Keratitis, Ichthyosis, and Deafness Syndrome with Endocarditis and Myelitis: A Rare Case Report

Abstract

Introduction

Keratitis-ichthyosis-deafness (KID) syndrome (MIM#148210) is a rare autosomal dominant genodermatosis caused by monoallelic deleterious variants in the GJB2 gene (MIM*121011). The syndrome is characterized by congenital neurosensory deafness, keratitis, and palmoplantar keratoderma.

Case Presentation

We report on a 32-year-old Caucasian male with KID syndrome who presented to the emergency department with high fever, severe headache, and chest pain exacerbated by coughing and deep breathing. His symptoms rapidly progressed to sepsis, and diagnostic evaluations confirmed endocarditis, complicated by parainfectious myelitis. Despite the severity of his condition, the patient achieved significant recovery, with minimal residual neurological deficits affecting the left leg.

Conclusion

We attribute the sepsis to systemic dissemination of Staphylococcus aureus, probably facilitated by impaired skin barrier due to KID syndrome. This case highlights the importance of comprehensive interprofessional management in managing rare genodermatoses and their complications.

Introduction

Keratitis-ichthyosis-deafness (KID) syndrome (MIM#148210) is a rare autosomal dominant genodermatosis first described by Skinner et al. in 1981 [1, 2]. This syndrome is characterized by a clinical triad: congenital bilateral sensorineural hearing loss, keratitis, and palmoplantar keratoderma. Its molecular cause is linked to heterozygous variants in the GJB2 gene (MIM*121011), which encodes Connexin 26, a protein involved in intercellular communication and carcinogenesis [3].

Congenital neurosensory deafness is present in nearly all patients, with varying severity [4]. In addition to palmoplantar keratoderma, patients often show angular cheilitis, alopecia totalis, nail dystrophy, and leukonychia [4]. Ocular involvement is reported in approximately 95% of cases, typically developing later than other clinical features [5].

KID syndrome is also associated with a high risk of chronic skin infections and sepsis, particularly in infancy, with septicemia reported in nearly 50% of patients [6]. Fungal infections, such as chronic mucocutaneous candidiasis, are common and are attributed to impaired epithelial barrier function or systemic immune deficiencies [6, 7]. Immune dysregulation involving both B- and T-cell compartments has also been documented [8].

Furthermore, individuals with KID syndrome are predisposed to developing skin tumors, with trichilemmal and squamous cell carcinomas being the most frequent ones. Complete surgical excisions are often recommended for effective management [6].

In this report (the CARE Checklist has been completed by the authors for this case report, attached as online suppl. material; for all online suppl. material, see https://doi.org/10.1159/000546019), we describe a case of a 32-year-old male with KID syndrome and beta-thalassemia minor who developed severe complications, including endocarditis and myelitis. The main events are shown in the timeline in Figure 1.

Fig. 1.

Timeline of the case.

Case Presentation

A 32-year-old Caucasian male presented to the emergency department with a 3-day history of high fever, severe headache, and chest pain exacerbated by coughing and deep breathing. The patient had a known diagnosis of KID syndrome, associated with the GJB2 gene variant c.148G>A(p.Asp50Asn) [9], though the parental origin of the mutation was not verified. The patient’s dermatological features are shown in Figure 2.

Fig. 2.

Clinical features of the patient. a Plantar keratoderma with pronounced thick scales and rhagades, characteristic of KID syndrome. b Palmar keratoderma presenting with velvety hyperkeratotic plaques. c Vascularizing keratitis, showing significant ocular involvement. d Cutaneous horn on the tip of the nose, highlighting hyperkeratosis-related changes.

His medical history was positive for beta-thalassemia minor, a condition affecting nearly all family members. No other genetic disorders or significant findings were reported in his family history. A detailed summary of the patient’s medical history is provided in Table 1.

Table 1.

Summary of the patient’s medical history

Characteristics	Details
Age	32 years
Sex	Male
Body mass index (BMI)	19.2
Family history	Beta-thalassemia minor affecting nearly all family members
Medical history	Superficial punctate keratitis with large corneal ulcers Use of hearing aids Right tympanoplasty with removal of ichthyotic ear plugs Periodic skin care for plantar ichthyosis, wound care, and periungual abscesses Amniotic membrane transplant on the right eye Right keratoplasty with acute rejection following immunosuppressive tapering
Chronic medications	None at the time of diagnosis

Upon admission, the patient’s body temperature was 40°C. Examination revealed negative Jordan, Murphy, and Bloomberg signs, as well as no indications of meningeal inflammation. A SARS-CoV-2 test was negative, and a chest X-ray showed no abnormalities.

