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Fanconi anemia complementation group F(FANCF)

MedGen UID:
854016
Concept ID:
C3469526
Disease or Syndrome
Synonyms: FANCF; FANCONI ANEMIA, COMPLEMENTATION GROUP F
 
Gene (location): FANCF (11p14.3)
 
Monarch Initiative: MONDO:0011325
OMIM®: 603467

Disease characteristics

Excerpted from the GeneReview: Fanconi Anemia
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]
Authors:
Parinda A Mehta  |  Christen Ebens   view full author information

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). Clinical features of FANCF include microcephaly, small or absent thumbs, short stature, microphthalmia, microtia, hearing loss, pigmentary anomalies (cafe-au-lait spots or hyperpigmentation), small or pelvic kidneys, and cardiac anomalies (Tryon et al., 2017; Zareifar et al., 2019). For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see 227650.  http://www.omim.org/entry/603467
From MedlinePlus Genetics
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.

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).

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.

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.  https://medlineplus.gov/genetics/condition/fanconi-anemia

Clinical features

From HPO
Cryptorchidism
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Vesicoureteral reflux
MedGen UID:
21852
Concept ID:
C0042580
Disease or Syndrome
Vesicoureteral reflux (VUR) is characterized by the reflux of urine from the bladder into the ureters and sometimes into the kidneys. It is a risk factor for urinary tract infections. Primary VUR results from a developmental defect of the ureterovesical junction (UVJ). In combination with intrarenal reflux, the resulting inflammatory reaction may result in renal injury or scarring, also called reflux nephropathy (RN). Extensive renal scarring impairs renal function and may predispose patients to hypertension, proteinuria, and renal insufficiency (summary by Lu et al., 2007). Genetic Heterogeneity of Vesicoureteral Reflux A locus designated VUR1 maps to chromosome 1p13. VUR2 (610878) is caused by mutation in the ROBO2 gene (602431) on chromosome 3p12; VUR3 (613674) is caused by mutation in the SOX17 gene (610928) on chromosome 8q11; VUR4 (614317) maps to chromosome 5; VUR5 (614318) maps to chromosome 13; VUR6 (614319) maps to chromosome 18; VUR7 (615390) maps to chromosome 12; and VUR8 (615963) is caused by mutation in the TNXB gene (600985) on chromosome 6p21. A possible X-linked form has been reported (VURX; 314550).
Pelvic kidney
MedGen UID:
67446
Concept ID:
C0221209
Congenital Abnormality
A developmental defect in which a kidney is located in an abnormal anatomic position within the pelvis.
Microphallus
MedGen UID:
66816
Concept ID:
C0240701
Finding
Length of penis more than 2 SD below the mean for age accompanied by hypospadias.
Renal hypoplasia
MedGen UID:
120571
Concept ID:
C0266295
Congenital Abnormality
Hypoplasia of the kidney.
Short thumb
MedGen UID:
98469
Concept ID:
C0431890
Congenital Abnormality
Hypoplasia (congenital reduction in size) of the thumb.
2-3 finger syndactyly
MedGen UID:
96573
Concept ID:
C0432055
Congenital Abnormality
Syndactyly with fusion of fingers two and three.
Hypoplasia of the radius
MedGen UID:
672334
Concept ID:
C0685381
Congenital Abnormality
Underdevelopment of the radius.
Absent thumb
MedGen UID:
480441
Concept ID:
C3278811
Finding
Absent thumb, i.e., the absence of both phalanges of a thumb and the associated soft tissues.
Patent ductus arteriosus
MedGen UID:
4415
Concept ID:
C0013274
Congenital Abnormality
In utero, the ductus arteriosus (DA) serves to divert ventricular output away from the lungs and toward the placenta by connecting the main pulmonary artery to the descending aorta. A patent ductus arteriosus (PDA) in the first 3 days of life is a physiologic shunt in healthy term and preterm newborn infants, and normally is substantially closed within about 24 hours after bith and completely closed after about three weeks. Failure of physiologcal closure is referred to a persistent or patent ductus arteriosus (PDA). Depending on the degree of left-to-right shunting, PDA can have clinical consequences.
Atrial septal defect
MedGen UID:
6753
Concept ID:
C0018817
Congenital Abnormality
Atrial septal defect (ASD) is a congenital abnormality of the interatrial septum that enables blood flow between the left and right atria via the interatrial septum.
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.
Duodenal atresia
MedGen UID:
75602
Concept ID:
C0266174
Congenital Abnormality
A developmental defect resulting in complete obliteration of the duodenal lumen, that is, an abnormal closure of the duodenum.
Conductive hearing impairment
MedGen UID:
9163
Concept ID:
C0018777
Disease or Syndrome
An abnormality of vibrational conductance of sound to the inner ear leading to impairment of sensory perception of sound.
Microtia
MedGen UID:
57535
Concept ID:
C0152423
Congenital Abnormality
Underdevelopment of the external ear.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Specific learning disability
MedGen UID:
871302
Concept ID:
C4025790
Mental or Behavioral Dysfunction
Impairment of certain skills such as reading or writing, coordination, self-control, or attention that interfere with the ability to learn. The impairment is not related to a global deficiency of intelligence.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
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.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Leukopenia
MedGen UID:
6073
Concept ID:
C0023530
Disease or Syndrome
An abnormal decreased number of leukocytes in the blood.
Pneumonia
MedGen UID:
10813
Concept ID:
C0032285
Disease or Syndrome
Inflammation of any part of the lung parenchyma.
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.
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.
Sacral dimple
MedGen UID:
98428
Concept ID:
C0426848
Finding
A cutaneous indentation resulting from tethering of the skin to underlying structures (bone) of the intergluteal cleft.
Placental abruption
MedGen UID:
49
Concept ID:
C0000832
Pathologic Function
Separation of the placenta from the uterus wall before delivery.
Polyhydramnios
MedGen UID:
6936
Concept ID:
C0020224
Pathologic Function
The presence of excess amniotic fluid in the uterus during pregnancy.
Single umbilical artery
MedGen UID:
278026
Concept ID:
C1384670
Congenital Abnormality
Single umbilical artery (SUA) is the absence of one of the two umbilical arteries surrounding the fetal bladder and in the fetal umbilical cord.
Decreased response to growth hormone stimulation test
MedGen UID:
1784655
Concept ID:
C5539399
Finding
Insufficient responses to growth hormone (GH) provocation tests. GH deficiency is defined as a serum peak GH concentration less than 10 ng/mL on provocation with a combination of at least two separate stimulation tests.
Microphthalmia
MedGen UID:
10033
Concept ID:
C0026010
Congenital Abnormality
Microphthalmia is an eye abnormality that arises before birth. In this condition, one or both eyeballs are abnormally small. In some affected individuals, the eyeball may appear to be completely missing; however, even in these cases some remaining eye tissue is generally present. Such severe microphthalmia should be distinguished from another condition called anophthalmia, in which no eyeball forms at all. However, the terms anophthalmia and severe microphthalmia are often used interchangeably. Microphthalmia may or may not result in significant vision loss.\n\nPeople with microphthalmia may also have a condition called coloboma. Colobomas are missing pieces of tissue in structures that form the eye. They may appear as notches or gaps in the colored part of the eye called the iris; the retina, which is the specialized light-sensitive tissue that lines the back of the eye; the blood vessel layer under the retina called the choroid; or in the optic nerves, which carry information from the eyes to the brain. Colobomas may be present in one or both eyes and, depending on their size and location, can affect a person's vision.\n\nPeople with microphthalmia may also have other eye abnormalities, including clouding of the lens of the eye (cataract) and a narrowed opening of the eye (narrowed palpebral fissure). Additionally, affected individuals may have an abnormality called microcornea, in which the clear front covering of the eye (cornea) is small and abnormally curved.\n\nBetween one-third and one-half of affected individuals have microphthalmia as part of a syndrome that affects other organs and tissues in the body. These forms of the condition are described as syndromic. When microphthalmia occurs by itself, it is described as nonsyndromic or isolated.
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.

