Bilineal Acute Leukemia Associated With Fanconi Syndrome: The First Case Report

AUTHORS

Ghasem Miri-Aliabad 1 , * , Maryam Sadat-Hosseini 2 , Akbar Dorgalaleh 3

1 Department of Pediatrics, Children and Adolescent Health Research Center, Zahedan University of Medical Sciences, Zahedan, IR Iran

2 Department of Hematology and Blood Transfusion, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran

3 Department of Hematology and Blood Transfusion, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, IR Iran

How to Cite: Miri-Aliabad G, Sadat-Hosseini M, Dorgalaleh A. Bilineal Acute Leukemia Associated With Fanconi Syndrome: The First Case Report, Iran J Pediatr. 2016 ; 26(3):e3723. doi: 10.5812/ijp.3723.

ARTICLE INFORMATION

Iranian Journal of Pediatrics: 26 (3); e3723
Published Online: May 28, 2016
Article Type: Case Report
Received: July 31, 2015
Revised: February 11, 2016
Accepted: February 24, 2016
Crossmark

Crossmark

CHEKING

READ FULL TEXT
Abstract

Fanconi syndrome is a metabolic disorder involving dysfunction of the renal proximal tubules, resulting in excessive urinary excretion of several metabolites. Various factors may lead to Fanconi syndrome, as it may be a genetic disease with primary or secondary etiologies, or may be acquired. In this study, we report a unique case of Fanconi syndrome with development of a relatively rare acute leukemia, a condition that has not been reported before. The case was an 8-year-old boy with familial occurrence of Fanconi syndrome, presenting with pallor, asthenia, recurrent infections, growth failure, and a variety of biochemical and hematological abnormalities. After physical examination, radiographic studies, and comprehensive laboratory analyses, Fanconi syndrome associated with bilineal acute leukemia, of myeloid and T-lymphoid lineages, was diagnosed.

Keywords

Fanconi Syndrome Renal Dysfunction Bilineal Leukemia

Copyright © 2016, Growth & Development Research Center. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.

1. Background

Fanconi syndrome (FS) is a rare metabolic disease identified by dysfunction of the renal proximal tubules. The low reabsorption capacity of the proximal tubules results in the abnormal urinary excretion of several metabolites, including phosphate, glucose, amino acids, uric acid, and various ions. Other biochemical findings include hypokalemia, hypouricemia, and metabolic acidosis (1, 2). This syndrome is highly associated with osteomalacia, osteoporosis, muscle weakness, and severe bone pain. The production of monoclonal light chains, especially kappa chains, which have toxic effects on the renal tubules, is also reported in these patients (3).

FS may be a genetic disease with primary or secondary causes, or may be acquired. A missense mutation in sodium phosphate cotransporter (NaPi-II) of the proximal tubular apical membrane accounts for primary FS. This syndrome may also develop secondary to systemic disease. The genetic and acquired causes of FS are indicated in Table 1. The causes of FS may also lead to renal tubular acidosis. Light-chain-associated FS is the most frequent among the acquired factors (4).

Table 1. Genetic and Acquired Causes of Fanconi Syndrome (4)
PrimaryMissense Mutation of NaPi-II Cotransporter
Secondary to inherited systemic diseases
Cystinosis
Tyrosinemia
Hereditary fructose intolerance
Galactosemia
Glycogen storage disease (type I)
Mitochondrial disorders
Wilson’s disease
Lowe’s syndrome
Den’s disease
Fanconi-Bickel syndrome
Acquired
Drugs (tenofovir, ifosfamide, cisplatin, valproic acid, aminoglycosides, cidofovir)
Heavy metals
Multiple myeloma
Amyloidosis
Vitamin D deficiency
Renal transplantation
Paroxysmal nocturnal hemoglobinuria

Dysglobulinemia is a feature of FS, and some studies in the literature report FS in association with myeloma, amyloidosis, and Bence-Jones proteinuria (5). In this study, we report a unique case of FS that was complicated by bilineal acute leukemia with myeloid and T-lymphoid lineages.