An ECG demonstrated sinus tachycardia at 140 bpm, incomplete right bundle branch block, and nonspecific ventricular repolarization abnormalities. Transthoracic echocardiography revealed minimal posterior pericardial detachment without hemodynamic significance. Arterial blood gas analysis was within normal limits; however, blood tests showed elevated troponin I (100 pg/mL), C-reactive protein (26.32 mg/dL), procalcitonin (12 ng/mL), serum creatinine (2.94 mg/dL), and liver enzymes (GOT and GPT, 300 UI/L). Decreases in hemoglobin (10.6 g/dL) and glomerular filtration rate (27 mL/min) were also detected.

Two days later, blood cultures were positive for methicillin-resistant S. aureus (MRSA). Empirical intravenous antibiotic therapy was initiated with linezolid (600 mg every 12 h) and meropenem (1 g every 12 h).

Computed tomography (CT) scans of the chest and abdomen were performed for further evaluation. The chest CT revealed clusters of increased parenchymal density in both lungs, characterized by a combination of consolidation and “ground-glass” patterns. Additional findings included diffuse thickening of the bronchial walls and a right-sided pleural effusion with a maximum thickness of 5 mm. No abnormalities were detected on the abdominal CT.

Despite antibiotic therapy, the patient’s fever persisted 6 days after admission. Because of the persistent fever and initial cardiac arrhythmias, endocarditis was suspected. Although three transthoracic echocardiograms were negative for valvular involvement, a transesophageal echocardiogram identified a 4 × 5 mm vegetative formation on the posteromedial scallop of the mitral valve (Fig. 3a). The aortic valve and the right heart sections showed no pathological changes.

Fig. 3.

Transesophageal echocardiography and spinal MRI images. a Transesophageal echocardiography reveals an echodense mass on the atrial surface of the mitral valve, consistent with vegetation. b Spinal MRI demonstrates a poorly defined intramedullary hyperintensity on T2-weighted imaging, indicative of parainfectious myelitis. MRI, magnetic resonance imaging.

On the seventh day of hospitalization, the patient reported burning pain and weakness (hypoasthenia) in the lower limbs, symptoms consistent with parainfectious myelitis. Magnetic resonance imaging of the brain and spine (Fig. 3b) revealed cortico-subcortical alterations in the left parieto-occipital region and swelling of the spinal cord in the cervico-dorsal area, extending from the first dorsal vertebra (D1) to D4. A lumbar puncture yielded 10 mL of clear cerebrospinal fluid with normal pressure, and chemical, physical, and microbiological analyses were unremarkable.

Electromyography of the upper and lower limbs showed diffuse nonspecific myogenic signs without evidence of active denervation, while electroneurography revealed predominantly sensory axonal polyneuropathy, more pronounced in the lower limbs.

On the same day, the patient developed acute anemia (Hb < 7 g/dL), probably exacerbated by his underlying thalassemia, necessitating a transfusion of erythrocyte concentrates. The anemia appeared to be a side effect of linezolid therapy [10], prompting an immediate switch to daptomycin (500 mg IV once daily) and cephazolin (1 g IV three times daily) for endocarditis treatment. Oral therapy was introduced after resolution of the infection.

On the 27th day of hospitalization, follow-up magnetic resonance imaging of the brain and spine revealed complete resolution of cortico-subcortical changes in the left occipital region and reduced medullary swelling in the proximal dorsal spinal cord. Residual pathological changes were noted at D2-D3 but were markedly improved.

By the 30th day, transesophageal echocardiogram confirmed the absence of vegetative formations on the mitral valve, with all other cardiac structures appearing normal. A final blood culture, performed on the 35th day, was negative, and inflammatory markers (e.g., C-reactive protein) were within normal limits, except for the blood count, which reverted to the patient’s baseline thalassemic state.

The patient was discharged with a regimen of doxycycline (100 mg every 12 h) and flucloxacillin (1 g every 8 h) for 10 days. Three days before discharge, after 28 days of intravenous corticosteroid therapy, 4 mg dexamethasone intravenous was switched to a daily oral dose of 25 mg. It was then gradually tapered and discontinued 14 days later. On discharge, the patient could walk with assistance, without sphincter dysfunction, and maintained the Mingazzini II sign without asymmetry.

