Improvement of SLC29A3 spectrum disorder-related sensorineural hearing loss after initiation of IL-6 inhibitor

Background

As increasing numbers of inborn errors of immunity are uncovered, the use of targeted therapies is an important component of this expanding field. Patient cases that demonstrate the use and benefit of novel therapies will lead to better care and improved outcomes for rare diseases. SLC29A3 spectrum disorder is a rare autosomal recessive autoinflammatory syndrome characterised by variants in the SLC29A3 gene (OMIM 612373), which encodes the human equilibrative nucleoside transporter 3 (hENT3). Patients harbouring this variant can present with a multisystem autoinflammatory disorder called ‘H syndrome’ with variety in presentation and a spectrum of severity. Patients are described as having some or all the following symptoms: hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, low height and hyperglycaemia (in the setting of immune mediated diabetes).1 Therapies to control autoinflammation in this disorder include steroids, anti-TNF, methotrexate, anti-interleukin 1 (IL-1) and the recent success of IL-6 inhibition (tocilizumab). The cytokineIL-6 plays an important role in the regulation of immune response and inflammation, and over-production of IL-6 is linked to inflammatory diseases such as rheumatoid arthritis.2 Tocilizumab is a recombinant humanised anti-IL-6 receptor monoclonal antibody approved for use in autoimmune conditions such as rheumatoid arthritis and in cytokine release syndromes. More recently, tocilizumab has been shown to have a role in the control of diseases of autoinflammation. We report a case of SLC29A3 spectrum disorder in a male child who experienced improvement and stabilisation of sensorineural hearing loss (SNHL) following the addition of IL-6 inhibitor therapy.

Case presentation

The patient is a boy toddler of Arab descent who was referred to the immunology clinic for immune evaluation in the setting of recurrent infections. He was born premature at 31 weeks due to maternal causes (pre-eclampsia and HELLP syndrome). He was intubated in the delivery room due to respiratory distress, received surfactant and was extubated to RAM cannula on day of life 1 (DOL1). By DOL4, he was weaned to high flow nasal cannula but further weaning of FiO2 and pressure led to persistent tachypnea, and he remained on 0.3 L O2 overnight and with naps. The patient completed a course of empiric antibiotics after delivery given temporary leucopenia and thrombocytopenia thought to be indicators of sepsis. He also received 7 days of gentamicin eye drops for purulent ocular drainage. During admission to the neonatal intensive care unit, his case was further complicated by hypotonia, diffuse bony demineralisation, hepatosplenomegaly and dysphagia (requiring nasogastric feeds and eventually a gastrointestinal tube for nutrition). He also failed two hearing screens, prompting workup for hearing loss. On Auditory Brainstem Response (ABR) attempt, middle ear effusions were noted resulting in ear, nose and throat (ENT) physicians recommending bilateral myringotomy tube placement, which was completed at 3 months of age, and steroid-antibiotic ear drops in case of infection. On third attempt at ABR, results showed moderate mixed hearing loss in both ears within 500–4000 Hz frequency. The hearing loss prompted screening for cytomegalovirus (CMV) in the urine which returned positive. Yet, given the lack of microcephaly, eye or liver involvement and a normal brain MRI, the CMV was determined to be postnatally acquired and did not require treatment.

The patienthad a history of sepsis at 3 months of age from Enterobacter for which he was treated empirically with vancomycin and ceftriaxone before quickly narrowing to ampicillin. No lumbar puncture was completed. Echocardiogram and ECG were normal. He also had frequent viral upper respiratory infections (URIs) and >10 diagnoses of acute otitis media by 15 months of age. However, immune workup was reassuring with normal IgG, IgE and IgM with a borderline elevated IgA and normal numbers of T-cells, B-cells and natural killer cells. Recurrent URIs were thought secondary to anatomic abnormalities and hypotonia, likely in the setting of prematurity. Exam was significant for short stature, a chronic hyperpigmented rash on the back and exotropia. There was no history of recurrent fevers or hyperglycaemia. There was a known family history of hearing loss (due to Rosai-Dorfman syndrome) in the maternal side of the family although no genetic testing was available. Given parental consanguinity, there was high suspicion for genetic aetiology of the hearing loss. Of note, both parents are healthy.

Investigations

Immunoglobulins were reassuring and as follows: IgG 1060 mg/dL (reference range: 331–1165 mg/dL), IgA 113 mg/dL (reference range: 14–105 mg/dL), IgM 99.3 mg/dL (reference range: 41–164 mg/dL) and IgE 9.98 KU/L (reference range: <29.2 KU/L). Laboratory evaluation was significant for systemic inflammation as determined by persistently elevated erythrocyte sedimentation rate (ESR) ranging 21–43 mm/hour (reference range: 0–20 mm/hour) and a C reactive protein (CRP) that also remained moderately elevated ranging from 2.5 to 10.4 mg/dL (reference range: <0.3 mg/dL). Given suspicion for genetic causes of the hearing loss, a microarray was sent. When this returned normal, a whole exome sequencing (WES) was completed which returned with a homozygous pathogenic variant in SCL29A3 (c.1309 G>A p.G437R), which has previously been reported in patients from a similar demographic background as this patient’s family.