2. Case Presentation

An 8-year-old boy was admitted to our center complaining of pallor, anemia, asthenia, and recurrent infections in January 2014. The patient was the first child of a family with three children. Physical examination revealed severe growth failure, with a weight of 12 kg weight, height of 97 cm, and head circumference of 46 cm. Hepatosplenomegaly was observed with a palpable liver and spleen 3 cm and 2 cm below the costal margin, respectively. On abdominal ultrasound, the sizes of the liver and spleen were 95 mm and 86 × 40 mm, respectively, and an echogenic focus in the left kidney was also detected. The patient presented with genu valgum and was not able to walk easily. Bilateral cataracts and lens opacity were found, with 6/10 and 7/10 visual acuity for the right and left eyes, respectively. Wrist radiography showed widening, fraying, and cupping, all suggestive of rickets, and bone age was 3.5 years. Complete blood count (Sysmex KX 21N, Japan) demonstrated a white blood cell count of 4.2 × 109/L with 87% lymphocytes, a hemoglobin level of 4.9 g/dL, mean corpuscular volume of 74 fl, and a platelet count of 73×109/L. The erythrocyte sedimentation rate was 104 mm/hr. The ferritin level was extremely high (2250 ng/mL; normal range is 12 - 142 for children). Venous blood gas analysis (ABL 735; Radiometer, Copenhagen, Denmark) was as follows: pH 7.30, pCO2 29 mmHg, HCO3 13 Meq/L, BE 10 Meq. Liver function tests, thyroid function tests, and evaluation for celiac disease by tissue transglutaminase IgA antibody (TTG IgA) were normal. The results of biochemical testing (Hitachi 917, Hitachi, Japan) are summarized in Table 2.

Table 2. Biochemical Test Results for the Patient
TestResultNormal ValuesLow/Normal or High According to Normal Values
Blood sugar (BS)91 mg/dL70 - 110 mg/dLNormal
Blood urea nitrogen (BUN)9 mg/dL7 - 18 mg/dLNormal
Serum creatinine (Cr)0.7 mg/dL0.6 - 1.2 mg/dLNormal
Sodium (Na)137 mEq/L135 - 145 mEq/LNormal
Potassium (K)3.3 mEq/L3.5 - 5.0 mEq/LLow
Calcium (Ca)8.7 mg/dL8.4 - 10.2 mg/dLNormal
Uric acid1.7 mg/dL3.0 - 8.2 mg/dLLow
Lactate dehydrogenase (LDH)463 U/L45 - 90 U/LHigh
Phosphorus (P) 1.1 mg/dL3.0 - 4.5 mg/dLLow

Immunologic analysis revealed a low IgG level (6 g/L, normal 6.46 - 14.51) but high IgM (2.7 g/L, normal 0.55 - 2.32) and IgA (2.3 g/L, normal 0.28 - 2.22). C-reactive protein was 3+ on the latex agglutination test. Urine analysis showed glucosuria and proteinuria, with a pH of 5. According to the physical examination results, clinical manifestations, radiologic findings, and laboratory results, FS was diagnosed. On microscopic examination of the bone marrow aspirate (BMA), two different populations of blasts were observed (Figure 1). Subsequent flow cytometric analysis (Partec, CyFlow® Space) revealed 98% blasts with positivity for CD2, cytoplasmic CD3, CD7, TdT, CD13, CD34, CD117, and myeloperoxidase. Common chromosomal translocations of acute leukemia, including t(4,11), t(12,21), t(1,19), and t(9,22) by the PCR method were all negative. According to the world health organization (WHO) 2008 classification (6), these findings are indicative of a bilineal acute leukemia with myeloid and T-lymphoid lineages.

Bone Marrow Aspiration Showing Two Different Populations of Blasts
Figure 1. Bone Marrow Aspiration Showing Two Different Populations of Blasts

Cerebrospinal fluid analysis and cytology was normal. The patient received Joulie’s solution for the FS, and a combined chemotherapy regimen that was effective for both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) (modified by the St. Jude XIII-B high risk protocol) (7). Despite supportive treatments and administration of wide spectrum antibiotics, the patient died at the end of the induction phase of chemotherapy due to sepsis and disseminated intravascular coagulation (DIC). Further examinations of family members revealed that the patient’s 4-year-old sister was similarly diagnosed with FS. The third child of this family, a newborn baby, was not investigated.

