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Primary ciliary dyskinesia 25(CILD25)

MedGen UID:
815971
Concept ID:
C3809641
Disease or Syndrome
Synonyms: CILD25; CILIARY DYSKINESIA, PRIMARY, 25, WITH OR WITHOUT SITUS INVERSUS
 
Gene (location): DNAAF4 (15q21.3)
 
Monarch Initiative: MONDO:0014203
OMIM®: 615482

Definition

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. [from OMIM]

Clinical features

From HPO
Infertility disorder
MedGen UID:
43876
Concept ID:
C0021359
Finding
Inability to conceive for at least one year after trying and having unprotected sex. Causes of female infertility include endometriosis, fallopian tubes obstruction, and polycystic ovary syndrome. Causes of male infertility include abnormal sperm production or function, blockage of the epididymis, blockage of the ejaculatory ducts, hypospadias, exposure to pesticides, and health related issues.
Dextrocardia
MedGen UID:
4255
Concept ID:
C0011813
Congenital Abnormality
The heart is located in the right hand sided hemithorax. That is, there is a left-right reversal (or "mirror reflection") of the anatomical location of the heart in which the heart is locate on the right side instead of the left.
Situs inversus
MedGen UID:
1642262
Concept ID:
C4551493
Congenital Abnormality
A left-right reversal (or mirror reflection) of the anatomical location of the major thoracic and abdominal organs.
Gastroesophageal reflux
MedGen UID:
1368658
Concept ID:
C4317146
Finding
A condition in which the stomach contents leak backwards from the stomach into the esophagus through the lower esophageal sphincter.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Bronchiectasis
MedGen UID:
14234
Concept ID:
C0006267
Disease or Syndrome
Persistent abnormal dilatation of the bronchi owing to localized and irreversible destruction and widening of the large airways.
Chronic bronchitis
MedGen UID:
3084
Concept ID:
C0008677
Disease or Syndrome
Chronic inflammation of the bronchi.
Primary ciliary dyskinesia
MedGen UID:
3467
Concept ID:
C0008780
Disease or Syndrome
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.
Chronic cough
MedGen UID:
507601
Concept ID:
C0010201
Sign or Symptom
A persistent cough, defined as a cough lasting longer than eight weeks in adults or longer than four weeks in children.
Chronic obstructive pulmonary disease
MedGen UID:
9818
Concept ID:
C0024117
Disease or Syndrome
Chronic obstructive pulmonary disease (COPD) is a common, complex disorder associated with substantial morbidity and mortality. COPD is defined by irreversible airflow obstruction due to chronic bronchitis, emphysema, and/or small airways disease. Airflow obstruction is typically determined by reductions in quantitative spirometric indices, including forced expiratory volume at 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) (Silverman et al., 2002; Celedon et al., 2004).
Productive cough
MedGen UID:
66781
Concept ID:
C0239134
Finding
A cough that produces phlegm or mucus.
Recurrent sinusitis
MedGen UID:
107919
Concept ID:
C0581354
Disease or Syndrome
A recurrent form of sinusitis.
Recurrent pneumonia
MedGen UID:
195802
Concept ID:
C0694550
Disease or Syndrome
An increased susceptibility to pneumonia as manifested by a history of recurrent episodes of pneumonia.
Immotile cilia
MedGen UID:
383738
Concept ID:
C1855672
Finding
Recurrent respiratory infections
MedGen UID:
812812
Concept ID:
C3806482
Finding
An increased susceptibility to respiratory infections as manifested by a history of recurrent respiratory infections.
Neonatal respiratory distress
MedGen UID:
924182
Concept ID:
C4281993
Finding
Respiratory difficulty as newborn.
Recurrent otitis media
MedGen UID:
155436
Concept ID:
C0747085
Disease or Syndrome
Increased susceptibility to otitis media, as manifested by recurrent episodes of otitis media.
Polysplenia
MedGen UID:
383959
Concept ID:
C1856659
Congenital Abnormality
Polysplenia is a congenital disease manifested by multiple small accessory spleens.
Chronic rhinitis
MedGen UID:
3086
Concept ID:
C0008711
Disease or Syndrome
Chronic inflammation of the nasal mucosa.

