Open Access

Monogenic polyarteritis: the lesson of ADA2 deficiency

  • Roberta Caorsi1,
  • Federica Penco1,
  • Francesca Schena1 and
  • Marco Gattorno1Email author
Pediatric Rheumatology201614:51

https://doi.org/10.1186/s12969-016-0111-7

Received: 26 April 2016

Accepted: 1 September 2016

Published: 8 September 2016

Abstract

The deficiency of Adenosine Deaminase 2 (DADA2) is a new autoinflammatory disease characterised by an early onset vasculopathy with livedoid skin rash associated with systemic manifestations, CNS involvement and mild immunodeficiency.

This condition is secondary to autosomal recessive mutations of CECR1 (Cat Eye Syndrome Chromosome Region 1) gene, mapped to chromosome 22q11.1, that encodes for the enzymatic protein adenosine deaminase 2 (ADA2). By now 19 different mutations in CECR1 gene have been detected.

The pathogenetic mechanism of DADA2 is still unclear. ADA2 in a secreted protein mainly expressed by cells of the myeloid lineage; its enzymatic activity is higher in conditions of hypoxia, inflammation and oncogenesis. Moreover ADA2 is able to induce macrophages proliferation and differentiation; it’s deficiency is in fact associated with a reduction of anti-inflammatory macrophages (M2). The deficiency of ADA2 is also associated with an up-regulation of neutrophils-expressed genes and an increased secretion of pro-inflammatory cytokines. The mild immunodeficiency detected in many DADA2 patients suggests a role of this protein in the adaptive immune response; an increased mortality of B cells and a reduction in the number of memory B cells, terminally differentiated B cells and plasmacells has been described in many patients. The lack of the protein is associated with endothelium damage; however the function of this protein in the endothelial homeostasis is still unknown.

From the clinical point of view, this disease is characterized by a wide spectrum of severity. Chronic or recurrent systemic inflammation with fever, elevation of acute phase reactants and skin manifestations (mainly represented by livedo reticularis) is the typical clinical picture. While in some patients the disease is mild and skin-limited, others present a severe, even lethal, disease with multi-organ involvement; the CNS involvement is rather common with ischemic or hemorrhagic strokes. In many patients not only the clinical picture but also the histopathologic features are undistinguishable from those of systemic polyarteritis nodosa (PAN). Of note, patients with an unusual phenotype, mainly dominated by clinical manifestations suggestive for an immune-disrective condition, have been described.

Due to its rarity, the response to treatment of DADA2 is still anecdotal. While steroids can control the disease’s manifestations at high dosage, none of the common immunosuppressive drugs turned out to be effective. Biologic drugs have been used only in few patients, without a clear effectiveness; anti-TNF drugs are those associated to a better clinical response. Hematopoietic stem cells transplantation was effective in patients with a severe phenotype.

Background

The deficiency of Adenosine Deaminase 2 (DADA2) is a recently identified disease, gathered in the family of autoinflammatory diseases, mainly characterised by early-onset polyarteritis, hemorrhagic and ischemic strokes and hypogammaglobulinemia.

In February 2014 two independent studies, one held by the American National Institutes of Health in Bethesda [1] and the other one by the Israeli Sharee Zedek Medical Center in Jerusalem [2], identified this new clinical entity, often familial, characterised by early onset livedoid rash associated with systemic inflammation (fever and elevation of acute phase reactants). Some patients presented ischemic or haemorrhagic cerebral stroke, other vasculopathy-related manifestations (hypertension, gastrointestinal symptoms), hepatosplenomegaly, peripheral neuropathy and mild immunodeficiency.

In many cases both the clinical manifestations and the histological findings were consistent with the diagnosis of polyarteritis nodosa (PAN), with childhood-onset.

The analysis of the whole exome-sequencing (WES) in unrelated affected patients identified autosomal recessive deleterious mutations in CECR1 gene, encoding for adenosine deaminase 2 (ADA2).

The marked reduction of both plasmatic levels and enzymatic activity of ADA2 detected in affected patients respect to healthy donors [1, 2], confirmed the hypothesis that the causative mutation determines the loss-of-function of the protein. The non-affected simple-heterozygous parents displayed intermediate values of both plasmatic levels and enzymatic activity [1].

CECR1 gene

The CECR1 (Cat Eye Syndrome Chromosome Region 1) gene, mapped to chromosome 22q11.1 and constituted by 10 exons [1, 2], encodes for the enzyme adenosine deaminase 2 (ADA2), a protein composed by 4 domains: the signal sequence, the dimerization domain, the putative receptor-binding domain and the catalytic domain.

The mutations detected in CECR1 gene so far are 19, with a different prevalence according to patient’s ethnicity (Table 1, Fig. 1) [113]. The G47R mutation has been detected in homozygous state in all patients of Georgian Jewish and Turkish origin. Based on the results of the molecular analysis performed in 246 healthy donors of Georgian Jewish origin, the estimated frequency of this mutation in this population is 10 % [2].
Table 1

CECR1 mutations so far detected

Mutation

Exon

HGVS sequence name

Aminoacid substitution

N° of patients

Enzymatic domain

M1T

2

c.2 T > C

Met1Thr

1 in compound heterozygosis

Signal peptide

K13del

2

c.37_39del

37_39del

2 in compound heterozygosis

Signal peptide (?)

28-kb-deletion

2

deletion

deletion

1 in compound heterozygosis

5′UTR (5′untranslated region)

G47R

2

c.139G > A

Gly47Arg

27 in homozygosis

Dimerization

1 in compound heterozygosis

G47A

2

c.140G > C

Gly47Ala

2 in compound heterozygosis

Dimerization

G47V

2

c.140G > T

Gly47Val

1 in compound heterozygosis

Dimerization

I93T

2

c.278 T > C

Ile93Thr

1 in compound heterozygosis

Dimerization

A109D

3

c.326C > A

Ala109Asp

1 in compound heterozygosis

Catalytic

H112Q

3

c.336C > G

His112Gln

1 in compound heterozygosis

Catalytic

T119A

3

c.355A > G

Thr119Ala

4 in compound heterozygosis

Catalytic

G142S

3

c.424G > A

Gly142Ser

4 in compound heterozygosis

Catalytic

R169Q

3

c.506G > A

Arg169Gln

15 in homozygosis

PBR (putative receptor-binding)

9 in compound heterozygosis

P193L

4

c.578C > T

Pro193Leu

1 in compound heterozygosis

Catalytic (?)

