Sections

Workup

Laboratory Studies

Systematic screening for Epstein-Barr virus, cytomegalovirus, hepatitis B virus, and hepatitis C virus is recommended (once a year or when infection is suspected).

Basis for diagnosis

The diagnosis is based on the characteristic phenotype and laboratory results. Laboratory studies helpful in diagnosing Nijmegen breakage syndrome include cytogenetic analysis, an evaluation of humoral and cellular immunity, and radiation-sensitivity testing. Molecular genetic analysis enables definite confirmation.

Cytogenetic analysis

Cytogenetic analysis allows detection of chromosomal instability, which is a characteristic feature of the disease, although the poor response of T lymphocytes to mitogens can often make diagnosis difficult.

In general, the constitutional karyotypes of patients with Nijmegen breakage syndrome are normal (46,XX or 46,XY). However, in a high proportion of phytohemagglutinin-stimulated lymphocytes (10-60%), spontaneous structural chromosomal rearrangements are observed (QFQ or GTG banding), as well as other aberrations such as chromatid and/or chromosome breaks and acentric fragments (after Giemsa-staining).

Most of these rearrangements specifically involve chromosomes 7 and 14, with breakpoints at bands 7p13, 7q35, 14q11, and 14q32, which are identical to those found in persons with ataxia-telangiectasia (A-T).

Immunoglobulin chain and T-cell receptor genes are located at these sites. The most frequently and constantly detected aberration is inv(7)(p13q35), followed by translocations 7/14, 7/7, and 14/14.

Immunologic testing

Diagnostic evaluation of the immunological profile is required at the time of diagnosis. Afterwards, the evolution of humoral (every 6 mo) and cellular immunity (once a year) needs to be systematically monitored (until immunoglobulin administration or immunomodulating therapy is started).

Evaluation of humoral immunity should include measurements of serum immunoglobulin levels (immunoglobulin G [IgG], immunoglobulin A [IgA], immunoglobulin M [IgM]) and IgG subclass levels. The most frequently observed defects are the combined deficit of IgG and IgA, followed by an isolated IgG deficiency. The most characteristic feature of humoral disturbances is a deficiency in one or more IgG subclasses, even with total IgG levels in the reference range; selective deficiency of IgG4 and IgG2 are the most common.^[56]

Evaluation of cell-mediated immunity should include measurements of T-cell lymphocyte subpopulations (CD3⁺, CD4⁺, CD8⁺, CD4⁺/CD8⁺; CD4/CD45RA⁺, CD4/CD45RO⁺), B cells (CD19⁺), and natural killer cells (CD16⁺, CD56⁺) and an assessment of the proliferative response to mitogens or antigens (phytohemagglutinin, anti-CD3). T-cell immunity is impaired in most patients with Nijmegen breakage syndrome.^[84]The most commonly reported defects are mild-to-moderate lymphopenia, expressed as a low percentage of CD3⁺ T cells, a low proportion of CD4⁺ (helper) T cells, and a decreased CD4⁺/CD8⁺ ratio. A deficiency of CD4/CD45RA⁺ (naive) cells and an excess of CD4/CD45RO⁺ (memory) cells has been observed, and a high number of natural killer cells has been noted in a proportion of patients.^[85]

Alpha-fetoprotein determination

Serum alpha-fetoprotein levels are within the reference range in patients with Nijmegen breakage syndrome, in contrast to elevated concentrations in approximately 90% of patients with A-T.

IR and RDS sensitivity analysis

IR induces a variety of DNA lesions, including single-strand breaks and DSBs. Some laboratories use the increased sensitivity of different types of cells (eg, lymphoblastoid cell lines [LCLs], cultured skin fibroblasts) to IR or to the radiomimetic agent bleomycin to confirm the diagnosis of Nijmegen breakage syndrome.

The increased frequency of induced chromosomal breakage in lymphocytes and fibroblasts clearly differentiates Nijmegen breakage syndrome cells from healthy cells. In a colony survival assay, Nijmegen breakage syndrome cells are 3-5 times more radiosensitive than control cells.

Examination of DNA replication in irradiated Nijmegen breakage syndrome cells, as well as cells in A-T and A-T–like disorder, reveals the phenomenon of RDS, which reflects a defect in control of the S-phase progression until the repair of DNA damage is complete.^{[10, 12]}

Immunoblotting assay

Western blotting allows demonstration of the presence or absence of the p95/nibrin protein in LCLs.^{[18, 20]}

Molecular genetic analysis

The cloning of the NBN (NBS1) gene, which was accomplished in 1998, provides the basis for both postnatal and prenatal diagnosis by means of mutation analysis.