Term Hierarchy

Professional guidelines

PubMed

Barber AT, Shapiro AJ, Davis SD, Ferkol TW, Atkinson JJ, Sagel SD, Dell SD, Olivier KN, Milla CE, Rosenfeld M, Li L, Lin FC, Sullivan KM, Capps NA, Zariwala MA, Knowles MR, Leigh MW
Ann Am Thorac Soc 2023 Mar;20(3):397-405. doi: 10.1513/AnnalsATS.202206-487OC. PMID: 36342963Free PMC Article
Peng B, Gao YH, Xie JQ, He XW, Wang CC, Xu JF, Zhang GJ
Orphanet J Rare Dis 2022 Jul 19;17(1):283. doi: 10.1186/s13023-022-02427-1. PMID: 35854386Free PMC Article
Dąbkowska S, Kucińska-Chahwan A, Beneturska A, Ilnicka A, Nowakowska B, Panek G, Roszkowski T, Bijok J
Prenat Diagn 2020 Apr;40(5):612-617. Epub 2020 Feb 12 doi: 10.1002/pd.5654. PMID: 32003477

Recent clinical studies

Etiology

Aliberti S, Ringshausen FC, Dhar R, Haworth CS, Loebinger MR, Dimakou K, Crichton ML, De Soyza A, Vendrell M, Burgel PR, McDonnell M, Skrgat S, Maiz Carro L, de Roux A, Sibila O, Bossios A, van der Eerden M, Kauppi P, Wilson R, Milenkovic B, Menendez R, Murris M, Borekci S, Munteanu O, Obradovic D, Nowinski A, Amorim A, Torres A, Lorent N, Van Braeckel E, Altenburg J, Shoemark A, Shteinberg M, Boersma W, Goeminne PC, Elborn JS, Hill AT, Welte T, Blasi F, Polverino E, Chalmers JD; EMBARC Registry Investigators
Eur Respir J 2024 Apr;63(4) Epub 2024 Apr 18 doi: 10.1183/13993003.01554-2023. PMID: 38609095Free PMC Article
Barber AT, Shapiro AJ, Davis SD, Ferkol TW, Atkinson JJ, Sagel SD, Dell SD, Olivier KN, Milla CE, Rosenfeld M, Li L, Lin FC, Sullivan KM, Capps NA, Zariwala MA, Knowles MR, Leigh MW
Ann Am Thorac Soc 2023 Mar;20(3):397-405. doi: 10.1513/AnnalsATS.202206-487OC. PMID: 36342963Free PMC Article
Valero-Moreno S, Castillo-Corullón S, Montoya-Castilla I, Pérez-Marín M
PLoS One 2020;15(1):e0227888. Epub 2020 Jan 23 doi: 10.1371/journal.pone.0227888. PMID: 31971980Free PMC Article
Davis SD, Rosenfeld M, Lee HS, Ferkol TW, Sagel SD, Dell SD, Milla C, Pittman JE, Shapiro AJ, Sullivan KM, Nykamp KR, Krischer JP, Zariwala MA, Knowles MR, Leigh MW
Am J Respir Crit Care Med 2019 Jan 15;199(2):190-198. doi: 10.1164/rccm.201803-0548OC. PMID: 30067075Free PMC Article
Harrison MJ, Shapiro AJ, Kennedy MP
Paediatr Respir Rev 2016 Mar;18:25-32. Epub 2015 Sep 26 doi: 10.1016/j.prrv.2015.09.003. PMID: 26545972

