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Dyskeratosis congenita, autosomal recessive 1(DKCB1)

MedGen UID:
341705
Concept ID:
C1857144
Disease or Syndrome
Synonyms: DKCB1; DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 1
 
Genes (locations): NHP2 (5q35.3); NOP10 (15q14)
 
Monarch Initiative: MONDO:0009136
OMIM®: 224230

Disease characteristics

Dyskeratosis congenita and related telomere biology disorders (DC/TBD) are caused by impaired telomere maintenance resulting in short or very short telomeres. The phenotypic spectrum of telomere biology disorders is broad and includes individuals with classic dyskeratosis congenita (DC) as well as those with very short telomeres and an isolated physical finding. Classic DC is characterized by a triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia, although this may not be present in all individuals. People with DC/TBD are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome or acute myelogenous leukemia, solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), taurodontism, liver disease, gastrointestinal telangiectasias, and avascular necrosis of the hips or shoulders. Although most persons with DC/TBD have normal psychomotor development and normal neurologic function, significant developmental delay is present in both forms; additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome and Coats plus syndrome). Onset and progression of manifestations of DC/TBD vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF. [from GeneReviews]
Authors:
Sharon A Savage  |  Marena R Niewisch   view full author information

Additional description

From OMIM
Dyskeratosis congenita is a bone marrow failure syndrome classically characterized by the triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa. Progressive bone marrow failure occurs in over 80% of cases and is the main cause of early mortality. The phenotype is highly variable, and affected individuals may have multiple additional features, including pulmonary fibrosis, liver cirrhosis, premature hair loss and/or graying, osteoporosis, atresia of the lacrimal ducts, and learning difficulties. Predisposition to malignancy is an important feature. The disorder is caused by defects in the maintenance of telomeres (summary by Kirwan and Dokal, 2008). For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (127550).  http://www.omim.org/entry/224230

Clinical features

From HPO
Palmoplantar hyperkeratosis
MedGen UID:
44017
Concept ID:
C0022596
Disease or Syndrome
Abnormal thickening of the skin localized to the palm of the hand and the sole of the foot.
Hepatic fibrosis
MedGen UID:
116093
Concept ID:
C0239946
Disease or Syndrome
The presence of excessive fibrous connective tissue in the liver. Fibrosis is a reparative or reactive process.
Esophageal stricture
MedGen UID:
1637009
Concept ID:
C4551650
Disease or Syndrome
A pathological narrowing of the esophagus that is caused by the development of a ring of scar tissue that constricts the esophageal lumen.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Aplastic anemia
MedGen UID:
8063
Concept ID:
C0002874
Disease or Syndrome
Aplastic anemia is a serious disorder of the bone marrow that affects between 2 and 5 persons per million per year. About 75% of these cases are classified as idiopathic (Young, 2000). In about 15% of cases a drug or infection can be identified that precipitates the aplasia, although why only some individuals are susceptible is unclear. In about 5 to 10% of patients, the aplastic anemia is constitutional--i.e., is familial or presents with one or more associated somatic abnormalities (summary by Vulliamy et al., 2002).
Pancytopenia
MedGen UID:
18281
Concept ID:
C0030312
Disease or Syndrome
An abnormal reduction in numbers of all blood cell types (red blood cells, white blood cells, and platelets).
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Bone marrow hypocellularity
MedGen UID:
383749
Concept ID:
C1855710
Finding
A reduced number of hematopoietic cells present in the bone marrow relative to marrow fat.
Osteoporosis
MedGen UID:
14535
Concept ID:
C0029456
Disease or Syndrome
Osteoporosis is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility. According to the WHO criteria, osteoporosis is defined as a BMD that lies 2.5 standard deviations or more below the average value for young healthy adults (a T-score below -2.5 SD).
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Pulmonary fibrosis
MedGen UID:
11028
Concept ID:
C0034069
Disease or Syndrome
Replacement of normal lung tissues by fibroblasts and collagen.
Carious teeth
MedGen UID:
8288
Concept ID:
C0011334
Disease or Syndrome
Caries is a multifactorial bacterial infection affecting the structure of the tooth. This term has been used to describe the presence of more than expected dental caries.
Oral mucosa leukoplakia
MedGen UID:
9738
Concept ID:
C0023532
Neoplastic Process
A thickened white patch on the oral mucosa that cannot be rubbed off.
Microdontia
MedGen UID:
66008
Concept ID:
C0240340
Congenital Abnormality
Decreased size of the teeth, which can be defined as a mesiodistal tooth diameter (width) more than 2 SD below mean. Alternatively, an apparently decreased maximum width of tooth.
Nasolacrimal duct obstruction
MedGen UID:
226915
Concept ID:
C1281931
Finding
Blockage of the lacrimal duct.
Sparse scalp hair
MedGen UID:
346499
Concept ID:
C1857042
Finding
Decreased number of hairs per unit area of skin of the scalp.
Pterygium
MedGen UID:
46202
Concept ID:
C0033999
Finding
Pterygia are 'winglike' triangular membranes occurring in the neck, eyes, knees, elbows, ankles or digits.
Hyperpigmentation of the skin
MedGen UID:
57992
Concept ID:
C0162834
Pathologic Function
A darkening of the skin related to an increase in melanin production and deposition.
Nail dystrophy
MedGen UID:
66368
Concept ID:
C0221260
Disease or Syndrome
Onychodystrophy (nail dystrophy) refers to nail changes apart from changes of the color (nail dyschromia) and involves partial or complete disruption of the various keratinous layers of the nail plate.
Small nail
MedGen UID:
537942
Concept ID:
C0263523
Finding
A nail that is diminished in length and width, i.e., underdeveloped nail.
Pterygium of nails
MedGen UID:
590415
Concept ID:
C0406438
Anatomical Abnormality
Inward advance of skin over the nail plate.
Sparse eyelashes
MedGen UID:
375151
Concept ID:
C1843300
Finding
Decreased density/number of eyelashes.
Reticular hyperpigmentation
MedGen UID:
338832
Concept ID:
C1851972
Finding
Increased pigmentation of the skin with a netlike (reticular) pattern.
Epiphora
MedGen UID:
57518
Concept ID:
C0152227
Disease or Syndrome
Abnormally increased lacrimation, that is, excessive tearing (watering eye).

