Acute myeloid leukemia (AML) accounts for 15-20% of
childhood leukemias. Certain genetic conditions like Down syndrome,
Bloom syndrome, Fanconi anemia, Diamond-Blackfan anemia and Kostmann
syndrome; exposure to drugs like alkylating agents, topoisomerase
inhibitors and ionizing radiation, are associated with greater risk of
developing AML. However, majority of children have no known predisposing
conditions. Familial predisposition to AML has not been proved although
there are reports of two or more members of a family develop-ing AML.
Here we report an uncommon occurrence of AML simultaneously in two
siblings, a three-year-old boy and his one-year-old sister.
Case Report
Sibling 1: A 3-year-old developmentally normal
male child, product of nonconsan-guineous marriage between parents of
North Indian origin, residing in Singapore for last 9 months had
complaints of high grade fever associated with cough for 10 days and
generalized rash for 2 days. There was no past history of recurrent
infections, anemia or blood transfusions, exposure to ionizing
radiations or chemotherapeutic agents. Child’s father had expired 10
months back following a brief illness comprising of fever, malaise and
scattered petechial rash for one week followed by sudden onset of
massive hematemesis, coma and death. He had no prior history of
hypertension, hematemesis or any other major systemic illness. He was
not investigated and the cause of death could not be established. There
was no history of abortions or sibling deaths and no history of
malignancies in the family. Both parents were computer professionals. On
examination, child was febrile, pale with presence of scattered
petechiae and no significant lymphadenopathy. There were no dysmorphic
features or abnormal skin pigmentation. Hepatomegaly of 3 cm and
splenomegaly of 2 cm below the costal margin were present.
Investigations revealed hemoglobin of 11.4 g/dL;
white blood cell (WBC) count 2700 cell/mm3 with peripheral smear showing
60% lymphocytes, 2% neutrophils, 38% atypical cells; and platelet count
of 1,27,000/mm3. A diagnosis of AML-MI subtype was made on bone marrow
aspiration based on morphology and cytochemistry (positive for Sudan
black and myeloperoxidase). Bone marrow cytogenetic studies showed two
abnormal clones one with an interstitial deletion of short arm of
chromosome 7 and another with an interstitial deletion of long arm of
chromosome 9. Cerebrospinal fluid (CSF) cytology was negative for
blasts. The parents decided against the use of chemotherapy. The patient
was thus managed symptomatically with antibiotics and transfusion
support. Two and a half months later he was brought in with fever and
altered sensorium. He was critically sick and was diagnosed to have
septicemia with pyogenic meningitis. He expired after 5 days inspite of
aggressive antibiotic therapy and supportive care.
Sibling 2: The younger sibling of the same
family, one-year old developmentally normal female child born at term by
cesarean section also had complaints of intermittent low-grade fever of
15 days duration without any localizing symptoms. While the older child
was being investigated, she developed two episodes of epistaxis.
Physical examination revealed pallor, hepatomegaly of 3 cm and
splenomegaly of 1 cm with no evidence of dysmorphism or abnormal skin
pigmentation. Investigations showed a WBC count of 11,000/mm3 with 63%
blasts on peripheral smear. A diagnosis of AML-M2 subtype based on
morphology and cytochemistry was established on bone marrow biopsy. CSF
was negative for blasts.
This child was started on chemotherapy consisting of
triple intrathecal therapy (methotrexate, hydrocortisone and cytosine
arabinoside), intravenous daunorubicin, etoposide and cytosine
arabinoside. However, four days later she developed fever and bilateral
chest crackles; chest radiograph showed bilateral pneumonitis associated
with an absolute neutrophil count of zero. She progressively worsened
despite broad-spectrum antibacterial and antifungal agents. She expired
after 15 days due to septic shock complicated by pulmonary hemorrhage.
Discussion
Simultaneous development of AML in two siblings is a
very rare occurrence. Although there are reports of AML developing in
two or more siblings or different generations of the same family in
world literature, no case has been reported to the best of our knowledge
in which two or more siblings were diagnosed with AML at the same time.
Also, this is the first report of familial AML from India.
Snyder, et al.(1) had reported six AML cases
in a family over three generations including three siblings aged 11, 3
and 6 years who were diagnosed to have AML at intervals of 5 and 9 years
between the first-second and second-third case respectively. Increased
susceptibility of skin fibroblasts to transformation by SV40 virus was
noted in one of the siblings with AML, her unaffected mother and
unaffected sibling who later developed AML. Goudsmit, et al.(2)
reported AML in two siblings, 7 year female and 14 year male diagnosed
11 years apart. Associated finding of high proportion of neutrophils
showing Dohle bodies was seen in all siblings.
Kaur, et al. reported(3) five siblings; two
died of AML diagnosed at an interval of 7 years, one died of
myelofibrosis and the two surviving siblings had hematological findings
consistent with preleukemia with bone marrow evidence of an abnormal
cytogenetic clone with an extra chromosome in C-group. In addition,
neutrophils of all 5 siblings revealed Felger Huet anomaly suggestive of
transmission of a specific genetic defect in an autosomal dominant
pattern.
Larsen, et al.(4) reported a family in which 3
siblings, aged 18, 21 and 14 year were diagnosed to have AML at
intervals of 8 months and 13 months from each other. Bone marrow
examination in two of these revealed monosomy in C-group chromosomes. In
a recent report(5), 4 male members of a family over 3 generations were
diagnosed to have AML at intervals of atleast 3 years, showing
phenomenon of anticipation, that is, successive generations getting
affected at younger ages. Cytogenetic anomaly of 6q deletion was found
in a second-generation affected patient. Other reports of AML diagnosed
in siblings at intervals of atleast two years from each other are
available in which no definite cytogenetic or immunological findings
were noted(6,7,8). In one case(6) both sibs developed AML of same
subtype (M4), while in the other(8) the two siblings had AML of
different subtypes (M1 and M6).
In another report AML of subtype Ml was seen in a
33-year-old male and myelodysplasia progressing to AML in his sister at
an interval of 2 years. This family had a familial platelet disorder
with predisposition to myeloid malignancies, and three out of 5 siblings
in this family were found to have single nucleotide mutation in CBF A2
gene on chromosome 21(9). Some investigators have also found the
cytogenetic abnormality of monosomy7(10) or loss of long arm of
chromosome 5(11) in cases of familial AML. However, till date the
molecular mechanisms for the occurrence of leukemia in multiple members
of a family have not been fully elucidated.
In the present cases, AML-MI and AML-M2 occurred
simultaneously in the two siblings. The cytogenetic studies in the older
sibling showed two abnormal clones, one with an interstitial deletion of
7p and another with an interstitial deletion of 9q. These abnormalities
have been reported in cases of AML. However, unfortunately cytogenetic
studies could not be obtained on the younger sibling.
Recent reports have established prenatal origins of
certain leukemia translocations like t(8:21) AML1-ETO translocation in
child-hood AML(12) suggesting thereby that an in utero genetic
alteration may be an initiating event in childhood AML and a subsequent
second event, possibly environmental exposure can lead to development of
AML. It may be speculated that a similar mechanism might have been
operative in the present case that led to simultaneous occurrence of AML
in both siblings.
Contributors: VJ drafted the manuscript. SB
drafted and edited the manuscript, and managed the patients. MYC
performed the initial management and diagnostic work up of the patients.
LSA managed the patients and will act as the guarantor of the
manuscript.
Funding: None.
Competing interests: None stated.
