Fanconi anemia leads to pancytopenia. Thus, a history with a decrease of all three blood cell lines, including red blood cells (RBCs), platelets, and leukocytes, is evident in the blood work. Shortness of breath, chest pain, dizziness, and fatigability are common manifestations of anemia. History of epistaxis, petechiae, unstoppable bleeding from the wound site is common due to thrombocytopenia. The risk of recurrent infections increases with the severity of leukopenia, which presents with fever and flu-like illness. History of low birth weight is present in some cases, and a history of weight loss is important to elicit from patients for cases complicated by cancer. Family history and marriage history are important, particularly where the prevalence of the consanguinity marriage system is high.

Approximately 75% of Fanconi anemia is associated with birth defects. On physical examination, the stature of the child may be short, and there are light-brown skin pigmentation ("cafe-au-lait" lesions) in more than 50% of cases.[17] Structural abnormalities of extremities are more common. Absent, bifid, supernumerary, low set, short or hypoplastic thumb, absent or hypoplastic radii, and dysplastic ulna are the usual upper limb abnormalities. Lower limb abnormalities include polydactyly, short toes, club foot, flat feet, hip dislocation, abnormal femur, and thigh osteoma. Other skeletal abnormalities consist of head and face anomalies, microcephaly and hydrocephaly, frontal bossing, flathead, micrognathia, sloped forehead, webbed and short neck, low hairline, spina bifida, scoliosis, abnormal ribs, and extra vertebrae. Hypogonadism is common in both sexes and includes less genitalia development, undescended and absent testis, phimosis, hypospadias, micropenis, and vaginal atresia.

Other additional anomalies include abnormal epicanthal fold, proptosis, ptosis, cataracts, blindness, epiphora, ear anomalies such as absent eardrum, small or large pinnae, and atresia of the ear canal. Physical signs of pancytopenia are sometimes visible, including pallor, petechiae and bruising in body, and coldness of the hands and feet. Gastrointestinal abnormalities such as imperforate anus, tracheoesophageal fistula, atresia of the intestine, Meckel diverticulum megacolon, and umbilical hernia are less common.

Diagnosis may be delayed until the bone marrow failure develops. Different studies have summed up the average age of diagnosis as 7 yrs, although the earlier diagnosis has been increased due to disease awareness and prenatal screening diagnostic enhancement. Early diagnosis may prevent severe complications.

Patients presenting with signs and symptoms of pancytopenia should be evaluated. Complete blood count reveals the level of RBCs, WBCs, and platelets. Raised mean corpuscular volume (MCV) indicates macrocytosis, and there can be high fetal hemoglobin levels due to increased stress. Serum erythropoietin is increased due to the low level of blood cells and the low response of hematopoietic stem cells. Bone marrow aspiration and biopsy reveals hypocellularity, aplasia with fatty marrow, absence of myeloid, erythroid, and megakaryocytes stem cell lines. Myelodysplastic cases show hypo- or hypergranularity, hyposegmentation of myeloid precursors, and hypolobulated or hyperlobulated megakaryocytes. Clonic malformations are seen in leukemic transformations.

Chromosomal breakage test is diagnostic testing and is indicated in those with severe pancytopenia, i.e., absolute neutrophil count (ANC) less than 100/mL, hemoglobin less than 10g/dL with reticulocyte less than 40000/mL, bone marrow cellularity less than 25%, and platelet count less than 50000/mL. Testing with DNA cross-linkers such as diepoxybutane or mitomycin C stimulates the breakage of DNA in the absence of a DNA repair system. These agents increase the chromatids' breaks, gaps, reduplications, or rearrangements. Cultured fibroblasts also show chromosome fragility. Skin fibroblast is preferred in such patients that show negative T-lymphocytes chromosome fragility test and in those who have already undergone Hematopoietic cell transplantation.[18]

Cell cycle analysis flow cytometry is an alternative to the chromosomal breakage test. In this test, those cells with impaired DNA repair undergo G2 arrest following DNA cross-linking agent exposure. Immunoblotting of GANCD2 mutation is less commonly used. FA gene sequencing is recommended in patients with positive chromosomal breakage testing. The identification of genetic defects is confirmatory and excludes other chromosome breakage syndromes. Prenatally, abnormal chromosome breakage can be analyzed with amniotic fluid cells or chorionic villous biopsy. An elevated level of serum alpha-protein is a rapid screening diagnostic test, but it may not be identified in many cases.[19]

Additional surveys are done to evaluate the other structural and birth defect abnormalities. A skeletal survey is done to identify bone defects. X-rays can detect the site and type of the exact defect. The X-ray of the head shows a crewcut appearance. Ultrasound of the abdomen is done to monitor the liver and kidney size and shape. Magnetic resonance imaging (MRI) is crucial to identify CNS abnormalities, such as the absence of corpus callosum, cerebellar hypoplasia, and small pituitary.

