Paediatric Cogan´s syndrome - review of literature, case report and practical approach to diagnosis and management

A previously healthy 8-year-old girl of non-consanguineous Rumanian origin was referred to our department with a 4-week history of anterior uveitis. This manifested as redness, decreased visual acuity and photophobia and initially responded well to topical steroids. In addition, hearing difficulties could be retrospectively discerned for several preceding months. A severe (left ear) and a moderate (right ear) sensorineural hearing deficit was subsequently confirmed by an audiometry and a brain stem evoked response audiometry (BERA). During the course of the disease the patient developed intermittent vertigo, low-grade fever, recurrent headache, abdominal pain, diarrhoea with rectal bleeding and repeated epistaxis.

Laboratory investigations revealed low inflammatory markers (CRP < 1 mg/l, ESR 17 mm/h), normal CBC (WBC 7,730/µl, Hb 12 g/dl and PLT 435,000/µl), normal electrolytes, creatine, urinalysis and liver enzymes. Workup for infections, including screening for CMV, Chlamydia, Syphilis, Lyme disease, Mycoplasma and Mycobacterium tuberculosis, was negative. The following tests were also negative or normal: ANA, ANCA, RF, LA, β2-GP and aCL antibodies, serum angiotensin-converting enzyme and calprotectin in stool. A chest X-ray, MRI of the brain and cerebrospinal fluid were normal as well. A whole-exome sequencing (WES) was indicated to exclude inborn disorders of hearing and revealed no relevant pathogenic variants. The combination of uveitis and sensorineural hearing deficit led to a diagnosis of CS. In addition, a contrast-enhanced MRI of the inner ear was performed and showed signal enhancement in the labyrinth and cochlea bilaterally raising suspicion of a bilateral labyrinthitis, a finding compatible with CS Fig. 1. An echocardiography excluded aortic dilatation.

Therapy was started with i.v. methylprednisolone (20 mg/kg, 3 doses over 3 consecutive days) repeated four times at 5-week intervals, followed each time by oral prednisolone at 1 mg/kg/day, methotrexate at 15 mg/m² weekly and topical steroid eyedrops. The uveitis regressed within 4 weeks. However, the patient developed a pronounced bilateral keratitis and had to be restarted on topical steroids and ciclosporin. As for her hearing capacity, she initially responded with a transient improvement in hearing. During further course of the disease the auditory function deteriorated again. Within 2 months the patient developed a secondary glaucoma and Cushing signs necessitating a reduction of the systemic steroid treatment. Additionally, infliximab (5 mg/kg at 2-week intervals initially, currently at 4-week intervals) was started with the aim to restore hearing. The auditory function normalized in the right ear as confirmed on the pure tone audiogram (Fig. 2), whereas the left ear remained deaf during the 8-month follow-up and the patient is being evaluated for unilateral cochlear implantation. During follow-up we could also confirm resolution of the inflammation within labyrinth and cochlea bilaterally (Fig. 1). This fact may, however, indicate intracochlear fibrosis on the deaf side and emphasize the urgency of CI. The inflammatory eye involvement resolved completely leaving posterior synechia. The patient still suffers from intermittent balance disorder, fatigue and recurrent epistaxis.

In order to provide the family of our patient with an evidence-based counselling and to support our therapeutic decision making, we performed a review of literature and identified altogether 55 paediatric CS case reports in PubMed under the keywords: “Cogan syndrome” and “children” or “childhood”. The clinical characteristics, treatment and outcome are presented in Table 2 and Supplementary material 1 [2‐4, 8‐42]. All the reported patients had sensorineural hearing deficit and ocular involvement with interstitial keratitis being the most common form detected in 62%, followed by uveitis found in 36%. Papilledema was seen in 3/55 patients. Vestibular symptoms included vertigo or tinnitus sometimes associated with vomiting and were reported in 69% of patients. Systemic symptoms such as fever, arthralgias/arthritis, neurological or skin involvement were reported in 29, 45, 31 and 18%, respectively. Among neurological symptoms, headache was the most commonly described complaint, however, meningitis and facial nerve palsy have also been reported in single cases [4, 8, 40]. Skin lesions included nodular, urticaria-like lesions, furuncles and ulceration at the site of TBC vaccination [10, 17, 19, 29‐32, 35, 37, 40]. Rarely, lymphadenopathy or hepatosplenomegaly, weight loss or anorexia have been reported [2, 8, 10, 12, 22, 27, 28, 31]. Renal involvement classified as glomerulonephritis or tubulointerstitial nephritis have been reported in three children [4, 8, 26]. The most common potentially fatal cardiovascular complications included an aortitis identified in 9/55 (16%), three of them required a surgical intervention, and a pericarditis found in 2/55 (4%) patients [2, 4, 10, 26, 27, 36‐39]. Two patients out of the whole cohort died. One was a 14 year old boy reported by Cogan in 1964. The patient received no systemic treatment and succumbed to an aortitis with a massive mural thrombus, aortic insufficiency and heart failure [2]. The second patient suffered from steroid dependent CS and died from a subarachnoid haemorrhage despite of treatment with high dose systemic steroids and cyclophosphamide [30].

The most common treatment by far were systemic corticosteroids used in 81%, followed by methotrexate in 26% of patients. Only 2 paediatric patients including ours have been treated with biologics so far, both of them with infliximab [19]. The outcome of ocular involvement has been shown much more favourable in comparison to the auditory-vestibular function with 68% of patients remaining deaf, severely or moderately affected.