++
Although many inherited bone marrow failure syndromes (IBMFSs)
are classically associated with only one cell lineage, many patients progress
to pancytopenia and general bone marrow failure. IBMFSs generally
present with macrocytic anemia, progressive pancytopenia, and congenital anomalies,
particularly of kidneys and the radial side of the forearm. Short
stature, intellectual limitation, and risk of malignancy are also
characteristic. All published reports of IMBFSs are limited by emphasizing
patients with a more severe course. Disease-specific registries
have been established to try to overcome this, but again may suffer
from the focus of physician experts’ and patients’ variable
degrees of willingness to participate. During the past decade, the
inherited mutations responsible for many of these syndromes have
been identified, increasing the precision of diagnosis and detection
of less severely involved patients, as well as furthering our understanding
of the mechanism of marrow failure.9-13 Furthermore,
ascertainment of the genetic basis of a specific patient’s IMBFS
is vital to accessing assisted reproductive technologies, including
preimplantation genetic testing, which offers families the possibility
of subsequent children without the serious genetic disorder.
++
Fanconi anemia is a syndrome of defective double-strand DNA repair
that is caused by a variety of inherited mutations. Inheritance
is nearly always autosomal recessive. The disease occurs in all
ethnic groups. The prevalence is estimated at 2 to 5 per million,
and the heterozygote carrier frequency at 1 in 300. Congenital
anomalies are present in more than half of the patients. Most common
are abnormalities of the thumb and radius ranging from hypoplasia
of the thenar eminence to absence of thumbs or radii, short stature,
microcephaly, and decreased or increased pigmentation, including
multiple and large café-au-lait spots. Other organ systems may
also be involved: renal—including horseshoe kidney, agenesis,
or duplicated collecting system; gastrointestinal—imperforate
anus or interrupted esophagus; genital—males with undescended
or atrophic testes, hypospadias, or phimosis and females with malformations
of the vagina, uterus, and ovary; and head and neck—microphthalmia,
strabismus, and ear anomalies. Adults may have hypogonadism and infertility,
and women usually have late menarche and early menopause. Growth
failure may be constitutional or due to abnormal growth hormone
secretion or hypothyroidism. Abnormal glucose tolerance and hyperinsulinemia may
also affect growth. However, up to 25% of patients with
FA, particularly those detected through the screening of siblings
of diagnosed patients, have no physical abnormalities.
++
Symptoms are determined by the degree of cytopenia. Thrombocytopenia
is usually observed first, generally prior to 4 years of age, and
macrocytosis is generally present at the time of diagnosis. Marrow
failure usually starts in the first decade of life. Patients are diagnosed
at a median age of 6 years and by 16 years of age in more than 90% of
cases.
++
The diagnosis is based on a hypocellular bone marrow biopsy and
aspirate, without pathologic or cytogenetic evidence of myelodysplastic syndrome
(MDS). A specific diagnosis of Fanconi anemia (FA) is made by confirmation
of increased chromosomal fragility (chromatid breaks, rearrangements,
gaps, endoreduplications, and chromatid exchanges) in peripheral blood
lymphocytes cultured with diepoxybutane (DEB) or mitomycin C (MMC).
Similar abnormalities can be seen in cultured skin fibroblasts.
Once a patient is diagnosed, all siblings should be tested for FA.
++
Understanding the genetics of FA has led a revelation about the
interrelationship of bone marrow failure syndromes with other malignancies.
Currently, 13 different Fanconi (FANC) proteins (FANC A-M) are known
to define different complementation groups, or types, of FA. Cells
from patients in different groups complement each other and can
restore the defect in DNA repair seen in homozygous-deficient patients. The
protein products of the nonmutated FANC genes that
define the different complementation groups of FA are components
of the BRCA II DNA damage repair pathway. The FANC core
complex is responsible for monoubiquitination of FANC-D2,
which repairs DNA damage in cells.14
++
Need for treatment is dictated by the degree of pancytopenia.
