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.

Peutz-Jeghers syndrome (PJS) is characterized by the association of gastrointestinal (GI) polyposis, mucocutaneous pigmentation, and cancer predisposition. PJS-type hamartomatous polyps are most common in the small intestine (in order of prevalence: jejunum, ileum, and duodenum) but can also occur in the stomach, large bowel, and extraintestinal sites including the renal pelvis, bronchus, gall bladder, nasal passages, urinary bladder, and ureters. GI polyps can result in chronic bleeding, anemia, and recurrent obstruction and intussusception requiring repeated laparotomy and bowel resection. Mucocutaneous hyperpigmentation presents in childhood as dark blue to dark brown macules around the mouth, eyes, and nostrils, in the perianal area, and on the buccal mucosa. Hyperpigmented macules on the fingers are common. The macules may fade in puberty and adulthood. Recognition of the distinctive skin manifestations is important especially in individuals who have PJS as the result of a de novo pathogenic variant as these skin findings often predate GI signs and symptoms. Individuals with PJS are at increased risk for a wide variety of epithelial malignancies (colorectal, gastric, pancreatic, breast, and ovarian cancers). Females are at risk for sex cord tumors with annular tubules (SCTAT), a benign neoplasm of the ovaries, and adenoma malignum of the cervix, a rare aggressive cancer. Males occasionally develop large calcifying Sertoli cell tumors of the testes, which secrete estrogen and can lead to gynecomastia, advanced skeletal age, and ultimately short stature, if untreated.

Pai syndrome is characterized by mild hypertelorism, midline cleft lip, nasal and facial polyps, pericallosal lipoma, ocular anomalies, and normal neuropsychologic development (Guion-Almeida et al., 2007).

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).

Primary ciliary dyskinesia is a disorder characterized by chronic respiratory tract infections, abnormally positioned internal organs, and the inability to have children (infertility). The signs and symptoms of this condition are caused by abnormal cilia and flagella. Cilia are microscopic, finger-like projections that stick out from the surface of cells. They are found in the linings of the airway, the reproductive system, and other organs and tissues. Flagella are tail-like structures, similar to cilia, that propel sperm cells forward.\n\nIn the respiratory tract, cilia move back and forth in a coordinated way to move mucus towards the throat. This movement of mucus helps to eliminate fluid, bacteria, and particles from the lungs. Most babies with primary ciliary dyskinesia experience breathing problems at birth, which suggests that cilia play an important role in clearing fetal fluid from the lungs. Beginning in early childhood, affected individuals develop frequent respiratory tract infections. Without properly functioning cilia in the airway, bacteria remain in the respiratory tract and cause infection. People with primary ciliary dyskinesia also have year-round nasal congestion and a chronic cough. Chronic respiratory tract infections can result in a condition called bronchiectasis, which damages the passages, called bronchi, leading from the windpipe to the lungs and can cause life-threatening breathing problems.\n\nSome individuals with primary ciliary dyskinesia have abnormally placed organs within their chest and abdomen. These abnormalities arise early in embryonic development when the differences between the left and right sides of the body are established. About 50 percent of people with primary ciliary dyskinesia have a mirror-image reversal of their internal organs (situs inversus totalis). For example, in these individuals the heart is on the right side of the body instead of on the left. Situs inversus totalis does not cause any apparent health problems. When someone with primary ciliary dyskinesia has situs inversus totalis, they are often said to have Kartagener syndrome.\n\nApproximately 12 percent of people with primary ciliary dyskinesia have a condition known as heterotaxy syndrome or situs ambiguus, which is characterized by abnormalities of the heart, liver, intestines, or spleen. These organs may be structurally abnormal or improperly positioned. In addition, affected individuals may lack a spleen (asplenia) or have multiple spleens (polysplenia). Heterotaxy syndrome results from problems establishing the left and right sides of the body during embryonic development. The severity of heterotaxy varies widely among affected individuals.\n\nPrimary ciliary dyskinesia can also lead to infertility. Vigorous movements of the flagella are necessary to propel the sperm cells forward to the female egg cell. Because their sperm do not move properly, males with primary ciliary dyskinesia are usually unable to father children. Infertility occurs in some affected females and is likely due to abnormal cilia in the fallopian tubes.\n\nAnother feature of primary ciliary dyskinesia is recurrent ear infections (otitis media), especially in young children. Otitis media can lead to permanent hearing loss if untreated. The ear infections are likely related to abnormal cilia within the inner ear.\n\nRarely, individuals with primary ciliary dyskinesia have an accumulation of fluid in the brain (hydrocephalus), likely due to abnormal cilia in the brain.