Diagnosis

Pieters ALP, van der Veer T, Meerburg JJ, Andrinopoulou ER, van der Eerden MM, Ciet P, Aliberti S, Burgel PR, Crichton ML, Shoemark A, Goeminne PC, Shteinberg M, Loebinger MR, Haworth CS, Blasi F, Tiddens HAWM, Caudri D, Chalmers JD
Am J Respir Crit Care Med 2024 Jul 1;210(1):87-96. doi: 10.1164/rccm.202311-2109OC. PMID: 38635862
Zawawi F, Shapiro AJ, Dell S, Wolter NE, Marchica CL, Knowles MR, Zariwala MA, Leigh MW, Smith M, Gajardo P, Daniel SJ
Otolaryngol Head Neck Surg 2022 Mar;166(3):540-547. Epub 2021 Jun 22 doi: 10.1177/01945998211019320. PMID: 34154450Free PMC Article
Davis SD, Rosenfeld M, Lee HS, Ferkol TW, Sagel SD, Dell SD, Milla C, Pittman JE, Shapiro AJ, Sullivan KM, Nykamp KR, Krischer JP, Zariwala MA, Knowles MR, Leigh MW
Am J Respir Crit Care Med 2019 Jan 15;199(2):190-198. doi: 10.1164/rccm.201803-0548OC. PMID: 30067075Free PMC Article
Yoo F, Suh JD
Curr Opin Otolaryngol Head Neck Surg 2017 Feb;25(1):54-63. doi: 10.1097/MOO.0000000000000329. PMID: 27841768
Harrison MJ, Shapiro AJ, Kennedy MP
Paediatr Respir Rev 2016 Mar;18:25-32. Epub 2015 Sep 26 doi: 10.1016/j.prrv.2015.09.003. PMID: 26545972

Therapy

Cardinale F, La Torre F, Tricarico LG, Verriello G, Mastrorilli C
Curr Pediatr Rev 2024;20(3):203-215. doi: 10.2174/1573396320666230912103056. PMID: 37702165
Peng B, Gao YH, Xie JQ, He XW, Wang CC, Xu JF, Zhang GJ
Orphanet J Rare Dis 2022 Jul 19;17(1):283. doi: 10.1186/s13023-022-02427-1. PMID: 35854386Free PMC Article
Goutaki M, Eich MO, Halbeisen FS, Barben J, Casaulta C, Clarenbach C, Hafen G, Latzin P, Regamey N, Lazor R, Tschanz S, Zanolari M, Maurer E, Kuehni CE; Swiss PCD Registry (CH-PCD) Working Group
Swiss Med Wkly 2019 Jan 1;149 Epub 2019 Jan 13 doi: 10.57187/smw.2019.20004. PMID: 30691261
Davis SD, Rosenfeld M, Lee HS, Ferkol TW, Sagel SD, Dell SD, Milla C, Pittman JE, Shapiro AJ, Sullivan KM, Nykamp KR, Krischer JP, Zariwala MA, Knowles MR, Leigh MW
Am J Respir Crit Care Med 2019 Jan 15;199(2):190-198. doi: 10.1164/rccm.201803-0548OC. PMID: 30067075Free PMC Article
Abitbul R, Amirav I, Blau H, Alkrinawi S, Aviram M, Shoseyov D, Bentur L, Avital A, Springer C, Lavie M, Prais D, Dabbah H, Elias N, Elizur A, Goldberg S, Hevroni A, Kerem E, Luder A, Roth Y, Cohen-Cymberknoh M, Ben Ami M, Mandelberg A, Livnat G, Picard E, Rivlin J, Rotschild M, Soferman R, Loges NT, Olbrich H, Werner C, Wolter A, Herting M, Wallmeier J, Raidt J, Omran H, Mussaffi H
Respir Med 2016 Oct;119:41-47. Epub 2016 Aug 23 doi: 10.1016/j.rmed.2016.08.015. PMID: 27692146