If there is no transfusion requirement, quarterly blood counts and periodic
bone marrow examinations to evaluate for the development of clonal
hematopoiesis under the supervision of a pediatric hematologist
may be all that is required. All bone marrow examinations should
include chromosome analysis by standard techniques for the development
of clonal abnormalities, suggesting progression to myelodysplastic syndrome
(MDS) and acute myelogenous leukemia (AML). If no abnormality is
found, fluorescence in situ hybridization (FISH)
for chromosomes 3, 5, 7, and 8, which are those most commonly involved
in clonal evolution of the marrow in Fanconi anemia (FA), should
be performed.
++
Treatment of bone marrow failure should begin when the hemoglobin
level is less than 8 g/dL, platelet count less than 30,000/μL,
and absolute neutrophil count less than 500/μL.
At that time, treatment with an oral androgen such as oxymetholone,
to support blood counts or stem cell transplantation (SCT), should
be discussed with the patient and family. Androgen therapy produces
an RBC response in about half of the patients within 2 months, but
it may take up to a year for platelets and white blood cells (WBCs)
to rise. Potential side effects of androgen therapy include masculinization, cholestasis,
peliosis hepatis (blood lakes in the liver), and growth acceleration.
In addition to monthly monitoring of blood counts, patients should
be monitored serially with hepatic ultrasound and physical examinations.
Most patients lose the response to androgens as the bone marrow
failure progresses.
++
SCT is the only curative modality for bone marrow failure, but
FA patients are abnormally sensitive to pretransplant conditioning
regimens (both radiation and chemotherapy) and experience excessive toxicity.
Reduced intensity conditioning has resulted in survival for sibling
donor transplants approaching 80%. However, SCT increases
the chances of “secondary” bone marrow malignancy
and solid tumors by more than fourfold.
+++
Prognosis and Outcome
++
The projected median survival of patients is 23 years of age.
The cumulative probability of cancer by 50 years of age is 85%,
with the mean age of reported cases being 15 years. In addition to
myelodysplastic syndrome (MDS)/acute myelogenous leukemia
(AML), patients with Fanconi anemia (FA) also have an increased
risk of squamous cell carcinoma of the head, neck, esophagus, anus,
and vulva. In some patients, squamous cell carcinoma, otherwise
very rare during childhood, may be the first sign of FA. Indeed,
some experts suggest that all patients diagnosed with these cancers
before 50 years of age should be screened for FA. In FA genotype/phenotype,
correlations are beginning to be established. Certain complementation groups
of FANC-D1 and N are associated with Wilms’ tumor and medulloblastoma,
solid tumors not seen in other FA groups. Furthermore, heterozygote
family members of FANC-D1, N, and J have an elevated risk of breast
cancer. Liver hepatomas and adenomas are usually associated with
androgen treatment of pancytopenia.15,16
++
Pearson marrow-pancreas syndrome is a disorder caused by large deletions
in mitochondrial DNA (mtDNA) that shares features with other inherited
bone marrow failure syndromes (IBMFSs), particularly Shwachman-Diamond syndrome
(SDS) and Fanconi anemia (FA). Patients present in the first years
of life with a refractory sideroblastic anemia often requiring RBC
transfusion, metabolic acidosis, and exocrine pancreatic insufficiency.
The bone marrow has a decreased number of cells, and erythroid and
myeloid precursors have prominent cytoplasmic vacuoles. Ringed sideroblasts
(mitochondria-containing iron) are also present. Mitochondrial gene
deletions of varying size result in impairment of multiple respiratory enzymes
involved in oxidative phosphorylation. Interestingly, the demonstrated
mitochondrial DNA deletions become smaller with advancing age. There
is also overlap with Kearns-Sayre syndrome, in which identical deletions
occur without hematologic findings. Patients fail to thrive and
have repeated metabolic crises with exacerbations of acidosis due
to depletion of respiratory enzymes. Treatment with enzymes such
as coenzyme Q, thiamine, riboflavin, and L-carnitine may reduce
the frequency and severity of these episodes. Median survival is
4 years with death, usually due to acidosis and renal or liver failure
rather than aplastic anemia.