M243R

4

NA

Met243Arg

2 in compound heterozygosis

Catalytic

P251L

4

c.752C > T

Pro251Leu

4 in compound heterozygosis

Catalytic

W264S

5

c.791G > C

Trp264Ser

1 in compound heterozygosis

Catalytic

R306*

6

c.916C > T

p.Arg306*

1 in compound heterozygosis

Catalytic (?)

N328K

7

c.1159C > A

Cys1159Arg

2 in compound heterozygosis

Catalytic

Y453C

9

c.1358A > G

Tyr453Cys

3 in compound heterozygosis

Catalytic

Legend: HGVS: Human Genome Variation Society

NA not available

Fig. 1

Cat Eye Syndrome Chromosome Region 1 (CECR1) gene and Adenosine Deaminase 2 (ADA2) protein with the mutations by now detected

Conversely, the R169Q is the mutation more frequently detected in the European Caucasian population [1, 2, 7, 12, 13].

The mutations so far detected affect the Signal peptide (n = 2), the 5’ untranslated region (n = 1), the dimerization domain (n = 4), the putative receptor binding (n = 1) and the catalytic domain (n = 11) (Table 1, Fig. 1) [113]. Moreover two patients with a homozygous deletion on 22.11.1 chromosome (encompassing CECR1 gene) have been recently described [14].

ADA2 protein and pathogenetic mechanisms

The enzyme Adenosine Deaminase (ADA) plays a key role in the purine metabolism converting adenosine to inosine and 2′-deoxyadenosine to 2′-deoxyinosine [15].

The two major ADA isoforms are ADA1, whose deficiency is cause of a severe combined immunodeficiency (SCID) [16], and ADA2.

Even if the two proteins have partial structural homology, the two isoenzymes differ in many aspects: the affinity of ADA2 for molecules of adenosine and deoxy-adenosine is about 100 times lower than that of ADA1; consequently, at physiological concentrations of substrate, the deaminase activity of ADA2 is almost absent [17].

While ADA1 is monomeric and acts primarily intracellularly, ADA2 is dimeric and secreted in the extracellular environment where it exerts its main functions. For this reason ADA2 is clearly detectable in the plasma. Finally, while ADA1 is ubiquitally expressed in all cell types, ADA2 is mostly expressed by monocytes and other cells of the myeloid lineage [17].

ADA2 is more stable at high temperatures and the optimum pH for its activity is generally acid (about 6.5), which suggests a specialized role of this enzyme in conditions of hypoxia, inflammation and oncogenesis; in these conditions its deaminase activity is higher [17] (Fig. 2).
Fig. 2

Production and physiological role of Adenosine Deaminase 2 (ADA2). ADA2 is produced and secreted by cells of myeloid lineage; it exerts its enzymatic activity in the extracellular space, especially in the presence of a low pH or high temperature. On monocytes (a) ADA2 acts as growth-factor with an autocrine activity: it induces monocytes’ proliferation and promote the differentiation of M2 anti-inflammatory macrophages. On neutrophils (b) ADA2 induces the gene of expression of some pro-inflammatory proteins, such as myeloperoxidase (MPO) and neutrophils’ activations, leading to the secretion of pro-inflammatory cytokines. There are indirect evidences of a possible role of ADA2 as growth-factor for endothelial cells (c)

The capacity of binding receptors involved in the signal transduction of different pathways (such as proteoglycans), confers to ADA2 a growth-factor like action; for this reason ADA2 is considered an Adenosine Deaminase-related Growth-Factor (ADGF) [1719] (Fig. 2).

ADA2 displays also an autocrine activity: the protein, released by activated monocytes, is able to induce monocyte proliferation and macrophage differentiation [20]; CECR1 silencing in myeloid cells is in fact associated to a reduced differentiation of monocytes to macrophages [1]. This activity has been demonstrated to be mediated by the direct binding of cellular receptors, and therefore to be independent from the enzymatic activity [20] (Fig. 2).

ADA2 seems to be also involved in the balance between pro-inflammatory (M1) and anti-inflammatory (M2) monocytes; its absence has been in fact associated with a defect in differentiation of M2 macrophages, which leads to a prevalence of pro-inflammatory M1 cells [1].

Microarray analysis in two DADA2 patients showed a marked up-regulation of neutrophils-expressed genes. Intracellular staining revealed an increased expression of myeloperoxidase (MPO) in peripheral blood mononuclear cells compared to controls [8] (Fig. 2). According with these findings, the assessment of cytokine levels performed in the serum of few described patients revealed an increase of pro-inflammatory cytokines: in the two patients carrying a homozygous deletion of 22q11.1 chromosome increased levels of both IL-1β and TNFα were detected [14], while in another case the detection of IL-6 revealed increased levels [7]. These data are in contrast with the results obtained in the NIH study, in which the cytokine assay performed in the supernatants of the whole blood cell cultured with different stimuli did not reveal any significant difference between patients and healthy donors [1]. Further studies on larger series of patients are therefore needed in order to investigate the cytokines’ pattern in DADA2; in particular the cytokines’ production should be assessed in stimulated PBMCs and should take into consideration the disease activity.

It has been also postulated that the deregulation of purinergic stimulation, due to the decrease of the enzymatic activity of ADA2, may play a pro-inflammatory role. Adenosine is in fact an important signaling molecule that can modulate the inflammatory response; its concentration in tissues is normally low and increases in condition of cellular stress, ischemia or inflammation [21]. The accumulation of adenosine can influence the inflammatory response by binding several receptors that lead to inflammation, tissue damage and fibrosis [21]. However, the plasmatic levels of adenosine and deoxiadenosine in few DADA2 patients has been detected within the normal range [1, 2].

