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Whilst global prevalence is unknown, the disease seems to occur worldwide, but has a much higher prevalence among Central and Eastern European Slavic populations due to a founder mutation. Average prevalence of NBS in patients with Eastern Slavic origin (Belarus, Ukraine, Russia, and Latvia) was recently estimated as 1/1,000,000 and, based on carrier frequency, the prevalence in the Western Slavic region (Poland, Slovakia and Czech Republic) is estimated at 1/330,000.

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), mild growth retardation and, in females, premature ovarian insufficiency are common. Various congenital anomalies have been reported, including central nervous system (hydrocephaly, schizencephaly, arachnoid cysts), respiratory tract (cleft lip/palate, choanal atresia), urogenital system (horseshoe kidney, ectopic/dystopic kidneys, hypospadias, cryptorchidism, ovary hypoplasia), mild skeletal anomalies (pre- and postaxial polydactyly, hypoplastic or duplicated thumb, clinodactyly of 5th fingers). Café au lait and/or vitiligo spots are frequently observed and, in some patients, multiple pigmented nevi occur. Other principal manifestations include immune deficiency with recurrent respiratory tract infections, a strong predisposition to malignancies (predominantly lymphoid, but solid tumors also occur), and radiosensitivity. By age 20, over 40% of patients develop a malignant disease and are prone to develop secondary malignancies. Cognitive development is close to the average (normal/borderline) in infancy and preschool age, but intellectual skills gradually decline with age (from mild to moderate).

Nijmegen breakage syndrome (NBS) is caused by mutations in the NBN gene (8q21-q24), specifically within exons 6-10, which lead to partially functional truncated fragments of nibrin, the gene product involved in repairing DNA double strand breaks. Over 90% of patients are homozygous for the founder mutation of Slavic origin (c.657_661del5).

Diagnosis is based on the clinical manifestations and confirmed by either single gene sequencing (typically for Slavic populations) or multigene next generation sequencing panels. Where genetic testing is unavailable, diagnosis can be supported by evidence of chromosomal instability (spontaneous and induced), increased cellular sensitivity to ionizing radiation in vitro, combined immunodeficiency, and complete absence of full-length nibrin. A family history (malignancies, microcephaly or hydrocephaly, early death of a sibling) can also support diagnosis.

Differential diagnosis includes Fanconi anemia, LIG4 syndrome, Cernunnos-XLF deficiency, NBS-like disorder, ataxia-telangiectasia-like disorder, Bloom syndrome.

Affected families may be offered prenatal diagnosis by molecular analysis if both disease-causing gene mutations are known.

The pattern of inheritance is autosomal recessive. Parents of an affected child are obligate carriers of NBN mutations and thus, for each pregnancy, there is a 25% risk that offspring inherit the disease. Carriers of a Slavic founder mutation should be offered monitoring for cancer, in particular breast in women and prostate in men.

There is no specific therapy. Early diagnosis is important to avoid severe recurrent infections, unnecessary radiation exposure for diagnostic purposes and adverse effects of radiotherapy of tumors. Patients require multidisciplinary management and long-term follow-up (malignancy, immunodeficiency, growth, hypergonadotropic hypogonadism in females). Monitoring of the immune system is extremely important throughout life; specific modes and types of immunization are necessary (acellular vaccines are recommended). In case of lymphoid malignancy, hematopoietic stem cell transplantation (HSCT) is recommended after the first complete remission. Females should be monitored for puberty progress from the age of 12 (endocrinologist/ gynecologist) and hormonal replacement therapy should be offered at appropriate age.

Prognosis is poor, with malignancy as the major cause of death. Patients who developed lymphoma or leukemia died from disease progression, relapses and secondary malignancies. A beneficial effect of HSCT on the long-term survival has been confirmed in recent studies.