Swamy vivekananda college of pharmacy.
Fanconi anemia (FA) is a rare inherited disorder characterized by bone marrow failure and chromosomal instability, primarily caused by biallelic mutations in FANC genes, particularly FANCA. This condition affects approximately 1 in 100,000 to 160,000 live births and leads to severe health risks, including increased susceptibility to cancers such as acute myeloid leukemia and solid tumors. Patients often present with physical abnormalities and hematological issues, typically diagnosed between ages 5 to 15. Treatment options include hematopoietic stem cell transplantation (HSCT) and supportive therapies, with ongoing monitoring essential for managing complications and improving outcomes. Lifelong multidisciplinary care is crucial for affected individuals to address the disorder's diverse manifestations and associated health risks.
In 1927, Dr. Guido Fanconi first identified Fanconi anemia (FA)after examining a family of three siblings who exhibited various physical defects and pernicious anemia.[1] Fanconi anemia is the inherited condition leading to bone marrow failure (BMF).[2] It is a rare genetic disorder characterized by chromosomal instability, impacting the proteins responsible for DNA repair and cell cycle regulation.FA is passed down through an autosomal recessive inheritance pattern, which causes gradual bone marrow failure, birth defects, and a heightened risk of developing solid and blood cancers at an earlier age than what is usually observed in the general population.[3] The FA genes, which are known to be mutated in patients with Fanconi anemia, are referred to as FANC genes. The most common among these are FANCA, FANCC, FANCG, and FANCD2.[4] With the exception of the extremely rare FANCB gene on the X chromosome, all other FANC genes are autosomal and the disease follows a recessive pattern. Fanconi anemia typically progresses through different clinical stages that are associated with the patient's age.[2,5,6,7] Fanconi Anemia (FA) shows physical signs at birth and early childhood, with diagnosis often with the ages between 5 to 15 due to bone marrow failure. Risks for AML and MDS/AML increase in adolescence, and solid cancers, especially oral cancer, in adulthood. Hematopoietic stem cell transplantation (HSCT) is the best treatment for severe cases.[8] HSCT decisions depend on clinical and biological factors such as age, cytopenia severity, bone marrow dysplasia, blast cell levels, cytogenetic abnormalities, and donor compatibility.[9]
Epidemiology:
An uncommon genetic bone marrow failure disease called Fanconi anemia (FA) affects roughly 1 in 100,000–160,000 live births.[10]
Etiology:
The primary cause of Fanconi anemia (FA) is the presence of biallelic pathogenic germline mutations in any of the 22 genes responsible for DNA repair.[11] All 22 known Fanconi anemia (FA) genes, ranging from FANCA to FANCW, can cause the condition through autosomal recessive mutations, with the exception of FANCB, which is located on the X chromosome.[12]
Pathophysiology:
The primary cause of Fanconi anemia (FA) pathophysiology is the inability of the FA/BRCA DNA repair pathway to efficiently eliminate DNA interstrand crosslinks. Pathogenic variations found in 23 genes—which are divided into complementation groups FANC-A through FANC-W—are the cause of this failure. Although the precise mutations can differ throughout alleles, the existence of biallelic pathogenic variations in a particular gene defines each complementation group. FANCA is the most often mutated gene in FA, accounting for 60–70% of cases. FANCC or FANCG mutations account for about 20% of instances in patients, whereas 0.1% to 4% of cases are caused by mutations in other FA genes. Notably, BRCA1 (FANCS) and BRCA2 (FANCD1) are two of these causal genes that are also linked to other cancer susceptibility factors.
Because of the accumulation of unrepaired DNA damage brought on by the disruption in the FA/BRCA pathway, there is a greater risk of bone marrow failure, an increased vulnerability to malignancies (particularly acute myeloid leukemia), and a variety of physical abnormalities. The clinical symptoms of FA, such as hematological diseases and developmental abnormalities, are ultimately caused by the decreased ability to repair DNA interstrand crosslinks.[10]
Types:
FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCI, FANCM, FANCN/PALB2, FANCO/RAD51C, FANCP/SLX4, FANCR/RAD51, FANCS/BRCA1, FANCV/REV7, and FANCW/RFWD3 are among the genes linked to Fanconi anaemia that have been found. These genes encode proteins that play different functions in the Fanconi anaemia DNA repair pathway.[13] The natural DNA repair pathway is activated by the processes of monoubiquitination and phosphorylation following DNA damage caused by different agents. Together with other proteins that are involved in DNA repair and resistance against DNA crosslinking and damaging agents like ionising radiation, hydroxyurea, and UV light irradiation, monoubiquitinated FANCD2 accumulates in nuclear foci. These proteins include BRCA1, FANCD1/BRCA2, RAD51, and FANCN/PALB2. After DNA damage, FANCI is phosphorylated and monoubiquitylated, although it does not play a significant role. Any genetic abnormality affecting this pathway's components reduces their tolerance to harmful substances, which eventually causes chromosome fragility. FANCC and FANCE, the Fanconi anaemia core complex proteins, localise to nuclear foci together with FANCD2, FANCG with BRCA2, and RAD51.The two main components of the Fanconi anaemia Nuclear foci synthesis and FANCD2 protein monoubiquitination are two phases in the DNA repair process. With the FANCM protein to assist, the Fanconi anaemia core protein complex stimulates translocase and ATPase, resulting in the hydrolysis of ATP and energising translocase to transfer the Fanconi anaemia core complex along the DNA strand. At the damaged location, ssDNA and the branching structures are bound by a different FAAP24 protein. The helicase and endonuclease domains found in FANCM also help to repair damaged DNA by cleaving the phosphodiester link at the location of damage and separating the double-stranded DNA. Another helicase that interacts and binds to BRCA1 is called FANCJ.[14]
Management:
Treatment for symptoms: Oral androgens (oxymetholone, for example) increase red blood cell and platelet counts in about 50% of FA patients; granulocyte colony-stimulating factor increases neutrophil counts in some patients; hematopoietic stem cell transplantation (HSCT) is the only treatment that can cure the disease's hematologic manifestations, but it also carries a high risk of solid tumors, which may even increase in HSCT recipients.