Differential diagnosis

Initially, the patient’s failed hearing test was considered a false positive given his young age (due to vernix in the ear canal, fluid in the middle ear or because of movement or crying during the test). Yet, repeat hearing tests remained abnormal. Accumulation of fluid in the ears was considered an aetiology of the hearing loss, but hearing did not improve with the placement of myringotomy tubes or with antibiotic ear drops. Despite the lack of information on antibiotics given empirically at birth, infants commonly receive amoxicillin and gentamicin, which was assumed to have been given to the patient. Gentamicin is ototoxic and can be considered as contributing to the patient’s hearing loss, but babies do not uncommonly receive a 7-day empiric course in the setting of fever or maternal infection without failed hearing screens. Similarly, the gentamicin eye drops are unlikely to have contributed to the patient’s hearing loss as ototoxicity to topicals may occur but primarily when applied to open wounds. As previously mentioned, urine CMV was positive but determined to be postnatally acquired given the lack of additional support for neonatal infection (absence of microcephaly, eye involvement and brain MRI calcifications). In addition, there were no intracranial abnormalities on brain MRI to suggest a structural aetiology of the hearing loss. While chronic infections can be a cause of conductive hearing loss secondary to scar tissue accumulation, the patient failed multiple hearing screens shortly after birth with recurrent infections occurring later.

Of note, two variants of unknown significance (VUS) were further investigated: a VUS in WWOX (c.28G>T p.D10Y), which is associated with spinocerebellar ataxia characterised by intellectual disability, cerebellar ataxia and seizures typically presenting around 9–12 months of age, was considered. However, reassuring brain MRI and lack of clinical findings made this variant unlikely pathogenic. WES was reanalysed also uncovered a VUS in ARSE gene (c.1098G>C p.Q366H). Hemizygous pathogenic variants in ARSE are associated with X-linked chondrodysplasia punctata 1 (CDPX1), which has the findings of stippled epiphyses, shortening of the distal phalanges, nasomaxillary hypoplasia, postnatal short stature, respiratory problems, cervical spine stenosis and instability, hearing loss and intellectual disability. The diagnosis is based on radiographic findings and the presence of a pathogenic variant in ARSE. A skeletal survey was pursued and showed diffuse bony demineralisation and metaphyseal cupping and fraying at the distal ulnar, distal radius and proximal humeri and mild widening of the anterior rib ends. Endocrinology was consulted and there was no evidence of hypophosphataemic or vitamin D deficient rickets. As imaging did not show shortening of the phalanges or stippling of the epiphyses, the presentation was not consistent with a diagnosis of CDPX1. The medical geneticist concluded that neither of these genes are pathological based on the overall clinical presentation. Although it is not clear to the authors if there are unknown gene to gene interaction that influenced the phenotype.

Ultimately, the family history of hearing loss and Arab descent, genetic testing results of a variant in SCL29A3, constellation of symptoms (including hypotonia, hyperpigmentation, low height, hepatosplenomegaly) and response to IL-6 inhibitor support the diagnosis of SCL29A3 spectrum disorder (‘H syndrome’) as the cause of the patient’s SNHL.

Treatment

After the patient’s hearing loss failed to improve with myringotomy tubes, he was started on oral steroids given the elevated inflammatory markers and concern for local inflammation of the middle ear impacting his hearing status. Despite systemic steroids, there was no clear improvement of hearing loss. His ESR stayed elevated to a maximum of 43 mm/hour and CRP remained detectable. As a next step, therapy with tocilizumab was pursued given the case reports of decreased inflammatory response in patients with SCL29A3 spectrum disorders and was preferred to avoid side effects of chronic steroid use.

Specific to his hearing loss, the patient was managed by ENT physicians and by an audiologist who continued to follow hearing tests while the patient was on therapy. His additional chronic issues including sleep apnoea, G-tube dependence, hepatomegaly, short height and hyperpigmentation were managed by an interdisciplinary team that included pulmonary, gastrointestinal, endocrinology and dermatology physicians.

Outcome and follow-up

The patient started on tocilizumab when he was 2 years old and had been on therapy for 18 months at the time of this writing. Three months into his tocilizumab treatment, the ESR levels dropped to 1 mm/hour (from greater than 40 mm/hour) and CRP to <0.3 mg/dL (figures 1 and 2). Repeated ABR testing showed improvement of the hearing from baseline testing prior to starting tocilizumab (figure 3). His hearing improvement was stable on repeat testing with mild to moderate SNHL bilaterally. Below are his most recent hearing test results:

Right ear: thresholds obtained between 40 and 55 dB HL at 1000 Hz and 4000 to 8000 Hz, consistent with mild to moderate SNHL.

Left ear: thresholds obtained between 40 and 50 dB HL from 1000 to 8000 Hz, consistent with mild to moderate SNHL.

While mild to moderate SNHL remains, the overall improvement and lack of progression of hearing loss followed the start of IL-6 inhibitor therapy. The patient wears hearing aids, but the family notes clinical improvement as he now responds to small sounds even when not wearing the devices, which is an improvement. He continues to receive subcutaneous injections of tocilizumab every 3 weeks at home by family, without side effects, rebound inflammation or progression of hearing loss. At this time, hearing tests are completed every 6–12 months with the patient’s audiologist team and labs (complete blood count with differential, CMP to evaluate liver/kidney function and inflammatory markers) are monitored while the patient is on tocilizumab. Given immunosuppression from tocilizumab, if a fever greater than 101°F were to develop, the patient was instructed to be evaluated by a medical provider.

In addition to the targeted assessment while on tocilizumab, given known presentations of patients with ‘H syndrome’, the patient is monitored for complications that may develop over time including hypertrichosis, hypogonadism and hyperglycaemia. Recent repeat brain MRI demonstrated stable mild dilatation of the lateral and third ventricles with a suggestion of diffuse volume loss of the deep white matter in the bilateral cerebral hemispheres, progressed since brain MRI at birth. Neurosurgery does not think the mild findings are related to the patient’s developmental delays, and he has not developed ataxia or seizures to support a diagnosis of spinocerebellar ataxia 12. Currently, no findings point to an alternative or additional diagnosis to H syndrome and the patient’s prematurity.

The patient continues regular follow-up via multidisciplinary care including ENT, endocrinology, gastroenterology, pulmonary, genetics, speech, nutrition and immunology/rheumatology.