Supportive treatment: Blood transfusions are the best supportive therapy for Fanconi anemia. Packed RBCs and platelet transfusions have an immediate effect. RBCs transfusion from family members should be avoided due to alloimmunization and graft-versus-host disease. Leukopenia has a good response to granulocyte-colony-stimulating factor, but this is reserved for those patients with ANC<200/mL. Extensive transfusion has poor outcomes in patients with hematopoietic cell transplantation.

Hematopoeitic stem cell transplantation (HCT): Cure of aplastic anemia and prevention of myelodysplastic syndrome can be achieved through bone marrow, peripheral blood cells, and cord blood transplantation. Bone marrow is the preferred method over the others from an HLA matched sibling. It is essential to do chromosome breakage testing of siblings or other related donors to exclude FA in donors. This method is not accessible for everyone and is reserved only for patients with severe myelodysplastic syndrome and leukemia, and failure of medical treatment. 50-75% of people respond, and it is a more permanent treatment.[20]

Androgen therapy: It is performed in those who are suitable for HCT. Oxymetholone is the most commonly used androgen. Other androgens less commonly used are danazol and oxandrolone. Androgens stimulate the hematopoietic stem cell proliferation, but it is not curative. Oxymetholone is used with a starting dose of 2-5mg/kg/day, but it is tapered to avoid toxicity. Patients with severe bone marrow hypocellularity have a poor response to androgen therapy. RBCs respond well, but platelets and leukocytes are less likely to respond.

Surgical treatment: Surgery is performed only for the management of structural deformities. Splitting of anomalies of the hand should be repaired early in life to avoid functional delays. Other surgeries include congenital heart defect surgery, repair of trachea-esophagus fistulas, and imperforate anus. Surgery may be required for cancers as well.

Gene therapy: The replacement of an abnormal gene by a normal gene is the modern developing technique. The correction of CD34+ in affected cells is now feasible.[21]

Fanconi anemia resembles a large variety of diseases. Other hematological problems that manifest clinical features of FA and congenital structural defects that are associated with FA should be excluded.[22]

Acquired aplastic anemia: It is due to acquired hematopoietic stem cells destruction of bone marrow following various toxicogenic agents. Pancytopenia is the cardinal feature of Fanconi anemia due to bone marrow failure. Hypocellularity of bone marrow is sufficient for the diagnosis of acquired aplastic anemia, which does not show chromosome fragility by chromosome breakage test. Fanconi anemia shows chromosome fragility test positive, and gene sequencing is required to confirm the diagnosis.[23][24]

Other inherited bone marrow failure syndrome: Because bone marrow failure is distinct in Fanconi anemia, differentiation of other causes bone marrow failure is essential. Diseases with short telomerase such as dyskeratosis congenital is associated with bone marrow aplasia. Bone marrow aplasia caused by reticular dysgenesis is a combined immunodeficiency disease due to AK2 gene mutation. However, sensorineural hearing loss and adaptive immune deficiency in infancy is a prominent feature of reticular dysgenesis. Diamond-Blackfan anemia is pure red cell aplasia that typically presents with bone marrow abnormalities.[25] Schwachman-diamond syndrome is bone marrow aplasia primarily associated with neutropenia in 88-100% of cases.[26] Congenital amegakaryocytic thrombocytopenia principally affects platelets.[27] All these diseases may show trilineage aplasia in bone marrow after an extended period of time.

Denovo myelodysplastic syndrome (MDS): It is a clonal myelodysplastic disease characterized by ineffective hematopoiesis and peripheral cytopenias. MDS is also associated with Fanconi anemia, but de novo MDS is not susceptible to chromosome breakage test, does not have FA mutation, or congenital anomalies. Suspected MDS patients with associated FA should be tested with skin fibroblasts chromosome breakage tests rather than peripheral lymphocytes.

Drug-induced or infection associated pancytopenia: Exposure of many cytotoxic drugs, mainly cancer chemotherapy, viral and bacterial infections, and chemicals cause transient bone marrow hypoplasia and pancytopenia in children, but unlike FA, this pancytopenia lacks congenital anomalies and also pancytopenia is reversible with removal of the agents. The chromosomal breakage test is negative.

Paroxysmal nocturnal hemoglobinuria (PNH): Mutations of PIGA gene encoding anchoring protein glycosylphosphatidylinositol (GPI), mainly in hematopoietic progenitor cells which leads to nocturnal hemolysis due to activation of the complement system in the acidic environment during shallow breathing at night. Patients are anemic, have an increased risk of thrombosis, hemoglobin in the urine, and jaundice. Bone marrow failure is mainly due to acquired autoimmunity rather than inherited. The abnormal chromosomal breakage test is absent.

