Page 436 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 29 Inherited Bone Marrow Failure Syndromes 357

Monoallelic carriers for FANCD1, FANCN, FANCJ, FANCS, is atypical for FA; fewer than 5% of patients are diagnosed during the
FANCP, and FANCO are at increased risk of developing cancer. first year of life. Neither CAMT nor the various thrombocytopenia
Female carriers of FANCD1/BRCA2 and FANCS/BRCA1 have an syndromes above show chromosome fragility, which separates them
increased risk of breast cancer ranging from 40% at age 80 years to from FA. Genetic testing is available for many of these disorders
a lifetime risk of about 80%, and of ovarian cancer with a risk of up (see Table 29.1). In TAR syndrome, thumbs are always preserved
to 20% at age 70 years. Male carriers have a 7% risk of breast cancer and intact despite the absence of radii, but in FA, the thumbs are
and a 20% risk of prostate cancer before age 80 years. Heterozygous hypoplastic or absent when the radii are absent.
mutations in FANCP and FANCO are also associated with breast and Seckel syndrome, or “bird-headed dwarfism” manifests with
ovarian cancers. Mutant FANCN and FANCJ are low-penetrance short stature, microcephaly, cognitive delay, sinopulmonary infec-
breast cancer susceptibility alleles with about a twofold increased risk tions, and a predisposition to developing lymphomas, pancytopenia,
in carriers compared with the general population. and AML. Some patients may show increased chromosomal breakage
in lymphocyte cultures with DEB or MMC and mimic FA. There
are several genes that have been linked to Seckel syndrome: mutant
Differential Diagnosis ATR has been associated with Seckel Type 1, RBBP8 with Type 2,
CENPJ with Type 4, CEP152 with Type 5, CEP63 with Type 6, and
About 30% of patients with FA do not have physical anomalies, and ATRIP with Type 8. Genotyping will distinguish FA from Seckel
such individuals may not be recognized until they present with syndrome.
aplastic anemia, MDS, AML, unilineage cytopenias, or macrocytic Nijmegen breakage syndrome (NBS) is an autosomal recessive
RBCs. Thus FA should be part of the differential diagnosis in children disorder caused by mutations in the NBS1 gene and is characterized
and adults with unexplained cytopenias; characteristic birth defects; by stunted growth, microcephaly, a distinctive facies, café-au-lait spots,
a diagnosis of aplastic anemia, MDS, or AML in patients mainly up immunodeficiency, and a predisposition to lymphoid malignancy.
to the age of 40 years, but sometimes also older; unusual sensitivity Some patients resemble those with FA, have BM failure, and may
to chemo- or radiotherapy; cancer typical of FA but at an atypical show increased chromosome breakage in lymphocyte cultures with
age such as cancer of the cervix when younger than 30 years; or MMC. The genetic defect is a mutant NBS1 gene whose wild-type
squamous cell carcinoma of the head and neck when younger than protein product is involved in DNA repair. Because NBS can mimic
50 years of age. Any of these should prompt consideration of FA as and be confused with FA, genotyping is essential and diagnostic.
the underlying problem. All patients with idiopathic aplastic anemia Cells from patients with Bloom syndrome show abnormal
who are younger than 40 years should have chromosomal fragility spontaneous breakage, but unlike FA cells, the breakage does not
testing. However, if the test was not performed at diagnosis, patients increase in vitro in response to DEB. Ataxia telangiectasia is char-
with “idiopathic” aplastic anemia who fail to respond to immunosup- acterized by sister chromatid exchange without hypersensitivity to
pressive therapy with antithymocyte globulin (ATG) and cyclosporine DEB or BM failure.
should be tested.
Although neutropenia is a consistent feature of SDS, anemia or
thrombocytopenia (or both) is seen in more than 50% of patients Natural History and Prognosis
and can be confused with FA. Because growth failure is also a mani-
festation of SDS, differentiating between the two disorders can ini- The most serious early consequence in most patients with FA is BM
tially be difficult. The major difference between them is that SDS is failure. The exceptions are patients with biallelic FANCD1/BRCA2
a disorder of exocrine pancreatic dysfunction that may or may not mutations who have a cumulative probability of 97% of developing
produce gut malabsorption. This can be confirmed by fecal fat analy- a malignancy by age 6 years, including AML, Wilms tumor, and
sis; by showing reduced levels of serum trypsinogen, serum isoamylase, medulloblastoma. Judging from the literature, the overall risk for
or fecal elastase; and by reduced levels of fat soluble vitamins such as patients with FA developing solid malignant tumors, liver tumors,
A, D, and E. Nowadays pancreatic stimulation studies using intrave- acute leukemia, and MDS is at least 15%, but it is likely higher in
nous secretin or cholecystokinin and measuring enzyme secretion is older patients. Treatment for cancer imposes additional problems and
rarely done. CT, ultrasonography, or magnetic resonance imaging probably increases the risk for additional cancers secondary to therapy.
(MRI) of the pancreas may also demonstrate fatty changes within the Thus the major causes of death in FA are sepsis and bleeding from
pancreas. Other skeletal distinguishing features found in some BM failure, complications of HSCT, and progressive cancer or con-
patients with SDS are short flared ribs, thoracic dystrophy at birth, sequences of its treatment.
delayed bone maturation, and metaphyseal dysostosis of the long Despite these serious issues, the prognosis for patients with FA is
bones. Chromosomes analyses do not show spontaneous breaks in improving. Based on a literature review of more than 2000 FA case
SDS, and there is no increased breakage after clastogenic stress testing reports, the median survival from 1927–1999 was 21 years. In con-
using DEB or MMC. Mutations in the SBDS gene can be demon- trast, the median survival from 2000–2009 was 29 years of age.
strated in 90% of patients with SDS. Patients with FA are now predicted to reach adulthood because more
DC shares some features with FA, including development of than 80% of patients reach age 18 years or more. Earlier diagnosis,
pancytopenia, a predisposition to cancer and leukemia, and skin especially of mild cases, diagnosis of FA in young adults with AML
pigmentary changes. However, the pigmentation pattern is somewhat or a solid tumor, comprehensive clinical and laboratory surveillance
different in DC and manifests with a lacy reticulated pattern affecting programs, timely therapeutic interventions, and HSCT are attributed
the face, neck, chest, and arms, often with a telangiectatic component. to the improved outlook.
At some point, usually in the first decade of life, patients with DC
also develop dystrophic nails of the hands and feet and, somewhat
later, leukoplakia involving the oral mucosa, especially the tongue. Therapy
Other findings seen only in DC and not in FA are teeth abnormalities
with dental decay and early tooth loss, hair loss, and hyperhidrosis Because of their clinical and psychosocial complexity, patients with
of the palms and soles. Chromosomal fragility with DEB testing is FA should be supervised by a hematologist at a tertiary care center
typically normal in patients with DC, who contrast sharply with using a comprehensive and multidisciplinary approach. On the initial
patients with FA. Molecular analysis of the DC genes is positive in visit, the practitioner should take a detailed personal and family
about three-quarters of the patients (see Table 29.1). history, a careful physical examination with emphasis on physical
Congenital amegakaryocytic thrombocytopenia (CAMT) and anomalies, complete blood counts and chemistries, a BM biopsy for
TAR syndrome both manifest in the neonatal period with thrombocy- cellularity and morphology, an aspirate for additional morphology,
topenia. Patients with CAMT develop impairment in other blood cell cytogenetics, and an iron stain for ringed sideroblasts. DEB or MMC
lineages soon after presentation. A neonatal hematologic presentation chromosome fragility testing on peripheral blood lymphocytes on