eMedicine Specialties > Dermatology > Pediatric Diseases
Nijmegen Breakage Syndrome: Differential Diagnoses & Workup
Updated: Oct 23, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Differential Diagnoses
Ataxia-Telangiectasia
Bloom Syndrome (Congenital Telangiectatic
Erythema)
Severe Combined Immunodeficiency
Other Problems to Be Considered
Primary microcephaly
Fanconi anemia
Ligase IV (LIG4) syndrome
Nijmegen breakage syndrome–like (RAD50 deficiency) disorder
Seckel syndrome
Dubowitz syndrome
A-T–like disease
Congenital cytomegalovirus infection
Workup
Laboratory Studies
- Basis for diagnosis of Nijmegen breakage syndrome (NBS)
- 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 for Nijmegen breakage syndrome
- 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 for Nijmegen breakage syndrome
- 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.41
- 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. 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.58
- 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 for Nijmegen breakage syndrome
- 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.4,6
- Immunoblotting assay: Western blotting allows demonstration of the presence or absence of the p95/nibrin protein in LCLs.12,14
- Molecular genetic analysis for Nijmegen breakage syndrome
- The cloning of the 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 NBS1 gene is required for definitive confirmation of Nijmegen breakage syndrome.
- In more than 90% of patients tested so far, the common 657del5 mutation is homozygous. The remaining patients have a heterozygous 657del5 deletion and a second unique mutation or a homozygous unique mutation.
- Testing for the 657del5 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 657del5, a further 15% are heterozygous for 657del5 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.
- NBS1 Gene Pathogenic Molecular Variants
Open table in new window
[ CLOSE WINDOW ]Table
Mutation Exon Mutation Type Change in Protein Number of Families and Origin Allelic Status 643C>T 6 Missense R215W 1†
CzechHe* 657del5
(657_661del5)6 Frameshift Truncated
protein (233 aa)>90%
Slavic
founder mutationHo‡
(He)681delT 6 Frameshift Truncated
protein (229 aa)1
RussianHe 698del4
(698_701del4)6 Frameshift Truncated
protein (236 aa)2
EnglishHo
He742insGG
(742_743insGG)7 Frameshift Truncated
protein (251 aa)1
ItalianHo 835del4
(835_838del4)7 Frameshift Truncated
protein (279 aa)1
ItalianHo 842insT
(842_843insT)7 Frameshift Truncated
protein (283 aa)1
MexicanHo 900del25
(900_924del25)8 Frameshift Truncated
protein (305 aa)1
MoroccanHo 976C>T 8 Nonsense Q326X 1
DutchHo 1089C>A 9 Nonsense Y363X 3
§
PakistaniHo 1142delC 10 Frameshift Truncated
protein (402 aa)2
CanadianHe *He - Heterozygous (compound with 657del5).Mutation Exon Mutation Type Change in Protein Number of Families and Origin Allelic Status 643C>T 6 Missense R215W 1†
CzechHe* 657del5
(657_661del5)6 Frameshift Truncated
protein (233 aa)>90%
Slavic
founder mutationHo‡
(He)681delT 6 Frameshift Truncated
protein (229 aa)1
RussianHe 698del4
(698_701del4)6 Frameshift Truncated
protein (236 aa)2
EnglishHo
He742insGG
(742_743insGG)7 Frameshift Truncated
protein (251 aa)1
ItalianHo 835del4
(835_838del4)7 Frameshift Truncated
protein (279 aa)1
ItalianHo 842insT
(842_843insT)7 Frameshift Truncated
protein (283 aa)1
MexicanHo 900del25
(900_924del25)8 Frameshift Truncated
protein (305 aa)1
MoroccanHo 976C>T 8 Nonsense Q326X 1
DutchHo 1089C>A 9 Nonsense Y363X 3
§
PakistaniHo 1142delC 10 Frameshift Truncated
protein (402 aa)2
CanadianHe
†Monozygotic twin-brothers (compound heterozygotes) with severe disease phenotype.59
‡Ho - Homozygous.
§Three nuclear families in 1 large family; proband diagnosed first as having Fanconi anemia (FA).55,56
- Endocrinologic evaluation in Nijmegen breakage syndrome
- Ovarian failure is expected in most female patients with Nijmegen breakage syndrome.7,40
- 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).
- Systematic screening for Epstein-Barr virus, cytomegalovirus, hepatitis B virus, and hepatitis C virus is recommended (once a year or when infection is suspected).
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.
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. Also see Media Files 11-13. 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. Also see Media Files 10, 12, and 13. 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. Also see Media Files 10, 11, and 13. 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. Also see Media Files 10-12. Reprinted with permission from the Journal of Medical Genetics. Copyright 2001, BMJ Publishing Group.
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.42
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 al60 in 2003.
More on Nijmegen Breakage Syndrome |
| Overview: Nijmegen Breakage Syndrome |
 Differential Diagnoses & Workup: Nijmegen Breakage Syndrome |
| Treatment & Medication: Nijmegen Breakage Syndrome |
| Follow-up: Nijmegen Breakage Syndrome |
| Multimedia: Nijmegen Breakage Syndrome |
| References |
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References
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Further Reading
Keywords
Nijmegen breakage syndrome, Nijmegen's breakage syndrome, NBS, Berlin breakage syndrome, BBS, Seemanova syndrome, ataxia-telangiectasia, AT-V1, AT-V2, A-T, congenital microcephaly, congenital immunodeficiency, chromosomal instability, microcephaly, microcephaly with normal intelligence, lymphoreticular malignancy, MIM 251260, OMIM 251260, MIM 602667, OMIM 602667
