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Fanconi anemia complementation group L(FANCL)

MedGen UID:
854018
Concept ID:
C3469528
Disease or Syndrome
Synonym: FANCL
 
Gene (location): FANCL (2p16.1)
 
Monarch Initiative: MONDO:0013566
OMIM®: 614083

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). For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see 227650.  http://www.omim.org/entry/614083
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.

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).

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
Unilateral renal agenesis
MedGen UID:
75607
Concept ID:
C0266294
Congenital Abnormality
A unilateral form of agenesis of the kidney.
Renal hypoplasia
MedGen UID:
120571
Concept ID:
C0266295
Congenital Abnormality
Hypoplasia of the kidney.
Aplasia of the uterus
MedGen UID:
98421
Concept ID:
C0425913
Finding
Aplasia of the uterus.
Micropenis
MedGen UID:
1633603
Concept ID:
C4551492
Congenital Abnormality
Abnormally small penis. At birth, the normal penis is about 3 cm (stretched length from pubic tubercle to tip of penis) with micropenis less than 2.0-2.5 cm.
Absent radius
MedGen UID:
235613
Concept ID:
C1405984
Congenital Abnormality
Missing radius bone associated with congenital failure of development.
Bilateral talipes equinovarus
MedGen UID:
332956
Concept ID:
C1837835
Congenital Abnormality
Bilateral clubfoot deformity.
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.
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.
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
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.
Esophageal atresia
MedGen UID:
4545
Concept ID:
C0014850
Congenital Abnormality
A developmental defect resulting in complete obliteration of the lumen of the esophagus such that the esophagus ends in a blind pouch rather than connecting to the stomach.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Microtia
MedGen UID:
57535
Concept ID:
C0152423
Congenital Abnormality
Underdevelopment of the external ear.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Anotia
MedGen UID:
152377
Concept ID:
C0702139
Congenital Abnormality
Complete absence of any auricular structures.
Hydrocephalus
MedGen UID:
9335
Concept ID:
C0020255
Disease or Syndrome
Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation.
Cerebellar hypoplasia
MedGen UID:
120578
Concept ID:
C0266470
Congenital Abnormality
Cerebellar hypoplasia is a descriptive term implying a cerebellum with a reduced volume, but a normal shape and is stable over time.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Attention deficit hyperactivity disorder
MedGen UID:
220387
Concept ID:
C1263846
Mental or Behavioral Dysfunction
Attention-deficit/hyperactivity disorder (ADHD) is a behavioral disorder that typically begins in childhood and is characterized by a short attention span (inattention), an inability to be calm and stay still (hyperactivity), and poor impulse control (impulsivity). Some people with ADHD have problems with only inattention or with hyperactivity and impulsivity, but most have problems related to all three features.\n\nIn people with ADHD, the characteristic behaviors are frequent and severe enough to interfere with the activities of daily living such as school, work, and relationships with others. Because of an inability to stay focused on tasks, people with inattention may be easily distracted, forgetful, avoid tasks that require sustained attention, have difficulty organizing tasks, or frequently lose items.\n\nHyperactivity is usually shown by frequent movement. Individuals with this feature often fidget or tap their foot when seated, leave their seat when it is inappropriate to do so (such as in the classroom), or talk a lot and interrupt others.\n\nIn most affected individuals, ADHD continues throughout life, but in about one-third of individuals, signs and symptoms of ADHD go away by adulthood.\n\nImpulsivity can result in hasty actions without thought for the consequences. Individuals with poor impulse control may have difficulty waiting for their turn, deferring to others, or considering their actions before acting.\n\nMore than two-thirds of all individuals with ADHD have additional conditions, including insomnia, mood or anxiety disorders, learning disorders, or substance use disorders. Affected individuals may also have autism spectrum disorder, which is characterized by impaired communication and social interaction, or Tourette syndrome, which is a disorder characterized by repetitive and involuntary movements or noises called tics.
Delayed CNS myelination
MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Delayed myelination in the central nervous system.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
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.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Hypoplastic sacrum
MedGen UID:
370356
Concept ID:
C1970816
Finding
Tracheoesophageal fistula
MedGen UID:
21228
Concept ID:
C0040588
Anatomical Abnormality
An abnormal connection (fistula) between the esophagus and the trachea.
Webbed neck
MedGen UID:
113154
Concept ID:
C0221217
Congenital Abnormality
Pterygium colli is a congenital skin fold that runs along the sides of the neck down to the shoulders. It involves an ectopic fibrotic facial band superficial to the trapezius muscle. Excess hair-bearing skin is also present and extends down the cervical region well beyond the normal hairline.
Upslanted palpebral fissure
MedGen UID:
98390
Concept ID:
C0423109
Finding
The palpebral fissure inclination is more than two standard deviations above the mean for age (objective); or, the inclination of the palpebral fissure is greater than typical for age.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Wide nasal bridge
MedGen UID:
341441
Concept ID:
C1849367
Finding
Increased breadth of the nasal bridge (and with it, the nasal root).
Depressed nasal tip
MedGen UID:
347214
Concept ID:
C1859717
Finding
Decreased distance from the nasal tip to the nasal base.
Cleft palate
MedGen UID:
756015
Concept ID:
C2981150
Congenital Abnormality
Cleft palate is a developmental defect of the palate resulting from a failure of fusion of the palatine processes and manifesting as a separation of the roof of the mouth (soft and hard palate).
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.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
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.
Chromosome breakage
MedGen UID:
91280
Concept ID:
C0376628
Cell or Molecular Dysfunction
Elevated rate of chromosomal breakage or interchanges occurring either spontaneously or following exposure to various DNA-damaging agents. This feature may be assayed by treatment of cultured lymphocytes with agents such as chemical mutagens, irradiation, and alkylating agents.
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