Since hypogammaglobulinemia has been described in some patients, adaptive immunity has been investigated in ADA2 patients. A reduction in the number of memory B cells, terminally differentiated B cells and plasmacells has been described [1, 7]; moreover co-culture experiments have enlightened an increased mortality of B cells [1]. Not univocal results have been detected concerning the T cells function. In fact, while in the NIH study ADA2 mutations seem not to affect T lymphocyte number and activation [1], in a more recent study an increase of regulatory T cells and a decrease of CD8+ and CD4 + memory T cells have been detected in one patient with DADA2 [7]. In addition a reduced number of Th1, Th2 and follicular T helper (Tfh) cells has been observed in the same patient.

The reason why endothelium represents the main target of inflammation in DADA2 is still largely unknown. ADA2 acts as a growth-factor for endothelial cells. In fact, even if it has been demonstrated that endothelial cells do not express CECR1 gene, the deficiency of ADA2 is associated to a damage of vascular endothelium and to an over expression of activation markers [1]. The knockdown animal model for CECR1 gene (zebrafish) displays cerebral haemorrhages without morphologic alteration in the vascular structure; these episodes recovered following the transfection of non-mutant human CECR1 messenger RNA [1]. In the same way, monocytes of patients with DADA2 led to destruction of co-cultured human microvascular endothelial cells [1].

Due to the rarity of the disease, all available data on the pathogenic consequences of ADA2 defect in humans come from few patients; further studies are therefore needed in order to better enlighten the activity of ADA2 in the innate and adaptive immune response and its role in the endothelium homeostasis.

Clinical manifestations

DADA2 can be defined as an inflammatory vasculopathy with a wide range of clinical manifestations, possibly associated with an immunodeficiency of variable severity.

The disease is mainly characterized by chronic or recurrent systemic inflammation with fever and elevation of acute phase reactants, usually associated with different possible skin manifestations, ranging from the most frequent livedo reticularis (Fig. 3) to maculopapular rash, nodules, purpura, erythema nodosum, Raynaud’s phenomenon, ulcerative lesions, digital necrosis [1, 2].
Fig. 3

Livedo reticularis in a patient with DADA2

The clinical picture is wide, ranging form a mild disease with a late onset skin-limited involvement to a very severe systemic phenotype (even fatal) with an early onset and a multi-organ involvement (Tables 2 and 3).
Table 2

Clinical manifestation of DADA2 patients so far described

Report

CECR1

Mutation

Ethnicity

Age at onset

Fever

Skin

CNS/PNS

Gastro-intestinal

Immune/Hematologic system

ANA

ANCA

Hypertension

Other

Navon et al.

1

G47R/G47R

Georgian

2 m

Yes

Ulcerations at extremities

No

Intestinal necrosis

No

neg

neg

Yes

Coronary aneurysms

2

G47R/G47R

Georgian

5 y

No

Livedo reticularis, nodules, purpuric rash

No

Intestinal vasculitis

No

neg

neg

No

No

3

G47R/G47R

Georgian

7 m

Yes

Livedo reticularis, papulo-nodular rash, Raynaud’s phenomenon

Ischemic stroke, peripheral paresis of cranial nerves

No

No

neg

neg

Yes

Arthritis

4

G47R/G47R

Georgian

3,5 y

Yes

Livedo reticularis, nodules, purpuric rash, erythema nodosum

Cranial nerve paralysis

No

No

pos

ND

No

No

5

G47R/G47R

Georgian

2,5 y

No

Maculopapular rash, nodules

Neurosensorial hearing loss

No

No

neg

neg

No

Arthritis

6

G47R/G47R

Georgian

2 m (died at 9 m)

Yes

Digital necrosis

Ventricular haemorrhage

Aneurism of celiac artery

No

neg

neg

No

No

7

G47R/G47R

Georgian

2 m

Yes

Livedo reticularis, Raynaud’s phenomenon

No

Abdominal pain

No

neg

ND

No

No

8

G47R/G47R

Georgian

6,5 y

Yes

Livedo reticularis, nodules, Raynaud’s phenomenon

No

Abdominal pain

No

neg

neg

No

No

9

G47R/G47R

Georgian

9 y

No

Livedo reticularis

No

No

No

neg

neg

No

No

10

G47R/G47R

Georgian

10 y

No

Livedo reticularis, nodules, Raynaud’s phenomenon, leg ulcers

No

No

No

neg

neg

No

No

11

G47R/G47R

Georgian

59 y

No

Leg ulcers

No

No

No

neg

ND

No

No

12

G47R/G47R

Georgian

childhood (died at 30 y)

No

Livedo reticularis, nodules, Raynaud’s phenomenon, leg ulcers with amputation

No

No

No

ND

ND

No

No

13

G47R/G47R

Georgian

1 y

No

Livedo reticularis, nodules, Raynaud’s phenomenon

Sensitive polyneuropathy

No

No

neg

neg

No

No

14

G47R/G47R

Georgian

4 y

Yes

Livedo reticularis, purpuric rash, skin nodules.

No

No

No

pos

ND

No

No

15

G47R/G47R

Georgian

1 y

Yes

Livedo reticularis

No

Abdominal pain

No

neg

neg

Yes

Mesenteric and renal infarcts

16

G47R/G47R

Georgian

18 y

No

No

No

No

No

neg

neg

No

No

17

G47R/G47R

Georgian

28 y

Yes

Raynaud’s phenomenon, purpuric rash, leg ulcers with digital amputation

Polyneuropathy

No

No

neg

neg

Yes

Panniculitis

18

G47R/G47R

Georgian

2 y

No

Skin nodules

Polyneuropathy

No

No

neg

neg

No

No

19

G47R/G47R

Georgian

16 y

No

Raynaud’s phenomenon, ulceration of extremities

No

No

No

pos

neg

Yes

No

20

R169Q/P251L

European Caucasian

1 y

Yes

Livedo reticularis

Ischemic stroke, cranial nerves (II,VI,VII) paralysis

No

No

neg

ND

Yes

No

21

R169Q/P251L

European Caucasian

12 y

No

No

Ischemic stroke, VII cranial nerve paralysis

No

No

pos

neg

No

No

22

R169Q/P251L

European Caucasian

1 y

No

Livedo reticularis, skin rash at extremities

Ischemic stroke

VI cranial nerve paralysis, neurosensorial hearing loss

No

No

neg

neg

No

No

23

R169Q/P251L

European Caucasian

3 m

No

Livedo reticularis, vasculitic exanthema of lower extremities

VII cranial nerve paralysis

No

No

ND

ND

No

Epididymitis

24

G47V/W264S

Turkish

10 y

Yes

Livedo reticularis

No

No

No

neg

ND

Yes

Myalgia, abdominal and renal aneurysm

Zhou et al.

