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Fanconi anemia complementation group D1(FANCD1)

MedGen UID:
325420
Concept ID:
C1838457
Disease or Syndrome
Synonym: BRCA2-Related Fanconi Anemia
 
Gene (location): BRCA2 (13q13.1)
 
Monarch Initiative: MONDO:0011584
OMIM®: 605724
Orphanet: ORPHA319462

Definition

Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA. [from GeneReviews]

Additional descriptions

From OMIM
Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by Deakyne and Mazin, 2011). For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see 227650.  http://www.omim.org/entry/605724
From MedlinePlus Genetics
Fanconi anemia is a condition that affects many parts of the body. People with this condition may have bone marrow failure, physical abnormalities, organ defects, and an increased risk of certain cancers.

The major function of bone marrow is to produce new blood cells. These include red blood cells, which carry oxygen to the body's tissues; white blood cells, which fight infections; and platelets, which are necessary for normal blood clotting. Approximately 90 percent of people with Fanconi anemia have impaired bone marrow function that leads to a decrease in the production of all blood cells (aplastic anemia). Affected individuals experience extreme tiredness (fatigue) due to low numbers of red blood cells (anemia), frequent infections due to low numbers of white blood cells (neutropenia), and clotting problems due to low numbers of platelets (thrombocytopenia). People with Fanconi anemia may also develop myelodysplastic syndrome, a condition in which immature blood cells fail to develop normally.

More than half of people with Fanconi anemia have physical abnormalities. These abnormalities can involve irregular skin coloring such as unusually light-colored skin (hypopigmentation) or café-au-lait spots, which are flat patches on the skin that are darker than the surrounding area. Other possible symptoms of Fanconi anemia include malformed thumbs or forearms and other skeletal problems including short stature; malformed or absent kidneys and other defects of the urinary tract; gastrointestinal abnormalities; heart defects; eye abnormalities such as small or abnormally shaped eyes; and malformed ears and hearing loss. People with this condition may have abnormal genitalia or malformations of the reproductive system. As a result, most affected males and about half of affected females cannot have biological children (are infertile). Additional signs and symptoms can include abnormalities of the brain and spinal cord (central nervous system), including increased fluid in the center of the brain (hydrocephalus) or an unusually small head size (microcephaly).

Individuals with Fanconi anemia have an increased risk of developing a cancer of blood-forming cells in the bone marrow called acute myeloid leukemia (AML) or tumors of the head, neck, skin, gastrointestinal system, or genital tract. The likelihood of developing one of these cancers in people with Fanconi anemia is between 10 and 30 percent.  https://medlineplus.gov/genetics/condition/fanconi-anemia

Clinical features

From HPO
Acute myeloid leukemia
MedGen UID:
9730
Concept ID:
C0023467
Neoplastic Process
A clonal expansion of myeloid blasts in the bone marrow, blood or other tissues. The classification of acute myeloid leukemias (AMLs) encompasses four major categories: 1) AML with recurrent genetic abnormalities; 2) AML with multilineage dysplasia; 3) Therapy-related AML; 4) AML not otherwise specified. The required bone marrow or peripheral blood blast percentage for the diagnosis of AML is 20% (WHO classification)
T-cell acute lymphoblastic leukemia
MedGen UID:
368378
Concept ID:
C1961099
Neoplastic Process
Acute lymphoblastic leukemia of T-cell origin. It comprises about 15% of childhood cases and 25% of adult cases. It is more common in males than females.
Short thumb
MedGen UID:
98469
Concept ID:
C0431890
Congenital Abnormality
Hypoplasia (congenital reduction in size) of the thumb.
Fetal growth restriction
MedGen UID:
4693
Concept ID:
C0015934
Pathologic Function
An abnormal restriction of fetal growth with fetal weight below the tenth percentile for gestational age.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Imperforate anus
MedGen UID:
1997
Concept ID:
C0003466
Congenital Abnormality
Congenital absence of the anus, i.e., the opening at the bottom end of the intestinal tract.
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.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Cafe-au-lait spot
MedGen UID:
113157
Concept ID:
C0221263
Finding
Cafe-au-lait spots are hyperpigmented lesions that can vary in color from light brown to dark brown with smooth borders and having a size of 1.5 cm or more in adults and 0.5 cm or more in children.
Chromosomal breakage induced by crosslinking agents
MedGen UID:
867372
Concept ID:
C4021737
Finding
Increased amount of chromosomal breaks in cultured blood lymphocytes or other cells induced by treatment with DNA cross-linking agents such as diepoxybutane and mitomycin C.