Beesetti S, Sirasanagandla S, Sakurada SM, Pruett-Miller SM, Sumpter R Jr, Levine B, Potts MB
Biochim Biophys Acta Mol Basis Dis 2022 Sep 1;1868(9):166453. Epub 2022 May 26 doi: 10.1016/j.bbadis.2022.166453. PMID: 35644338Free PMC Article
Shah A, George M, Dhangar S, Rajendran A, Mohan S, Vundinti BR
Mol Biol Rep 2021 Jan;48(1):585-593. Epub 2021 Jan 4 doi: 10.1007/s11033-020-06101-2. PMID: 33394227
Yang Y, Guo T, Liu R, Ke H, Xu W, Zhao S, Qin Y
Hum Mutat 2020 May;41(5):1033-1041. Epub 2020 Feb 24 doi: 10.1002/humu.23997. PMID: 32048394
van Twest S, Murphy VJ, Hodson C, Tan W, Swuec P, O'Rourke JJ, Heierhorst J, Crismani W, Deans AJ
Mol Cell 2017 Jan 19;65(2):247-259. Epub 2016 Dec 13 doi: 10.1016/j.molcel.2016.11.005. PMID: 27986371
Zhang Y, Zhou X, Huang P
J Genet Genomics 2007 Jul;34(7):573-80. doi: 10.1016/S1673-8527(07)60065-4. PMID: 17643942

Diagnosis

Beesetti S, Sirasanagandla S, Sakurada SM, Pruett-Miller SM, Sumpter R Jr, Levine B, Potts MB
Biochim Biophys Acta Mol Basis Dis 2022 Sep 1;1868(9):166453. Epub 2022 May 26 doi: 10.1016/j.bbadis.2022.166453. PMID: 35644338Free PMC Article
Shah A, George M, Dhangar S, Rajendran A, Mohan S, Vundinti BR
Mol Biol Rep 2021 Jan;48(1):585-593. Epub 2021 Jan 4 doi: 10.1007/s11033-020-06101-2. PMID: 33394227
Frost MG, Mazloumi Aboukheili AM, Toth R, Walden H
Biosci Rep 2020 Jun 26;40(6) doi: 10.1042/BSR20191304. PMID: 32420600Free PMC Article
Yang Y, Guo T, Liu R, Ke H, Xu W, Zhao S, Qin Y
Hum Mutat 2020 May;41(5):1033-1041. Epub 2020 Feb 24 doi: 10.1002/humu.23997. PMID: 32048394
Tian Y, Shen X, Wang R, Klages-Mundt NL, Lynn EJ, Martin SK, Ye Y, Gao M, Chen J, Schlacher K, Li L
J Biol Chem 2017 Dec 8;292(49):20184-20195. Epub 2017 Oct 11 doi: 10.1074/jbc.M117.814780. PMID: 29021208Free PMC Article