1

A109D/Y453C

European Caucasian

2 y

Yes

Livedo reticularis

Ischemic stroke

Splenomegaly

No

pos

neg

No

No

2

G47A/Y453C

European Caucasian

1 y

Yes

Livedo reticularis, erythematous and urticarial rash

Ischemic and haemorrhagic strokes

Hepatomegaly, splenomegaly. Portal hypertension.

Pancytopenia, hypoIg

pos

neg

No

No

3

R169Q/deletion

European Caucasian

1,5 y

Yes

Livedo reticularis, urticarial rash

Ischemic and haemorrhagic strokes

Hepatomegaly, splenomegaly, chronic gastritis

Leucopoenia, hypoIg

neg

neg

No

No

4

G47A/H112Q

European Caucasian

5 m

Yes

Livedo reticularis, urticarial rash

Ischemic and haemorrhagic strokes

Hepatomegaly, splenomegaly, portal hypertension.

Pancytopenia, HypoIg

neg

neg

No

No

5

R169Q/Y453C

European Caucasian

1,5 y

Yes

Livedo reticularis

Ischemic stroke

Hepatomegaly, splenomegaly.

Leucopoenia, hypoIg

neg

neg

No

No

6

M1T/I93T

European Caucasian

1,5 y (died 16 y)

Yes

Non-Langerhans cell

histiocytosis

Ischemic stroke

Hepatomegaly, splenomegaly. portal hypertension.

No

neg

neg

Yes

Evans syndrome

7

G47R/G47R

Turkish

3,5 y

Yes

Livedo reticularis, erythema nodosum

Ischemic stroke

III cranial nerve paralysis

No

No

neg

neg

No

No

8

G47R/G47R

Tukish

4 y

Yes

Livedo reticularis, erythema nodosum

Ischemic stroke

Bowel perforation

No

neg

neg

No

Macrophage activation syndrome

9

G47R/G47R

Turkish

9 y (died 22 y)

Yes

Livedo reticularis, ulceration of extremities

No

Hepatomegaly, splenomegaly

Leucopoenia

pos

neg

No

Renal amyloidosis, necrotising pneumonia

van Montfrans et al.

1

R169Q/R169Q

NA

6 m

No

Livedo reticularis

No

Hepatomegaly, splenomegaly

Granulocytopenia, red-cell aplasia

NA

NA

No

No

2

R169Q/R169Q

NA

6 y

Yes

Livedo reticularis

Stroke

Hepatomegaly, splenomegaly

HypoIg, lymphopenia

NA

NA

No

No

Bras et al.

1

T119A/G142S

European Caucasian

>10 y

Yes

Livedo reticularis, ulcerations of extremities

Stroke

No

No

NA

NA

No

No

2

T119A/G142S

European Caucasian

>10 y

Yes

Livedo reticularis, ulcerations of extremities

Stroke

No

No

NA

NA

No

No

3

T119A/G142S

European Caucasian

>10 y

Yes

Livedo reticularis, ulcerations of extremities

Stroke

No

No

NA

NA

No

No

4

T119A/G142S

European Caucasian

>10 y

Yes

Livedo reticularis, ulcerations of extremities

Stroke

No

No

NA

NA

No

No

Van Eyck et al.

1

G47R/G47R

NA

5 y

Yes

No

No

Splenomegaly

Lymphadenopathy, anaemia, thrombocytosis

NA

NA

No

 

Garg et al.

1

G47R/R306*

Turkish

1,5 y (died 5 y)

Yes

Skin rash

Hemorrhagic and ischemic stroke.

intraparenchymal haemorrhage

No

No

neg

neg

No

Acute respiratory distress syndrome

Van Eyck et al.

1

R169Q/R169Q

African/ Caucasian

6 m

No

No

Haemorrhagic stroke

Splenomegaly

Pancytopenia, hypoIg, lymphadenopathy, recurrent viral infections

NA

NA

No

No

2

R169Q/R169Q

African/ Caucasian

5 m

No

No

TIA

Bowel perforation (ulcerative bowel disease, no signs of vasculitis)

Leucopoenia, hypoIg, lymphadenopathy, recurrent viral infections

NA

NA

No

No

Belot et al.

1

R169Q/P193L

European Caucasian

First year

Yes

Livedo reticularis, ulceration of extremities

TIA, ischemic stroke, sensitive polyneuropathy, intracerebral haemorrhage.

Bowel stenosis

HypoIg

neg

neg

No

Oral aphtae

2

G47R/G47R

Asian

1 m

Yes

Erythema nodosum, vasculitic rash

Intracerebral haemorrhage, Ischemic stroke, Optic neuritis

No

No

NA

NA

Yes

Dactylitis, aneurysm of abdominal vessels

Westendorp et al.

1

R169Q/R169Q

European Caucasian

3 y

No

Livedo reticularis, nodules

Ischemic stroke, peripheral neuropathy

neurosensorial hearing loss

No

No

NA

NA

No

No

2

R169Q/R169Q

European Caucasian

2 y

No

Livedo reticularis

Ischemic stroke

No

No

NA

NA

No

Autism

Gonzales Santiago et al.

1

K13del/N328K

European Caucasian

2 y

Yes

Livedo racemosa

No

No

HypoIg

NA

neg

No

No

2

K13del/N328K

European Caucasian

5 y

No

Nodules, erytema of lower extremities

No

No

HypoIg, recurrent infections

NA

NA

No

No

Batu et al.

