Orolaryngeal manifestations of Urbach-Wiethe disease: a case report

INTRODUCTION

Urbach-Wiethe disease also referred to as Lipoid proteinosis or hyalinosis cutis et mucosae, is an uncommon, autosomal recessive genodermatosis, characterised by the accumulation of hyaline like material into the mucous membranes, skin and other organs of the body. The condition was first described by Urbach and Wiethe in year 1929.¹ Since then, fewer than 400 cases have been reported globally.² Underlying genetic defect involves mutation in gene encoding for ECM-1 protein located on chromosome 1q21.³ Earliest consistent feature in patients with this condition is hoarseness, which begins early in childhood, attributed to the thickening of arytenoids and irregular morphology of vocal cords.⁴ Additional findings may include thickened epiglottis and arytenoids, pebbled oral mucosa, and woody tongue causing restricted mobility. Dermatological manifestations present as vesicles and papules that heal with pox like acneiform scars over the skin. The highly characteristic feature is the presence of beaded papules along the eyelids-Moniliform blepharosis which is highly pathognomonic.⁵ Magnetic resonance imaging of the brain reveals symmetrical calcifications in the amygdala and mesial temporal lobes, a hallmark feature.⁶ Histopathology examination of lesions shows deposition of PAS-positive, with/without diastase-resistant hyaline material in the mucous membranes.¹ Management is largely supportive and multidisciplinary. Acitretin, a vit-A derivative has shown partial benefit, improving skin and sometimes voice. In severe cases, surgical excision of laryngeal deposits may lead to voice improvement.^4,7

CASE REPORT

Patient 1

Patient information

A 14-year-old girl referred to the otolaryngology clinic by dermatologist for the complaints of hoarseness since early childhood, on general examination it was found that patient had papular deposits along eyelid margins along with thickened, waxy skin over face and upper limbs.

Clinical findings

Local examination revealed deposits over the lateral tongue border and buccal mucosa with restricted tongue mobility. Office laryngeal examination showed thickened vocal folds, deposits over arytenoids, laryngeal surface of epiglottis and posterior pharyngeal wall.

Diagnostic assessment

Routine haematological and biochemical investigations were normal. In view of patient's mucocutaneous and airway involvement of uncertain cause, a direct laryngoscopy with biopsy was performed. Histopathology demonstrated hyperplastic squamous epithelium with pink amorphous eosinophilic material, which was positive for Periodic Acid-Schiff stain and diastase-resistant. The clinical features, laryngeal and mucocutaneous lesions in conjunction with the characteristic findings and histopathology, led to the diagnosis of Urbach-Wiethe disease. Magnetic resonance imaging of the brain was obtained for further workup, which revealed bilateral symmetrical calcifications in the mesial temporal lobes involving both amygdalae, along with patchy basal ganglia calcifications, although the patient had no neurological symptoms.

Therapeutic intervention

Serum lipid profile, liver function tests, limb and spine X-rays were obtained followed by the initiation of oral acitretin, intraoral triamcinolone ointment and speech therapy.

Follow-up and outcomes

On a yearly follow-up, the patient reported subjective improvement in her voice quality and skin lesions.

Patient 2

Patient information

Two years old boy was referred to otolaryngology department by dermatologist for evaluation of weak cry since childhood. The patient had pock-like scars over the face and the shoulders and two beaded papules along the right upper eyelid margin.

Clinical findings

Tongue was depapillated with reduced mobility and office laryngeal examination showed thickening of true vocal folds but no submucosal deposits.

Diagnostic assessment

Biopsy of the skin lesions revealed hyperkeratosis and irregular acanthosis but no amorphous material was identified. Owing to high suspicion genomic analysis was obtained which revealed frameshift mutation at Exon 7/Exon 10 of ECM-1 gene confirming the disease.

Therapeutic intervention

Lipid profile and liver function tests were obtained followed by oral acitretin therapy.

Follow-up and outcomes

The child is kept on a close follow up.

DISCUSSION

Lipoid Proteinosis, also known as Urbach-Wiethe disease, is a rare autosomal recessive condition affecting skin and the mucous membranes characterized by the systemic deposition of amorphous, hyaline-like material in the skin, mucous membranes, and other internal organs.⁸ While it occurs globally, a significant portion of cases are concentrated in South Africa.³

Pathogenesis and genetics

The disease occurs from loss-of-function mutations in the extracellular matrix protein-1 (ECM-1) gene.⁹ ECM-1 is a secreted glycoprotein that functions as a "biological superglue", regulating basement membrane integrity and skin homeostasis. It has a role in endothelial cell proliferation, angiogenesis, epidermal differentiation, binding of dermal collagens and proteoglycans, therefore, helps in wound healing.^10,11 Mutations in this gene disrupts these functions and protein interactions, leading to duplication of the basement membrane and the subsequent accumulation of hyaline material. Research indicates that exons 6 and 7 are the most common sites for these mutations.^8,10 Although some reports suggest that mutations in exon 7 may result in a slightly milder phenotype in regards to skin and airway, it is also seen that severe hoarseness and skin manifestations can occur regardless of the specific mutation site.¹²

Clinical manifestations

The clinical presentation of Lipoid Proteinosis is remarkably consistent across different populations. Similar to our patient, the earliest hallmark feature is often a weak cry or hoarseness caused by hyaline infiltration of the vocal cords.¹³ Disease activity in early phase is marked by vesicles and haemorrhagic crusts, seen at the sites of friction or minor trauma.¹⁴ These lesions eventually heal, leaving behind acneiform or pock-like scars, particularly on the face and extremities. A pathognomonic sign is moniliform blepharosis, a row of beaded papules along the eyelid margins.¹³ The tongue and frenulum as seen in the oral cavity examination becomes thickened and woody, which restricts lingual movement and further hinders speech. Patients develop bilateral intracranial calcifications within the amygdala and temporal lobes. Although our patient was asymptomatic, but, these neurological changes can manifest as epilepsy, memory impairment, or neuropsychiatric disorders such as schizophrenia.¹⁴

Management and prognosis

There is currently no curative treatment for lipoid proteinosis, management focuses on symptom reduction and preventing complications.¹⁵ Pharmacological approaches include the use of oral retinoids like acitretin, which may improve cutaneous lesions and hoarseness in some patients.¹⁶ Other treatments such as dimethyl sulfoxide (DMSO) and D-penicillamine have not yielded promising results.¹⁵ Recent researches highlights a hybrid approach involving surgery followed by intensive voice therapy, which has shown significant objective improvements in vocal mass and glottic closure.¹⁶

CONCLUSION

In conclusion, lipoid proteinosis is generally compatible with a normal life span. It is a progressive condition that may require multidisciplinary inputs from otolaryngologists, dermatologists and neurologists. Although tracheostomy is rarely required, early recognition and examination is vital to manage respiratory risks and provide genetic counselling for affected families.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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