The demonstration of disease-causing mutations in both alleles of the NBN gene is required for definitive confirmation of Nijmegen breakage syndrome.

In more than 90% of patients tested so far, the common c.657_661del5 mutation is homozygous. The remaining patients have a heterozygous c.657_661del5 deletion and a second unique mutation or a homozygous unique mutation.

Testing for the c.657_661del5 mutation is available on a clinical basis (and is always performed first); tests for other mutations are used in research studies.

In the United States, approximately 70% of individuals tested to date are homozygous for the common allele c.657_661del5, a further 15% are heterozygous for c.657_661del5 and a second unique mutation, and the remaining 15% are homozygous for a unique mutation. See GeneReviews, Nijmegen Breakage Syndrome .

If further testing is requested, an LCL is established and the nuclear lysate is analyzed by means of Western blot for nibrin and by colony survival assay for radiosensitivity. If nibrin is absent or truncated and the cells are sensitive to IR, DNA is analyzed by direct sequencing for NBS1 mutations.

Table 2. Selected NBN Gene Pathogenic Molecular Variants (Open Table in a new window)

Mutation	Exon	Mutation Type	Change in Protein	Number of Families and Origin	Allelic Status
c.643C>T	6	Missense	R215W	1^a Czech	He^b
c.657_661del5 (657del5)	6	Frameshift	Truncated protein (233 aa)	>90% Slavic founder mutation	Ho^c (He)
c.681delT	6	Frameshift	Truncated protein (229 aa)	1 Russian	He
c.698_701del4 (698del4)	6	Frameshift	Truncated protein (236 aa)	2 English	Ho He
c.742_743insGG (742insGG)	7	Frameshift	Truncated protein (251 aa)	1 Italian	Ho
c.835_838del4 (835del4)	7	Frameshift	Truncated protein (279 aa)	1 Italian	Ho
c.842_843insT (842insT)	7	Frameshift	Truncated protein (283 aa)	1 Mexican	Ho
c.900_924del25 (900del25)	8	Frameshift	Truncated protein (305 aa)	1 Moroccan	Ho
c.976C>T	8	Nonsense	Q326X	1 Dutch	Ho
c.1089C>A	9	Nonsense	Y363X	3^d Pakistani	Ho
c.1142delC	10	Frameshift	Truncated protein (402 aa)	2 Canadian	He
^aMonozygotic twin-brothers (compound heterozygotes) with severe disease phenotype.^[86] ^bHe - Heterozygous (compound with 657del5). ^cHo - Homozygous. ^dThree nuclear families in 1 large family; proband diagnosed first as having Fanconi anemia (FA).^{[47, 48]}

Endocrinologic evaluation

Ovarian failure is expected in most female patients with Nijmegen breakage syndrome.^{[13, 54]} A study of the pituitary-gonadal axis (ie, plasma concentrations of follicle-stimulating hormone [FSH], luteinizing hormone, and estradiol [E2]) in females reaching pubertal age is recommended. A serum FSH level exceeding 40 IU/L and a low E2 level indicate ovarian failure (hypergonadotropic hypogonadism).

Imaging Studies

Because patients with Nijmegen breakage syndrome have an inherited hypersensitivity to IR, CT scanning is contraindicated; therefore, MRI and ultrasonography are the methods of choice when imaging studies are necessary.

Cranial MRI may reveal CNS developmental abnormalities or solid tumor.

MRI of chest or abdomen/pelvis allows demonstration/detection of a tumor mass.

Ultrasonography of the abdomen depicts urinary tract abnormalities, multiple or accessory spleens, and enlarged lymph nodes

In general, pelvic ultrasonograms in females show small homoechoic ovaries resembling streaks and an infantile uterus.

Note the images below.

MRI in a patient with Nijmegen breakage syndrome shows large cerebrospinal fluid space that communicates with the left lateral ventricle and underdevelopment of the parietal lobes. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.

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MRI in a patient with Nijmegen breakage syndrome. Note compression of the posterior fossa and the lack of cerebellar atrophy. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.

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MRI in a patient with Nijmegen breakage syndrome. Note the small frontal lobes and the narrow frontal horns of the lateral ventricles. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.

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Histologic Findings

Data yielded from histopathologic analysis of tissue biopsy and autopsy specimens from patients with Nijmegen breakage syndrome are limited. Findings suggestive of a lymphoproliferative disorder are the most common indications for lymph node biopsy, but only a few reports on the histologic and immunophenotypic features of lymphomas are available. In 2000, Gladkowska-Dura et al reported a detailed study of lymphomas in 11 Nijmegen breakage syndrome patients.^[59]

Although at least 50 patients with Nijmegen breakage syndrome are known to have died, extensive autopsy findings are well documented in only 1 patient, and limited information is available in a few others. Markedly reduced brain weight and thymus dysplasia or aplasia were consistent findings in all cases. No cerebellar degeneration was confirmed, which is in contrast to persons with A-T. A detailed neuropathological study of the first-recognized Nijmegen breakage syndrome case was reported by Lammens et al^[87]in 2003.

Treatment & Management

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Media Gallery

A 6-month-old infant with Nijmegen breakage syndrome. Note microcephaly, the slightly upward-slanting palpebral fissures, and small chin.
Lateral facial features with sloping forehead and receding mandible are shown in a 6-month-old infant.
Typical facial features in a 9-year-old girl with Nijmegen breakage syndrome. Note the markedly upward-slanting palpebral features.
Lateral profile. This view shows a relatively long nose and receding mandible.
Cutaneous sarcoidosis in a patient with Nijmegen breakage syndrome. Note syndactyly of the second and third toes.
Vitiligo spots in a patient with Nijmegen breakage syndrome.
Progressive vitiligo in a patient with Nijmegen breakage syndrome.
Café au lait–like spots in a patient with Nijmegen breakage syndrome.
Preaxial polydactyly of the hand in a patient with Nijmegen breakage syndrome.
MRI in a patient with Nijmegen breakage syndrome shows large cerebrospinal fluid space that communicates with the left lateral ventricle and underdevelopment of the parietal lobes. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
MRI in a patient with Nijmegen breakage syndrome. Note compression of the posterior fossa and the lack of cerebellar atrophy. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
MRI in a patient with Nijmegen breakage syndrome. Note the small frontal lobes and the narrow frontal horns of the lateral ventricles. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
MRI in a patient with Nijmegen breakage syndrome. Note the partial defect of the corpus callosum. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.

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Table 1.Syndromes to be Considered in the Differential Diagnosis of Nijmegen Breakage Syndrome

Clinical and Cellular Phenotype	Nijmegen Breakage Syndrome	Nijmegen Breakage Syndrome‒Like Disorder ^{[39, 77]}	DNA LIG4 Deficiency ^{[37, 38, 78]}	NHEJ1 Syndrome ^{[40, 41]}	XRCC4 Deficiency ^{[42, 43]}	Fanconi Anemia ^{[47, 48, 79]}	Warsaw Breakage Syndrome ^{[80, 81]}	Bloom Syndrome ^{[82, 83]}
Online Mendelian Inheritance in Man (OMIM)	251260	604040	606593	611291	616541	227650	613398	210900
Gene	NBN	RAD50	DNA LIG4	NHEJ1	XRCC4	FANC^a	DDX11	RECQL3
Microcephaly	Severe, disproportionate	Severe	Severe	Severe	Severe	In ~30%	Severe, disproportionate	Severe, proportionate
Growth Deficiency	Mild to moderate	Severe	Moderate to severe	Severe	Severe, disproportionate	Mild to moderate	Severe	Severe
Congenital Malformations	Heart, kidney, polydactyly	Not reported	Polydactyly, syndactyly	Polydactyly	Not reported	Heart, kidney radial bone defects (~50%)	Heart	Kidney, polydactyly
Puberty and Fertility	Primary amenorrhea (hypergonadotropic hypogonadism)	Normal puberty	Amenorrhea	Not reported	Primary amenorrhea	Males, infertility; females, early menopause	Normal puberty	Males, infertility; females, early menopause
Other Endocrinologic Problems	Not reported	Not reported	Hypothyroidism, type 2 diabetes	Not reported	Early-onset metabolic syndrome	Type 2 diabetes mellitus	Not reported	Type 2 diabetes mellitus
Recurrent Infections	Yes	No	Rare	Yes	No	No	No	Yes
Immunodeficiency	Combined (B- and T-cell)	No	Combined (B- and T-cell)	Combined (B- and T-cell)	No	No	No	B-cell type
Hematologic Findings	Myelodysplastic syndrome (incidentally)	Not reported	Pancytopenia, myelodysplastic syndrome	Pancytopenia, myelodysplastic syndrome	Thrombocytopenia, pancytopenia	Progressive bone marrow failure, myelodysplastic syndrome	Not reported	Myelodysplastic syndrome
Malignancy Type	Predominantly lymphoid origin	Not reported	Predominantly lymphoid origin	Not reported	Tumor	Acute myeloid leukemia, solid tumors (early onset)	Not reported	Lymphoid origin, acute myeloid leukemia, solid tumors
Chromosomal Instability	Breakages, including 7/14 rearrangements	Breakages, 7/14 rearrangements	Breakages, no 7/14 rearrangements	Breakages, not specified	Not reported	Breakages, figures (asymmetric)	Breakages and cohesinopathy	Breakages, figures (symmetric), high sister chromatid exchange rate
Sensitivity to Damaging Agents (in vitro)	Ionizing radiation, bleomycin; mitomycin C and diepoxybutane, mild	Ionizing radiation, bleomycin	Ionizing radiation, bleomycin	Ionizing radiation (variable)	Ionizing radiation (extreme)	Mitomycin C and diepoxybutane; ionizing radiation, mild	Mitomycin C, camptothecin	Ultraviolet
Mental Retardation	Mild to moderate	Moderate	Mild to moderate	Yes, not defined	Moderate to severe	Moderate to severe	Moderate to severe	Normal to mild
^aFANC: Genetic and phenotypic heterogeneity; 19 genes known (OMIM).

Table 2. Selected NBN Gene Pathogenic Molecular Variants

Mutation	Exon	Mutation Type	Change in Protein	Number of Families and Origin	Allelic Status
c.643C>T	6	Missense	R215W	1^a Czech	He^b
c.657_661del5 (657del5)	6	Frameshift	Truncated protein (233 aa)	>90% Slavic founder mutation	Ho^c (He)
c.681delT	6	Frameshift	Truncated protein (229 aa)	1 Russian	He
c.698_701del4 (698del4)	6	Frameshift	Truncated protein (236 aa)	2 English	Ho He
c.742_743insGG (742insGG)	7	Frameshift	Truncated protein (251 aa)	1 Italian	Ho
c.835_838del4 (835del4)	7	Frameshift	Truncated protein (279 aa)	1 Italian	Ho
c.842_843insT (842insT)	7	Frameshift	Truncated protein (283 aa)	1 Mexican	Ho
c.900_924del25 (900del25)	8	Frameshift	Truncated protein (305 aa)	1 Moroccan	Ho
c.976C>T	8	Nonsense	Q326X	1 Dutch	Ho
c.1089C>A	9	Nonsense	Y363X	3^d Pakistani	Ho
c.1142delC	10	Frameshift	Truncated protein (402 aa)	2 Canadian	He
^aMonozygotic twin-brothers (compound heterozygotes) with severe disease phenotype.^[86] ^bHe - Heterozygous (compound with 657del5). ^cHo - Homozygous. ^dThree nuclear families in 1 large family; proband diagnosed first as having Fanconi anemia (FA).^{[47, 48]}

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Author

Krystyna H Chrzanowska, MD, PhD Professor and Head of Genetic Counseling Unit, Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland

Krystyna H Chrzanowska, MD, PhD is a member of the following medical societies: European Association for Cancer Research, European Society of Human Genetics, Polish Academy of Sciences, Polish Genetics Society, Polish Pediatric Society, Polish Society of Human Genetics

Disclosure: Nothing to disclose.

Coauthor(s)

Camila K Janniger, MD Clinical Professor of Dermatology, Clinical Associate Professor of Pediatrics, Chief of Pediatric Dermatology, Rutgers New Jersey Medical School

Camila K Janniger, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

David F Butler, MD Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Association of Military Dermatologists, Phi Beta Kappa, Texas Dermatological Society

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, New York Academy of Medicine, Royal College of Physicians of Edinburgh, Sigma Xi, The Scientific Research Honor Society

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.

Additional Contributors

Noah S Scheinfeld, JD, MD, FAAD † Assistant Clinical Professor, Department of Dermatology, Weil Cornell Medical College; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Assistant Attending Dermatologist, New York Presbyterian Hospital; Assistant Attending Dermatologist, Lenox Hill Hospital, North Shore-LIJ Health System; Private Practice

Noah S Scheinfeld, JD, MD, FAAD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.