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Fanconi anemia, complementation group S(FANCS)

MedGen UID:
1632414
Concept ID:
C4554406
Disease or Syndrome
Synonym: FANCS
 
Gene (location): BRCA1 (17q21.31)
 
Monarch Initiative: MONDO:0054748
OMIM®: 617883

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 description

From OMIM
Fanconi anemia complementation group S is an autosomal recessive disorder characterized by developmental delay apparent from infancy, short stature, microcephaly, and coarse dysmorphic features. Laboratory studies show defective DNA repair and increased chromosomal breakage during stress. Some patients may have radial ray anomalies, anemia, and increased risk of cancer; patients often have a family history of cancer in family members who have heterozygous mutations (summary by Freire et al., 2018). For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see 227650.  http://www.omim.org/entry/617883

Clinical features

From HPO
Neoplasm of ovary
MedGen UID:
181539
Concept ID:
C0919267
Neoplastic Process
A tumor (abnormal growth of tissue) of the ovary.
Ovarian carcinoma
MedGen UID:
1648335
Concept ID:
C4721610
Neoplastic Process
A malignant neoplasm originating from the surface ovarian epithelium.
Proximal placement of thumb
MedGen UID:
356033
Concept ID:
C1865572
Finding
Proximal mislocalization of the thumb.
Clinodactyly
MedGen UID:
1644094
Concept ID:
C4551485
Congenital Abnormality
An angulation of a digit at an interphalangeal joint in the plane of the palm (finger) or sole (toe).
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.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
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.
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.
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.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Blepharophimosis
MedGen UID:
2670
Concept ID:
C0005744
Congenital Abnormality
A fixed reduction in the vertical distance between the upper and lower eyelids with short palpebral fissures.
Dental malocclusion
MedGen UID:
9869
Concept ID:
C0024636
Anatomical Abnormality
Dental malocclusion refers to an abnormality of the occlusion, or alignment, of the teeth and the way the upper and lower teeth fit together, resulting in overcrowding of teeth or in abnormal bite patterns.
Macrodontia
MedGen UID:
82729
Concept ID:
C0266036
Finding
Increased size of the teeth, which can be defined as a mesiodistal tooth diameter (width) more than 2 SD above mean for age. Alternatively, an apparently increased maximum width of the tooth.
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.
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Narrow palate
MedGen UID:
278045
Concept ID:
C1398312
Finding
Width of the palate more than 2 SD below the mean (objective) or apparently decreased palatal width (subjective).
Underdeveloped nasal alae
MedGen UID:
322332
Concept ID:
C1834055
Congenital Abnormality
Thinned, deficient, or excessively arched ala nasi.
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Low anterior hairline
MedGen UID:
331280
Concept ID:
C1842366
Finding
Distance between the hairline (trichion) and the glabella (the most prominent point on the frontal bone above the root of the nose), in the midline, more than two SD below the mean. Alternatively, an apparently decreased distance between the hairline and the glabella.
Coarse facial features
MedGen UID:
335284
Concept ID:
C1845847
Finding
Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues.
Thick upper lip vermilion
MedGen UID:
339521
Concept ID:
C1846423
Finding
Height of the vermilion of the upper lip in the midline more than 2 SD above the mean. Alternatively, an apparently increased height of the vermilion of the upper lip in the frontal view (subjective).
Prominent nasal bridge
MedGen UID:
343051
Concept ID:
C1854113
Finding
Anterior positioning of the nasal root in comparison to the usual positioning for age.
Long eyelashes
MedGen UID:
342955
Concept ID:
C1853738
Finding
Mid upper eyelash length >10 mm or increased length of the eyelashes (subjective).
Sparse hair
MedGen UID:
1790211
Concept ID:
C5551005
Finding
Reduced density of hairs.
Breast carcinoma
MedGen UID:
146260
Concept ID:
C0678222
Neoplastic Process
The presence of a carcinoma of the breast.
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.

Professional guidelines

PubMed

Yoshimura A, Imoto I, Iwata H
Int J Mol Sci 2022 Jul 5;23(13) doi: 10.3390/ijms23137481. PMID: 35806485Free 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

Recent clinical studies

Etiology

Kwong A, Shin VY, Ho JC, Kang E, Nakamura S, Teo SH, Lee AS, Sng JH, Ginsburg OM, Kurian AW, Weitzel JN, Siu MT, Law FB, Chan TL, Narod SA, Ford JM, Ma ES, Kim SW
J Med Genet 2016 Jan;53(1):15-23. Epub 2015 Jul 17 doi: 10.1136/jmedgenet-2015-103132. PMID: 26187060Free PMC Article
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Anticancer Agents Med Chem 2015;15(1):4-14. doi: 10.2174/1871520614666141020153543. PMID: 25329591
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Front Biosci (Landmark Ed) 2014 Jan 1;19(4):605-18. doi: 10.2741/4230. PMID: 24389207Free PMC Article
Filippini SE, Vega A
Front Biosci (Landmark Ed) 2013 Jun 1;18(4):1358-72. doi: 10.2741/4185. PMID: 23747889
Elstrodt F, Hollestelle A, Nagel JH, Gorin M, Wasielewski M, van den Ouweland A, Merajver SD, Ethier SP, Schutte M
Cancer Res 2006 Jan 1;66(1):41-5. doi: 10.1158/0008-5472.CAN-05-2853. PMID: 16397213

