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Ciliary dyskinesia, primary, 2(CILD2)

MedGen UID:
338258
Concept ID:
C1847554
Disease or Syndrome
Synonyms: CILD2; CILIARY DYSKINESIA, PRIMARY, 2, WITH OR WITHOUT SITUS INVERSUS; Primary Ciliary Dyskinesia; Primary Ciliary Dyskinesia 2: DNAAF3-Related Primary Ciliary Dyskinesia
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
 
Gene (location): DNAAF3 (19q13.42)
OMIM®: 606763

Disease characteristics

Excerpted from the GeneReview: Primary Ciliary Dyskinesia
Primary ciliary dyskinesia (PCD) is associated with situs abnormalities, abnormal sperm motility, and abnormal ciliary structure and function that result in retention of mucus and bacteria in the respiratory tract leading to chronic otosinopulmonary disease. More than 75% of full-term neonates with PCD have ‘neonatal respiratory distress’ requiring supplemental oxygen for days to weeks. Chronic airway infection, apparent in early childhood, results in bronchiectasis that is almost uniformly present in adulthood. Nasal congestion and sinus infections, apparent in early childhood, persist through adulthood. Chronic/recurrent ear infection, apparent in most young children, can be associated with transient or later irreversible hearing loss. Situs inversus totalis (mirror-image reversal of all visceral organs with no apparent physiologic consequences) is present in 40%-50% of individuals with PCD; heterotaxy (discordance of right and left patterns of ordinarily asymmetric structures that can be associated with significant malformations) is present in approximately 12%. Virtually all males with PCD are infertile as a result of abnormal sperm motility. [from GeneReviews]
Authors:
Maimoona A Zariwala  |  Michael R Knowles  |  Margaret W Leigh   view full author information

Additional description

From GHR
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.In 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.Some 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.Approximately 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.Primary 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.Another 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.Rarely, individuals with primary ciliary dyskinesia have an accumulation of fluid in the brain (hydrocephalus), likely due to abnormal cilia in the brain.  https://ghr.nlm.nih.gov/condition/primary-ciliary-dyskinesia

Clinical features

Situs inversus viscerum
MedGen UID:
52359
Concept ID:
C0037221
Congenital Abnormality
A left-right reversal (or \
Hearing impairment
MedGen UID:
5453
Concept ID:
C0018772
Finding
A decreased magnitude of the sensory perception of sound.
Otitis media
MedGen UID:
45253
Concept ID:
C0029882
Disease or Syndrome
Inflammation or infection of the middle ear.
Bronchiectasis
MedGen UID:
14234
Concept ID:
C0006267
Disease or Syndrome
Persistent abnormal dilatation of the bronchi.
Primary ciliary dyskinesia
MedGen UID:
3467
Concept ID:
C0008780
Disease or Syndrome
Primary ciliary dyskinesia (PCD) is associated with situs abnormalities, abnormal sperm motility, and abnormal ciliary structure and function that result in retention of mucus and bacteria in the respiratory tract leading to chronic otosinopulmonary disease. More than 75% of full-term neonates with PCD have ‘neonatal respiratory distress’ requiring supplemental oxygen for days to weeks. Chronic airway infection, apparent in early childhood, results in bronchiectasis that is almost uniformly present in adulthood. Nasal congestion and sinus infections, apparent in early childhood, persist through adulthood. Chronic/recurrent ear infection, apparent in most young children, can be associated with transient or later irreversible hearing loss. Situs inversus totalis (mirror-image reversal of all visceral organs with no apparent physiologic consequences) is present in 40%-50% of individuals with PCD; heterotaxy (discordance of right and left patterns of ordinarily asymmetric structures that can be associated with significant malformations) is present in approximately 12%. Virtually all males with PCD are infertile as a result of abnormal sperm motility.
Respiratory distress
MedGen UID:
96907
Concept ID:
C0476273
Sign or Symptom
Difficulty in breathing. The physical presentation of respiratory distress is generally referred to as labored breathing, while the sensation of respiratory distress is called shortness of breath or dyspnea.
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.
Absent inner and outer dynein arms
MedGen UID:
868587
Concept ID:
C4022986
Finding
Complete absence of the dynein arms of respiratory motile cilia, that is, absence of the inner and the outer dynein arms, which normally are situated inside and outside of the peripheral microtubules of motile cilia. This feature is usually appreciated by electron microscopy.
Infertility
MedGen UID:
43876
Concept ID:
C0021359
Finding
Infertility means not being able to become pregnant after a year of trying. If a woman can get pregnant but keeps having miscarriages or stillbirths, that's also called infertility. Infertility is fairly common. After one year of having unprotected sex, about 15 percent of couples are unable to get pregnant. About a third of the time, infertility can be traced to the woman. In another third of cases, it is because of the man. The rest of the time, it is because of both partners or no cause can be found. There are treatments that are specifically for men or for women. Some involve both partners. Drugs, assisted reproductive technology, and surgery are common treatments. Happily, many couples treated for infertility go on to have babies. NIH: National Institute of Child Health and Human Development.
Otitis media
MedGen UID:
45253
Concept ID:
C0029882
Disease or Syndrome
Inflammation or infection of the middle ear.
Sinusitis
MedGen UID:
14608
Concept ID:
C0030469
Disease or Syndrome
Diseases affecting or involving the PARANASAL SINUSES and generally manifesting as inflammation, abscesses, cysts, or tumors.
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.
Sinusitis
MedGen UID:
14608
Concept ID:
C0030469
Disease or Syndrome
Diseases affecting or involving the PARANASAL SINUSES and generally manifesting as inflammation, abscesses, cysts, or tumors.
Nasal polyposis
MedGen UID:
6524
Concept ID:
C0027430
Finding
Focal accumulations of EDEMA fluid in the NASAL MUCOSA accompanied by HYPERPLASIA of the associated submucosal connective tissue. Polyps may be NEOPLASMS, foci of INFLAMMATION, degenerative lesions, or malformations.
Sinusitis
MedGen UID:
14608
Concept ID:
C0030469
Disease or Syndrome
Diseases affecting or involving the PARANASAL SINUSES and generally manifesting as inflammation, abscesses, cysts, or tumors.