1

G47R/G47R

Turkish

6,5 y

Yes

Livedo reticularis,

No

Abdominal pain

No

NA

NA

No

No

2

G47R/G47R

Turkish

4 y

Yes

Livedo reticularis, erythema nodosum, necrotic ulcers

Stroke

Abdominal pain, hypertransaminasemia

No

pos

NA

Yes

Glomerulosclerosis

3

G47R/G47R

Turkish

10 y

Yes

Livedo reticularis

No

Abdominal pain

No

NA

NA

No

No

Van Montfrans et al.

1

R169Q/R169Q

European Caucasian

1 y

Yes

Livedo reticularis, erythema nodosum, eczema, Raynaud phenomenon

Ischemic stroke, III cranial nerve paralysis

Abdominal pain, hepatomegaly

Adenopathy, hypoIg, pancytopenia

neg

neg

No

Oral aphtae, arthralgia

GH deficiency

2

R169Q/R169Q

European Caucasian

Birth

No

Livedo reticularis, eczema

No

Abdominal pain, hepatomegaly, splenomegaly

HypoIg, anaemia

ND

ND

No

Jugular vein thrombosis, GH deficiency

3

R169Q/R169Q

European Caucasian

6 y

No

Livedo reticularis, ulceration of extremities and trunk

No

Hepatomegaly, splenomegaly

Adenopathy, anaemia

neg

neg

No

No

4

R169Q/R169Q

European Caucasian

3 y

No

Livedo racemosa, erythema nodosum, Raynaud phenomenon

Ischemic stroke, VI cranial nerve paralysis

Hepatomegaly, splenomegaly

HypoIg, recurrent infections, anaemia

neg

neg

No

No

5

R169Q/R169Q

European Caucasian

1y

No

Eczema

Ischemic stroke, IV cranial nerve paralysis

Splenomegaly

HypoIg, anaemia, leucopoenia

neg

ND

No

Autism

6

R169Q/R169Q

European Caucasian

9 m

Yes

Eczema

Ischemic stroke, IV cranial nerve paralysis

Abdominal pain, hepatomegaly, splenomegaly

HypoIg, pancytopenia

pos

pos

Yes

Oral aphtae, arthralgia

7

R169Q/R169Q

European Caucasian

8 y

Yes

Rash

Ischemic stroke, III cranial nerve paralysis

Abdominal pain, acute liver failure

HypoIg, recurrent infections, anaemia,lymphopenia

neg

neg

No

Oral aphtae, arthralgia

8

R169Q/R169Q

African/Caucasian

6 m

No

Eczema

Intracranial haemorrhage

Hepatomegaly, splenomegaly

HypoIg, adenopath, thrombocytopenia, leucopoenia

neg

neg

No

No

9

R169Q/R169Q

African/Caucasian

5 m

No

No

No

Bowel ulcerations, colitis, hepatomegaly, splenomegaly

HypoIg, recurrent infections, adenopathy

neg

neg

No

No

Fellmann et al.

1

Homozygous 22q11.1 deletion (IL17RA and CECR1)

Asian

Birth (Died 16 y)

No

Ichthyosiform rash, oro-vaginal ulcerations

No

No

Recurrent infection (C. Albicans, S. aureus), neutropenia

neg

neg

No

Chronic systemic inflammation, failure to thrive

2

Homozygous 22q11.1 deletion (IL17RA and CECR1)

Asian

2 y

No

Ichthyosiform rash

No

Splenomegaly

Oro-vaginal candidiasis, Staphylococcal skin infections

neg

neg

No

Retinal vasculitis

Schepp et al.

1

R169Q/

M243R

NA

18 y

No

No

No

Splenomegaly

HypoIg, recurrent respiratory infections

NA

NA

No

Arthralgia

2

R169Q/M243R

NA

2 m (Died 17 y)

Yes

Erythema nodosum

Intracranial haemorrhage

Splenomegaly

HypoIg, lymphopenia, recurrent urinary tract and respiratory infections

neg

NA

No

Arthritis

Failure to thrive.

Legend: CNS central nervous system

PNS peripheral nervous system

TIA transitory ischemic attack

GH growth hormone

HypoIg Hypogammaglobulinemia

ND not done

NA not available

Table 3

genotype/phenotype correlation in DADA2

Mutation

Exon

N° of patients

Associated symptoms (% of patients)

M1T

2

1 in heterozygosis

Fever

Skin: Non-Langerhans cell histiocytosis

CNS/PNS: ischemic stroke

Visceral: involvement: hepatomegaly, splenomegaly. portal hypertension, hypertension (100 %)

K13del

2

2 in heterozygosis

Fever (50 %)

Skin: Livedo racemosa (50 %), skin nodules (50 %)

Immune/hematologic system: hypogammaglobulinemia (100 %), recurrent infections (50 %)

28-kb-deletion

2

1 in heterozygosis

Fever

Skin: Livedo reticularis, urticarial rash

CNS/PNS: ischemic and haemorrhagic strokes

Visceral involvement: hepatomegaly, splenomegaly. chronic gastritis

Immune/hematologic system: leukopenia, hypogammaglobulinemia (100 %)

G47R

2

27 in homozygosis

Fever (64 %)

Skin: Livedo reticularis (60 %), skin nodules (35 %), ulcerations at extremities/digital necrosis (32 %), Raynaud’s phenomenon (28 %), purpuric/vasculitic rash (18 %), erythema nodosum (18 %), panniculitis (3 %)

CNS/PNS: ischemic stroke (21 %), hemorrhagic stroke (7 %), intracranial haemorrhage (11 %), cranial nerve paralysis (14 %), polineuropathy (11 %), neurosensorial hearing loss (3 %).

Visceral involvement: abdominal pain (21 %), intestinal vasculitis (14 %), hepatomegaly (3 %), splenomegaly (7 %), hypertransaminasemia (3 %), hypertension (25 %).

Immune/hematologic system: Leucopoenia (3 %), anaemia (3 %), lymphadenopathy (3 %).