Bare lymphocyte syndrome type I (BLS I) is an inherited disorder of the immune system (primary immunodeficiency). Immunodeficiencies are conditions in which the immune system is not able to protect the body effectively from foreign invaders such as bacteria or viruses. Starting in childhood, most people with BLS I develop recurrent bacterial infections in the lungs and airways (respiratory tract). These recurrent infections can lead to a condition called bronchiectasis, which damages the passages leading from the windpipe to the lungs (bronchi) and can cause breathing problems.\n\nMany people with BLS I also have open sores (ulcers) on their skin, usually on the face, arms, and legs. These ulcers typically develop in adolescence or young adulthood. Some people with BLS I have no symptoms of the condition.\n\nPeople with BLS I have a shortage of specialized immune proteins called major histocompatibility complex (MHC) class I proteins on cells, including infection-fighting white blood cells (lymphocytes), which is where the condition got its name.

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).

Primary ciliary dyskinesia-19 (CILD19) is an autosomal recessive ciliopathy characterized by chronic sinopulmonary infections, asthenospermia, and immotile cilia. Respiratory epithelial cells and sperm flagella of affected individuals lack both the inner and outer dynein arms. About 50% of patients have situs inversus (summary by Kott et al., 2012). For a phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see 244400.

Primary ciliary dyskinesia-22 (CILD22) is an autosomal recessive disorder caused by defective structure and function of cilia or flagella. Ciliary dysfunction causes respiratory distress in term neonates, impaired mucociliary clearance, chronic cough, sinusitis, bronchiectasis, and male infertility. Defective motility of embryonic nodal cilia leads to situs abnormalities in about 50% of patients. CILD22 is characterized by defects of the inner and outer dynein arms (summary by Zariwala et al., 2013). For a phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (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).

Any primary ciliary dyskinesia in which the cause of the disease is a mutation in the CCDC151 gene.

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).