Recent clinical studies

Etiology

Loomba RS, Danduran M, Nielsen KG, Ring AM, Kovach J, Anderson RH
Pediatr Cardiol 2017 Feb;38(2):410-417. Epub 2016 Nov 23 doi: 10.1007/s00246-016-1531-3. PMID: 27878633
Hosie PH, Fitzgerald DA, Jaffe A, Birman CS, Rutland J, Morgan LC
J Paediatr Child Health 2015 Jul;51(7):722-6. Epub 2014 Dec 15 doi: 10.1111/jpc.12791. PMID: 25510893
Santamaria F, Esposito M, Montella S, Cantone E, Mollica C, De Stefano S, Mirra V, Carotenuto M
Respirology 2014 May;19(4):570-5. Epub 2014 Mar 24 doi: 10.1111/resp.12273. PMID: 24661455
Horani A, Brody SL, Ferkol TW
Pediatr Res 2014 Jan;75(1-2):158-64. Epub 2013 Nov 5 doi: 10.1038/pr.2013.200. PMID: 24192704Free PMC Article
Degano B, Valmary S, Serrano E, Brousset P, Arnal JF
Hum Pathol 2011 Dec;42(12):1855-61. Epub 2011 Jun 12 doi: 10.1016/j.humpath.2011.01.027. PMID: 21663943

Diagnosis

Xu X, Gong P, Wen J
J Assist Reprod Genet 2017 Feb;34(2):275-281. Epub 2016 Dec 17 doi: 10.1007/s10815-016-0849-3. PMID: 27988889Free PMC Article
Honoré I, Burgel PR
Rev Mal Respir 2016 Feb;33(2):165-89. Epub 2015 Dec 1 doi: 10.1016/j.rmr.2015.10.743. PMID: 26654126
Takeuchi K, Kitano M, Ishinaga H, Kobayashi M, Ogawa S, Nakatani K, Masuda S, Nagao M, Fujisawa T
Auris Nasus Larynx 2016 Jun;43(3):229-36. Epub 2015 Oct 31 doi: 10.1016/j.anl.2015.09.012. PMID: 26527516
Shapiro AJ, Tolleson-Rinehart S, Zariwala MA, Knowles MR, Leigh MW
Cardiol Young 2015 Apr;25(4):752-9. Epub 2014 Jun 6 doi: 10.1017/S1047951114000912. PMID: 24905662Free PMC Article
Türkoğlu K, Orhan K, Demir P, Karabulut B, Can-Karabulut DC
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010 Oct;110(4):e49-56. doi: 10.1016/j.tripleo.2010.05.054. PMID: 20868986

Therapy

Andersen TN, Alanin MC, von Buchwald C, Nielsen LH
Int J Pediatr Otorhinolaryngol 2016 Oct;89:164-8. Epub 2016 Aug 18 doi: 10.1016/j.ijporl.2016.08.011. PMID: 27619050
Frommer A, Hjeij R, Loges NT, Edelbusch C, Jahnke C, Raidt J, Werner C, Wallmeier J, Große-Onnebrink J, Olbrich H, Cindrić S, Jaspers M, Boon M, Memari Y, Durbin R, Kolb-Kokocinski A, Sauer S, Marthin JK, Nielsen KG, Amirav I, Elias N, Kerem E, Shoseyov D, Haeffner K, Omran H
Am J Respir Cell Mol Biol 2015 Oct;53(4):563-73. doi: 10.1165/rcmb.2014-0483OC. PMID: 25789548Free PMC Article
Pifferi M, Bush A, Michelucci A, Di Cicco M, Piras M, Caramella D, Mazzei F, Neri M, Pioggia G, Tartarisco G, Saggese G, Simi P, Boner AL
Pediatr Pulmonol 2015 Feb;50(2):179-86. Epub 2014 Apr 19 doi: 10.1002/ppul.23026. PMID: 24753481
Mullowney T, Manson D, Kim R, Stephens D, Shah V, Dell S
Pediatrics 2014 Dec;134(6):1160-6. doi: 10.1542/peds.2014-0808. PMID: 25422025Free PMC Article
Yasuhara J, Yamada Y, Hara K, Suhara R, Hattori Y, Yamaguchi T, Mizuno Y, Kizu R, Bamba M
Pediatr Int 2014 Apr;56(2):258-61. doi: 10.1111/ped.12268. PMID: 24730627

