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Nijmegen breakage syndrome is a rare genetic disease presenting at birth with microcephaly, dysmorphic facial features, becoming more noticeable with age, growth delay, and later-onset complications such as malignancies and infections. Prevalence and incidence are not known. 150 patients have been reported in the literature but many more are recorded in patient registries. The disease seems to occur worldwide, but has a much higher prevalence among Central and Eastern European Slavic populations due to a founder mutation. Clinical manifestations are not pathognomonic and may vary in severity. The main signs are microcephaly, present at birth and progressing with age, dysmorphic facial features (prominent midface emphasized by a sloping forehead and receding mandible). Other facial characteristics are more subtle and diverse, e.g. upwardly slanted palpebral fissures, long and beaked nose or short nose with anteverted upturned nostrils. In a few patients, cleft lip/palate or choanal atresia have been described. Mild growth retardation, and, in females, premature ovarian insufficiency are common. Minor skeletal anomalies, such as clinodactyly of the 5th fingers and partial syndactyly of the 2nd and 3rd toes are found (50% of patients). Delayed speech development is common. Café au lait spots and/or vitiligo spots are observed (50-70%). Hair in NBS is usually thin and sparse in infancy but improves with age. Hair greying can appear as early as in the 2nd or 3rd decade. Congenital renal anomalies (hypoplasia/aplasia, horseshoe or double kidney, ectopic/dystopic kidneys) are relatively frequent. Hypospadias, cryptorchidism, urethro-anal fistula are also found. Immune deficiency with recurrent respiratory tract infections that may be life-threatening and a strong predisposition to malignancies (predominantly lymphoid) and radiosensitivity are other integral manifestations. By age 20, over 40% of patients develop a malignant disease. NBS is caused by mutations in the NBN gene (8q21-q24) which lead to partially functional truncated fragments of nibrin, the gene product involved in repairing DNA double strand breaks. Diagnosis is based on the clinical manifestations, chromosomal instability (spontaneous and induced), increased cellular sensitivity to ionizing radiation in vitro, combined immunodeficiency, mutations in both alleles of the NBN gene, and complete absence of full-length nibrin. Early diagnosis is very important to avoid severe recurrent infections, unnecessary exposure to radiation for diagnostic purposes, and adverse effects of radiotherapy for treatment of tumors. Analysis of the family pedigree can also support diagnosis (malignancies, microcephaly or hydrocephaly, early death of a sibling). Molecular testing confirms diagnosis. Differential diagnosis includes Fanconi anemia, Bloom syndrome, NBS-like disorder, ataxia-telangectasia-like disorder, LIG4 syndrome, NHEJ1 syndrome and Seckel syndrome (see these terms). Affected families may be offered prenatal diagnosis by molecular analysis if both disease-causing gene mutations are known. Parents of an affected child are obligate carriers of NBN mutations (25% risk for each pregnancy). Parents should be offered monitoring for cancer. NBS follows an autosomal recessive pattern of inheritance. There is no specific therapy for NBS. Due to the specific defect underlying immune deficiency and sensitivity to IR radiation, patients require multidisciplinary management and long term follow-up (malignancy, immunodeficiency, growth, hypergonadotropic hypogonadism in females). Prognosis is poor, with malignancy as the major cause of death.
Quelle: Orphanet: an online rare disease and orphan drug data base. Copyright, INSERM 1997. Available on Accessed 25.04.2014

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