1 in heterozygosis

G47A

2

2 in heterozygosis

Fever (100 %)

Skin: Livedo reticularis (100 %), urticarial rash (100 %)

CNS/PNS: ischemic and haemorrhagic strokes (100 %)

Visceral involvement: hepatomegaly (100 %), splenomegaly (100 %), portal hypertension (100 %)

Immune/hematologic system: Pancytopenia (100 %), hypogammaglobulinemia (100 %).

G47V

2

1 in heterozygosis

Fever

Skin: Livedo reticularis

Visceral involvement: hypertension, abdominal and renal aneurysm (100 %).

I93T

2

1 in heterozygosis

Fever

Skin: Non-Langerhans cell histiocytosis

CNS/PNS: ischemic stroke

Visceral: involvement: hepatomegaly, splenomegaly. portal hypertension, hypertension (100 %)

A109D

3

1 in heterozygosis

Fever

Skin: Livedo reticularis

CNS/PNS: ischemic stroke

Visceral involvement: splenomegaly (100 %).

H112Q

3

1 in heterozygosis

Fever

Skin: Livedo reticularis, urticarial rash

CNS/PNS: ischemic and haemorrhagic strokes

Visceral involvement: hepatomegaly, splenomegaly, portal hypertension

Immune/hematologic system: Pancytopenia, hypogammaglobulinemia (100 %).

T119A

3

4 in heterozygosis

Fever (100 %)

Skin: Livedo reticularis, ulceration of extremities (100 %)

CNS/PNS: ischemic and haemorrhagic strokes (100 %)

G142S

3

4 in heterozygosis

Fever (100 %)

Skin: Livedo reticularis, ulceration of extremities (100 %)

CNS/PNS: ischemic and haemorrhagic strokes (100 %)

R169Q

3

15 in homozygosis

Fever (37 %)

Skin: Livedo reticularis (58 %), skin nodules (4 %), ulcerations at extremities/digital necrosis (8 %), Raynaud’s phenomenon (8 %), purpuric/vasculitic rash (13 %), erythema nodosum (13 %), eczema (20 %)

CNS/PNS: ischemic stroke (54 %), hemorrhagic stroke (13 %), intracranial haemorrhage (13 %), cranial nerve paralysis (37 %), polineuropathy (8 %), neurosensorial hearing loss (8 %).

Visceral involvement: abdominal pain (17 %), bowel ulcerations (8 %), chronic gastritis (4 %), bowel stenosis (4 %), colitis (4 %), hepatomegaly (45 %), splenomegaly (58 %), acute liver failure (4 %), hypertension (8 %).

Immune/hematologic system: hypogammaglobulinemia (62 %), pancytopenia (8 %), leucopoenia (20 %), lymphopenia (13 %), granulocytopenia (4 %), anaemia (25 %), thrombocytopenia (4 %),

lymphadenopathy (25 %), recurrent infections (29 %).

9 in heterozygosis

P193L

4

1 in heterozygosis

Fever

Skin: Livedo reticularis, ulcerations at extremities

CNS/PNS: ischemic stroke, TIA, intracranial haemorrhage, polineuropathy

Visceral involvement: bowel stenosis, oral aphtae

Immune/hematologic system: hypogammaglobulinemia (100 %).

M243R

4

2 in heterozygosis

Fever (50 %)

Skin: erythema nodosum (50 %)

CNS/PNS: intracranial haemorrhage (50 %)

Visceral involvement: splenomegaly (100 %)

Immune/hematologic system: hypogammaglobulinemia (100 %), recurrent infections (100 %).

P251L

4

4 in heterozygosis

Fever (25 %)

Skin: Livedo reticularis (75 %), vasculitic rash (50 %)

CNS/PNS: ischemic stroke (75 %), cranial nerve paralysis (100 %), neurosensorial hearing loss (25 %).

Visceral involvement: hypertension (25 %), epididymitis (25 %)

W264S

5

1 in heterozygosis

Fever

Skin: Livedo reticularis

Visceral involvement: hypertension, abdominal and renal aneurysm (100 %).

R306*

6

1 in heterozygosis

Fever

Skin: rash

CNS/PNS: ischemic stroke, hemorrhagic stroke, intracranial haemorrhage (100 %)

N328K

7

2 in heterozygosis

Fever (50 %)

Skin: Livedo racemosa (50 %), skin nodules (50 %)

Immune/hematologic system: hypogammaglobulinemia (100 %), recurrent infections (50 %)

Y453C

9

3 in heterozygosis

Fever (100 %)

Skin: Livedo reticularis (100 %), urticarial rash (33 %)

CNS/PNS: ischemic stroke (100 %), haemorrhagic strokes (33 %)

Visceral involvement: hepatomegaly (66 %), splenomegaly (100 %), portal hypertension (33 %)

Immune/hematologic system: Pancytopenia (66 %), hypogammaglobulinemia (66 %).

In most patients, a neurological involvement, affecting both the peripheral and central nervous system, has been described.

The severity of the CNS involvement is rather variable. In some patients a transitorily ischemic attack (TIA) has been described (with negative cerebral CT and/or MRI), while others developed an ischemic or hemorrhagic stroke (in few cases a ventricular haemorrhage has also been detected). Typically, the strokes associated to DADA2 are lacunar with a wide range of clinical manifestations ranging from clinically silent episodes in few cases, to severe ones leading to a permanent disability [1, 2, 10, 12].

The neuropathy ranges from a transient mononeuritis (such as a cranial nerve transient paralysis) to a permanent polyneuropathy; moreover, few patients suffered from optic neuritis. In few cases, persistent neurosensorial hearing loss has also been described [1, 2, 12].

Most patients have gastrointestinal manifestations: abdominal pain, significant weight loss, chronic gastritis, hepatomegaly, splenomegaly, portal hypertension, bowel perforation or stenosis.

While nephrogenic hypertension is rather common in this condition, in few patients focal glomerulosclerosis and renal amyloidosis have also been described [11]. Lung involvement with necrotising pneumonia (lethal) has been reported in one patient [11].

The blood tests usually reveal an elevation of acute phase reactants (ERS, CRP), low haemoglobin levels and neutrophilic leukocytosis [1, 2]; however in few patients cytopenia (pancytopenia, leucopoenia) has been detected [1, 7, 12]. Auto-antibody are usually negative.

