyngeal lymphoid hypertrophy, with adenoid overgrowth, frequent upper airway infections, and sleep apnea. Macrocephaly without structural brain abnormalities is present, and patients exhibit increased weight for height as well as delayed gross motor and impaired intellectual development; autistic features and attention-deficit hyperactivity disorder have also been reported. An increased fraction of fetal hemoglobin has been observed in some patients (Ohishi et al., 2020; von der Lippe et al., 2022).

Autosomal recessive agammaglobulinemia-8B (AGM8B) is characterized by onset of recurrent infections in early childhood. Laboratory studies of affected individuals show decreased circulating immunoglobulins and decreased peripheral B cells. More variable features may include dysmorphic facies and subtle abnormalities of other immune cells, such as T cells. One patient who developed childhood B-cell acute lymphocytic leukemia (B-ALL) has been described (summary by Ben-Ali et al., 2017).

Developmental delay, hypotonia, and impaired language (DEDHIL) is a neurodevelopmental disorder characterized by variably impaired intellectual development usually with hypotonia, mild motor delay, and language difficulties. Affected individuals may also have nonspecific dysmorphic facial features, gastrointestinal problems, and abnormalities on brain imaging (Stephenson et al., 2022).

Primary ciliary dyskinesia-48 without situs inversus (CILD48) is an autosomal recessive disorder characterized by recurrent upper and lower respiratory infections due to impaired ciliary movement and clearance. Affected individuals often develop chronic lung disease. Since the defect involves the radial spokes and central pairs of microtubules in motile cilia, situs abnormalities do not occur (summary by Cho et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).

X-linked spermatogenic failure-6 (SPGFX6) is characterized by male infertility due to asthenoteratozoospermia. Patient spermatozoa show reduced progressive motility, and multiple morphologic abnormalities of the flagella (MMAF) are observed, primarily short and coiled flagella. Pregnancy can be achieved by intracytoplasmic sperm injection (ICSI) (Liu et al., 2021). For a general phenotypic description and discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Autosomal dominant intellectual developmental disorder-71 with behavioral abnormalities (MRD71) is a neurodevelopmental disorder characterized by global developmental delay with hypotonia, speech delay, and variably impaired cognitive development. Almost all affected individuals show marked behavioral manifestations, including autism spectrum disorder (ASD), ADHD, hypersensitivity, and aggression. Many have dysmorphic features, although there is not a common gestalt (Harris et al., 2021).