Ech of these treatmfents carries a risk of serious harm. The cornerstone of therapy for solid tumors continues to be early identification and surgical excision. As directed by the specialist care provider, treat growth deficiency, limb anomalies, ocular anomalies, renal malformations, genital anomalies, hypothyroidism, cardiac anomalies, and dermatologic symptoms.[15] According to an otolaryngologist, hearing aids may be beneficial for hearing loss; additional food as supplier. As advised by an otolaryngologist, hearing aids, vitamin D supplementation, early intervention for developmental delays, individualized education plans for school-age children, speech, occupational, and physical therapy as needed, liberal use of sunscreen and rash guards, social work, and care coordination are all potential treatments for hearing loss. Preventing primary manifestations: Vaccinating against the human papilloma virus (HPV) may lower the incidence of mouth cancer in general and gynecologic cancer in women. Preventing secondary complications involves T-cell depletion of the donor graft to lower the likelihood of graft-versus-host disease and radiation-free conditioning before hematopoietic stem cell transplantation to lower the chance of
solid tumor development afterward.Clinical evaluation of growth, eating, nutrition, spine, and ophthalmic problems at every visit during childhood is known as surveillance.[16] Assessment of pubertal stage and hormone levels at puberty and every two years until puberty is finished; annual evaluation with an endocrinologist, including TSH, free T4, 25-hydroxy vitamin D, two-hour glucose tolerance testing, and insulin levels; blood counts every three to four months or as needed; annual developmental review; follow-up hearing evaluation if exposure to ototoxic medications; After the age of two years, at least once a year, bone marrow aspirate and biopsy to assess morphology and cellularity, FISH and cytogenetics to assess for the emergence of a malignant clone; liver function tests every three to six months, and liver ultrasound examination every six to twelve months in individuals receiving androgen annual gynecologic examination for genital lesions starting at age 13; annual vulvo-vaginal exams and Pap smears starting at age 18; oral tumor examinations every six months starting at age nine to ten; annual nasolaryngoscopy starting at age ten; annual evaluation by dermatologists every six to twelve months; annual brain MRI and abdominal ultrasound in individuals with BRCA2-related FA. For those with FA linked to BRCA1, BRCA2, PALB2, BRIP1-, and RAD51C, there will be further cancer surveillance.[17]
DISCUSSION:
Fanconi anemia (FA) is a rare inherited disorder initially identified by Dr. Guido Fanconi in 1927, characterized by bone marrow failure and chromosomal instability. It is caused by biallelic pathogenic mutations in any of the 22 FANC genes, with FANCA being the most commonly impacted . FA manifests through various physical defects, particularly in childhood, and poses severe health risks, including heightened susceptibility to cancers such as acute myeloid leukemia (AML) and solid tumors. The occurrence of Fanconi Anemia (FA) is estimated to be about 1 in every 100,000 to 160,000 live births, with a greater frequency observed in certain ethnic populations. This disorder disrupts the FA/BRCA DNA repair pathway, leading to DNA damage accumulation and cellular dysfunction. Treatment options include hematopoietic stem cell transplantation (HSCT) and supportive therapies like androgens and granulocyte colony-stimulating factors. Regular monitoring for complications and early intervention for related health issues are vital. While HSCT can potentially cure hematologic manifestations, it carries inherent risks, necessitating ongoing surveillance for cancer and other complications to enhance patient outcomes.
CONCLUSION:
Fanconi anemia (FA) is a rare, inherited disorder caused by mutations in FANC genes, particularly FANCA. It leads to bone marrow failure, physical abnormalities, and increased cancer risk, including acute myeloid leukemia. Patients exhibit chromosomal instability and impaired DNA repair, resulting in symptoms such as aplastic anemia and congenital defects. Treatment focuses on managing symptoms, with hematopoietic stem cell transplantation and androgens as primary therapies. Lifelong, multidisciplinary care is essential for monitoring health and cancer risks.
REFERENCES
R. Subashini, S. B. Tanuvarthini, S. Aishwarya, V. Hema, R. Priyadharshini, S. Sreelakshmi, Advances In Gene Therapy for Fanconi Anemia Using Hematopoietic Stem Cells: Current Approaches and Future Directions, Int. J. of Pharm. Sci., 2024, Vol 2, Issue 12, 2929-2934. https://doi.org/10.5281/zenodo.14545790