Prognosis

Cardinale F, La Torre F, Tricarico LG, Verriello G, Mastrorilli C
Curr Pediatr Rev 2024;20(3):203-215. doi: 10.2174/1573396320666230912103056. PMID: 37702165
Zafar A, Hall M
Pediatr Pulmonol 2023 Feb;58(2):475-483. Epub 2022 Nov 2 doi: 10.1002/ppul.26213. PMID: 36268989
Davis SD, Rosenfeld M, Lee HS, Ferkol TW, Sagel SD, Dell SD, Milla C, Pittman JE, Shapiro AJ, Sullivan KM, Nykamp KR, Krischer JP, Zariwala MA, Knowles MR, Leigh MW
Am J Respir Crit Care Med 2019 Jan 15;199(2):190-198. doi: 10.1164/rccm.201803-0548OC. PMID: 30067075Free PMC Article
Takeuchi K, Kitano M, Sakaida H, Usui S, Masuda S, Ogawa S, Ikejiri M, Nagao M, Fujisawa T, Nakatani K
Otol Neurotol 2017 Dec;38(10):e451-e456. doi: 10.1097/MAO.0000000000001599. PMID: 29135867
Yoo F, Suh JD
Curr Opin Otolaryngol Head Neck Surg 2017 Feb;25(1):54-63. doi: 10.1097/MOO.0000000000000329. PMID: 27841768

Clinical prediction guides

Marozkina N
Int J Mol Sci 2024 Sep 18;25(18) doi: 10.3390/ijms251810043. PMID: 39337527Free PMC Article
Pieters ALP, van der Veer T, Meerburg JJ, Andrinopoulou ER, van der Eerden MM, Ciet P, Aliberti S, Burgel PR, Crichton ML, Shoemark A, Goeminne PC, Shteinberg M, Loebinger MR, Haworth CS, Blasi F, Tiddens HAWM, Caudri D, Chalmers JD
Am J Respir Crit Care Med 2024 Jul 1;210(1):87-96. doi: 10.1164/rccm.202311-2109OC. PMID: 38635862
Niziolek M, Bicka M, Osinka A, Samsel Z, Sekretarska J, Poprzeczko M, Bazan R, Fabczak H, Joachimiak E, Wloga D
Int J Mol Sci 2022 Feb 3;23(3) doi: 10.3390/ijms23031749. PMID: 35163666Free PMC Article
Zawawi F, Shapiro AJ, Dell S, Wolter NE, Marchica CL, Knowles MR, Zariwala MA, Leigh MW, Smith M, Gajardo P, Daniel SJ
Otolaryngol Head Neck Surg 2022 Mar;166(3):540-547. Epub 2021 Jun 22 doi: 10.1177/01945998211019320. PMID: 34154450Free PMC Article
Davis SD, Rosenfeld M, Lee HS, Ferkol TW, Sagel SD, Dell SD, Milla C, Pittman JE, Shapiro AJ, Sullivan KM, Nykamp KR, Krischer JP, Zariwala MA, Knowles MR, Leigh MW
Am J Respir Crit Care Med 2019 Jan 15;199(2):190-198. doi: 10.1164/rccm.201803-0548OC. PMID: 30067075Free PMC Article

Recent systematic reviews

Junior JHMF, Junior SP, Pustilnik HN, de Almeida Leão L, da Paz MGDS, Araujo TB, de Deus FOG, Alcântara T, Dourado JC, de Avellar LM
Childs Nerv Syst 2024 Jul;40(7):2161-2168. Epub 2024 Mar 9 doi: 10.1007/s00381-024-06346-3. PMID: 38459147
Zafar A, Hall M
Pediatr Pulmonol 2023 Feb;58(2):475-483. Epub 2022 Nov 2 doi: 10.1002/ppul.26213. PMID: 36268989
Peng B, Gao YH, Xie JQ, He XW, Wang CC, Xu JF, Zhang GJ
Orphanet J Rare Dis 2022 Jul 19;17(1):283. doi: 10.1186/s13023-022-02427-1. PMID: 35854386Free PMC Article
Inaba A, Furuhata M, Morimoto K, Rahman M, Takahashi O, Hijikata M, Knowles MR, Keicho N
BMC Pulm Med 2019 Jul 25;19(1):135. doi: 10.1186/s12890-019-0897-4. PMID: 31345208Free PMC Article
Kouis P, Yiallouros PK, Middleton N, Evans JS, Kyriacou K, Papatheodorou SI
Pediatr Res 2017 Mar;81(3):398-405. Epub 2016 Dec 9 doi: 10.1038/pr.2016.263. PMID: 27935903

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