+++
Diamond Blackfan Anemia
++
Diamond Blackfan anemia (DBA) is clinically heterogeneous disorder, the
hallmark of which is RBC aplasia. The incidence is 6 to 7 per million
with no ethnic or gender predilection. Although DBA usually presents
in the first year of life, genetic testing has allowed definitive diagnosis
of new cases in adults as well. Patients often have low birth weight,
growth retardation, learning difficulties, and congenital abnormalities
involving the head (microcephaly, hypertelorism, cleft palate), thumbs
(hypoplastic or duplex/bifid), heart (atrial septal defect [ASD],
ventricular septal defect [VSD], coarctation of
the aorta), or genitourinary system (hypospadias, horseshoe or absent
kidney). The disorder results from a cellular defect in ribosome
biosynthesis in which erythroid cells are highly sensitive to death
by apoptosis, leading to failure of RBC production.
++
Classical Diamond Blackfan anemia (DBA) presents with macrocystic
anemia and reticulocytopenia in the first year of life but near-normal
absolute neutrophil and platelet counts. Fetal hemoglobin is elevated,
and the I antigen in erythrocytes is often expressed. The bone
marrow shows normal cellularity with a virtual absence of RBC precursors.
Erythrocyte adenosine deaminase (eADA) concentration is elevated
by 3 or more standard deviations in 80% to 85% of
patients.
++
To date, mutations have been identified in six different ribosomal protein
genes in about 50% of DBA patients. RPS 19 (19q13.2),
which is mutated in 25% of patients, is essential for the maturation
of the 40S ribosomal subunit. RPS 24 (10q22-q23), RPS
17 (15q25.2), and large (60S) ribosomal subunit–associated
proteins RPL 5, RPL 11, and RPL
135a have been described in 2%, 2%, 10%,
6.5%, and 2% of DBA patients, respectively. Thus,
DBA is now seen as a disorder of ribosome biogenesis and/or
function. All mutations involve one allele only, suggesting protein
haploinsufficiency or loss of function as a mechanism of action.
Homozygotes or compound heterozygosity for DBA proteins have not
been described.
++
About 40% to 45% of DBA cases are familial
with autosomal-dominant inheritance, and the others are sporadic
or occasionally autosomal recessive. Indeed, there is no clear association
between the type of mutation even within the RPS 19 gene
and the degree of hematologic findings or clinical phenotype.
++
More recently, a consensus conference attempted to codify diagnostic
criteria for DBA. Classical DBA is diagnosed if all of the following
criteria are present: age younger than 1 year, macrocytic anemia
with no other significant cytopenias, reticulocytopenia, and normal
marrow cellularity with a paucity of erythroid precursors. If there
is a family history of a similar disorder, an otherwise normal individual
(without the diagnostic criteria) should be considered to have “nonclassical” DBA
if they have the same genetic mutation as other family members.
Sporadic, nonclassical DBA occurs in a person suspected of having
DBA, but with insufficient diagnostic criteria when a reported mutation
is present. “Probable” DBA occurs if there are
various combinations of diagnostic and supporting criteria.
++
Although their mechanism of action is unknown, corticosteroid therapy
results in rising hemoglobin in 80% of patients. There
is no reliable way to predict steroid responsiveness, but an increase
in hemoglobin concentration is usually seen within 2 to 4 weeks
of starting oral corticosteroid therapy. The dose is then tapered
to the lowest dose, preferably on an alternate day schedule, that
will maintain hemoglobin of 8 to 10 g/dL. Steroid nonresponders
and patients with unacceptable steroid toxicity, or those who lose
their response to steroids over time, require chronic RBC transfusions with
the need for chelation to avoid transfusion iron overload.
++
Diamond Blackfan anemia (DBA) patients also require close monitoring
for growth impairment (particularly if the child is receiving corticosteroids)
and periodic blood count monitoring. If new abnormalities appear
on the blood counts, a bone marrow examination should be performed
for morphology and cytogenetic testing.