Professional guidelines

PubMed

Kasuga A, Okamoto T, Udagawa S, Mori C, Mie T, Furukawa T, Yamada Y, Takeda T, Matsuyama M, Sasaki T, Ozaka M, Ueki A, Sasahira N
Int J Mol Sci 2022 Jan 21;23(3) doi: 10.3390/ijms23031205. PMID: 35163129Free PMC Article
Daly MB, Pal T, Berry MP, Buys SS, Dickson P, Domchek SM, Elkhanany A, Friedman S, Goggins M, Hutton ML; CGC, Karlan BY, Khan S, Klein C, Kohlmann W; CGC, Kurian AW, Laronga C, Litton JK, Mak JS; LCGC, Menendez CS, Merajver SD, Norquist BS, Offit K, Pederson HJ, Reiser G; CGC, Senter-Jamieson L; CGC, Shannon KM, Shatsky R, Visvanathan K, Weitzel JN, Wick MJ, Wisinski KB, Yurgelun MB, Darlow SD, Dwyer MA
J Natl Compr Canc Netw 2021 Jan 6;19(1):77-102. doi: 10.6004/jnccn.2021.0001. PMID: 33406487
Walker-Smith TL, Peck J
Nurs Womens Health 2019 Dec;23(6):518-525. Epub 2019 Oct 25 doi: 10.1016/j.nwh.2019.09.003. PMID: 31669147

Curated

Fanconi Anemia Clinical Care Guidelines, Fifth Edition.

Fanconi Anemia Research Fund, Guidelines for Diagnosis and Management, 2008 (See 2020 Update)

Suggested Reading

PubMed

Offit K, Levran O, Mullaney B, Mah K, Nafa K, Batish SD, Diotti R, Schneider H, Deffenbaugh A, Scholl T, Proud VK, Robson M, Norton L, Ellis N, Hanenberg H, Auerbach AD
J Natl Cancer Inst 2003 Oct 15;95(20):1548-51. doi: 10.1093/jnci/djg072. PMID: 14559878

Recent clinical studies

Etiology

Radulovic I, Schündeln MM, Müller L, Ptok J, Honisch E, Niederacher D, Wiek C, Scheckenbach K, Leblanc T, Larcher L, Soulier J, Reinhardt D, Schaal H, Andreassen PR, Hanenberg H
Hum Mol Genet 2023 May 18;32(11):1836-1849. doi: 10.1093/hmg/ddad017. PMID: 36721989
Maxwell KN, Patel V, Nead KT, Merrill S, Clark D, Jiang Q, Wubbenhorst B, D'Andrea K, Cohen RB, Domchek SM, Morrissette JJD, Greenberg RA, Babushok DV, Nathanson KL
Clin Genet 2023 Jan;103(1):119-124. Epub 2022 Sep 26 doi: 10.1111/cge.14231. PMID: 36089892Free PMC Article
Radulovic I, Kuechler A, Schündeln MM, Paulussen M, von Neuhoff N, Reinhardt D, Hanenberg H
Eur J Med Genet 2021 Aug;64(8):104260. Epub 2021 Jun 10 doi: 10.1016/j.ejmg.2021.104260. PMID: 34118472
Skvarova Kramarzova K, Osborn MJ, Webber BR, DeFeo AP, McElroy AN, Kim CJ, Tolar J
Int J Mol Sci 2017 Jun 14;18(6) doi: 10.3390/ijms18061269. PMID: 28613254Free PMC Article
Offit K, Levran O, Mullaney B, Mah K, Nafa K, Batish SD, Diotti R, Schneider H, Deffenbaugh A, Scholl T, Proud VK, Robson M, Norton L, Ellis N, Hanenberg H, Auerbach AD
J Natl Cancer Inst 2003 Oct 15;95(20):1548-51. doi: 10.1093/jnci/djg072. PMID: 14559878