Recent clinical studies

Etiology

Singh DK, Gamboa RS, Singh AK, Walkemeier B, Van Leene J, De Jaeger G, Siddiqi I, Guerois R, Crismani W, Mercier R
Nucleic Acids Res 2023 Apr 11;51(6):2516-2528. doi: 10.1093/nar/gkac1244. PMID: 36652992Free PMC Article
Thompson AS, Saba N, McReynolds LJ, Munir S, Ahmed P, Sajjad S, Jones K, Yeager M, Donovan FX, Chandrasekharappa SC, Alter BP, Savage SA, Rehman S
Mol Genet Genomic Med 2021 Jul;9(7):e1693. Epub 2021 May 7 doi: 10.1002/mgg3.1693. PMID: 33960719Free PMC Article
Zahnreich S, Weber B, Rösch G, Schindler D, Schmidberger H
DNA Repair (Amst) 2020 Dec;96:102992. Epub 2020 Oct 6 doi: 10.1016/j.dnarep.2020.102992. PMID: 33069004
Lyakhovich A, Surralles J
Cancer Lett 2006 Jan 28;232(1):99-106. Epub 2005 Oct 21 doi: 10.1016/j.canlet.2005.07.038. PMID: 16246487
Yamashita T, Nakahata T
Int J Hematol 2001 Jul;74(1):33-41. doi: 10.1007/BF02982547. PMID: 11530803

Diagnosis

Thompson AS, Saba N, McReynolds LJ, Munir S, Ahmed P, Sajjad S, Jones K, Yeager M, Donovan FX, Chandrasekharappa SC, Alter BP, Savage SA, Rehman S
Mol Genet Genomic Med 2021 Jul;9(7):e1693. Epub 2021 May 7 doi: 10.1002/mgg3.1693. PMID: 33960719Free PMC Article
Tryon R, Zierhut H, MacMillan ML, Wagner JE
Am J Med Genet A 2017 Jan;173(1):260-263. Epub 2016 Oct 7 doi: 10.1002/ajmg.a.37998. PMID: 27714961
Olopade OI, Wei M
Cancer Cell 2003 May;3(5):417-20. doi: 10.1016/s1535-6108(03)00111-9. PMID: 12781358
Siddique MA, Nakanishi K, Taniguchi T, Grompe M, D'Andrea AD
Exp Hematol 2001 Dec;29(12):1448-55. doi: 10.1016/s0301-472x(01)00754-8. PMID: 11750104
Holmes RK, Harutyunyan K, Shah M, Joenje H, Youssoufian H
Blood 2001 Dec 15;98(13):3817-22. doi: 10.1182/blood.v98.13.3817. PMID: 11739191