++
Eventually, 20% of patients will have a spontaneous
remission and maintain adequate hemoglobin values without steroid
treatment, whereas 40% will continue on corticosteroids
and 40% will require transfusions. The projected median
survival of patients in the literature is 39 years of age, but survival
in the North American Diamond Blackfan Anemia Registry (DBAR) is
75% at 40 years. Crude estimates suggest that there is
a 2% to 6% risk of malignancy compared to the
population average of less than 1% by age 15 years. However,
the cumulative probability of cancer is 52% by 50 years
of age. Acute myelogenous leukemia (AML), myelodysplastic syndrome
(MDS), sarcoma (primarily osteogenic), Hodgkin disease, and hepatocellular carcinoma
are the most common malignancies observed in patients with Diamond
Blackfan anemia (DBA). Marrow cellularity decreases with age, and
patients may develop pancytopenia or frank aplastic anemia. Such
patients and others receiving chronic transfusions may elect to
undergo stem cell transplantation (SCT). As with other disorders,
better survival is seen with a sibling donor and if the transplant
occurs prior to 10 years of age.17-19
+++
Transient Erythroblastopenia
of Childhood
++
Transient erythroblastopenia of childhood (TEC) is the most common
disorder that must be distinguished from Diamond Blackfan anemia
(DBA).
++
Transient erythroblastopenia of childhood (TEC) is the spontaneous cessation
of erythropoiesis in otherwise healthy children without congenital
abnormalities. It usually presents in children between 6 months
and 3 years of age and persists for weeks to several months. Although
the RBC lineage is always involved, rarely neutropenia and sometimes
thrombocytopenia may also occur.
++
Transient erythroblastopenia of childhood (TEC) is a diagnosis
of exclusion and is confirmed only after the fact, when normal erythropoiesis
is spontaneously restored. The RBC size or mean cell volume (MCV)
is normal, fetal hemoglobin is not elevated, and the erythrocyte
adenosine deaminase (eADA) concentration is normal in 90% of cases. Bone
marrow examination is usually not required, but when performed shows
a paucity of erythroid precursors but no other abnormalities. Although
there may be some seasonal variation and clustering of cases, there
is no clear association with any specific viral infection. The
cause of TEC is not known.
++
Management is supportive with RBC transfusion as needed. Hemoglobin
and reticulocyte counts should be monitored until normal.
+++
Prognosis and
Outcome
++
Once normal hematopoiesis is restored, the disorder does not
usually recur.20
+++
Shwachman-Diamond
Syndrome
++
Shwachman-Diamond syndrome (SDS), sometimes called Shwachman-Bodian-Diamond
syndrome (SBDS), is characterized by neutropenia and pancreatic
insufficiency (also discussed in Chapter 417). Neutropenia commonly
presents in infancy. It is chronic in one third of patients and
intermittent in others. Anemia, either normocytic or macrocytic
but with inappropriately normal reticulocyte counts, has been reported
in 42% to 66% of patients, with the typical elevated fetal
hemoglobin levels seen in inherited bone marrow failure syndromes (IBMFSs).
Thrombocytopenia occurs in 24% to 60% of patients, and
bleeding problems may occur. Pancytopenia develops in 10% to
44% of patients. Although a variety of subtle immunologic
and neutrophil chemotactic abnormalities have been described, their
clinical significance with respect to infection risk has not been
determined.
++
Pancreatic insufficiency with steatorrhea and failure to thrive
begins in infancy. There may be hepatomegaly with elevated serum
transaminase levels. Exocrine pancreatic function and hepatic transaminase
levels improve with age in many patients. Many SDS patients have
short stature with half being below the third percentile for age,
despite the prompt administration of pancreatic enzyme supplementation.
Skeletal abnormalities are common, particularly short ribs with
flared anterior ends, leading to a bell-shaped chest and metaphyseal
dysostosis, particularly involving the femoral head.
++
Shwachman-Diamond syndrome (SDS) is suggested by neutropenia (persistent,
intermittent, or rarely cyclic) with a documented absolute neutrophil
count (ANC) < 1500/uL on three occasions over at least
3 months, in a child with short stature, bony abnormalities, and/or
pancreatic insufficiency. The bone marrow has no pathognomonic features,
but aspiration needs to be undertaken to exclude other diagnoses
and monitor for the development of clonal abnormalities.
