Deficiency of Adenosine Deaminase 2 (DADA2) Presenting As Familial Hodgkin Lymphoma

Familial Hodgkin Lymphoma (HL) accounts for 4.5% of HL. Both genetic susceptibility and shared environmental factors can play a role. The usual presentation of HL is cervical lymphadenopathy/ mediastinal mass. Subdiaphragmatic presentation is rare and hepatosplenomegaly is associated with advanced HL.

Adenosine deaminase 2 (ADA2) act as an outside extracellular growth factor for integrity of endothelial cells and in the development of certain immune cells. Deficiency of ADA2 (DADA2) is a recently described inborn error of immunity caused by biallelic mutations in adenosine deaminase 2 (ADA2) gene (formerly known as CECR1). It is an auto-inflammatory disorder with a spectrum of vascular, inflammatory, hematological and immunodeficiency phenotypes. The condition is inherited in an autosomal recessive pattern.The association of DADA2 with lymphoproliferation such asT-LGL like condition and ALPS like disease have been reported, however, HL has not previously been reported in DADA2.

Herein we describe two siblings with DADA2 who presented with Hodgkin Lymphoma. The first patient is the third child of Saudi first degree related parents. He is known to have bronchial asthma on bronchodilators. At the age of 5 years, he was referred from primary care clinic for investigation of hepatosplenomegaly. He was otherwise well with growth along the fifth centile. His complete blood count (CBC) showed mild lymphopenia, other lab results including liver function tests were within normal. Few months later, he developed non-tender mobile cervical lymph nodes enlargement. Viral serology including EBV was negative based on PCR testing. Lymph node biopsy revealed the diagnosis of HL, mixed cellularity type, EBV negative (Figure 1). Whole exome analysis sequencing identified a homozygous variant in ADA2 gene c.1447_1451del. This variant has been confirmed by Sanger sequencing. Plasma assay of ADA2 enzyme activity revealed undetectable levels compatible with ADA2 deficiency.

The patient started on prednisone 2 mg/kg/day, which showed good response in the form of being off blood support and regression of splenomegaly. Few months later, the course was complicated by recurrent infections. The patient remained stable for three years on small dose of prednisone, monthly IVIG due to hypogammaglobulinemia. Recently, etanercept was started to control disease progression.

Nine months after the diagnosis of first patient, his younger brother who is known to have mild bronchial asthma on bronchodilators presented at the age of five years with hepatosplenomegaly and generalized lymphadenopathy. Lymph node biopsy revealed the diagnosis of classical HL, lymphocyte-rich subtype. Similar to his sibling, whole exome analysis identified the same mutation (a homozygous variant in ADA2 gene c.1447_1451del). This variant has been confirmed by Sanger sequencing and plasma level of ADA2 enzyme activity was undetectable. After the diagnosis of DADA2, screening for serum immunoglobulin levels showed hypogammaglobulinemia. The patient continues to be off treatment. Both patients were treated with chemotherapy with or without radiotherapy showing good response and they remained in remission at respectively and months after cessation of chemotherapy.

This study is important for several reasons. First, this is the first report of HL in the context of DADA2. This again widens the clinical spectrum of DADA2. Interestingly, the boys presented two different forms of HL at the cellular level with no evidence of viral infection. The reported siblings presented with subdiaphragmatic diseases, which is uncommon in HL but in line with the sites of lymphoproliferation in DADA2. In addition, the age of presentation in the two siblings is uncommon in HL (less than 10 years).

Second, we report an novel mutation in ADA2 gene. It creates a shift in the reading frame starting at codon Ser483. The new reading frame ends in a stop codon 4 positions downstream. This description and the description of the HL occurrence further expands the spectrum of DADA2. Our data, call for judicious exclusion of ADA2 deficiency in the HL patient with an aberrant course and additional symptoms / signs.

In summary, we report familial HL in two patients with a novel deleterious mutation in ADA2 gene. This expands the spectrum of this disease to include cancer and should alert the hemato-oncologist to the possibility of DADA2 as an underlying diagnosis in HL.

Figure 1.

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Figure 1.

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