Long-term follow-up of lipoid proteinosis laryngeal manifestations

Article Outline

• Abstract
• 1. Introduction
• 2. Methods
• 3. Results
• 4. Discussion
• 5. Conclusion
• Conflict of interest statement
• Acknowledgements
• References
• Copyright

Abstract 

The disease course, management, and outcome of 5 cases of lipoid proteinosis followed up in our clinic for 10–16 years are presented. Two patients were males. Diagnosis was made at an age of <1 to 11 years but was missed originally in 3 patients due to unfamiliarity with the disease. Three patients underwent microlaryngoscopical excision of laryngeal lesions, 1 with a CO₂ laser and 2 with conventional microlaryngoscopy. Laryngeal symptoms as well as the other clinical manifestations of the disease improve as the child reaches puberty. Laryngeal surgical intervention should be reserved only for cases with compromised airways.

Keywords: Lipoid proteinosis, Urbach–Wiethe disease, Hoarseness, Carbon dioxide laser, Microlaryngeal surgery

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1. Introduction 

Lipoid proteinosis (LP), also known as hyalinosis cutis et mucosae or Urbach–Wiethe disease is a rare, autosomal-recessive disorder of unknown etiology in which there is deposition of an eosinophilic, hyaline-like material in the skin, larynx, mucous membranes, brain, and other internal organs. The gold standard for definitive diagnosis is histology. The first manifestation of the disease is voice change secondary to laryngeal involvement occurring at birth followed by skin lesions.

Recently, it has been shown that lipoid proteinosis results from loss-of-function mutations in the extracellular matrix protein 1 (ECM1) gene [1], which has 4 splice variants whose expressed products are believed to be involved in skin differentiation, endochondral bone formation, and angiogenesis, as well as possessing a “biological super-glue” action. The course of the disease, as well as the therapeutic possibilities is still debated due to lack of data. Here, we report our experience with laryngeal manifestations of the disease in a 5 patients.

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2. Methods 

Five cases with LP were followed up over a 10–16-year period (mean 13.5 years) in a single tertiary care center. The diagnosis was based on characteristic laryngoscopic and dermatological findings, as well as histopathology.

A detailed history and complete general physical and ENT examinations were carried out, and flexible fiberoptic laryngoscopy, stroboscopy, routine hematological and biochemical investigations, and a CT scan of the brain were performed on all patients. Pediatric and dermatology referrals were also completed. Histological examination of representative laryngeal, skin, and/or mucous membrane lesions was accomplished. In addition, 2 patients underwent molecular diagnosis for the type of ECM1 mutations.

All the children were followed up regularly every 6 months for the last 10–16 years with clinical assessment, laryngoscopy, stroboscopy, and the multidimensional voice program (MDVP), for quantitative acoustic assessment of voice quality along with digital recording.

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3. Results 

Of the 5 children included in the study 3 were females and 2 were males. The ages of the patients at diagnoses were 11, 3, 6, and 5 years respectively, while 1 patient presented 7 days after birth (Table 1).

Table 1. Summary of personal history complaints, treatment, and outcome of the patients.

	Case number
	1	2	3	4	5
Personal history
Sex	M	F	F	F	M
Age at diagnosis (years)	11	3	6	5	0
Present age (years)	21	16	20	19	14
Follow-up (years)	10	13	16	14	14
Other family members suffering from disease	+	+	−	+	+
	Sister	Brother		Brother	Sister
	(case 2)	(case 1)		(case 5)	(case 4)
First-degree consanguineous parents	+	+	−	−	−
Symptoms
Hoarseness	+	+	+	+	+
Skin/eye lesions	+	+	+	+	+
Stridor/dyspnea	−	+	–	+	+
Neurological symptoms	Mild mental retardation	Mild mental retardation	−	−	−
Initial diagnoses
	Ichthyosis xeroderma pigmentosum	Ichthyosis xeroderma pigmentosum	Chronic laryngitis/skin eczema	Lipoid proteinosis	Lipoid proteinosis
Investigations
CT brain scan	Negative	Negative	Negative	Negative	Negative
Genotyped	ECM1 gene mutations	ECM1 gene mutations	Not done	Not done	Not done
Treatment and outcome
Treatment	Urea cream 6% and isotretinoin 10mg	Urea cream 6% and isotretinoin 5mg	Moisturizing creams	Local retinol cream	None
Duration of treatment (years)	5	4	Continuous	Continuous	0
Outcome	Improvement in skin appearance and hoarseness	Improvement in skin appearance and hoarseness	Improvement in skin appearance and hoarseness	Improvement in skin appearance and hoarseness	Improvement in skin appearance and hoarseness

Hoarseness was the first sign noticed by parents of all the patients during the first year, followed by the skin and eye lesions.