Therapy

Hess CJ, Ameziane N, Schuurhuis GJ, Errami A, Denkers F, Kaspers GJ, Cloos J, Joenje H, Reinhardt D, Ossenkoppele GJ, Zwaan CM, Waisfisz Q
Cell Oncol 2008;30(4):299-306. doi: 10.3233/clo-2008-0426. PMID: 18607065Free PMC Article

Prognosis

Shah A, George M, Dhangar S, Rajendran A, Mohan S, Vundinti BR
Mol Biol Rep 2021 Jan;48(1):585-593. Epub 2021 Jan 4 doi: 10.1007/s11033-020-06101-2. PMID: 33394227
Chandrasekharappa SC, Chinn SB, Donovan FX, Chowdhury NI, Kamat A, Adeyemo AA, Thomas JW, Vemulapalli M, Hussey CS, Reid HH, Mullikin JC, Wei Q, Sturgis EM
Cancer 2017 Oct 15;123(20):3943-3954. Epub 2017 Jul 5 doi: 10.1002/cncr.30802. PMID: 28678401Free PMC Article
Wu W, Liu Y, Zhou Q, Wang Q, Luo F, Xu Z, Geng Q, Li P, Zhang HZ, Xie J
Eur J Med Genet 2017 Jul;60(7):369-373. Epub 2017 Apr 15 doi: 10.1016/j.ejmg.2017.04.008. PMID: 28419882
Panneerselvam J, Xie G, Che R, Su M, Zhang J, Jia W, Fei P
J Proteome Res 2016 Apr 1;15(4):1333-41. Epub 2016 Mar 16 doi: 10.1021/acs.jproteome.6b00076. PMID: 26956768Free PMC Article
Lhota F, Zemankova P, Kleiblova P, Soukupova J, Vocka M, Stranecky V, Janatova M, Hartmannova H, Hodanova K, Kmoch S, Kleibl Z
Clin Genet 2016 Oct;90(4):324-33. Epub 2016 Mar 4 doi: 10.1111/cge.12748. PMID: 26822949

Clinical prediction guides

Shah A, George M, Dhangar S, Rajendran A, Mohan S, Vundinti BR
Mol Biol Rep 2021 Jan;48(1):585-593. Epub 2021 Jan 4 doi: 10.1007/s11033-020-06101-2. PMID: 33394227
Frost MG, Mazloumi Aboukheili AM, Toth R, Walden H
Biosci Rep 2020 Jun 26;40(6) doi: 10.1042/BSR20191304. PMID: 32420600Free PMC Article
Chandrasekharappa SC, Chinn SB, Donovan FX, Chowdhury NI, Kamat A, Adeyemo AA, Thomas JW, Vemulapalli M, Hussey CS, Reid HH, Mullikin JC, Wei Q, Sturgis EM
Cancer 2017 Oct 15;123(20):3943-3954. Epub 2017 Jul 5 doi: 10.1002/cncr.30802. PMID: 28678401Free PMC Article
Lhota F, Zemankova P, Kleiblova P, Soukupova J, Vocka M, Stranecky V, Janatova M, Hartmannova H, Hodanova K, Kmoch S, Kleibl Z
Clin Genet 2016 Oct;90(4):324-33. Epub 2016 Mar 4 doi: 10.1111/cge.12748. PMID: 26822949
Medhurst AL, Laghmani el H, Steltenpool J, Ferrer M, Fontaine C, de Groot J, Rooimans MA, Scheper RJ, Meetei AR, Wang W, Joenje H, de Winter JP
Blood 2006 Sep 15;108(6):2072-80. Epub 2006 May 23 doi: 10.1182/blood-2005-11-008151. PMID: 16720839Free PMC Article

Supplemental Content

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    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.

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