As stated above, a mild immunodeficiency can be observed; some patients present hypogammaglobulinemia that may affect IgM or all Ig subclasses [1, 13]. Of note, despite the low immunoglobulins’ levels, only few cases displayed an increased susceptibility to infections, that was rather severe in exceptional cases [1, 3, 7, 12, 13].

MRI is the most useful tool in the diagnosis of cerebral strokes; in fact CT scan as well as conventional angiography may not detect the smaller lacunar strokes and therefore underestimate the entity of involvement of the CNS [1].

Some patients underwent an angiographic investigation, that revealed the presence of stenosis and/or aneurysms of abdominal artery, particularly mesenteric, celiac, hepatic and renal arteries; the histological analysis, when done, revealed a necrotizing vasculitis [1, 2].

In patients with symptoms suggestive for organ involvement but without pathologic finding in not-invasive radiologic studies, conventional angiography can be of help revealing aneurism and or stenosis in the middle sizes arteries.

Skin biopsy revealed, in most cases, a non-granulomatous, necrotizing vasculitis of small and medium-sized vessels, with the same histopathologic features of polyarteritis nodosa [1, 2, 9].

In few cases the histology was less specific showing a leucocytoclastic vasculitis or a panniculitis.

Polyarteritis nodosa (PAN) is, according to the Chapel Hill classification, a “Necrotizing arteritis of medium or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules, and not associated with antineutrophil cytoplasmic antibodies (ANCAs)” [22]. It’s gathered in the medium-sized vessels vasculitis, even if it can affect arteries of any size [22].

Being DADA2 a vasculitis with a genetic basis, it has been proposed to group this disease in the vasculitis with a probable cause according to the Chapel Hill classification [11, 22].

Notably, most of the DADA2 patients not only received the histological diagnosis of PAN but also met the EULAR/PRINTO/PRES diagnostic criteria for childhood polyarteritis nodosa (Table 4) [23].
Table 4

EULAR/PRINTO/PRES classification criteria for childhood Polyarteritis nodosa (PAN) [23]

 

Histopathology or angiographic abnormalities (mandatory) plus one of the five following criteria:

- Histology: necrotising vasculitis in medium or small-sized arteries.

- Angiography: aneurysm, stenosis or occlusion of a medium or small sized artery,

EULAR/PRINTO/PRES classification criteria for childhood Polyarteritis nodosa (c-PAN)

1. Skin involvement

Livedo reticularis, skin nodules, superficial ulcers, peripheral tissue necrosis

2. Myalgia/muscle tenderness

Muscle pain or tenderness

3. Hypertension

Blood pressure > 95th centile

4. Peripheral neuropathy

Sensory or motor neuropathy

5. Renal involvement

Proteinuria, haematuria, impaired function

Unusual phenotypes

Even if most of the patients with DADA2 have a clinical phenotype consistent with a systemic inflammatory vasculopathy, a recent report has enlighten that the disease may be dominated by clinical manifestations suggestive for an immune-disrective condition, such as cytopenia, lymphadenopathy, hepatosplenomegaly and immunodeficiency with severe viral infections [7]. The two patients described did not present skin involvement and one of them developed a vascular involvement only after bone-marrow transplantation. Of note, the mutations found in these two patients were the same described in patients with a “typical” inflammatory clinical picture.

Similarly a third patient with a lymphoprolipherative clinical picture, resembling Castleman’s syndrome, has been reported by the same group [5].

A more recent clinical series of 9 DADA2 patients with the homozygous R169Q mutation has enlightened that the presence of cytopenia is a common finding of the disease, together with the common inflammatory manifestations [12].

In the two patients carrying homozygous 22q11.1 deletion, encompassing both copies of the IL-17 receptor A (IL17RA) and the CECR1 gene, the clinical phenotype was dominated by muco-cutaneous infections and dermatitis associated to persistent inflammation and, in one patient, vasculitis responding to steroids [14]. Livedo reticularis, stroke and other DADA2 clinical manifestations were not described.

Finally two brothers with a clinical picture consistent with the diagnosis of common variable immunodeficiency (CVID) were found to be affected by DADA2 by whole exome-sequencing; of note only one of them displayed clinical sign and symptoms consistent with a vasculopathy [13].

Outcome

Being a disease of recent identification, the clinical outcome has not been well investigated. However, from the clinical data by now available is clear that the spectrum of severity of the disease is wide, ranging from patients with neonatal onset and a severe organ involvement to patients with onset in the adulthood and the presence of only skin manifestations (Tables 2 and 3); of note, even between patients carrying the same mutations in CECR1 gene the clinical picture can be widely different (Tables 2 and 3).

The disease turned out to be lethal in seven out of the 65 patients by now described [1, 2, 6, 13, 14]: in three cases the severity of the visceral involvement was lethal [1, 2], two patients died for respiratory complications following intracranial haemorrhage [6, 13], while one patient developed necrotising pneumonia [1, 11]; finally one of the two patients carrying the homozygous deletion on 22.11.1 chromosome died for septic shock.

Treatment

DADA2 is a newly recognised condition and the number of patients so far described is limited; for this reason the response to treatment is largely anecdotal and still controversial (Table 5).
Table 5

Treatment administrated and clinical response in the described DADA2 patients (1-14)

Therapy

Case report (number of treated patients)

Response to treatment

Steroids (orally or i.v.)

Navon et al. (17)

In 2 cases complete control of the disease with on demand steroidal therapy. In other patients steroid-dependence.

Zhou et al. (9)

Partial control of diseases manifestations with high doses of corticosteroids

Van Eyck et al. (2)

Steroid-dependence

Belot et al. (2)

Steroid-dependence

Garg et al. (1)

Steroid-dependence

Van Montfrans et al. (6)

Partial response in 3 patients

Schepp et al. (1)

Partial response

cyclophosphamide (orally or i.v.)

Navon et al. (9)

Good response in 2 patients.