3. Discussion

Given that dysglobulinemia is a feature of FS, it may be commonly associated with myeloma, amyloidosis, and Bence-Jones proteinuria (5). Ma et al. suggested acquired FS as a complication of monoclonal gammopathy in adults (8). Messiaen et al. reported several cases of multiple myeloma that subsequently developed FS (9). Rochman et al. reported a case of FS as the result of chronic lymphocytic leukemia (10). There is also a study by Bridoux et al. reporting the development of FS in a patient with Waldenström’s macroglobulinemia (11). The authors suggested that the accumulation of kappa light chains may have played a significant role in the development of FS in the reported patients (9, 11). Another study reported a case with chronic myelogenic leukemia, who developed partial FS after receiving imatinib mesylate (Gleevec) (12).

Considering the familial occurrence and the childhood onset of FS in our patient, an inherited background is probable. The unusual event in our patient is the development of an almost rare acute leukemia, a condition which has not been reported before.

Although the majority of acute leukemias can be classified as myeloid, B lymphoid, or T lymphoid lineages through morphology, immunophenotyping, cytogenetic, and molecular analyses, there are also rare cases that manifest the characteristics of at least two lineages and account for 2% - 5% of all acute leukemias (13). Generally, two main types can be located in this group: biphenotypic leukemia and bilineal leukemia. The former refers to leukemias in which divergent features present in a single blast population, while the latter describes leukemias with two different populations of blasts (14). In the WHO 2008 classification, both types are termed as mixed-phenotype acute leukemia (MPAL) (6). The lineage-specific markers suggested by the WHO 2008 are listed in Table 3. Accordingly, positivity of myeloperoxidase and cytoplasmic CD3 in either a single or distinct population of blasts (as was found in our patient) are sufficient for a diagnosis of MPAL with T/myeloid differentiation. In this classification, MPAL with BCR-ABL1 fusion or MLL gene rearrangements with the most common partner gene, AF4 at the 4q21 location, have been regarded as separate entities (6).

In our patient, there was no evidence of t(9,22)(q34;q11), which leads to BCR-ABL1 fusion, or of t(4,11)(q21;q23), which most commonly involves the MLL gene. Meeting the WHO 2008 criteria, MPAL T/myeloid, not otherwise specified was the diagnosis in our patient.

Table 3. WHO 2008 Classification of Mixed-Phenotype Acute Leukemias (6)
LineageMarkers
MyeloidMyeloperoxidase Or Monocytic differentiation (at least two of the following: non-specific esterase, CD11c, CD14, CD64, lysozyme)
T lymphoidCytoplasmic CD3 or Surface CD3
B lymphoidStrong CD19 and at least one of the following with strong expression: CD79a, cytoplasmic CD22, or CD10 or Weak CD19 and at least two of the following with strong expression: CD79a, cytoplasmic CD22, or CD10

Like other acute leukemias, the clinical presentations of MPAL are mainly a result of BM failure, and according to the literature, these include fatigue, infections, and bleeding disorders (6). Hepatosplenomegaly, thrombocytopenia, and severe anemia with high levels of ferritin in our patient were supportive of BM failure, but no bleeding tendency was found. According to the published studies, the outcome of MPAL is generally poor (15). The study by Lee et al. indicated that patients with myeloid/T-lymphoid have an even lower chance of survival than patients affected by the rest of the MPALs (16). Currently, there is no agreement on the treatment of MPAL patients, but a chemotherapy regimen effective for both AML and ALL has been suggested (6). However, Killick et al. noted that such a therapeutic protocol is associated with a high rate of early death in these patients (17). Consistent with the therapeutic strategy elected for in the study by Al-Seraihy et al. we chose the modified St. Jude XIII-B high-risk protocol for our patient, since they suggested that this type of therapy is effective at gaining and maintaining complete remission (18).

References

  • 1.

    Kinoshita-Katahashi N, Fukasawa H, Ishigaki S, Isobe S, Imokawa S, Fujigaki Y, et al. Acquired Fanconi syndrome in patients with Legionella pneumonia. BMC Nephrol. 2013; 14 : 171 [DOI][PubMed]

  • 2.

    Ghiculescu RA, Kubler PA. Aminoglycoside-associated Fanconi syndrome. Am J Kidney Dis. 2006; 48(6) -93 [DOI][PubMed]

  • 3.

    Pham T, Furno-Steib S, Daumen-Legre V, Acquaviva PC, Lafforgue P. Bilateral symmetric polyarthralgia revealing Fanconi's syndrome. Joint Bone Spine. 2002; 69(2) : 209 -13 [PubMed]

  • 4.

