Chromosome Instability Syndromes

Article Author:
Hatem Kaseb
Article Editor:
Sameh Hozayen
6/2/2020 6:37:33 PM
PubMed Link:
Chromosome Instability Syndromes


Chromosomal instability syndromes are a group of inherited disorders associated with chromosomal instability and breakage either spontaneously or in response to DNA damaging agents. The majority of these syndromes are significant because they have associations with variable degrees of immunodeficiency, infectious disease, and the risk of developing certain types of malignancies.

The following chromosomal instability syndromes are rare but well described. The current review will focus on the following syndromes. 

1. Ataxia telangiectasia (AT)

2. Bloom syndrome (BS)

3. Fanconi anemia (FA)

4. Nijmegen breakage syndrome (NBS).

Other rare syndromes include ataxia telangiectasia-like disorder, immunodeficiency/centromeric instability/facial anomalies syndrome, Cockayne syndromes, trichothiodystrophy, xeroderma pigmentosum, DNA ligase I deficiency, PMS2 deficiency, and DNA recombinase repair defects (DNA-PKcs, Artemis, DNA ligase 4, Cernunnos/XLF).


Chromosomal instability syndromes show chromosomal instability because of defective proteins or enzymes leading to chromosomal breakage either spontaneously or in response to DNA damaging agents.


1. AT is a rare syndrome with an incidence of 1 in 40,000 to 100,000 live births.[1]

2. BS is a rare syndrome that was reported across different ethnicities but is common in the Eastern European (Ashkenazi) Jews with an estimated carrier frequency of 1 in 120.[2][3]

3. FA is a rare syndrome, but it is a common inherited bone marrow failure syndrome. The disease has cases reported across all races and ethnic groups.

4. NBS is a rare syndrome which is more common in individuals with Eastern European ancestry.[4]


1. AT is an autosomal recessive which primarily presents with cerebellar ataxia. It results from a mutation in ATM (ataxia telangiectasia mutated) gene, which leads to total loss of ATM protein (classic type) or a reduction of its level (wild type). The ATM protein in normal conditions recognize DNA damage and activates DNA repair mechanisms to reduce genetic damage. The defect in the regulatory functions of the ATM gene causes somatic mutations that lead to the manifestations of the disease.

2. Bloom syndrome (BS) is an autosomal recessive disease caused by a lack of BLM helicase enzyme, the result of a mutation in the BLM gene. BLM gene encodes a RecQ helicase and RECQL3, referred to as the Bloom syndrome protein (Blm), which helps maintain DNA stability especially during recombination repair and replication. The protein is also involved with other molecules involved in the DNA damage surveillance and repair.[5][6]

3. FA is a DNA repair disorder where cells cannot repair DNA damage caused by interstrand cross-links (ICLs). This defect eventually leads to chromosomal instability, particularly upon exposure to cytotoxic therapies and a general predisposition to certain cancers. FA can result from a mutation in any of the 17 different FA genes (FANCA to FANCQ) genes. The most commonly mutated genes in patients with FA are FANCA, FANCC, and FANCG. Inheritance patterns include AR, autosomal dominant (AD) and X-linked.

4. NBS is an autosomal recessive chromosome instability syndrome associated with immunodeficiency. NBS is a result of mutations in the nibrin (NBN) gene on 8q21. The protein product is involved in DNA double-strand breaks repair, base excision repair, meiotic recombination, and telomere maintenance.[7][8]

History and Physical

1. In classic form, AT patients present at an early age with ataxia (gait impairment, hand incoordination, and eye movement dysfunction) and conjunctival telangiectasias occur during school age. Recurrent sinopulmonary infections are secondary to reduction of immunoglobulins and reduction of newly produced B and T cells. These infections can further progress into bronchiectasis and pulmonary fibrosis. Young adults have an increased risk of hematological malignancies including lymphoma and leukemia. Other cancers such as breast, liver and esophageal cancer are also possible. There is also a higher incidence of diabetes mellitus. Neurological manifestations occur later in life with dystonia and choreoathetosis.

2. BS patients can present with a variable combination of symptoms that include disproportionately short stature, microcephaly, immunodeficiency, sinopulmonary infections, decreased intellectual ability, facial anomalies, an erythematous rash associated with sun exposure, café-au-lait spot/hypopigmented skin lesions, infertility, a predisposition to hematological malignancies, solid carcinomas and insulin resistance. The most striking early symptom that usually drives patients to medical attention is short stature.[5][9][3]

3. FA is an inherited bone marrow failure condition characterized by pancytopenia, cancer predisposition, short stature, microcephaly, developmental delay, and variable anomalies. Anomalies in FA include[10][11]:

  • Skin hyper- or hypopigmentation
  • Thumb or other radial ray abnormalities
  • Hand abnormalities such as clinodactyly
  • Axial skeletal abnormalities such as short/webbed neck and vertebral anomalies
  • Eye malformations
  • Renal and urinary tract malformations
  • Gonadal/genital malformations
  • Ear abnormalities such as middle ear anomalies or atretic ear canal
  • Congenital heart disease, including patent ductus arteriosus and ventricular septal defect

Gastrointestinal anomalies and central nervous system abnormalities.

