Internuclear Ophthalmoplegia in a Child With Deficiency of Adenosine Deaminase 2

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease resulting in a syndrome which includes small-sized and medium-sized vessel vasculitis, immunodeficiency, and hematological disease (1,2). Loss-offunction; mutations in ADA2 are responsible for the disease (1).

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Internuclear Ophthalmoplegia in a Child With Deficiency of Adenosine Deaminase 2 Murtaza M. Mandviwala, MD, James W. Verbsky, MD, PhD, Alexander J. Khammar, MD, Ryan D. Walsh, MD D eficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease resulting in a syndrome which includes small-sized and medium-sized vessel vasculitis, immunodeficiency, and hematological disease (1,2). Loss-offunction mutations in ADA2 are responsible for the disease (1). Although the exact function of ADA2 is unclear, the protein is expressed in myeloid cells and produced by monocytes, macrophages, and dendritic cells (2,3). Signs and symptoms are broad and can include intermittent fevers, skin rashes, arthralgias, ischemic and hemorrhagic strokes, inflammatory bowel disease, liver disease, kidney disease, spastic paraplegia, peripheral polyneuropathy, ataxia, neurosensory hearing loss, labyrnthitis, encephalopathy, and cerebral atrophy (2). To the best of our knowledge, only 2 cases of ocular misalignment associated with DADA2 have been previously reported in the literature (4). In this article, we describe a child with a newly diagnosed internuclear ophthalmoplegia (INO), which led to the diagnosis of DADA2. CASE A 4-year-old Caucasian girl presented to the emergency department with acute-onset constant, horizontal, and binocular diplopia. On ophthalmologic examination in the emergency department, the patient was somewhat fussy, with normal vital signs (including no fever). The patient was not cooperating with formal visual acuity testing, but she was able to count fingers at 3 feet in each eye. Her pupillary, external, anterior segment, and posterior segment examinations were unremarkable in both eyes. Motility examination demonstrated severely limited adduction (unable to adduct past midline) and slowing of the adducting saccade of the right eye with otherwise full ductions consistent with a right INO. Department of Ophthalmology and Visual Sciences (MMM, AJK, RDW), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Rheumatology (JWV), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Ophthalmology (AJK), Children’s Hospital of Wisconsin, Milwaukee, Wisconsin; and Department of Neurology (RDW), Medical College of Wisconsin, Milwaukee, Wisconsin. The authors report no conflicts of interest. Address correspondence to Murtaza M. Mandviwala, MD, Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, 925 N. 87th Street, Milwaukee, WI 53226; E-mail: [e-mail] e12 Her left eye ductions were full with subtle abducting nystagmus of the left eye on attempted left gaze. There was associated exotropia in primary gaze. The patient had a somewhat complex recent medical course otherwise. Seven months before her presentation with INO, the patient had been hospitalized for evaluation of fevers, abdominal pain, nausea, decreased appetite, and fatigue. She was found to have an elevated white blood cell count (WBC), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). She underwent multiple investigations with specialists in rheumatology and infectious diseases, initially without a clear source identified for her symptoms. Her thorough workup included a whole-body positron emission tomography (PET)/ MRI study which was unremarkable. Ultimately, a Bartonella henselae IgG titer was found to be elevated at a value of 1:128 (reference range: ,1:64). A subsequent Bartonella test demonstrated a rising titer of 1:256 in the definitively positive range confirming infection, and she was treated with azithromycin. There was no known exposure to cats, but she had sustained a dog bite before being diagnosed with Bartonella. The patient improved after her azithromycin treatment, until several weeks before her current presentation with INO, when she again developed low-grade fevers and pains in her abdomen, extremities, and inguinal region. For her acute INO and ongoing unexplained febrile illness, multiple further investigations were undertaken. MRI of the brain with and without contrast was unremarkable aside from a 12-mm septate pineal cyst which seemed to have minimal contact with the superior tectum. CT angiogram of the head was normal. Echocardiogram was unremarkable. Laboratory studies again revealed significantly elevated inflammatory markers including WBC, ESR, CRP, CH50, procalcitonin, and C3 complement. Other laboratory studies including immunoglobulin studies, antinuclear, Epstein‒Barr virus, cytomegalovirus, severe acute respiratory syndrome coronavirus 2, Lyme, human immunodeficiency virus, ganglioside GQ1B, acetylcholine receptor, Brucella, and Coxiella antibodies were all unremarkable. MRI of the brain was repeated 3 weeks later and was unchanged from prior; MRA of the brain was also obtained at that point and was normal. A repeat whole-body PET scan revealed low-level fluoro-2deoxy-D-glucose avidity associated with areas of focal softtissue edema-like signal within the musculature of the proximal extremities. Her sister also had a febrile episode with Mandviwala et al: J Neuro-Ophthalmol 2023; 43: e12-e13 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence abdominal pain and elevated inflammatory markers. Her sister’s evaluation was unrevealing, and her fevers resolved, but her elevated inflammatory markers remained. A genetic evaluation of 207 genes for primary immunodeficiency was performed, which revealed 2 pathogenic heterozygous variants, c.140G.C (p.Gly47Ala) and c.973-2A.G (splice acceptor), in ADA2. Although these 2 variants have been identified as definitely pathogenic, the data obtained from the test cannot determine whether