Fanconi Anemia in a Young Adult Male Presenting with Pancytopenia and Bilateral Ectopic Kidneys

Abstract

Fanconi anemia (FA) is a rare inherited disorder of bone marrow failure that presents with progressive pancytopenia, multiple congenital abnormalities, and an increased predisposition to various malignancies. We describe a 19-year-old male who reported generalized weakness, shortness of breath on exertion, and a dry cough persisting for 1 month. He had undergone three blood transfusions within the preceding 3 months. Clinical examination revealed marked pallor without evidence of jaundice, cyanosis, clubbing, or lymphadenopathy. Laboratory investigations showed pancytopenia, while bone marrow biopsy demonstrated normocellular marrow with trilineage hematopoiesis and mild hemophagocytosis. Radiological assessment identified bilateral ectopic kidneys, and serum ferritin levels were significantly elevated (2753.93 ng/mL). These findings raised a strong clinical suspicion of FA, which was subsequently confirmed through comprehensive genetic testing. This case underscores the importance of considering FA in young adults with unexplained pancytopenia and congenital anomalies, highlighting the need for an integrated, multidisciplinary diagnostic and management approach.

INTRODUCTION

Fanconi anemia (FA) is a rare autosomal recessive disorder first described by Guido Fanconi in 1927. It is characterized by progressive bone marrow failure, congenital anomalies, and an elevated risk of malignancies, particularly acute myeloid leukemia and certain solid tumors.[1] The disorder results from mutations in at least 22–23 genes crucial for DNA repair, leading to chromosomal instability and impaired hematopoiesis.[2] These mutations interfere with the repair of DNA interstrand crosslinks, causing genomic instability and greater cellular susceptibility to environmental and endogenous DNA-damaging agents.[3] The FA pathway consists of multiple proteins, including FANCA, FANCC, and FANCG, that collaborate to ensure DNA repair and genomic stability; defects in these components disrupt hematopoietic stem cell function and increase malignancy risk.[4]

Clinical features of FA are highly variable. Hematologic manifestations often represent the first clinical signs, ranging from mild macrocytic anemia to pancytopenia, with bone marrow failure typically developing in childhood though adult-onset cases are increasingly recognized.[2] Congenital malformations may involve several organ systems. Skeletal defects such as radial ray abnormalities, hypoplastic thumbs, and short stature are frequent, while renal anomalies like hypoplastic or ectopic kidneys occur in some patients. Dermatologic features, including café-au-lait spots and endocrine disturbances, are also reported.[3]

The diagnosis of FA poses challenges due to its diverse clinical manifestations. Laboratory assessments typically reveal cytopenias on peripheral blood smears, while bone marrow biopsies may indicate hypoplastic or normocellular marrow with trilineage hematopoiesis. Chromosomal breakage tests, using agents such as diepoxybutane (DEB) or mitomycin C (MMC), remain the standard diagnostic method, with genetic testing playing a crucial role in identifying causative mutations and informing prognosis and management. Timely diagnosis is vital for monitoring, genetic counseling, and prompt consideration of hematopoietic stem cell transplantation (HSCT), the definitive treatment for severe bone marrow failure.[5] This report details a 19-year-old male who presented with pancytopenia and bilateral ectopic kidneys, leading to a diagnosis of FA. It underscores the necessity of comprehensive clinical evaluation, laboratory tests, and imaging studies in diagnosing rare congenital disorders that manifest in young adults.

CASE REPORT

A 19-year-old male presented to the outpatient department with complaints of generalized weakness and exertional breathlessness for the past 3 months. The onset was insidious, and the symptoms were nonprogressive. He also reported a persistent dry cough over the same period. There was no history of fever, weight loss, night sweats, abdominal pain, nausea, vomiting, hematuria, or gastrointestinal bleeding. The patient had received three blood transfusions over the preceding 3 months due to symptomatic anemia. He had no known chronic illnesses or prior hospitalizations. Family history was noncontributory.

On physical examination, the patient appeared pale, but was otherwise afebrile and hemodynamically stable, with a blood pressure of 120/70 mmHg, pulse rate of 82 beats per minute, and respiratory rate of 18 breaths per minute. No icterus, cyanosis, clubbing, or lymphadenopathy was noted. Cardiovascular and respiratory examinations were unremarkable. Abdominal examination revealed no hepatosplenomegaly or tenderness.

