A Rare Case of Pancytopenia

Abstract

Pancytopenia is a reduction in all the three peripheral blood cell lineages and presents as anemia, leukopenia, and thrombocytopenia. Aplastic anemia is pancytopenia with bone marrow hypocellularity. Aplastic anemia can be constitutional or acquired. Genetic diseases such as Fanconi anemia and dyskeratosis congenita usually present as pancytopenia with typical physical anomalies and are usually seen in early childhood. Fanconi anemia is a rare cause of pancytopenia, which is an autosomal recessive disorder and manifests as progressive pancytopenia with congenital developmental anomalies and an increased risk of malignancy. Here, we present a case of Fanconi anemia who presented with pancytopenia, short stature, and hypoplastic thumb of the right hand and was diagnosed on the basis of bone marrow biopsy and chromosomal breakage test.

INTRODUCTION

Pancytopenia can be either due to hypocellular marrow or with cellular marrow. Causes of pancytopenia with hypocellular marrow are aplastic anemia, hypocellular myelodysplastic syndrome (MDS), rare aleukemic leukemia, and acute lymphoid leukemia. Pancytopenia with cellular marrow is seen in conditions such as MDSs, aleukemic leukemia, myelophthisis, bone marrow lymphoma, and hairy cell leukemia. Conditions such as systemic lupus erythematosus, hypersplenism, Vitamin B12 deficiency, brucellosis, sarcoidosis, and tuberculosis also presents with pancytopenia with cellular marrow. The hypoproliferative anemias are normochromic, normocytic, or macrocytic and are characterized by a low retic count. Hypoproliferative anemia is also a prominent feature of hematologic diseases that are described as bone marrow failure states which include aplastic anemia, MDS, pure red cell aplasia, and myelophthisis.^[1]

Fanconi anemia is an autosomal recessive disorder. Overall, the incidence is 1 out of 136,000.^[2] It usually presents in childhood, and the average age of diagnosis is 7 years. Patients with Fanconi anemia typically have short stature, café au lait spots, and anomalies involving the thumb, radius, and genitourinary tract. At least 17 different genetic defects have been defined. The most common is Type A Fanconi anemia which is due to mutation of FANCA. Most of the Fanconi anemia gene products undergo monoubiquitination and form a protein complex, and activate FANCD2 which plays an important role in the cellular response to DNA damage and especially interstrand cross-linking which is the basis for the diagnostic test.^[1]

CASE REPORT

A 20-year-old female came with complaints of breathlessness, easy fatiguability, and generalized weakness for 3 months. She had no prior blood transfusions or admissions to the hospital. She had no major illness in the past. There is no significant family and drug history. On examination, the patient was conscious, well oriented to time, place, and person. General examination revealed short stature with the right-hand hypoplastic thumb [Figure 1]. The patient’s height was 148 cm, and the upper segment length-to-lower segment length ratio was 1.2. She had pallor and mild pitting pedal edema. There was no evidence of cyanosis, clubbing, or lymphadenopathy. Systemic examination was unremarkable.

Figure 1: Right-hand hypoplastic thumb

Routine laboratory investigations showed pancytopenia with hemoglobin of 3.4 g% with total leukocyte count (3800 cells/cmm) and platelet count (48,000 cells/cmm). The mean corpuscular volume was elevated (111 fL), and there was a decrease in the packed cell volume (9.6%). Absolute retic count was low (0.6%) indicating decreased erythropoiesis. Vitamin B12 levels (283 pg/mL) and lactate dehydrogenase levels (198 U/L) were normal.

Bone marrow aspiration was a dry tap, and bone marrow biopsy showed marrow spaces mostly occupied by mature adipocytes and markedly reduced hematopoietic cells which were suggestive of aplastic anemia.

X-ray of the right hand showed right short and thin first metacarpal, proximal and distal phalanx, and significant gap was noted at first carpometacarpal joint [Figure 2].

Figure 2: X-ray of the right hand showing shortened right first finger with short and thin metacarpal, proximal, and distal phalanx, and significant gap was noted at first carpometacarpal joint

Ultrasound of abdomen and pelvis was normal. As the patient had pancytopenia with short stature and skeletal abnormalities, chromosomal breakage test was done to confirm the diagnosis of Fanconi anemia.

The chromosomal breakage test showed increase in chromosomal breaks and chromatid exchange radial formations caused by mitomycin C suggestive of Fanconi anemia [Figure 3]. Hence, the final diagnosis was Fanconi anemia was made. The chromosome breakage test is the definitive test for the diagnosis of Fanconi anemia. Further molecular genetic workup was not done due to the financial constraints, and also the plan of treatment is same in all the genetic variants.

Figure 3: Chromosomal breakage test showing chromosomal breaks and chromatid exchange radial formations

Hence, our patient was started on tablet danazol 200 mg BD and was counseled regarding bone marrow transplantation. The patient is on regular follow-up every 3 months for monitoring liver function tests and alpha-fetoprotein.

DISCUSSION

Clinically, Fanconi anemia patients present with bleeding, pallor, and/or recurring infections. One study of 388 Fanconi anemia patients showed that the risk of developing hemopoietic abnormalities and death from hematological causes by the age of 40 years to be 98% and 81%, respectively.^[3] There is altered growth both in utero and postnatally in Fanconi anemia patients as a result of which there is a low birth weight, and also the median height of Fanconi anemia patients lies around the 5^th centile.^[4] This can sometimes be related to growth hormone deficiency or hypothyroidism. Male Fanconi anemia patients have a higher incidence of genital abnormalities such as undescended testes, hypogenitalia, hypospadias, and infertility is also common. There have been reports of males with Fanconi anemia fathering children.^[5] Females with Fanconi anemia may have underdeveloped genitalia and uterine anomalies. Older females may have oligomenorrhea but can become pregnant if not on androgen therapy.^[6] The main causes of morbidity and mortality in Fanconi anemia are aplastic anemia, myelodysplasia, acute myeloid leukemia, and solid tumors at older ages in those who have survived the hematological malignancies in childhood.^[4] There is a higher risk of development of malignancies in Fanconi anemia patients. Leukemia occurs in approximately 10% of cases, and there is an increasing risk of incidence with age. The risk for MDSs is less commonly recognized (approximately 5%).^[7]

In Fanconi anemia cells, there is chromosomal hypersensitivity to cross-linking agents^[8] such as mitomycin C and diepoxybutane. This is the basis for the diagnostic assay.^[9]

Patients with bone marrow failure show response to supportive measures such as blood transfusions, androgens, and cytokines initially.^[4] Androgens such as oral oxymetholone enhance the production and urinary excretion of erythropoietin and increase bone marrow cellularity are often used therapeutically. The doses should be tapered over a period of 3 months if the patient is responding to reduce side effects such as masculinization, acne, hyperactivity, growth spurt followed by premature closure of the epiphyses which results in short stature, deranged liver enzymes, hepatic adenomas, and also potential risk of hepatic adenocarcinomas. While the patient is on androgen therapy, monitoring of liver function tests and alpha-fetoprotein every 2 to 3 months and yearly liver ultrasound scans is mandatory. The definitive treatment of choice is hemopoietic stem cell transplantation as most patients become refractory to androgen therapy eventually.^[4] A follow-up surveillance for solid malignancies becomes increasingly important for those patients who have survived the hematological complications in childhood.^[7]Table 1 shows some of the case reports on Fanconi anemia globally including in India.

Table 1: Literature review of fanconi anemia

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Conflicts of interest

There are no conflicts of interest.