the mutations are in cis or trans configuration without genetic testing from family members (5). Functional testing demonstrated severely decreased ADA2 activity in both her and her sister. Both were diagnosed with DADA2. Genetic testing has not been performed on her sister or other family members. The patient’s maternal grandfather and great grandfather had an unidentified vasculitis condition, and the father has psoriasis. The family history otherwise seems unremarkable without evidence of consanguinity or founder effect. Our patient was started on prednisolone 15 mg daily at that point (approximately 2 months after presentation with INO); subcutaneous etanercept (10 mg every week) was started a month later. The mainstay of treatment typically includes steroids to control the acute flare and antitumor necrosis factor (anti-TNF) agents for chronic therapy because the disease has a tendency to recur when steroids are tapered (2). Before starting prednisolone, there had been some gradual improvement of the right eye adduction from severe limitation to mild limitation, but with continued slowing of the adducting saccade, and small exotropia by Hirschberg with associated diplopia. However, within about 1 week of starting prednisolone, the patient’s mother felt the patient’s eye motility/alignment had returned to normal and the patient was no longer complaining of double vision. Her steroid dose was gradually tapered over a 3-month period. On repeat neuro-ophthalmologic examination 5 months after presentation, and several days after completion of the steroid taper, she had full motility in both eyes and a flick exophoria with a normal Hirschberg test. Her low-grade fevers, abdominal pain, and extremity pain had all resolved. DISCUSSION Manifestations of DADA2 include a broad range of features stemming from vasculitis that affects essentially all organs (2). Although initial reports describe ischemic and hemorrhagic strokes in patients with DADA2, only one report thus far documents cases related to ocular misalignment (1,4). Uettwiller et al described a 7-year-old girl with DADA2 who developed a left INO, which occurred despite steroid use and only resolved over 1 year after starting anti-TNF therapy. They also reported her 3-year-old sister with DADA2 who developed a transient oculomotor nerve palsy, which also resolved with anti-TNF therapy over 1 year. We describe a patient who presented clinically with a right INO, which we believe was caused by her underlying DADA2. INO is Mandviwala et al: J Neuro-Ophthalmol 2023; 43: e12-e13 unusual in children, and the patient did not have any examination or imaging findings to suggest a more likely etiology. The fact that the INO arose in the setting of the patient having other signs and symptoms of vasculitis (including elevated inflammatory markers, low-grade fevers, fatigue, anorexia, and abdominal pain), in conjunction with positive genetic and functional testing for DADA2, makes this condition the most likely etiology of her INO. Although MRI did not demonstrate a correlative lesion, her examination was indicative of a deficit of the right medial longitudinal fasciculus (MLF), which we suspect occurred on an inflammatory or ischemic basis. We believe the pineal gland cyst noted on MRI was incidental. She did not have any examination findings to suggest dorsal midbrain syndrome, and her improved course with stable imaging argues against the pineal cyst being symptomatic. We suspect that systemic vasculitis caused by DADA2 likely resulted in a small region of ischemia affecting the MLF causing an INO. Because DADA2 affects small-sized and medium-sized vessels, the arteries supplying the MLF may have become inflamed resulting in decreased blood flow to the region. Vasculitis is a welldocumented cause of INO (6). Similar to our patient, Uettwiller et al reported resolution of ocular misalignment symptoms after initiation of immunosuppressive therapy again likely indicating an inflammatory etiology (4). In conclusion, we report an unusual presentation of DADA2 with right INO and subsequent resolution after initiating immunosuppressive therapy. Clinicians may benefit from having a higher index of suspicion of DADA2 when presented with any young patient with INO and systemic vasculitis symptoms. REFERENCES 1. Zhou Q, Yang S, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, Stone DL, Chae JJ, Rosenzweig SD, Bishop K, Barron KS, Kuehn HS, Hoffmann P, Negro A, Tsai WL, Cowen EW, Pei W, Milner JD, Silvin C, Heller T, Chin DT, Patronas NJ, Barber JS, Lee CR, Wood GM, Ling A, Kelly SJ, Kleiner DE, Mullikin JC, Ganson NJ, Kong HH, Hambleton S, Candotti F, Quezado MM, Calvo KR, Alao H, Barham BK, Jones A, Meschia JF, Worrall BB, Kasner SE, Rich SS, Goldbach-Mansky R, Abinun M, Chalom E, Gotte AC, Punaro M, Pascual V, Verbsky JW, Torgerson TR, Singer NG, Gershon TR, Ozen S, Karadag O, Fleisher TA, Remmers EF, Burgess SM, Moir SL, Gadina M, Sood R, Hershfield MS, Boehm M, Kastner DL, Aksentijevich I. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engld J Med. 2014;370:911–920. 2. Meyts I, Aksentijevich I. Deficiency of adenosine deaminase 2 (DADA2): updates on the phenotype, genetics, pathogenesis, and treatment. J Clin Immunol. 2018;38:569–578. 3. Zavialov AV, Gracia E, Glaichenhaus N, Franco R, Zavialov AV, Lauvau G. Human adenosine deaminase 2 induces differentiation of monocytes into macrophages and stimulates proliferation of T helper cells and macrophages. J Leukoc Biol. 2010;88:279–290. 4. Uettwiller F, Sarrabay G, Rodero MP, Rice GI, Lagrue E, Marot Y, Deiva K, Touitou I, Crow YJ, Quartier P. ADA2 deficiency: case report of a new phenotype and novel mutation in two sisters. RMD Open. 2016;2:e000236. 5. Aksentijevich I, Moura NS, Barron K. Adenosine deaminase 2 deficiency. GeneReviews. 2019. 6. Keane JR. Internuclear ophthalmoplegia unusual causes in 114 of 410 patients. Arch Neurol. 2005;62:714–717. e13 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.