Zhou et al. (7)

Not specified

Belot et al. (2)

Partial response

Garg et al. (1)

Poor response

Batu et al. (4)

Poor response

Azathioprine

Navon et al. (7)

No patients with complete response

Van Eyck et al. (2)

Poor response

Belot et al. (1)

Good response in association to methotrexate

Batu et al. (3)

Poor response

Van Montfrans et al. (5)

Not specified

Methotrexate

Navon et al. (3)

Good response in association with other immunosuppressive and biologics

Belot et al. (1)

Good response in association with azathioprine

Batu et al. (3)

Poor response

Schepp et al. (1)

Partial response

Cyclosporine

Van Eyck et al. (1)

Poor response

Colchicine

Batu et al. (5)

Good response in one patient, none response in 4 patients

Mycophenolate

Zhou et al. (2)

Not specified

Van Eyck et al. (1)

Poor response

Belot et al. (1)

Partial response in association with cyclophosphamide

Batu et al. (2)

Good response in one patient, poor in the other

Sirolimus

Van Eyck et al. (2)

Good response in one patient

Poor response in one patient

Tacrolimus

Van Eyck et al. (2)

Good response in one patient

Poor response in one patient

I.v. immunoglobulins

Navon et al. (1)

Not specified

Zhou et al. (5)

Not specified

Van Eyck et al. (2)

Prophylactic dosage

Belot et al. (1)

Prophylactic dosage

Schepp et al. (2)

Prophylactic dosage

Anakinra

Zhou et al. (5)

Not specified

Garg et al. (1)

Initial partial response than relapse

Van Montfrans et al. (1)

Good response

Canakinumab

Garg et al. (1)

Initial partial response than relapse

Etanercept

Navon et al. (5)

Complete response in 5 patients

Partial response in 1 patient

Zhou et al. (6)

Not specified

van Montfrans et al. (3)

Partial response in 1 pateint

Complete response in 2 patients

Batu et al. (3)

Partial response in 2 patients, complete in 1

Adalimumab

Navon et al. (3)

Complete response in 2 patients, exacerbation in 1 patient

Infliximab

Navon et al. (2)

Complete response in 1 patient

Partial response in 1 patient

Tocilizumab

Zhou et al. (1)

Not specified

Van Eyck et al. (1)

Complete response

Batu et al. (1)

Poor response

Rituximab

Zhou et al. (1)

Poor response

Belot et al. (1)

Poor response

Being an inflammatory condition, high doses of steroids are usually able to control the clinical manifestations [1, 2, 8, 9, 11, 12]. However, due to the severity of the condition, a steroid-dependence is often described. None of the most common immunosuppressive drugs (cyclophosphamide, azathioprine, methotrexate) was effective [1, 2, 6, 8, 11, 13].

Navon et al. reported ten patients treated with anti-TNF drugs (etanercept, adalimumab, infliximab) with complete response in 8, even after the failure of immunosuppressive therapies [2]; good results with anti-TNF agents were also reported in other small series [3, 11, 12]. By now, the reason why this drug is effective is still unclear.

According to the report of Zhou et al., neither immunosuppressive nor biologic drugs were able to completely control the disease manifestations in all treated patients; the enzymatic substitutive treatment (fresh frozen plasma or recombinant enzyme) was postulated to be of help. This approach was tempted in two patients reported by Batu et al. with a transient good response in one and a not-satisfactory response in the other [11].

A possible role of hematopoietic stem cell transplantation (HSCT) has been postulated to be effective by Zhou et al. and Navon et al., being able to provide ADA2 producing monocytes and therefore to normalize the plasmatic levels of the enzyme [1, 2]. This therapeutic strategy, performed in one of the two patients reported by Van Eyck et al. [7] and in a patient reported by the NIH group [3], was able to normalize the plasmatic levels of ADA2 and to control the disease manifestations [3, 7]; early complications occurred in one of them. More recently two additive patients who displayed a complete response to HSCT have been described [12].

Van Eyck et al. conclude that HSCT should be suggested only for those patients with a severe disease, since DADA2 patients present an increased risk of HSCT-related complications due to the persistent inflammation and the compromised endothelial integrity [7]. Of note, the other patient described in this paper displayed a complete response to treatment with sirolimus; the authors assume that this drug may be of help in the control of the clinical manifestations related to ADA2-deficiency, being able to reduce the M1 macrophage differentiation and the production of IL-6 [7].

Conclusion

In conclusion DADA2 is a genetic condition mainly characterized by an inflammatory vasculopathy resembling polyarteritis nodosa (PAN). From the clinical data so far available, the age at onset, the disease manifestations and severity are widely variable. Further clinical studies are therefore needed in order to better understand the phenotypic viability of this condition and the genotype-phenotype correlation.

In light of the data by now available, we consider the genetic analysis of CECR1 gene suggested in the following clinical pictures: patients with an inflammatory vasculopathy with early onset in infancy, patients with a diagnosis of PAN or cPAN with early onset and/or severe organ involvement (above all stroke), especially in case of a positive family history or consanguinity/endogamy in the parents. Moreover DADA2 should be ruled out in patients with an immune-disreactive condition without an underlying diagnosis, especially in presence of signs or symptoms of vasculitis.

Finally, a better enlightenment of the pathogenetic mechanisms of the disease is needed; these data will be of help also in the identification of an effective treatment.

Declarations

Acknowledgements

Not applicable.

Funding

Not applicable.

Availability of data and material

The datasets supporting the conclusions of this article are included within the article (and its additional files).

Authors’ contributions

RC carried out the review of the available papers on the disease, performed the revision of the genetic and clinical manifestations and drafted the manuscript. FP and FS reviewed the pathogenetic studies of the disease and draft the pathogenesis chapter of the review. MG conceived of the review, participated in its design and helped to draft the manuscript. All authors read and approved the final manuscript.

Competing interests

Marco Gattorno received speaker’s fees from Sobi and Novartis and grant for the Eurofever project from Sobi and Novartis.

Consent for publication

The consent to publish the clinical image (Fig. 3) has been obtained from the patient’s parents.

Ethics approval and consent to participate

Not applicable.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
UO Pediatria II, Istituto G. Gaslini

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Copyright

© The Author(s). 2016

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