Discussion

KID syndrome is a rare genodermatosis with an estimated prevalence of approximately 100 cases worldwide, according to MedlinePlus [11] (accessed November 21, 2024). This case underscores the critical importance of meticulous management of chronic cutaneous lesions in patients with KID syndrome to achieve favorable clinical outcomes. Due to the rarity of the condition, clinical experience in managing its dermatological manifestations and systemic complications is limited.

Regarding the potential contribution of beta-thalassemia minor to the patient’s clinical course, several dermatological features have been reported in patients with this condition, including xerosis, freckles, and pruritus [12]. Xerosis is a common condition resulting from inadequate hydrolipids in the skin. This condition can lead to roughness and tightness that can trigger pruritus, resulting in excoriations and an elevated susceptibility to skin infections [13]. The protective acid mantle of the skin is a thin hydrolipid layer (with a pH of 4.0–6.5) consisting of lipids produced by sebaceous glands, sweat and remnants of keratinocytes that have been sloughed off. A pH that is too high can lead to increased degradation of barrier lipids and a reduced defense against cutaneous infections [13]. Our patient complains of recurrent skin infections, especially in the feet, due to his extreme skin xerosis.

Because chronically transfused patients have a higher propensity for hemosiderosis, serum ferritin levels were evaluated in a recent study [12]. However, significantly elevated serum ferritin levels were only observed in patients presenting with freckles [12]. In our case, the patient did not exhibit freckles, but his xerosis likely contributed to the formation of deep rhagades, which may have served as entry points for S. aureus, ultimately leading to sepsis.

We hypothesize that endocarditis in this patient resulted from the systemic dissemination of S. aureus originating from periungual abscesses and chronic skin rhagades (Fig. 4). This hypothesis is supported by the known background of atopy and abnormal innate immunity in KID syndrome, which predisposes patients to recurrent infections [7]. Lethal variants impacting the initial portion of GJB2 have been identified in patients with severe neonatal phenotypes, often leading to early fatal septicemia within the first year of life [14]. Specifically, gain-of-function mutation in GJB2 results in increased hemichannel activity, disrupting the epithelial and likely facilitating skin infections [14]. Although there is no documented association between KID syndrome and functional or structural cardiac anomalies, a cutaneous origin of the endocarditis appears most plausible in this case. Similarly, we attribute the myelitis to a secondary infectious focus stemming from endocarditis.

Fig. 4.

Deep rhagades and periungual abscess. a Destructive nail dystrophy with large erosion of the right toe. b Thick plantar keratoderma with deep rhagades.

The role of lifelong systemic antimicrobial therapy in managing KID syndrome remains uncertain. Decisions regarding its use require careful evaluation by an experienced microbiology team to assess the risk of systemic septicemia and the patient’s response to topical and systemic treatments. Long-term follow-up in KID syndrome focuses primarily on regular surveillance for mucosal carcinomas due to the increased malignancy risk. Additionally, ophthalmologic and otolaryngologic evaluations are recommended to monitor progressive keratitis and hearing impairment, ensuring timely interventions when necessary. Inclusion in specialized programs for combined hearing and vision loss may further aid in optimizing patient care, including consideration of cochlear implants where appropriate [15, 16]. This case highlights the need for continuous, proactive management of chronic inflammatory skin lesions in KID syndrome to prevent severe complications.

Statement of Ethics

Ethics approval was not required, in accordance with the guidelines of the Istituto Superiore di Sanità (ISS), the National Ethics Committee. Written informed consent was obtained from the patient for the publication of this medical case and any accompanying images.

Conflict of Interest Statement

The authors declare no conflicts of interest.

Funding Sources

This study did not receive funding from any sponsors or organizations.

Author Contributions

Conceptualization, methodology, writing – original draft preparation, and project administration: G.G., D.D., S.C.T., and L.S.; software, writing – review and editing, and validation: G.G., S.C.T., and L.S.; investigation: G.G.; resources and visualization: G.G., D.D., G.P., M.G., M.I.A., S.C.T., and L.S.; and supervision: S.C.T. All authors have read and approved the final version of the manuscript.

Funding Statement

This study did not receive funding from any sponsors or organizations.

Data Availability Statement

The data underlying this article are fully included within the manuscript. Further inquiries can be directed to the corresponding author.