Diagnosis

Cleary JM, Aguirre AJ, Shapiro GI, D'Andrea AD
Mol Cell 2020 Jun 18;78(6):1070-1085. Epub 2020 May 26 doi: 10.1016/j.molcel.2020.04.035. PMID: 32459988Free PMC Article
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J Clin Oncol 2020 Jun 20;38(18):2080-2106. Epub 2020 Apr 3 doi: 10.1200/JCO.20.00299. PMID: 32243226
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Semin Oncol 2016 Oct;43(5):543-547. Epub 2016 Sep 20 doi: 10.1053/j.seminoncol.2016.08.005. PMID: 27899185
Lalloo F, Evans DG
Clin Genet 2012 Aug;82(2):105-14. Epub 2012 Apr 13 doi: 10.1111/j.1399-0004.2012.01859.x. PMID: 22356477

Therapy

Cleary JM, Aguirre AJ, Shapiro GI, D'Andrea AD
Mol Cell 2020 Jun 18;78(6):1070-1085. Epub 2020 May 26 doi: 10.1016/j.molcel.2020.04.035. PMID: 32459988Free PMC Article
Jonsson P, Bandlamudi C, Cheng ML, Srinivasan P, Chavan SS, Friedman ND, Rosen EY, Richards AL, Bouvier N, Selcuklu SD, Bielski CM, Abida W, Mandelker D, Birsoy O, Zhang L, Zehir A, Donoghue MTA, Baselga J, Offit K, Scher HI, O'Reilly EM, Stadler ZK, Schultz N, Socci ND, Viale A, Ladanyi M, Robson ME, Hyman DM, Berger MF, Solit DB, Taylor BS
Nature 2019 Jul;571(7766):576-579. Epub 2019 Jul 10 doi: 10.1038/s41586-019-1382-1. PMID: 31292550Free PMC Article
Litton JK, Rugo HS, Ettl J, Hurvitz SA, Gonçalves A, Lee KH, Fehrenbacher L, Yerushalmi R, Mina LA, Martin M, Roché H, Im YH, Quek RGW, Markova D, Tudor IC, Hannah AL, Eiermann W, Blum JL
N Engl J Med 2018 Aug 23;379(8):753-763. Epub 2018 Aug 15 doi: 10.1056/NEJMoa1802905. PMID: 30110579Free PMC Article
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Anticancer Agents Med Chem 2015;15(1):4-14. doi: 10.2174/1871520614666141020153543. PMID: 25329591
Foulkes WD, Smith IE, Reis-Filho JS
N Engl J Med 2010 Nov 11;363(20):1938-48. doi: 10.1056/NEJMra1001389. PMID: 21067385

Prognosis

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Sun J, Chu F, Pan J, Zhang Y, Yao L, Chen J, Hu L, Zhang J, Xu Y, Wang X, Cao W, Xie Y
J Clin Oncol 2023 Feb 10;41(5):991-999. Epub 2022 Dec 8 doi: 10.1200/JCO.22.00833. PMID: 36480783
Cleary JM, Aguirre AJ, Shapiro GI, D'Andrea AD
Mol Cell 2020 Jun 18;78(6):1070-1085. Epub 2020 May 26 doi: 10.1016/j.molcel.2020.04.035. PMID: 32459988Free PMC Article
Foulkes WD, Smith IE, Reis-Filho JS
N Engl J Med 2010 Nov 11;363(20):1938-48. doi: 10.1056/NEJMra1001389. PMID: 21067385
King MC, Marks JH, Mandell JB; New York Breast Cancer Study Group
Science 2003 Oct 24;302(5645):643-6. doi: 10.1126/science.1088759. PMID: 14576434

Clinical prediction guides

Cleary JM, Aguirre AJ, Shapiro GI, D'Andrea AD
Mol Cell 2020 Jun 18;78(6):1070-1085. Epub 2020 May 26 doi: 10.1016/j.molcel.2020.04.035. PMID: 32459988Free PMC Article
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Adv Exp Med Biol 2020;1292:1-12. doi: 10.1007/5584_2018_147. PMID: 29687286
Tung N, Lin NU, Kidd J, Allen BA, Singh N, Wenstrup RJ, Hartman AR, Winer EP, Garber JE
J Clin Oncol 2016 May 1;34(13):1460-8. Epub 2016 Mar 14 doi: 10.1200/JCO.2015.65.0747. PMID: 26976419Free PMC Article
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Nature 2002 Jan 31;415(6871):530-6. doi: 10.1038/415530a. PMID: 11823860

Recent systematic reviews

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Baretta Z, Mocellin S, Goldin E, Olopade OI, Huo D
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