Prognosis

Andersen TN, Alanin MC, von Buchwald C, Nielsen LH
Int J Pediatr Otorhinolaryngol 2016 Oct;89:164-8. Epub 2016 Aug 18 doi: 10.1016/j.ijporl.2016.08.011. PMID: 27619050
Honoré I, Burgel PR
Rev Mal Respir 2016 Feb;33(2):165-89. Epub 2015 Dec 1 doi: 10.1016/j.rmr.2015.10.743. PMID: 26654126
Davis SD, Ferkol TW, Rosenfeld M, Lee HS, Dell SD, Sagel SD, Milla C, Zariwala MA, Pittman JE, Shapiro AJ, Carson JL, Krischer JP, Hazucha MJ, Cooper ML, Knowles MR, Leigh MW
Am J Respir Crit Care Med 2015 Feb 1;191(3):316-24. doi: 10.1164/rccm.201409-1672OC. PMID: 25493340Free PMC Article
Mullowney T, Manson D, Kim R, Stephens D, Shah V, Dell S
Pediatrics 2014 Dec;134(6):1160-6. doi: 10.1542/peds.2014-0808. PMID: 25422025Free PMC Article
Horani A, Brody SL, Ferkol TW
Pediatr Res 2014 Jan;75(1-2):158-64. Epub 2013 Nov 5 doi: 10.1038/pr.2013.200. PMID: 24192704Free PMC Article

Clinical prediction guides

Davis SD, Ferkol TW, Rosenfeld M, Lee HS, Dell SD, Sagel SD, Milla C, Zariwala MA, Pittman JE, Shapiro AJ, Carson JL, Krischer JP, Hazucha MJ, Cooper ML, Knowles MR, Leigh MW
Am J Respir Crit Care Med 2015 Feb 1;191(3):316-24. doi: 10.1164/rccm.201409-1672OC. PMID: 25493340Free PMC Article
Pifferi M, Bush A, Michelucci A, Di Cicco M, Piras M, Caramella D, Mazzei F, Neri M, Pioggia G, Tartarisco G, Saggese G, Simi P, Boner AL
Pediatr Pulmonol 2015 Feb;50(2):179-86. Epub 2014 Apr 19 doi: 10.1002/ppul.23026. PMID: 24753481
Mullowney T, Manson D, Kim R, Stephens D, Shah V, Dell S
Pediatrics 2014 Dec;134(6):1160-6. doi: 10.1542/peds.2014-0808. PMID: 25422025Free PMC Article
Santamaria F, Esposito M, Montella S, Cantone E, Mollica C, De Stefano S, Mirra V, Carotenuto M
Respirology 2014 May;19(4):570-5. Epub 2014 Mar 24 doi: 10.1111/resp.12273. PMID: 24661455
Horani A, Brody SL, Ferkol TW
Pediatr Res 2014 Jan;75(1-2):158-64. Epub 2013 Nov 5 doi: 10.1038/pr.2013.200. PMID: 24192704Free PMC Article

Recent systematic reviews

Shapiro AJ, Zariwala MA, Ferkol T, Davis SD, Sagel SD, Dell SD, Rosenfeld M, Olivier KN, Milla C, Daniel SJ, Kimple AJ, Manion M, Knowles MR, Leigh MW; Genetic Disorders of Mucociliary Clearance Consortium.
Pediatr Pulmonol 2016 Feb;51(2):115-32. Epub 2015 Sep 29 doi: 10.1002/ppul.23304. PMID: 26418604Free PMC Article
Brower KS, Del Vecchio MT, Aronoff SC
BMC Pediatr 2014 Dec 10;14:4. doi: 10.1186/s12887-014-0299-y. PMID: 25492164Free PMC Article
Collins SA, Gove K, Walker W, Lucas JS
Eur Respir J 2014 Dec;44(6):1589-99. Epub 2014 Oct 16 doi: 10.1183/09031936.00088614. PMID: 25323224
Mener DJ, Lin SY, Ishman SL, Boss EF
Int Forum Allergy Rhinol 2013 Dec;3(12):986-91. Epub 2013 Oct 4 doi: 10.1002/alr.21227. PMID: 24124045
Busquets RM, Caballero-Rabasco MA, Velasco M, Lloreta J, García-Algar Ó
Arch Bronconeumol 2013 Mar;49(3):99-104. Epub 2012 Dec 23 doi: 10.1016/j.arbres.2012.10.007. PMID: 23265970

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