Therapy

Lin S, Yu L, Song X, Bi J, Jiang L, Wang Y, He M, Xiao Q, Sun M, Olopade OI, Zhao L, Wei M
Cell Death Dis 2019 Sep 11;10(9):666. doi: 10.1038/s41419-019-1871-z. PMID: 31511498Free PMC Article
Kessous R, Octeau D, Klein K, Tonin PN, Greenwood CMT, Pelmus M, Laskov I, Kogan L, Salvador S, Lau S, Yasmeen A, Gotlieb WH
Gynecol Oncol 2018 Mar;148(3):553-558. Epub 2018 Feb 1 doi: 10.1016/j.ygyno.2018.01.017. PMID: 29395310
Swisher EM, Gonzalez RM, Taniguchi T, Garcia RL, Walsh T, Goff BA, Welcsh P
Mol Cancer 2009 Jul 14;8:48. doi: 10.1186/1476-4598-8-48. PMID: 19602291Free PMC Article
Chen CC, Taniguchi T, D'Andrea A
J Mol Med (Berl) 2007 May;85(5):497-509. Epub 2007 Jan 13 doi: 10.1007/s00109-006-0153-2. PMID: 17221219
Taniguchi T, Tischkowitz M, Ameziane N, Hodgson SV, Mathew CG, Joenje H, Mok SC, D'Andrea AD
Nat Med 2003 May;9(5):568-74. Epub 2003 Apr 7 doi: 10.1038/nm852. PMID: 12692539

Prognosis

Moes-Sosnowska J, Rzepecka IK, Chodzynska J, Dansonka-Mieszkowska A, Szafron LM, Balabas A, Lotocka R, Sobiczewski P, Kupryjanczyk J
Cancer Biol Ther 2019;20(6):843-854. Epub 2019 Mar 1 doi: 10.1080/15384047.2019.1579955. PMID: 30822218Free PMC Article
Zhang X, Shi Y, Song L, Shen C, Cai Q, Zhang Z, Wu J, Fu G, Shen W
Acta Biochim Biophys Sin (Shanghai) 2018 Jul 1;50(7):685-692. doi: 10.1093/abbs/gmy052. PMID: 29767669
Kessous R, Octeau D, Klein K, Tonin PN, Greenwood CMT, Pelmus M, Laskov I, Kogan L, Salvador S, Lau S, Yasmeen A, Gotlieb WH
Gynecol Oncol 2018 Mar;148(3):553-558. Epub 2018 Feb 1 doi: 10.1016/j.ygyno.2018.01.017. PMID: 29395310
Tryon R, Zierhut H, MacMillan ML, Wagner JE
Am J Med Genet A 2017 Jan;173(1):260-263. Epub 2016 Oct 7 doi: 10.1002/ajmg.a.37998. PMID: 27714961
Ding JJ, Wang G, Shi WX, Zhou HH, Zhao EF
Reprod Sci 2016 Jan;23(1):24-30. Epub 2015 Oct 27 doi: 10.1177/1933719115612136. PMID: 26507869

Clinical prediction guides

Zahnreich S, Weber B, Rösch G, Schindler D, Schmidberger H
DNA Repair (Amst) 2020 Dec;96:102992. Epub 2020 Oct 6 doi: 10.1016/j.dnarep.2020.102992. PMID: 33069004
Türke C, Horn S, Petto C, Labudde D, Lauer G, Wittenburg G
Int J Oncol 2017 Jun;50(6):2207-2220. Epub 2017 Apr 24 doi: 10.3892/ijo.2017.3974. PMID: 28440438
Kusayanagi T, Tsukuda S, Shimura S, Manita D, Iwakiri K, Kamisuki S, Takakusagi Y, Takeuchi T, Kuramochi K, Nakazaki A, Sakaguchi K, Kobayashi S, Sugawara F
Bioorg Med Chem 2012 Nov 1;20(21):6248-55. Epub 2012 Sep 16 doi: 10.1016/j.bmc.2012.09.015. PMID: 23026082
Tumini E, Plevani P, Muzi-Falconi M, Marini F
DNA Repair (Amst) 2011 Feb 7;10(2):149-58. Epub 2010 Nov 24 doi: 10.1016/j.dnarep.2010.10.006. PMID: 21109493
Holmes RK, Harutyunyan K, Shah M, Joenje H, Youssoufian H
Blood 2001 Dec 15;98(13):3817-22. doi: 10.1182/blood.v98.13.3817. PMID: 11739191

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • Bookshelf
      See practice and clinical guidelines in NCBI Bookshelf. 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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