++
Fecal fat excretion is increased in the absence of intestinal
pathology, and pancreatic enzyme secretion is decreased in response
to formal testing. Pathologically, the pancreas is replaced with
fat with few acini and sparing of ducts and islets, a finding that
can be demonstrated by ultrasound and computed tomographic imaging.
Sweat chloride testing is normal. Serum trypsinogen and isoamylase
levels are low in young children with SDS, but the trypsinogen level may
normalize by age 3 years.
++
More than 90% of patients will have a variety of mutations
in the Shwachman-Bodian-Diamond syndrome (SBDS) gene at 7q11 that
results in decreased SBDS protein expression. About 60% of patients
carry two mutations.
++
Blood counts should be monitored every 3 to 4 months and families
educated to seek medical attention for every febrile illness. Consideration should
be given to treatment with granulocyte colony-stimulating factor
(G-CSF) for invasive infections, persistent severe neutropenia, severe
gingivitis, or recurrent febrile illnesses. G-CSF therapy does not
appear to further increase the risk of myelodysplastic syndrome (MDS)/acute
myelogenous leukemia (AML) over its already high risk in SDS. Treatment
of the pancreatic insufficiency is discussed in Chapters 417 and 514. Bone marrow aspiration and biopsy should be performed every
1 to 2 years, and more often if karyotypic changes are present or
with significant changes in blood counts, in order to rule out progression
to MDS and AML. Stem cell transplantation (SCT) should be considered
if aplastic anemia or MDS/AML occurs. SDS patients appear
to have a higher incidence of cardiac and pulmonary failure if cyclophosphamide
or radiation is used in the transplant conditioning regimen. Survival
after SCT for aplasia is 88%, but drops to 60% after
MDS or AML.
++
Patients receive replacement pancreatic enzymes and monitoring
of the levels of fat-soluble vitamins A, D, E, and K. They should
be evaluated for short stature, altered glucose metabolism, and
thyroid function.
+++
Prognosis and Outcome
++
The projected median survival is 35 years, with 22% of
patients in the literature dead by 16 years of age. The cumulative
probability of cancer by 40 to 50 years of age is estimated to be
71% with the median age of the patients diagnosed with
cancer being 18 years. No solid tumors have been associated with
Shwachman-Diamond syndrome (SDS). However, clonal abnormalities
of the marrow, most commonly, monosomy 7 [–7],
7q deletion, isochromosome 7 [i(7q)], plus trisomy
8 [+8], and deletion 12 [del20(q12)],
are very common. Interestingly, although –7, 7q deletion,
and +8 likely herald the progression of myelodysplastic
syndrome (MDS) or acute myelogenous leukemia (AML), i(7q) and del
20(q12) have been observed in some SDS patients for nearly 10 years
without evidence of progression.21,22
+++
Dyskeratosis Congenita
++
The diagnostic triad of dyskeratosis congenita (DC) is lacy reticulated
pigmentation, dysplastic nails, and oral leukoplakia. None of these
finding are usually present in childhood. Other features of the
disease are sparse, early graying hair, hypogonadism, urethral strictures,
pulmonary fibrosis, and esophageal strictures. Hoyeraal-Hreidarsson
syndrome (intrauterine growth retardation [IUGR] and
developmental delay with microcephaly, immunodeficiency, bone marrow
failure, and cerebellar hypoplasia) and Revesz syndrome (similar
features plus exudative retinopathy) are two more severe pediatric variants.23 The
median age at diagnosis is 15 years with a 4:1 male predominance.
++
The features of the classical triad of dyskeratosis congenita
(DC) and cytopenias suggest the diagnosis, yet it can be confirmed
in only 40% of cases by genetic testing. Four genes are
known: the X-linked DKC1, whose product dyskerin
is involved in ribosome biogenesis and telomere maintenance; two
autosomal-dominantly inherited genes (TERC and TERT),
which code for messenger RNA for telomerase and the telomerage gene,
respectively; and the fourth (NOP10), which is
autosomal recessive. Telomeres are repeated nucleoside sequences
that cap the ends of chromosomes and protect them from damage. These
genes are part of the telomere maintenance pathway that prevents
the ends of chromosomes from shortening with each replication. Very
short telomeres are associated with DC, so the bone marrow failure
may be related to the decreased proliferative potential of the stem
cells. Short telomeres, seen in DC and other inherited bone marrow
failure syndromes (IBMFSs), may promote the genomic instability and
malignant progression that is observed in these disorders.