Of the patients, there were 2 two pairs of siblings (brother and sister) with established LP whereas the fifth child was an isolated patient in his family. There is a strong family history of LP as shown by presentation of the disease in the two pairs. Three of our patients had laryngeal surgery (cases 1–3): the first patient had laser surgery while the second had conventional surgery; the third patient had 3 procedures done, 2 of which had been carried out before she was seen in our institute. We noted that surgical intervention makes hoarseness worse and all 3 patients developed granulation tissue followed by fibroses and scar tissue formation postoperatively (Table 2). However, it was also observed that the laryngeal symptoms and skin lesions improved with time. As the children became older and approached puberty the disease followed a stable course (Fig. 1, Fig. 2).

Table 2. Microlaryngeal findings.

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• Fig. 1. 

  Endoscopic picture of the larynx for case 1 at 11 years old showing irregular thickened vocal folds and arytenoids.

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• Fig. 2. 

  Case 1 at age 21 with marked improvement.

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4. Discussion 

Siebenmann [2] first described lipoid proteinosis in 1908 although it was not until 1929 that Urbach and Wiethe provided first detailed review [3]. However, there is a paucity of information regarding the course of the disease due to its rarity, short follow-up, and poor documentation of reported cases.

While the disorder appears to occur throughout the world, it seems more frequent in some countries in which consanguinity is common. However, few cases have been reported in Saudi Arabia, a country where parental consanguinity is quite high, and this might be attributed to under-diagnosis of the condition. In 2004, Al-Bitar and Samdani reported 2 brothers with multiple organ involvement in the kingdom [4].

Hoarseness is usually the earliest feature of LP, and it develops soon after birth or in the first year of life or, more rarely, after a few years. In our case series, all 5 patients presented with hoarseness of voice that was noticed by the parents as early as a few days and as late as 2 years after birth. In fact, 1 child was diagnosed as a case of LP when the mother noted an abnormal cry at birth, having been sensitized by the same condition in her son, who was also one of our patients.

Despite early presentation, definitive diagnosis was delayed by 3–11 years in our series (mean 5 years), the reason being lack of familiarity of the condition on the part of the treating physicians.

In their case report, Savage et al. describe endoscopic findings as thickening, modularity, and fullness of the vocal cords, with aryepiglottic folds and valleculae [5]. These findings are consistent with the findings in our patients (Table 2).

Excision of the lesions using microlaryngoscopy instruments has been shown to improve the airway and quality of the voice [6]. Three of our patients underwent excision of laryngeal deposits, one using a CO₂ laser. In addition, the 2 other patients had excision of the lesions using microlaryngoscopy instruments with no definite improvement in the quality of voice as determined by preoperative and postoperative digital recordings and MDVP.

We think surgical intervention should be reserved only for cases in which there is airway obstruction. The use of surgical therapies is questionable because, according to some authors, trauma seems to increase the deposition of hyaline-like material in skin and mucous membranes [7].

The course of the disease in our patients was protracted, with a tendency to slow down when the child reached the age of puberty age. This trend toward a longitudinal improvement is in accordance with some other reports [8].

The reason why not all but only certain patients with LP develop spontaneous improvement is still unclear. So far, there is no clear association between the clinical phenotype and the course of LP. We observed not only a therapeutic, but also a spontaneous improvement in our patients with skin as well as laryngeal lesions, indicating that early onset of the disease could lead to a slight improvement as the child grows to adulthood. The decrease of symptom severity with age suggests that several pathogenetic mechanisms might be involved in spontaneous improvement.

Because LP is an autosomal-recessive disease caused by mutations in the ECM1 gene this could provide a basis for development of a rational treatment, including trials of recombinant gene protein for skin and respiratory mucosa. Moreover, further study of the ECM1 protein interaction may help to elucidate its role as modifier of dermal architecture and epidermal differentiation in normal skin.

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5. Conclusion 

Lipoid proteinosis is a chronic disease that presents with a variable, clinical, histopathological, and radiological spectrum. From our close follow-up of 5 patients for 10–16 years, we have found that laryngeal and other clinical manifestations of the disease improve with time. As the child reach puberty we believe that laryngeal surgical intervention should be reserved only for cases with a compromised airway. Although rare, nonetheless, this disease is important to otolaryngologists, and should be included in the differential diagnosis of voice change and hoarseness in infants and children. The unfamiliarity of many otolaryngologists and speech pathologist with the disease often causes delay of diagnosis and treatment.

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Conflict of interest statement 

We declare that we have no financial support or relation of any kind with any commercial organization or funding source.

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Acknowledgements 

Written informed consent was obtained from the patients or relatives for publication of this report.

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References 

1. Hamada T, McLean WH, Ramsay M, Ashton GH, Nanda A, Jenkins T, et al. Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1). Hum. Mol. Genet. 2002;11:833–840
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3. Urbach E, Wiethe C. Lipoidosis cutis et mucosae. Virchows Arch. Pathol. Anat. 1929;273:285–319
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4. Al-Bitar Y, Samdani AJ. Lipoid proteinosis in two brothers with multiple organ involvement from Saudi Arabia. Int. J. Dermatol. 2004;43:360–361
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7. Hofer PA, Bergenholtz A. Oral manifestations in Urbach–Wiethe disease (lipoglycoproteinosis; lipoid proteinosis; hyalinosis cutis et mucosae). Odontol. Revy. 1975;26:39–57
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