Primary ciliary dyskinesia is a genetically heterogeneous autosomal recessive disorder resulting from loss of function of different parts of the primary ciliary apparatus, most often dynein arms. Kartagener (pronounced KART-agayner) syndrome is characterized by the combination of primary ciliary dyskinesia and situs inversus (270100), 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). Genetic Heterogeneity of Primary Ciliary Dyskinesia Other forms of primary ciliary dyskinesia include CILD2 (606763), caused by mutation in the DNAAF3 gene (614566) on 19q13; CILD3 (608644), caused by mutation in the DNAH5 gene (603335) on 5p15; CILD4 (608646), mapped to 15q13; CILD5 (608647), caused by mutation in the HYDIN gene (610812) on 16q22; CILD6 (610852), caused by mutation in the TXNDC3 gene (607421) on 7p14; CILD7 (611884), caused by mutation in the DNAH11 gene (603339) on 7p15; CILD8 (612274), mapped to 15q24-q25; CILD9 (612444), caused by mutation in the DNAI2 gene (605483) on 17q25; CILD10 (612518), caused by mutation in the DNAAF2 gene (612517) on 14q21; CILD11 (612649), caused by mutation in the RSPH4A gene (612647) on 6q22; CILD12 (612650), caused by mutation in the RSPH9 gene (612648) on 6p21; CILD13 (613193), caused by mutation in the DNAAF1 gene (613190) on 16q24; CILD14 (613807), caused by mutation in the CCDC39 gene (613798) gene on 3q26; CILD15 (613808), caused by mutation in the CCDC40 gene (613799) on 17q25; CILD16 (614017), caused by mutation in the DNAL1 gene (610062) on 14q24; CILD17 (614679), caused by mutation in the CCDC103 gene (614677) on 17q21; CILD18 (614874), caused by mutation in the DNAAF5 gene (614864) on 7p22; CILD19 (614935), caused by mutation in the LRRC6 gene (614930) on 8q24; CILD20 (615067), caused by mutation in the CCDC114 gene (615038) on 19q13; CILD21 (615294), caused by mutation in the DRC1 gene (615288) on 2p23; CILD22 (615444), caused by mutation in the ZMYND10 gene (607070) on 3p21; CILD23 (615451), caused by mutation in the ARMC4 gene (615408) on 10p; CILD24 (615481), caused by mutation in the RSPH1 gene (609314) on 21q22; CILD25 (615482), caused by mutation in the DYX1C1 gene (608706) on 15q21; CILD26 (615500), caused by mutation in the C21ORF59 gene (615494) on 21q22; CILD27 (615504), caused by mutation in the CCDC65 gene (611088) on 12q13; CILD28 (615505), caused by mutation in the SPAG1 gene (603395) on 8q22; CILD29 (615872), caused by mutation in the CCNO gene (607752) on 5q11; CILD30 (616037), caused by mutation in the CCDC151 gene (615956) on 19p13; CILD32 (616481), caused by mutation in the RSPH3 gene (615876) on 6q25; CILD33 (616726), caused by mutation in the GAS8 gene (605178) on 16q24; CILD34 (617091), caused by mutation in the DNAJB13 gene (610263) on 11q13; CILD35 (617092), caused by mutation in the TTC25 gene (617095) on 17q21; CILD36 (300991), caused by mutation in the PIH1D3 gene (300933) on Xq22; CILD37 (617577), caused by mutation in the DNAH1 gene (603332) on 3p21; CILD38 (618063), caused by mutation in the CFAP300 gene (618058) on 11q22; CILD39 (618254), caused by mutation in the LRRC56 gene (618227) on 11p15; CILD40 (618300), caused by mutation in the DNAH9 gene (603330) on 17p12; CILD41 (618449), caused by mutation in the GAS2L2 gene (611398) on 17q12; CILD42 (618695), caused by mutation in the MCIDAS gene (614086) on 5q11; CILD43 (618699), caused by mutation in the FOXJ1 gene (602291) on 17q25; CILD44 (618781), caused by mutation in the NEK10 gene (618726) on 3p24; CILD45 (618801), caused by mutation in the TTC12 gene (610732) on 11q23; CILD46 (619436), caused by mutation in the STK36 gene (607652) on 2q35; CILD47 (619466), caused by mutation in the TP73 gene (601990) on 1p36; CILD48 (620032), caused by mutation in the NME5 gene (603575) on chromosome 5q31; CILD49 (620197), caused by mutation in the CFAP74 gene (620187) on chromosome 1p36; CILD50 (620356), caused by mutation in the DNAH7 gene (610061) on chromosome 2q32; CILD51 (620438), caused by mutation in the BRWD1 gene (617824) on chromosome 21q22; CILD52 (620570), caused by mutation in the DAW1 gene (620279) on chromosome 2q36; and CILD53 (620642), caused by mutation in the CLXN gene (619564) on chromosome 8q11. Ciliary abnormalities have also been reported in association with both X-linked and autosomal forms of retinitis pigmentosa. Mutations in the RPGR gene (312610), which underlie X-linked retinitis pigmentosa (RP3; 300029), are in some instances (e.g., 312610.0016) associated with recurrent respiratory infections indistinguishable from immotile cilia syndrome; see 300455. Afzelius (1979) gave an extensive review of cilia and their disorders. There are also several possibly distinct CILDs described based on the electron microscopic appearance of abnormal cilia, including CILD with transposition of the microtubules (215520), CILD with excessively long cilia (242680), and CILD with defective radial spokes (242670).

Primary ciliary dyskinesia-42 (CILD42) is an autosomal recessive disorder characterized by a defect in motile cilia and ciliary clearance resulting in the onset of respiratory insufficiency soon after birth, and associated with recurrent upper and lower respiratory infections with chronic progressive lung disease. Other more variable features may include infertility and mild hydrocephalus. Patients with this form of the disorder do not have situs abnormalities. The disorder is considered to be a type of ciliopathy known as 'reduced generation of multiple motile cilia' (RGMC) (summary by Boon et al., 2014). For a discussion of genetic heterogeneity of primary ciliary dyskinesia, CILD1 (244400).

Primary ciliary dyskinesia-49 (CILD49) without situs inversus is an autosomal recessive disorder characterized by the onset of recurrent respiratory infections, chronic cough, and bronchiectasis in early childhood due to defective ciliary clearance. Affected males also show infertility due to defective flagellar morphology and function. Nasal nitric oxide (NO) levels are normal and situs abnormalities are not observed (Sha et al., 2020; Biebach et al., 2022). For a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).