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Fanconi anemia, complementation group A(FANCA)

MedGen UID:
483333
Concept ID:
C3469521
Disease or Syndrome
Synonyms: FANCA; FANCA-Related Fanconi Anemia; Fanconi Anemia
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
 
Gene (location): FANCA (16q24.3)
OMIM®: 227650

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 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, gastrointestinal tract, and genitourinary tract – are more common in individuals with FA. [from GeneReviews]

Additional descriptions

From GeneReviews Overview
Esophageal atresia (EA) is a developmental defect of the upper gastrointestinal tract in which the continuity between the upper and lower esophagus is lost. EA can occur with or without tracheoesophageal fistula (TEF), an abnormal connection between the trachea and the esophagus.  https://www.ncbi.nlm.nih.gov/books/NBK5192
From OMIM
Fanconi anemia 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). Soulier et al. (2005) noted that the FANCA, -C, -E, -F, -G, and -L proteins are part of a nuclear multiprotein core complex which triggers activating monoubiquitination of the FANCD2 protein during S phase of the growth cycle and after exposure to DNA crosslinking agents. The FA/BRCA pathway is involved in the repair of DNA damage. Some cases of Fanconi anemia have presented with a VACTERL (192350) or VACTERL-H (276950, 314390) phenotype. In a group of 27 patients with Fanconi anemia group D1 (605724) due to biallelic mutations in the BRCA2 gene (600185), Alter et al. (2007) found that 5 patients had 3 or more VATER association anomalies and 1 was diagnosed with VACTERL-H. A VATER phenotype has also been reported in Fanconi anemia of complementation groups A, C (227645), E (600901), F (603467), and G (602956); VACTERL-H has also been described in patients with FANCB (300515) mutations (McCauley et al., 2011). Savage et al. (2015) added patients with FANCI (609053) to this list and stated that patients with FANCD2 (227646) and FANCL (614083) had also been reported to have features of VACTERL association. Genetic Heterogeneity of Fanconi Anemia Other Fanconi anemia complementation groups include FANCB (300514), caused by mutation in the FANCB (300515) on chromosome Xp22; FANCC (227645), caused by mutation in the FANCC (613899) on chromosome 9q22; FANCD1 (605724), caused by mutation in the BRCA2 (600185) on chromosome 13q12; FANCD2 (227646), caused by mutation in the FANCD2 gene (613984) on chromosome 3p25; FANCE (600901), caused by mutation in the FANCE gene (613976) on chromosome 6p21; FANCF (603467), caused by mutation in the FANCF gene (613897) on chromosome 11p15; FANCG (614082), caused by mutation in the XRCC9 gene (FANCG; 602956) on chromosome 9p13; FANCI (609053), caused by mutation in the FANCI gene (611360) on chromosome 15q26; FANCJ (609054), caused by mutation in the BRIP1 gene (605882) on chromosome 17q22; FANCL (614083), caused by mutation in the PHF9 gene (FANCL; 608111) on chromosome 2p16; FANCN (610832), caused by mutation in the PALB2 gene (610355) on chromosome 16p12; FANCO (613390), caused by mutation in the RAD51C (602774) on chromosome 17q22; FANCP (613951), caused by mutation in the SLX4 gene (613278) on chromosome 16p13; FANCQ (615272), caused by mutation in the ERCC4 gene (133520) on chromosome 16p13; FANCR (617244), caused by mutation in the RAD51 gene (179617) on chromosome 15q15; FANCS (617883), caused by mutation in the BRCA1 gene (113705) on chromosome 17q21; FANCT (616435), caused by mutation in the UBE2T gene (610538) on chromosome 1q31; FANCU (617247), caused by mutation in the XRCC2 gene (600375) on chromosome 7q36; FANCV (617243), caused by mutation in the MAD2L2 gene (604094) on chromosome 1p36; and FANCW (617784), caused by mutation in the RFWD3 gene (614151) on chromosome 16q23. The previously designated FANCH complementation group (Joenje et al., 1997) was found by Joenje et al. (2000) to be the same as FANCA. A patient originally reported to have Fanconi anemia of complementation group M (FANCM) due to mutation in the FAAP250 gene (609644) by Meetei et al. (2005) was subsequently found by Singh et al. (2009) to have FANCA.  http://www.omim.org/entry/227650
From GHR
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://ghr.nlm.nih.gov/condition/fanconi-anemia

