Continuing Education Activity

Chromosomal instability syndromes are a group of rare, inherited disorders characterized by a predisposition to chromosomal instability and breakage, either spontaneously or in response to deoxyribonucleic acid (DNA)-damaging agents. These syndromes are caused by defects in proteins or enzymes essential for DNA repair and chromosomal maintenance, leading to a higher risk of immunodeficiency, infections, and the development of certain cancers. Well-known examples include ataxia-telangiectasia, Bloom syndrome, Fanconi anemia, and Nijmegen breakage syndrome. Diagnosis often requires genetic testing and the evaluation of chromosomal breakage. Given the complexity of these disorders, patients require a comprehensive management approach that includes genetic counseling, tailored cancer surveillance, and infectious disease consultation.

This course educates participants on the clinical evaluation, diagnosis, and management of chromosomal instability syndromes, including how to recognize their genetic and clinical features. This course highlights the importance of early detection and intervention to mitigate complications such as immunodeficiency and cancer. Collaboration among an interprofessional team—including geneticists, oncologists, infectious disease specialists, and primary care clinicians—is crucial for creating personalized care plans. By working together, the team can enhance patient outcomes through coordinated care, ongoing surveillance, and effective treatment strategies that address the multifaceted needs of these patients.

Objectives:

• Identify the clinical signs and symptoms associated with major chromosomal instability syndromes such as ataxia-telangiectasia, Bloom syndrome, and Fanconi anemia.

• Differentiate between various chromosomal instability syndromes based on genetic and clinical findings, including immunodeficiency and cancer risk.

• Screen patients with recurrent infections or unexplained malignancies for potential chromosomal instability through appropriate genetic testing.

• Communicate the role of the health professional team in coordinating the care of a patient with chromosomal instability syndromes.

Introduction

Chromosomal instability syndromes are a group of inherited disorders associated with chromosomal instability and breakage spontaneously or in response to deoxyribonucleic acid (DNA)-damaging agents.[1] Most of these syndromes are significant because they are associated with variable degrees of immunodeficiency, infectious disease, and the risk of developing certain malignancies.[2] The following chromosomal instability syndromes are rare but well-described:

• Ataxia-telangiectasia [3]
• Bloom syndrome [4]
• Fanconi anemia [5]
• Nijmegen breakage syndrome [6]

Other rare syndromes include ataxia telangiectasia-like disorder; immunodeficiency, centromeric instability, and facial anomalies syndromes; Cockayne syndrome; trichothiodystrophy; xeroderma pigmentosum; DNA ligase I deficiency; PMS2 deficiency; and DNA recombinase repair defects (DNA-phosphatidylinositol 3-kinase, Artemis, DNA ligase 4, Cernunnos).[7][8][9][10][11][12][13]

Etiology

Chromosomal instability syndromes show chromosomal instability because defective proteins or enzymes spontaneously lead to chromosomal breakage or in response to DNA-damaging agents. [2]

Epidemiology

Incidence rates for the following rare chromosomal instability syndromes are:

• Ataxia-telangiectasia: One in 40,000 to 100,000 live births have this condition.[14]
• Bloom syndrome: This condition has been reported across different ethnicities but is common in Eastern European (Ashkenazi) Jews; estimated carrier frequency of 1 in 120.[15][16]
• Fanconi anemia: Although a rare syndrome, it's a common inherited bone marrow failure syndrome; cases are reported across all racial and ethnic groups.[17]
• Nijmegen breakage syndrome: This is more common in individuals with Eastern European ancestry.[18]

Pathophysiology

Although the pathophysiology of these disorders is secondary to different deficits, the final common pathway to chromosomal instability is due to an increased risk of DNA damage or defective DNA repair mechanisms.

Ataxia-Telangiectasia

Ataxia-telangiectasia is an autosomal recessive disorder that primarily presents with cerebellar ataxia; this results from a mutation in the ataxia telangiectasia mutated (ATM) gene, which leads to a total loss of ATM protein (classic type) or a reduction of its level (wild-type).[3] In normal conditions, the ATM protein recognizes 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.

Bloom Syndrome

Bloom syndrome is an autosomal recessive disease caused by a lack of BLM helicase enzyme, resulting from 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 DNA damage surveillance and repair.[19][20]

Fanconi Anemia

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

Nijmegen Breakage Syndrome

Nijmegen breakage syndrome is an autosomal recessive chromosome instability syndrome associated with immunodeficiency. Nijmegen breakage syndrome results from 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.[21][22]

History and Physical

Ataxia-Telangiectasia

In classic form, ataxia-telangiectasia patients present early with ataxia (gait impairment, hand incoordination, and eye movement dysfunction), and conjunctival telangiectasias occur during school age.[23] Recurrent sinopulmonary infections are secondary to the reduction of immunoglobulins and the reduction of newly produced B and T cells.[24] These infections can further progress into bronchiectasis and pulmonary fibrosis. Young adults have an increased risk of hematological malignancies, including lymphoma and leukemia.[25][26] 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.[23]

Bloom Syndrome

Patients with Bloom syndrome 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. Short stature is the most striking early symptom that usually drives patients to medical attention.[16][19][27]

Fanconi Anemia

Fanconi anemia is an inherited bone marrow failure condition characterized by pancytopenia, cancer predisposition, short stature, microcephaly, developmental delay, and variable anomalies. Anomalies in Fanconi anemia include:

• Skin hyper- or hypopigmentation
• Thumb or other radial ray abnormalities
• Hand abnormalities such as clinodactyly
• Axial skeletal abnormalities such as short or 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 [28][29]

Nijmegen Breakage Syndrome 

Nijmegen breakage syndrome shows progressive symptoms that include microcephaly, facial deformities with "bird-like" faces, intrauterine growth retardation, intellectual disability, immunodeficiency with recurrent sinopulmonary infections, a predisposition to lymphoid malignancies, primary ovarian insufficiency, and radiosensitivity.[30]

Evaluation

Ataxia-Telangiectasia

Diagnostic evaluation for ataxia-telangiectasia includes a combination of ataxia with 1 or more of the following: telangiectasia, sinopulmonary disease, or imaging studies (especially with brain magnetic resonance imaging) showing diffuse cerebellar atrophy. Investigations for ataxia-telangiectasia should include a complete blood count (CBC) with lymphopenia; serological testing shows increased alpha-fetoprotein (the most consistent test in ataxia-telangiectasia)[31] and decreased immunoglobulin (Ig)A, IgG, and IgE. The most specific test is for the genetic mutation in the ATM gene or lack of ATM protein kinase. Of note is that antenatal diagnosis is possible by identifying ATM gene mutations.[23]

Bloom Syndrome

The investigation for Bloom syndrome focuses on assessing immunodeficiency. Tests include serology and CBC, where CBC shows lymphopenia. Serological testing shows decreased immunoglobulin levels (IgA, IgG, and IgE).

Fanconi Anemia

Investigation for Fanconi anemia includes chromosomal stress testing and next-generation sequencing panels. Chromosomal stress testing involves the assessment of chromosomal breakage in T-lymphocytes from peripheral blood upon exposure of cells to diepoxybutane or mitomycin C. The test is sensitive but not specific because other rare genetic diseases can also show breakage. Flow cytometry, which assesses cell cycle analysis upon exposure to DNA cross-linking agents, is another helpful test in evaluating this condition. In Franconi anemia, cells cannot repair DNA damage and undergo cell cycle arrest in G2, leading to a higher percentage of cells in G2. Gene sequencing for this condition is generally used as a confirmatory tool for patients with positive breakage studies.[32]

Nijmegen Breakage Syndrome

Investigation for Nijmegen breakage syndrome focuses on the assessment of immunodeficiency. Tests include assessment of immunoglobulin levels, cluster of differentiation (CD) 4, 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 the absence of fibrin protein.[30]

Treatment / Management

Ataxia-Telangiectasia

Treatment of ataxia-telangiectasia is symptomatic and supportive and includes physical rehabilitation to cope with the ataxia, prompt treatment of infections, and management of diabetes mellitus.

Bloom Syndrome

Treatment of Bloom syndrome is symptomatic and includes immediate treatment of infections and periodic surveillance for cancer; patients should avoid sun and radiation exposure.

Fanconi Anemia

Management of Fanconi anemia focuses on managing bone marrow failure, cancer surveillance, and control of organ dysfunction. The only curative option for this condition is allogeneic hematopoietic cell transplantation. Supportive therapeutic options include androgen therapy to increase blood cell count, the use of granulocyte colony-stimulating factor, and blood product transfusions.[33]

Nijmegen Breakage Syndrome

Management of Nijmegen breakage syndrome focuses on symptomatic treatment. Prompt management of immunodeficiency as appropriate with antibiotics and intravenous immunoglobulins to reduce morbidity and mortality in Nijmegen breakage syndrome patients.[34]

Differential Diagnosis

Ataxia-Telangiectasia

The differential diagnoses of ataxia-telangiectasia include:

• Cerebral palsy
• Friedreich ataxia
• Gaucher disease
• Niemann-Pick disease

Bloom Syndrome

The differential diagnoses of Bloom syndrome include other disorders that present with short stature, including:

• Skeletal dysplasia
• Growth hormone deficiency
• Constitutional delay

Fanconi Anemia

The differential diagnoses of Fanconi anemia 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
• Nijmegen breakage syndrome
• Bloom syndrome
• Ataxia-telangiectasia
• DNA ligase IV syndrome 
• Non-homologous end-joining factor 1 deficiency 
• Seckel syndrome (ATR)
• Roberts syndrome (ESCO2)
• Warsaw breakage syndrome (DDX11)
• De novo myelodysplastic syndrome 

Nijmegen breakage syndrome

The differential diagnoses of Nijmegen breakage syndrome include:

• Ataxia-telangiectasia
• Ataxia-telangiectasia–like disease
• Fanconi anemia
• Bloom syndrome
• RAD50 deficiency
• Seckel syndrome [35][36]

Cancers in Chromosomal Instability Disorders 

Differentials for cancers in chromosomal instability disorders include cancer syndromes secondary to oncogene and tumor suppressor gene mutations.[37][38]

Prognosis

The prognoses for these chromosomal instability syndromes are as follows:

• Ataxia-Telangiectasia: This condition has a variable rate of progression; with the classic form, most patients have a poor quality of life and high mortality by early adulthood. 
• Bloom Syndrome: Most patients with Bloom syndrome survive to adulthood; cancer surveillance has demonstrated an association with improved outcomes.
• Fanconi anemia: This condition is stratified and managed based on the severity of bone marrow failure.
• Nijmegen breakage syndrome: This condition depends on the severity of the patient's symptoms and infection management strategies.

Complications

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 to a better prognosis for 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.