4. NBS shows progressive symptoms that include microcephaly, facial deformities with "bird-like" face, intrauterine growth retardation, intellectual disability, immunodeficiency with recurrent sinopulmonary infections, a predisposition to lymphoid malignancies, primary ovarian insufficiency, and radiosensitivity.[12]


1. Diagnostic evaluation for AT includes a combination of ataxia with one or more of the following:  telangiectasia, sinopulmonary disease, and imaging studies (especially with brain MRI) showing diffuse cerebellar atrophy. Investigations for AT should include CBC  with lymphopenia; serological testing will show increased alpha-fetoprotein  (the most consistent test in AT) and decreased IgA, IgG, and IgE.  The most specific test will be testing for the genetic mutation in the ATM  gene or lack of ATM protein kinase. Of note, antenatal diagnosis possible through identification of ATM gene mutation.

2. Investigation for BS focusses on the assessment of immunodeficiency. Tests include serology testing and CBC. Serological testing will show decreased immunoglobulin levels (IgA, IgG, and IgE). CBC will show lymphopenia.

3. Investigation for FA includes chromosomal stress testing and next-generation sequencing (NGS) panels. Chromosomal stress testing involves the assessment of chromosomal breakage in T lymphocytes from peripheral blood upon exposure of cells to diepoxybutane (DEB) or mitomycin C (MMC). The test is sensitive but not specific because other rare genetic diseases can also show breakage. Flow cytometry to assess cell cycle analysis upon exposure to DNA cross-linking agents is another useful test in assessing FA. In FA, cells cannot repair DNA damage and undergo cell cycle arrest in G2, leading to a higher percentage of cells in G2. FA gene sequencing generally is useful as a confirmatory tool for patients with positive breakage studies.[13]

4. Investigation for NBS focusses on the assessment of immunodeficiency. Tests include assessment of immunoglobulin levels, CD4, CD8, CD19, CD57 and class switching of memory B cells. Karyotyping sometimes shows structural chromosomal aberrations in T lymphocytes at chromosomes 7 and 14. There is also sensitivity to ionizing radiation. There are also mutations in the NBN gene and absence of nibrin protein.[12]

Treatment / Management

1. Treatment of AT is symptomatic and supportive.  It includes physical rehabilitation to cope with the ataxia and prompt treatment of the infections and management of diabetes mellitus.

2. Treatment of BS is symptomatic and includes immediate treatment of infections and periodic surveillance for cancer. Patients should avoid sun and radiation exposure.

3. Management of FA focuses on management of BM failure, cancer surveillance, and control of organ dysfunction. The only curative option for FA is allogeneic hematopoietic cell transplantation (HCT). Supportive therapeutic options include androgen therapy to increase blood cell count, use of granulocyte colony-stimulating factor and blood product transfusions.[14]

4. Management of NBS focusses on symptomatic treatment. Prompt management of immunodeficiency as appropriate with antibiotics and IV immunoglobulins to reduce morbidity and mortality in NBS patients.

Differential Diagnosis

1. Differential diagnosis of AT include cerebral palsy, Friedreich ataxia, Gaucher disease, and Niemann-Pick disease

2. Differential diagnosis of BS includes other disorders that present with short stature, including skeletal dysplasia, growth hormone deficiency, and constitutional delay.

3. Differential diagnosis of FA include other diseases presenting with bone marrow failure such as acquired aplastic anemia, paroxysmal nocturnal hemoglobinuria, other inherited bone marrow failure syndromes, drug-induced or infection-associated pancytopenia, NBS, BS, AT, LIG4 syndrome (LIG4), NHEJ1 deficiency (NHEJ1), Seckel syndrome (ATR),  Roberts syndrome (ESCO2), Warsaw breakage syndrome (DDX11) and De novo myelodysplastic syndrome (MDS)

4. Differential diagnosis of NBS includes AT, AT-like disease, FA, BS, RAD50 deficiency and Seckel syndrome.


1. AT shows a variable rate of progression, however, most patients have a poor quality of life and high mortality by early adulthood with the classic form.

2. Most patients with BS survive to adulthood; cancer surveillance has been shown to associate with improved outcome.

3. FA is stratified and managed based on the severity of bone marrow failure.

4. NBS prognosis depends on the severity of the patient symptoms and management strategies of infections.


Complications of chromosomal instability include an increased predisposition to cancer, infections and organ dysfunction.

Deterrence and Patient Education

Many chromosomal instability syndromes run in families; early management can be the key for better prognosis of these patients.

Enhancing Healthcare Team Outcomes

Chromosomal instability syndromes are rare disease entities that need interprofessional team management including genetic counseling, infectious disease consultation, and tailored cancer surveillance programs.


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