An adult patient with Nijmegen Breakage Syndrome and Hodgkin's Lymphoma

Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive DNA repair disorder [1] characterized by a 5 bp deletion in the NBS1 gene on chromosome 8q21, which leads to a truncated and insufficiently functioning protein Nibrin [2]. By mediating the phospho ATM-driven assembly of BRCA, MRE11 and Rad50 on double strand breaks, nibrin carries a central role in the cellular response to DNA damage [3]. Homozygous state of the above mentioned mutation causes immune deficiency, microcephaly, mental retardation and a disposition for the development of leukemias as well as Hodgkin and Non-Hodgkin lymphomas (HL; NHL) [4–6]. To the best of our knowledge we here describe the first adult patient with NBS and HL.

NBS is an autosomal recessive DNA repair disorder similar to Ataxia Teleangiectasia (AT), which predisposes for the development of HL and NHL. So far, 25 pediatric, adolescent and young adult patients with DNA repair disorder – Ataxia Teleangiactasia or Nijmegen Breakage Syndrome - and HL have been identified [8, 9]. The median age at time of diagnosis was 9.4 years with two ATM patients being of adult age (20 and 25 years). One NBS patient with HL described in the literature was six years old and died 12 months after diagnosis [8]. The other, a five-year old, however, reached sustained remission after intensive chemotherapy [10]. To the best of our knowledge we here describe the first adult patient with NBS and HL.

Although the pathogenetic basis of both conditions resemble each other, NBS and AT display distinct clinical features. NBS, first described in 1981 [11], is characterized by microcephaly, typical facies, immunodeficiency, and chromosomal instability [1]. It lacks the typical cerebellar ataxia that lends its name to AT, but shares the tendency to develop lymphoid malignancies [6, 12].

Our patient was affected with microcephaly, reduced intelligence and the typical craniofacial features but never suffered from severe infectious complications despite the lymphocytopenia, IgG4 deficiency and chromosomal instability. When sequencing of the NBS1 gene was performed at the time of diagnosis no known mutations were identified. Parental genotyping was declined. The patient was thus included into the Nijmegen Breakage Registry based on clinical signs and symptoms, i.e. microcephaly, immunodeficiency and chromosomal instability. Among the cases published within the first report of the Nijmegen Breakage Registry in 2000 [7], in nine out of 55 (16%) patients no mutation was identified and 37 children (67%) presented without a family history.

The overall mild phenotype might explain the late onset of malignant disease: with an age of 23 years he is the second oldest patient with HL and DNA repair disorder described so far. The most common NBS1 mutation (c.675del5) is hypomorphic [13] and indirectly leads to a N terminally truncated, alternatively translated NBS protein (p70), the level of which determines damage sensitivity in lymphoid cells. Likewise, our patient’s genetic aberration might give rise to a particularly high level of functioning truncated Nibrin protein. However, the genotype-phenotype correlation is unsatisfactory [7] and our patient’s mild phenotype in childhood and adolescence was probably more predictive for treatment tolerance and success than the genetic background could have been.

Although the majority of patients with DNA repair disorder and HL are diagnosed in a far advanced stage of the malignancy [14] the presence of multi organ failure in this clinical setting has not been reported so far. While liver failure was clearly due to HL infiltration, the origin of renal failure could have been a consequence of either sepsis or high cell turn-over but was certainly aggravated by hypovolemia (high fever without adequat fluid substitution) and hepato-renal mechanisms. Tumor infiltration of the kidneys appears unlikely as this was not identified on magnetic resonance scan. Patients with stage IV disease at diagnosis (HL or NHL or other malignancies accompanying this disorder) never survived more than half a year [14]. In our case, the early and rather aggressive initial treatment (anthracyclin, vinca alkaloid and alkylating agent) completely restored organ function by leading to fast and sustained remission of HL. However, the patient described here suffered from two episodes of severe infection, both from fungi rather than bacteria. It has been described that the incidence of fungal infections is higher in NBS patients due to reduced cellular and humoral immunity [15]. In our patient, who had never suffered from infectious complications before, chemotherapy-induced neutropenia might have tipped him over the edge to systemic fungal infection.

Although the patient might have to face secondary malignancy from treatment within the next years, the hitherto clinical course provides strong support for an initial standard ABVD treatment strategy in patients with underlying DNA repair disorder. Importantly, additional iatrogenic DNA damage should be avoided using clinical examination as well as MRT or PET-MRT instead of CT for imaging.

In summary, this is – to the best of our knowledge - the first adult patient with NBS and HL described so far. Despite presenting with multiple organ failure and stage IV disease, he achieved sustained remission with early standard chemotherapy.

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. At the time of publication the patient himself was able to evaluate his consent despite his mild mental retardation. However, during the course of his disease, he was legally represented by his parents. Therefore, consent for publication of this work was also obtained from them. A copy of the written consent is available for review by the Editor of this journal.