++
Hematologic parameters govern the frequency of peripheral blood
count monitoring required, and routine marrow assessment may not
be necessary. Although treatment with oral androgens may stabilize
declining blood counts, stem cell transplantation (SCT) should be
pursued when there is aplasia.
+++
Prognosis and Outcome
++
The cumulative incidence of marrow failure is more than 90% by
age 40 years, with a 35% cumulative incidence for malignancies
by age 50 years. The majority of the cancers are carcinomas, particularly
of the head, neck, and esophagus, but myelodysplastic syndrome (MDS) and
acute myelogenous leukemia (AML) have been reported. The median
survival is predicted to be 45 years.24,25
+++
Amegakaryocytic Thrombocytopenia
++
Patients with amegakaryocytic thrombocytopenia (AMT) usually present
as neonates with bruises and petechiae due to thrombocytopenia,
which then may progress to aplastic anemia or myelodysplastic syndrome
(MDS) and acute myelogenous leukemia (AML). There are no specific
physical abnormalities. The usual platelet count is around 20,000/uL,
with normal size and appearance on peripheral blood smear.
++
Bone marrow aspirate shows normal cellularity and reduced to
absent megakaryocytes. The plasma levels of thrombopoietin (TPO), the
endogenous hematopoietic growth factor that stimulates platelet
production, are high, confirming that this is defect of production. All
cases of AMT exhibit recessive mutations in cMPL, the
gene for the TPO receptor. There appears to be a genotype-phenotype
correlation with AMT patients having a null mutation that results
in severe early thrombocytopenia. AMT patients’ missense
mutations may have a slower progression to marrow aplasia.
++
Historically, AMT patients with pancytopenia were believed to
have an increase in their blood counts in response to oral androgens.
However, today patients are encouraged to consider stem cell transplantation
(SCT) as soon as the diagnosis is made because of the transitory
duration of androgen response.
+++
Prognosis and Outcome
++
The cumulative estimated incidence of aplastic anemia is 50% by
5 years of age and 91% by 13 years. Malignancy may rapidly
occur with the incidence of AML being 55% by 17 years of
age.26
+++
Thrombocytopenia Absent
Radii
++
Thrombocytopenia absent radii (TAR) syndrome is usually recognized
at birth in a child with bilaterally absent radii but present, albeit hypoplastic
or misplaced thumbs. This is in contrast to Fanconi anemia where
thumbs may be absent. Children with TAR may also have short or absent
ulnae or humeri, dislocated hips, abnormal knees, short stature,
macrocephaly, capillary hemangiomas, and cardiac defects. Platelets
appear normal in size on blood smear. Eosinophilia and a leukemoid
reaction (often attributed to a milk protein allergy) are common.
++
The genetics of TAR are unclear. The MPL gene
is normal in contrast to amegakaryocytic thrombocytopenia (AMT).
However, serum levels of thrombopoietin are elevated, suggesting
a block in differentiation of megakaryocytes. Bone marrow aspiration
shows decreased and abnormal megakaryocytes. More recent data suggest that
an interstitial deletion of 220kb on chromosome 1q21.1 is present
both in patients and their unaffected parents, suggesting a bigenic
inheritance pattern. Most cases are autosomal recessive, but autosomal-dominant
inheritance has also been reported.
++
Most patients require only supportive care. In infancy, gastrointestinal
bleeding is the major challenge. Patients should be transfused with
platelets only for severe bleeding.
+++
Prognosis and
Outcome
++
In most patients, the platelet counts begin to increase by the second
year of life, facilitating any required orthopedic intervention for
the upper limb anomalies. Platelet counts do not usually become
completely normal. Among the first 300 patients in the literature,
there were four cases of leukemia and three cases with multiple
solid tumors. This disorder should therefore be reclassified as
one of the inherited bone marrow failure syndromes (IBMFSs). Survival
is reported to plateau at 78% at 5 years of age. Aplastic
anemia has not been reported.