Clinical features

Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
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).
Heart, malformation of
MedGen UID:
6748
Concept ID:
C0018798
Congenital Abnormality
An anatomical defect of a gross structure of the heart.
Leukemia
MedGen UID:
9725
Concept ID:
C0023418
Neoplastic Process
A cancer of the blood and bone marrow characterized by an abnormal proliferation of leukocytes.
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.People 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.People 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.Between 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.
Pancytopenia
MedGen UID:
18281
Concept ID:
C0030312
Disease or Syndrome
A finding of low numbers of red and white blood cells and platelets in the peripheral blood.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
Misalignment of the visual axes of the eyes. In comitant strabismus the degree of ocular misalignment does not vary with the direction of gaze. In noncomitant strabismus the degree of misalignment varies depending on direction of gaze or which eye is fixating on the target. (Miller, Walsh & Hoyt's Clinical Neuro-Ophthalmology, 4th ed, p641)
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A laboratory test result indicating that there is an abnormally small number of platelets in the circulating blood.
Cafe-au-lait spot
MedGen UID:
113157
Concept ID:
C0221263
Finding
A light brown, sharply demarcated skin patch. It is a manifestation of neurofibromatosis type 1 and McCune-Albright syndrome.
Horseshoe kidney
MedGen UID:
65140
Concept ID:
C0221353
Congenital Abnormality
A congenital abnormality in which the two kidneys fuse together during fetal development to create a horseshoe-shaped structure.
Small for gestational age
MedGen UID:
65920
Concept ID:
C0235991
Finding
Smaller than normal size according to sex and gestational age related norms, defined as a weight below the 10th percentile for the gestational age.
Ectopic kidney
MedGen UID:
68661
Concept ID:
C0238207
Congenital Abnormality
A developmental defect in which a kidney is located in an abnormal anatomic position.
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).
Bruising susceptibility
MedGen UID:
140849
Concept ID:
C0423798
Finding
An ecchymosis (bruise) refers to the skin discoloration caused by the escape of blood into the tissues from ruptured blood vessels. This term refers to an abnormally increased susceptibility to bruising. The corresponding phenotypic abnormality is generally elicited on medical history as a report of frequent ecchymoses or bruising without adequate trauma.
Microcephaly
MedGen UID:
473122
Concept ID:
C0424688
Finding
Occipito-frontal (head) circumference (OFC) less than -3 standard deviations compared to appropriate, age matched, normal standards (Ross JJ, Frias JL 1977, PMID:9683597). Alternatively, decreased size of the cranium.
Short thumb
MedGen UID:
98469
Concept ID:
C0431890
Congenital Abnormality
A congenital abnormality characterized by hypoplasia or absence of the thumb. It may be associated with other congenital abnormalities.
Renal agenesis
MedGen UID:
154237
Concept ID:
C0542519
Congenital Abnormality
A congenital abnormality characterized by the absence of one or both kidneys.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
A decrease in the number of neutrophils in the peripheral blood.
Reticulocytopenia
MedGen UID:
167812
Concept ID:
C0858867
Finding
A reduced number of reticulocytes in the peripheral blood.
Hypergonadotropic hypogonadism
MedGen UID:
184926
Concept ID:
C0948896
Disease or Syndrome
Ovarian or testicular dysfunction associated with high levels of gonadotropins.(NICHD)
Abnormality of skin pigmentation
MedGen UID:
224697
Concept ID:
C1260926
Finding
An abnormality in the formation or distribution of pigment in the skin, hair or nails.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Absent radius
MedGen UID:
235613
Concept ID:
C1405984
Congenital Abnormality
Missing radius bone associated with congenital failure of development.
Duplicated collecting system
MedGen UID:
346936
Concept ID:
C1858565
Anatomical Abnormality
A duplication of the collecting system of the kidney, defined as a kidney with two (instead of, normally, one) pyelocaliceal systems. The pyelocaliceal system is comprised of the renal pelvis and calices. The duplicated renal collecting system can be associated with a single ureter or with double ureters. In the latter case, the two ureters empty separately into the bladder or fuse to form a single ureteral orifice.
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.
Complete duplication of thumb phalanx
MedGen UID:
767638
Concept ID:
C3554724
Finding
A complete duplication affecting one or more of the phalanges of the thumb. As opposed to a partial duplication were there is still a variable degree of fusion between the duplicated bones, a complete duplication leads to two separate bones appearing side to side (radio-ulnar axis) as seen on x-rays. A duplication leading to an accesory bone appearing in the proximo-distal axis on x-rays, this is actually a different entity called a Pseudoepiphyses (see according terms) sometimes also refered to as Hyperphalangism.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
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.
Prolonged G2 phase of cell cycle
MedGen UID:
871165
Concept ID:
C4025639
Cell or Molecular Dysfunction
Deficient excision of UV-induced pyrimidine dimers in DNA
MedGen UID:
871166
Concept ID:
C4025640
Finding
Anemic pallor
MedGen UID:
871323
Concept ID:
C4025811
Sign or Symptom
A type of pallor that is secondary to the presence of anemia.

Recent clinical studies

Etiology

Svahn J, Lanza T, Rathbun K, Bagby G, Ravera S, Corsolini F, Pistorio A, Longoni D, Farruggia P, Dufour C, Cappelli E
Exp Hematol 2015 Apr;43(4):295-9. Epub 2014 Dec 19 doi: 10.1016/j.exphem.2014.11.010. PMID: 25534205
Kumaresan KR, Lambert MW
Carcinogenesis 2000 Apr;21(4):741-51. PMID: 10753211
Hang B, Yeung AT, Lambert MW
Nucleic Acids Res 1993 Sep 11;21(18):4187-92. PMID: 8414972Free PMC Article

Clinical prediction guides

Kumaresan KR, Lambert MW
Carcinogenesis 2000 Apr;21(4):741-51. PMID: 10753211

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