    Haque SK, Ariceta G, Batlle D. Proximal renal tubular acidosis: a not so rare disorder of multiple etiologies. Nephrol Dial Transplant. 2012; 27(12) : 4273 -87 [DOI][PubMed]

  • 5.

    Maldonado JE, Velosa JA, Kyle RA, Wagoner RD, Holley KE, Salassa RM. Fanconi syndrome in adults. A manifestation of a latent form of myeloma. Am J Med. 1975; 58(3) : 354 -64 [PubMed]

  • 6.

    Weinberg OK, Arber DA. Mixed-phenotype acute leukemia: historical overview and a new definition. Leukemia. 2010; 24(11) : 1844 -51 [DOI][PubMed]

  • 7.

    Pui CH, Sandlund JT, Pei D, Campana D, Rivera GK, Ribeiro RC, et al. Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood. 2004; 104(9) : 2690 -6 [DOI][PubMed]

  • 8.

    Ma CX, Lacy MQ, Rompala JF, Dispenzieri A, Rajkumar SV, Greipp PR, et al. Acquired Fanconi syndrome is an indolent disorder in the absence of overt multiple myeloma. Blood. 2004; 104(1) : 40 -2 [DOI][PubMed]

  • 9.

    Messiaen T, Deret S, Mougenot B, Bridoux F, Dequiedt P, Dion JJ, et al. Adult Fanconi syndrome secondary to light chain gammopathy. Clinicopathologic heterogeneity and unusual features in 11 patients. Medicine (Baltimore). 2000; 79(3) : 135 -54 [PubMed]

  • 10.

    Rochman J, Lichtig C, Osterweill D, Tatarsky I, Eidelman S. ASdult Fanconi's syndrome with renal tubular acidosis in association with renal amyloidosis: occurrence in a patient with chronic lymphocytic leukemia. Arch Intern Med. 1980; 140(10) : 1361 -3 [PubMed]

  • 11.

    Bridoux F, Sirac C, Hugue V, Decourt C, Thierry A, Quellard N, et al. Fanconi's syndrome induced by a monoclonal Vkappa3 light chain in Waldenstrom's macroglobulinemia. Am J Kidney Dis. 2005; 45(4) : 749 -57 [PubMed]

  • 12.

    Francois H, Coppo P, Hayman JP, Fouqueray B, Mougenot B, Ronco P. Partial fanconi syndrome induced by imatinib therapy: a novel cause of urinary phosphate loss. Am J Kidney Dis. 2008; 51(2) : 298 -301 [DOI][PubMed]

  • 13.

    Yan L, Ping N, Zhu M, Sun A, Xue Y, Ruan C, et al. Clinical, immunophenotypic, cytogenetic, and molecular genetic features in 117 adult patients with mixed-phenotype acute leukemia defined by WHO-2008 classification. Haematologica. 2012; 97(11) : 1708 -12 [DOI][PubMed]

  • 14.

    Bleahu ID, Vladasel R, Gheorghe A. A special case of acute leukemia in childhood. J Med Life. 2011; 4(3) : 297 -301 [PubMed]

  • 15.

    Weir EG, Ali Ansari-Lari M, Batista DA, Griffin CA, Fuller S, Smith BD, et al. Acute bilineal leukemia: a rare disease with poor outcome. Leukemia. 2007; 21(11) : 2264 -70 [DOI][PubMed]

  • 16.

    Lee JH, Min YH, Chung CW, Kim BK, Yoon HJ, Jo DY, et al. Prognostic implications of the immunophenotype in biphenotypic acute leukemia. Leuk Lymphoma. 2008; 49(4) : 700 -9 [DOI][PubMed]

  • 17.

    Killick S, Matutes E, Powles RL, Hamblin M, Swansbury J, Treleaven JG, et al. Outcome of biphenotypic acute leukemia. Haematologica. 1999; 84(8) : 699 -706 [PubMed]

  • 18.

    Al-Seraihy AS, Owaidah TM, Ayas M, El-Solh H, Al-Mahr M, Al-Ahmari A, et al. Clinical characteristics and outcome of children with biphenotypic acute leukemia. Haematologica. 2009; 94(12) : 1682 -90 [DOI][PubMed]

  • COMMENTS

    LEAVE A COMMENT HERE: