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Nijmegen Breakage syndrome
Was ist Nijmegen Breakage syndrome?
It is a rare genetic syndrome that seems to be more prevalent amongst the Slavic populations of Eastern Europe. It is defined by a short stature, a very small head, intellectual disability and an increased risk of cancer.
This syndrome is also known as:
Ataxia-telangiectasia Variant V1; At-v1 Immunodeficiency, Microcephaly, And Chromosomal Instability Microcephaly With Normal Intelligence, Immunodeficiency, And Lymphoreticular Malignancies Nbs Nonsyndromal Microcephaly, Autosomal Recessive, With Normal Intelligence Seemanova Syndrome II
Was Genveränderungen verursachen Nijmegen Breakage syndrome?
Veränderungen im NBN-Gen sind für die Auslösung des Syndroms verantwortlich. Es wird autosomal-rezessiv vererbt.
Autosomal-rezessive Vererbung bedeutet, dass eine betroffene Person von jedem ihrer Elternteile eine Kopie eines mutierten Gens erhält, wodurch sie zwei Kopien eines mutierten Gens erhält. Eltern, die nur eine Kopie der Genmutation tragen, zeigen im Allgemeinen keine Symptome, haben jedoch eine 25% ige Chance, die Kopien der Genmutationen an jedes ihrer Kinder weiterzugeben.
Was sind die wichtigsten symptome von Nijmegen Breakage syndrome?
Slow growth during infancy is one of the main symptoms of the syndrome. The rate of growth usually normalizes after early childhood but affected individuals remain shorter than average.
Distinct facial features of the syndrome include a very small head, a sloping forehead, prominent nose, large ears, and a small jaw. These distinct features are usually noticed in early childhood.
The syndrome also presents with an immune system that does not function properly due to low levels of immune system proteins. This in turn leads to a shortage of immune system cells ( T cells) leaving individuals with the syndrome more susceptible to infections that reoccur. These infections include bronchitis, pneumonia and sinusitis.
Affected individuals also have a higher chance of developing cancer. Specifically non-Hodgkin lymphoma. 50% of affected individuals develop this form of cancer before their 15th birthday. Individuals are also at a higher risk for developing brain tumors and a cancer of the muscle tissue. They are believed to be 50 times more likely to develop cancer than those without the syndrome.
Intellectual disability develops with time, and children who were developing normally tend to regress with their development.
The syndrome also affects the reproductive systems of females leading to delayed puberty and infertility.
Possible clinical traits/features:
Malabsorption, Short stature, Hemolytic anemia, Glioma, Depressed nasal bridge, Freckling, Hearing abnormality, Cognitive impairment, Hyperactivity, Hydronephrosis, Diarrhea, Decreased body weight, Cleft upper lip, Dysgammaglobulinemia, Deep philtrum, Acute leukemia, Anal stenosis, Anal atresia, Skeletal muscle atrophy, Abnormality of the upper urinary tract, Cleft palate, Choanal atresia, Convex nasal ridge, Attention deficit hyperactivity disorder, Autoimmune hemolytic anemia, B lymphocytopenia, Cafe-au-lait spot, Bronchiectasis, Aplasia/Hypoplasia of the thymus, Abnormality of chromosome stability, Abnormal immunoglobulin level, Abnormal nasal morphology, Micrognathia, Mastoiditis, Medulloblastoma, Malar prominence, Lymphoma, Low anterior hairline, Sloping forehead, Long nose, Thrombocytopenia, Muscle weakness, Intellectual disability, Intrauterine growth retardation, Abnormality of neuronal migration, Neurodegeneration, Macrotia, Abnormal hair quantity, Recurrent bronchitis, Rhabdomyosarcoma, Microcephaly
Wie wird jemand getestet? Nijmegen Breakage syndrome?
Die ersten Tests für Nijmegen Breakage syndrome kann mit einem Gesichtsanalyse-Screening beginnen, durch die FDNA Telehealth Telegenetik-Plattform, die die Schlüsselmarker der syndrom und skizzieren Sie die Notwendigkeit weiterer Tests. Es folgt ein Beratungsgespräch mit einem genetischen Berater und dann einem Genetiker.
Basierend auf dieser klinischen Konsultation mit einem Genetiker werden die verschiedenen Optionen für Gentests geteilt und die Zustimmung für weitere Tests eingeholt.
Medizinische Informationen zu Nijmegen Breakage syndrome
Nijmegen Breakage syndrome is characterized by progressive microcephaly, short stature, recurrent respiratory tract infections, premature ovarian failure, intellectual disability, and an increased risk of cancer. This autosomal-recessive disorder is caused by mutations in the NBN gene. Nijmegen Breakage syndrome has cytogenetic features of ataxia-telangiectasia but without the characteristic clinical features.
Two brothers, the offspring of second cousins, were described by Weemaes et al., (1981). They both had mental retardation, short stature, microcephaly, cafe au lait spots and immunodeficiency. The latter consisted of greatly reduced IgG in one case, reduced IgA in both cases and reduced IgE in the one case tested. Other cases have had T-cell deficiency. Cytogenetic studies in the proband revealed multiple rearrangements, mainly involving chromosomes 7 and 14. Similar cytogenetic abnormalities were found in the father and three normal sibs, but with much less frequency. Webster et al., (1982) and Conley et al., (1986) described similarly affected females. Photosensitivity may be another component of the condition.
Barbi et al., (1991) reported a similar case, but without evidence of immunodeficiency. Green et al., (1995) reported sibs with severe microcephaly but normal development in one at the age of 3 years. Chrzanowska et al., (1995) reported eleven cases from Poland. One case developed a B-cell lymphoma. Van der Burgt et al., (1996) provide a good review of the clinical and pathological features of the condition. The immunological abnormalities are characterised by agammaglobulinaemia, IgA deficiency, IgG2 and IgG4 deficiency. There may be lymphopenia with decreased CD3+ and CD4+ (helper) cells and a decreased CD4+: CD8+ (suppressor) cell ratio. The facial features in this condition are somewhat characteristic with a receding forehead, a prominent mid-face, a long nose and philtrum, a receding mandible, upward slanting palpebral fissures, and large ears with malformed helices. Scleral telangiectasia and cutaneous telangiectasia have been noted in some patients. There may be some sensitivity of the eyelids. Freckles are common, particularly on the face. Anal atresia, preaxial polydactyly, hydrocephalus and occipital cyst, choanal atresia, cleft lip and palate, hypospadias, and a single ectopic kidney have been reported in individual cases (reviewed by van der Burgt et al., 1996). Tupler et al., (1997) reported an Italian boy with features of the condition including immunodeficiency and the development of a B cell lymphoma. Chromosomal instability was detected in T and B lymphocytes and fibroblasts but chromosomes 7 and 14 were not preferentially involved. Studies of DNA synthesis after irradiation showed intermediate results between normal and ataxia-telangiectasia cells. The locus does not appear to map to the ataxia-telangiectasia region on 11q23 (Stumm et al., 1995). Saar et al., (1997) and Matsuura et al., (1997) mapped the gene to 8q21. Matsuura et al., (1998) demonstrated mutations in the NBS1 gene that codes for a protein that might be involved in meiotic recombination. A 5bp deletion was found in 13 individuals from Germany, Canada, and the USA, suggesting a founder effect. Cerosaletti et al., (1998) also presented evidence for a founder effect by looking at haplotypes around the gene. Varon et al., (1998) and Carney et al., (1998) found mutations in the same gene which they say codes for p95, a member of the hMre11/hRad50 double-strand break repair complex.
It appears that the ataxia-telangiectasia protein is required for the phosphorylation of the Nijmegen breakage protein gene, induced by ionising radiation (Zhao et al., 2000; Wu et al., 2000). Bekiesinska-Figatowska et al., (2000) reviewed the neuroradiogical findings. Four out of ten patients had agenesis of the corpus callosum. Other features were colpocephaly and dilatation of the temporal horns of the lateral ventricles. Varon et al., (2000) found a carrier frequency of 1 in 177 in three Slav populations. Kleier et al., (2000) report a further case with a homozygous 657del5 mutation. Maser et al., (2001) showed that the common 657del6 frameshift mutation encodes a partially functional protein. Yamada et al., (2001) reported a girl with immunodeficiency, chromosome instability, preaxial polydactyly and growth deficiency. Nijmegen Breakage syndrome was thought to be unlikely because of the absence of hyperpigmented spots and mental retardation. In addition, no mutations were found in the NBS1 gene. Hiel et al., (2001) reported a 20-month-old boy with clinical and cytogenetic features of the condition. However, a mutation in the NBS gene was not found and the protein nibrin was normally expressed. Maraschio et al., (2001) reported a case with proven mutations who had pre-axial polydactyly of the thumb, fifth finger clinodactyly, 4-5 cutaneous syndactyly of the toes, agenesis of the corpus callosum, dilatation of the ventricles and cerebral atrophy. There were also several hypopigmented striae on the back and one hyperpigmented spot. Chrzanowska et al., (2002) pointed out that agenesis of the corpus callosum is quite common. Resnick et al., (2002) studied seven cases from Russia. Six were homozygous for the 657del5 mutation and one was a compound heterozygote with a 657del5 mutation but in addition a 681delT mutation. Resnick et al., (2003) investigated the possibility that carriers may have a cancer predisposition. They found two carriers in 68 patients with lymphoid malignancies but no carriers in 548 controls in a Russian population. They concluded that the preliminary data suggest that NBS1 mutation carriers can be predisposed to malignant disorders. Prenatal diagnosis was achieved by Muschke et al., (2004), after retrospective diagnosis in the deceased first born. Varon et al., (2006) state that the 657del5 mutation accounts for over 90% of patients. They describe a phenotypically mild case, due to alternative splicing. This condition accounts for 13% of primary microcephaly in Czech children (Seeman et al., 2004). Seemanova et al., (2006) reported monozygotic twins, with severe microcephaly (and suture synostosis) intractable seizures, and poor gyration of the brain, who were compound heterozygous for an NBS1 mutation. Chromosome instability was not present.
A radiosensitivity test (or diepoxybutane/mitomycin C) for chromosome breakage needs to be carried out for the diagnosis, but these will also be positive in Fanconi or ataxia telangiectasia-like syndromes (Cale and New, 2007). Many cases develop lymphomas. One patient has developed a glioma and one a medulloblastoma. Maraschio et al., (2003) reported a boy with an NBS clinical phenotype but no mutation in either the NBS1 or the LIG4 genes. The same situation was reported by Berardinelli et al., (2007). Note too, that the patient reported by Barbi et al., (1991) with a Nijmegen-like condition (there were no recurrent or severe infections) has been found (Waltes et al., 2009) to have a RAD50 mutation. MRE111/RAD50/NBN complex is involved in recognizing DNA double-strand breaks. Cystic areas in the brain have been reported (Chrzanowska et al., 2001) and polyarthritis (Pasic et al., 2013)
See Seckel-like syndrome-mitomycin C sensitivity-pancytopenia for a similar or overlapping syndrome.
Wolska-Kuśnierz et al. (2015) published a retrospective analysis on clinical and immunological features and long-term outcome. The main risk factor affecting survival was high incidence of malignancies, mostly non-Hodgkin's lymphomas.
* This information is courtesy of the L M D.
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