Laboratory investigations demonstrated pancytopenia, with hemoglobin of 4 g/dL, white blood cell count of 2000/µL, and platelet count of 20,000/µL. Peripheral blood smear revealed moderate anisocytosis, mild poikilocytosis, mild polychromasia, occasional teardrop cells, and occasional microspherocytes. Serum ferritin was markedly elevated at 2753.93 ng/mL, suggestive of an acute phase response or chronic inflammation.

Bone marrow aspiration and biopsy showed a normocellular marrow with trilineage hematopoiesis and mild evidence of hemophagocytosis. Megaloblastic changes were observed in the erythroid series, and the myeloid series demonstrated normal maturation. No evidence of granulomas, fibrosis, or malignant infiltration was found. The findings prompted consideration of hemophagocytic lymphohistiocytosis (HLH) as a differential diagnosis, and a correlation with clinical and laboratory parameters was advised [Figures 1 and 2].

Figure 1.

Bone marrow aspiration showing a normocellular marrow with trilineage hematopoiesis.

Figure 2.

Bone marrow biopsy showing mild evidence of hemophagocytosis. Megaloblastic changes were observed in the erythroid series, and the myeloid series demonstrating normal maturation

Ultrasonography of the abdomen and pelvis revealed bilateral ectopic kidneys. The right kidney was located in the right iliac fossa measuring 80 mm × 44 mm, and the left kidney was in the left iliac fossa measuring 85 mm × 45 mm, both with preserved corticomedullary differentiation and no evidence of hydronephrosis or calculi. Other abdominal organs, including the liver, gallbladder, spleen, and pancreas, were normal.

Based on the constellation of clinical features – pancytopenia, congenital renal anomalies, and laboratory findings – FA was suspected. Genetic testing and chromosomal breakage studies were planned for confirmation. Supportive management included packed red blood cell transfusions, folic acid, and Vitamin B12 supplementation, with close hematologic follow-up.

DISCUSSION

FA is an uncommon genetic disorder characterized by intricate multisystem involvement, primarily resulting from mutations in genes crucial for DNA repair. These mutations lead to chromosomal instability, impaired hematopoiesis, and an increased risk of malignancies.[6] Our patient, a 19-year-old male, presented with pancytopenia and bilateral ectopic kidneys, underscoring the diverse presentation of FA and its potential to manifest even during late adolescence.

Hematologic manifestations

Hematologic abnormalities represent the most frequent initial manifestation of FA. Patients generally develop cytopenias, which may appear as isolated anemia, thrombocytopenia, leukopenia, or pancytopenia. The onset typically occurs in childhood; however, cases of adult-onset presentations, as observed in our patient, are increasingly documented in the literature.[7] A review by Auerbach[8] indicated that FA patients exhibited a variable age of hematologic manifestation, with some presenting in late adolescence or adulthood, suggesting that FA should be considered in older patients with unexplained cytopenias. Our patient exhibited severe pancytopenia, with hemoglobin levels at 4 g/dL, leukopenia, and thrombocytopenia, which is consistent with the progressive marrow failure seen in FA. Peripheral smear findings revealed anisopoikilocytosis, occasional tear-drop cells, and mild polychromasia. These observations are akin to those reported in studies by Alter, where peripheral smear abnormalities in FA were often subtle at first and progressed over time. The elevated serum ferritin level in our patient (2753 ng/mL) may indicate chronic inflammation, repeated transfusions, or ineffective erythropoiesis, aligning with previous reports that ferritin can act as a marker of bone marrow stress in FA patients.[7]

Bone marrow analysis indicated a normocellular marrow with trilineage hematopoiesis and mild hemophagocytosis. Mild megaloblastic alterations in erythroid precursors were observed. This observation is consistent with earlier research, including that of MacMillan et al., which indicates that marrow cellularity in FA can vary from hypoplastic to normocellular based on the stage of the disease and the history of transfusions.[9] The detection of hemophagocytosis raised the possibility of HLH as a differential diagnosis, underscoring the importance of interpreting bone marrow findings within the clinical context.[10]

Congenital anomalies

Congenital malformations occur in approximately 60%–75% of patients with FA, with skeletal and renal anomalies being the most common. Our patient presented with bilateral ectopic kidneys, a relatively uncommon manifestation of FA. Prior studies, such as those conducted by Ceccaldi et al. have reported renal anomalies in 10%–20% of FA patients, which include hypoplastic, dysplastic, or ectopic kidneys.[11] The occurrence of bilateral ectopia, as observed in this case, is rare but has been documented in isolated case reports. Renal anomalies hold clinical significance as they may influence management decisions, particularly concerning nephrotoxic therapies or stem cell transplantation.