Other rare chromosomal breakage syndromes (CBS): A number of chromosomal instability diseases in the presence of irradiation, DNA cross-linkers, and chemicals are evident but rare, which mimic the FA and necessitates their exclusion for an accurate diagnosis and treatment plan. These disorders include Bloom syndrome,[28] LIG4 syndrome, Ataxia-telangiectasia,[29] Nijmegen breakage syndrome,[30] Seckel syndrome,[31][32] NHEJ1 deficiency, Warsaw breakage syndrome, and cohesinopathies such as Robert syndrome.[33] These diseases, like FA, show an abnormal chromosomal breakage test as well as congenital anomalies such as short stature, microcephaly, malignancy. So it's quite difficult to differentiate. However, bone marrow failure is not typical to CBS, and also there are spectral differences in congenital anomalies and malignancy between FA and CBS. Therefore, genomic sequencing of mutation helps to differentiate FA from CBS.

Several clinical trials are ongoing to investigate therapy and prevention of Fanconi anemia. Clinicians should be aware of these trials and refer their patients for ones for which they may qualify. 

The prognosis of Fanconi anemia is poor. Severe aplastic anemia is the main cause of mortality that leads to death before 10 yrs of age in the absence of a diagnosis. Survival has been improved in developed countries due to a reduction in mortality by bleeding, or infection complications but, living well into adulthood has increased the chances of cancer development. Most of the individuals finally develop acute myelogenous leukemia. Regular monitoring of patients is needed for cancer in those who have undergone a bone marrow transplant. Most of the patients have other associated birth defects, such as developmental delay, kidney problems, and microcephaly.

The major complications of FA are aplastic anemia, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and specific solid tumors.[34]

The propensity of cancer: FA is associated with various cancers as the defective FA gene is associated with a wide variety of cancers.[35] Defects of genes of the FA pathway responsible for DNA repair and cell cycle checkpoints are involved in the hypersensitivity of cancer cells to chemotherapeutic drugs, viruses, and radiation. Impairment of the DNA repair system and lack of stability in cell cycle-checkpoints leads to the uncontrolled proliferation of cells. Common variants of cancer include squamous cell carcinomas of the head, neck, and upper esophagus and carcinomas of vulva, anus, and cervix, which has a 50-fold higher risk as compared to the absence FA association. Myelodysplastic syndrome is the most common malignancy, which has a 6000-fold higher chance as compared to the general population. Acute myelogenous leukemia is the second most common cancer, which has a 700-fold higher chance as compared to the general population. Clonal mosaicism in Fanconi anemia has been demonstrated in aging and cancers.[36]

Bone marrow failure: Fanconi anemia registries reveal around 90% of patients suffer from bone marrow failure by the age of 40 years.[37] Bone marrow failure ultimately leads to pancytopenia.[38]

Endocrine disorders: A wide range of endocrine disorders are either intrinsic to molecular defects or HCT-associated and androgen therapies. Structural disruption of the hypothalamus-pituitary axis may lead to short stature due to growth hormone deficiency, hypothyroidism is found in around 60% of patients,[39] adrenal dysfunction that responds to exogenous ACTH, and dysfunction of pancreatic islets associated with glucose intolerance, dyslipidemia, and infertility due to hypogonadism. Androgen therapy causes benign and malignant liver tumors and peliosis hepatis.[40]

Information and understanding of Fanconi anemia are essential for family members because of the genetic inheritance pattern of the disease, and the patient is usually a child at the time of clinical presentation and diagnosis. Genetic counseling for the disease helps the family members have enough patient education to increase the compliance and the patient-doctor relationship. Fanconi anemia in a child necessitates the testing of the disease in other family members, most importantly, siblings, to either catch the disease in the early-stage or to prevent future childbirth with genetic defects.

It is also important to perform the abnormal chromosomal breakage test and HLA matching of siblings in order to evaluate for possible hematopoietic stem cell transplantation between the siblings. Level of knowledge regarding the disease process, signs and symptoms, and the treatment plan should be a part of the education of parents. Parents should be informed about any interventions to be made, benefits of one over other options, and health hazards. After complete clarification, they should be provided the opportunity to choose the best treatment plan.

Fanconi anemia, like other diseases, requires an interprofessional team approach. Healthcare outcomes are enhanced by the teamwork of many healthcare providers. Disease extent determines the need for a number of health professionals from different specialties. Fanconi anemia, although mainly a hematological problem, is associated with multiple diseases, including birth defects, and solid as well as hematological cancers. It requires the care of primary clinicians, oncologists, hematologists, gynecologists, pathologists, radiologists, nurses, genetic analysts, pharmacists, physiotherapists, and the support and care of family and friends.