Diagnosis

Maxwell KN, Patel V, Nead KT, Merrill S, Clark D, Jiang Q, Wubbenhorst B, D'Andrea K, Cohen RB, Domchek SM, Morrissette JJD, Greenberg RA, Babushok DV, Nathanson KL
Clin Genet 2023 Jan;103(1):119-124. Epub 2022 Sep 26 doi: 10.1111/cge.14231. PMID: 36089892Free PMC Article
Ip E, McNeil C, Grimison P, Scheinberg T, Tudini E, Ho G, Scott RJ, Brown C, Sandroussi C, Guitera P, Spurdle AB, Goodwin A
J Med Genet 2022 Sep;59(9):912-915. Epub 2021 Oct 25 doi: 10.1136/jmedgenet-2021-108072. PMID: 34697207
Svojgr K, Sumerauer D, Puchmajerova A, Vicha A, Hrusak O, Michalova K, Malis J, Smisek P, Kyncl M, Novotna D, Machackova E, Jencik J, Pycha K, Vaculik M, Kodet R, Stary J
Eur J Med Genet 2016 Mar;59(3):152-7. Epub 2015 Dec 2 doi: 10.1016/j.ejmg.2015.11.013. PMID: 26657402
Offit K, Levran O, Mullaney B, Mah K, Nafa K, Batish SD, Diotti R, Schneider H, Deffenbaugh A, Scholl T, Proud VK, Robson M, Norton L, Ellis N, Hanenberg H, Auerbach AD
J Natl Cancer Inst 2003 Oct 15;95(20):1548-51. doi: 10.1093/jnci/djg072. PMID: 14559878

Therapy

Svojgr K, Sumerauer D, Puchmajerova A, Vicha A, Hrusak O, Michalova K, Malis J, Smisek P, Kyncl M, Novotna D, Machackova E, Jencik J, Pycha K, Vaculik M, Kodet R, Stary J
Eur J Med Genet 2016 Mar;59(3):152-7. Epub 2015 Dec 2 doi: 10.1016/j.ejmg.2015.11.013. PMID: 26657402

Prognosis

Radulovic I, Schündeln MM, Müller L, Ptok J, Honisch E, Niederacher D, Wiek C, Scheckenbach K, Leblanc T, Larcher L, Soulier J, Reinhardt D, Schaal H, Andreassen PR, Hanenberg H
Hum Mol Genet 2023 May 18;32(11):1836-1849. doi: 10.1093/hmg/ddad017. PMID: 36721989

Clinical prediction guides

Radulovic I, Schündeln MM, Müller L, Ptok J, Honisch E, Niederacher D, Wiek C, Scheckenbach K, Leblanc T, Larcher L, Soulier J, Reinhardt D, Schaal H, Andreassen PR, Hanenberg H
Hum Mol Genet 2023 May 18;32(11):1836-1849. doi: 10.1093/hmg/ddad017. PMID: 36721989
Maxwell KN, Patel V, Nead KT, Merrill S, Clark D, Jiang Q, Wubbenhorst B, D'Andrea K, Cohen RB, Domchek SM, Morrissette JJD, Greenberg RA, Babushok DV, Nathanson KL
Clin Genet 2023 Jan;103(1):119-124. Epub 2022 Sep 26 doi: 10.1111/cge.14231. PMID: 36089892Free PMC Article
Skvarova Kramarzova K, Osborn MJ, Webber BR, DeFeo AP, McElroy AN, Kim CJ, Tolar J
Int J Mol Sci 2017 Jun 14;18(6) doi: 10.3390/ijms18061269. PMID: 28613254Free PMC Article
Offit K, Levran O, Mullaney B, Mah K, Nafa K, Batish SD, Diotti R, Schneider H, Deffenbaugh A, Scholl T, Proud VK, Robson M, Norton L, Ellis N, Hanenberg H, Auerbach AD
J Natl Cancer Inst 2003 Oct 15;95(20):1548-51. doi: 10.1093/jnci/djg072. PMID: 14559878

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • FARF, 2020
      Fanconi Anemia Clinical Care Guidelines, Fifth Edition.
    • FARF, 2008
      Fanconi Anemia Research Fund, Guidelines for Diagnosis and Management, 2008 (See 2020 Update)

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