Professional guidelines

Curated

Dokal I, Vulliamy T, Mason P, Bessler M
Eur J Hum Genet 2011 Nov;19(11) Epub 2011 May 25 doi: 10.1038/ejhg.2011.90. PMID: 21610750Free PMC Article

Recent clinical studies

Etiology

Rolles B, Caballero-Oteyza A, Proietti M, Goldacker S, Warnatz K, Camacho-Ordonez N, Prader S, Schmid JP, Vieri M, Isfort S, Meyer R, Kirschner M, Brümmendorf TH, Beier F, Grimbacher B
Clin Immunol 2023 Dec;257:109837. Epub 2023 Nov 8 doi: 10.1016/j.clim.2023.109837. PMID: 37944684
Vittal A, Niewisch MR, Bhala S, Kudaravalli P, Rahman F, Hercun J, Kleiner DE, Savage SA, Koh C, Heller T, Giri N
Hepatology 2023 Dec 1;78(6):1777-1787. Epub 2023 May 16 doi: 10.1097/HEP.0000000000000461. PMID: 37184208Free PMC Article
Savage SA
Hematology Am Soc Hematol Educ Program 2022 Dec 9;2022(1):637-648. doi: 10.1182/hematology.2022000394. PMID: 36485133Free PMC Article
Khincha PP, Savage SA
Semin Fetal Neonatal Med 2016 Feb;21(1):57-65. Epub 2015 Dec 24 doi: 10.1016/j.siny.2015.12.003. PMID: 26724991Free PMC Article
Vulliamy TJ, Dokal I
Biochimie 2008 Jan;90(1):122-30. Epub 2007 Jul 31 doi: 10.1016/j.biochi.2007.07.017. PMID: 17825470

Diagnosis

Rolles B, Caballero-Oteyza A, Proietti M, Goldacker S, Warnatz K, Camacho-Ordonez N, Prader S, Schmid JP, Vieri M, Isfort S, Meyer R, Kirschner M, Brümmendorf TH, Beier F, Grimbacher B
Clin Immunol 2023 Dec;257:109837. Epub 2023 Nov 8 doi: 10.1016/j.clim.2023.109837. PMID: 37944684
Tummala H, Walne A, Buccafusca R, Alnajar J, Szabo A, Robinson P, McConkie-Rosell A, Wilson M, Crowley S, Kinsler V, Ewins AM, Madapura PM, Patel M, Pontikos N, Codd V, Vulliamy T, Dokal I
Am J Hum Genet 2022 Aug 4;109(8):1472-1483. doi: 10.1016/j.ajhg.2022.06.014. PMID: 35931051Free PMC Article
Niewisch MR, Giri N, McReynolds LJ, Alsaggaf R, Bhala S, Alter BP, Savage SA
Blood 2022 Mar 24;139(12):1807-1819. doi: 10.1182/blood.2021013523. PMID: 34852175Free PMC Article
Khincha PP, Savage SA
Semin Fetal Neonatal Med 2016 Feb;21(1):57-65. Epub 2015 Dec 24 doi: 10.1016/j.siny.2015.12.003. PMID: 26724991Free PMC Article
Vulliamy TJ, Dokal I
Biochimie 2008 Jan;90(1):122-30. Epub 2007 Jul 31 doi: 10.1016/j.biochi.2007.07.017. PMID: 17825470

Therapy

Niewisch MR, Giri N, McReynolds LJ, Alsaggaf R, Bhala S, Alter BP, Savage SA
Blood 2022 Mar 24;139(12):1807-1819. doi: 10.1182/blood.2021013523. PMID: 34852175Free PMC Article

Prognosis

Rolles B, Caballero-Oteyza A, Proietti M, Goldacker S, Warnatz K, Camacho-Ordonez N, Prader S, Schmid JP, Vieri M, Isfort S, Meyer R, Kirschner M, Brümmendorf TH, Beier F, Grimbacher B
Clin Immunol 2023 Dec;257:109837. Epub 2023 Nov 8 doi: 10.1016/j.clim.2023.109837. PMID: 37944684
Vittal A, Niewisch MR, Bhala S, Kudaravalli P, Rahman F, Hercun J, Kleiner DE, Savage SA, Koh C, Heller T, Giri N
Hepatology 2023 Dec 1;78(6):1777-1787. Epub 2023 May 16 doi: 10.1097/HEP.0000000000000461. PMID: 37184208Free PMC Article

Clinical prediction guides

Vittal A, Niewisch MR, Bhala S, Kudaravalli P, Rahman F, Hercun J, Kleiner DE, Savage SA, Koh C, Heller T, Giri N
Hepatology 2023 Dec 1;78(6):1777-1787. Epub 2023 May 16 doi: 10.1097/HEP.0000000000000461. PMID: 37184208Free PMC Article
Niewisch MR, Giri N, McReynolds LJ, Alsaggaf R, Bhala S, Alter BP, Savage SA
Blood 2022 Mar 24;139(12):1807-1819. doi: 10.1182/blood.2021013523. PMID: 34852175Free PMC Article
Ning Y, Yongshan Y, Pai GS, Gross AJ
Cancer Genet Cytogenet 1992 May;60(1):31-4. doi: 10.1016/0165-4608(92)90229-2. PMID: 1375530

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