Skeletal anomalies, such as radial ray defects and short stature, are noted in 40%–60% of FA patients. Our patient did not display these characteristics, highlighting the variable expressivity of FA. This aligns with the literature that stresses the fact that the absence of classic skeletal malformations does not rule out a diagnosis of FA, and clinicians must depend on a combination of hematologic, radiologic, and genetic findings.[12] Dermatologic manifestations like café-au-lait spots and endocrine irregularities, although frequently reported, were not present in this patient, further demonstrating the phenotypic variability.

Renal anomalies

Renal anomalies are frequently observed in patients with FA, with a prevalence that varies between 10% and 50%. These anomalies may manifest as hypoplastic, dysplastic, or ectopic kidneys. A study conducted by Sathyanarayana et al.[13] examined 30 patients with FA and discovered that patients exhibited anatomical abnormalities in their kidneys, including two instances of severe phenotype accompanied by chronic kidney disease at the time of diagnosis. In our case, bilateral ectopic kidneys were identified, which is a relatively uncommon presentation of FA. This observation highlights the necessity of comprehensive imaging studies in the assessment of FA patients, as renal anomalies can influence management strategies, especially concerning nephrotoxic treatments or stem cell transplantation.

Diagnostic evaluation

The diagnosis of FA necessitates the integration of clinical characteristics with laboratory and genetic analyses. Chromosomal breakage tests utilizing DEB or MMC are considered the gold standard, demonstrating distinctive chromosomal instability in patients with FA. In this case, the presence of pancytopenia alongside ectopic kidneys raised significant clinical suspicion for FA. The findings from the bone marrow were supportive, and genetic testing is scheduled to confirm the diagnosis and inform management strategies.[14]

Timely diagnosis is crucial to avert complications, track disease progression, and facilitate prompt intervention. HSCT is the definitive treatment for bone marrow failure associated with FA and has been proven to enhance survival, especially when conducted prior to the onset of severe cytopenias or malignancies. Supportive care, which includes transfusions, Vitamin B12, and folate supplementation, is vital before the initiation of definitive therapy.

Comparison with previous literature

This case highlights several aspects consistent with prior studies while adding novel insights. Hematologic findings and bone marrow morphology align with existing literature, where normocellular marrow with trilineage hematopoiesis is documented in early or transfused FA patients.[15] The occurrence of bilateral ectopic kidneys, while rare, is consistent with the spectrum of renal anomalies reported in FA. Notably, the absence of classical skeletal anomalies underscores the need for high clinical suspicion even when hallmark congenital malformations are absent, a concept emphasized in studies by Alter and Ceccaldi et al.[1,11]

This case reinforces that FA can present beyond childhood and may involve atypical organ anomalies. Comprehensive evaluation, including peripheral smear, bone marrow examination, and imaging studies, is crucial for early identification. The integration of these findings with genetic confirmation allows for accurate diagnosis, prognostication, and management planning, aligning with recommendations from contemporary FA guidelines.

CONCLUSIONS

FA is a rare genetic disorder characterized by a broad spectrum of clinical manifestations, which can complicate early diagnosis. This case exemplifies the necessity of considering FA in adolescents and young adults who present with unexplained pancytopenia, even in the absence of classic skeletal anomalies. The identification of bilateral ectopic kidneys in our patient emphasizes the variety of congenital defects linked to FA and highlights the critical role of comprehensive imaging studies. Prompt recognition is vital for the initiation of supportive care, the provision of genetic counseling, and the assessment of patients for HSCT, which continues to be the primary treatment for bone marrow failure. Healthcare professionals should uphold a heightened level of suspicion for FA in individuals exhibiting unusual congenital characteristics and cytopenias, as an early diagnosis can greatly enhance clinical outcomes and inform effective management approaches.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.