Intra-Familial Variability of Lipoid Proteinosis: An Indian Case Series.

Sir,

Urbach-Weithe disease or lipoid proteinosis is a rare autosomal recessive genodermatosis reported with higher prevalence in South Africa and Europe.[1] Genotypicially, a loss of function mutation in extracellular matrix protein 1 (ECM1) gene mapped to Chromosome 1q21 correlates clinically with widespread disease associated with variable degree of scarring and infiltration of skin, involving the oral cavity, larynx, and mucosae.[2] In this case series, we describe the various phenotypic variations in four brothers out of the six siblings affected by this condition.

Case Series

Case 1

A 42-year-old man, oldest of the six siblings, born to parents of a third-degree consanguineous marriage, who was asymptomatic at birth, developed hoarseness of voice in his infancy followed by spontaneous vesiculation over his face, arms, shoulders, back, and over buttocks in childhood up till the age of 16 years, which healed with atrophic scarring. Further, he developed progressive thickening of his skin with the development of yellowish tiny lesions along the margins of his eyelids, neck and both hands, and warty lesions over the sites of trauma. He gave history of increased discomfort during summer and multiple episodes of seizures over the past 16 years. There was history of dysphagia and episodes of dyspnea that exacerbated with concurrent upper respiratory tract infections. Patient also gave a peculiar history of observing spontaneous and incomplete resolution of his skin lesions.

Examination revealed short stature (height 152.52 cm) with moniliform blepharosis [Figure 1a] along with confluent yellowish-brown waxy papules over the face, neck, upper trunk, arms, forearms, legs, scrotum, and dorsum of hands. Hyperpigmented verrucous lesions [Figure 1b] were seen over bilateral elbows, knees, in axillae, intergluteal cleft, and over lateral malleous. Scarring alopecia was noticed over the scalp along with lateral one-third of supraciliary madarosis. Thickened waxy skin over the face along with multiple variable sized pox-like scars gave an appearance of leonine-like facies [Figure 1c]. Oral mucosal examination showed induration of both lips, angular chelitis, thickened infiltrated fissured tongue [Figure 1d], and frenulum with an inability to protrude along with multiple dental caries and loss of teeth.

Figure 1

Common findings in lipoid proteinosis as seen in our cases. (a) Moniliform blepharosis. (b) Infiltrated tongue (c) Verrucous plaques over the knees. (d) Pox-like scars over the face

On slit-lamp examination, features of dry eye were documented. Video-laryngoscopy showed thickened epiglottis and vocal cords with narrowed airway opening. X-ray skull showed presence of a radio-opacity in the pituitary region.

Case 2

A 40-year-old man, sibling of case 1, developed hoarseness of voice around the age of 6, followed by a similar progression of clinical events such as the formation of vesicles until the age of 14 years that ultimately healed with atrophic scarring. He, however, gave no history of dysphagia, dyspnoea, seizures, or photosensitivity. He too had a short stature (height 146.436 cm) with diffusely thickened nonpinch-able skin, numerous confluent yellowish waxy papules, and atrophic scars present over face, back, shoulders, back, and buttocks along with moniliform blepharosis. Thick verruocus hyperpigmented plaques were seen in axillae, elbows, buttocks, knees, lateral malleoli, and over knuckles of both hands along with infiltrated lips, angular chelitis [Figure 2a], thickened tongue and frenulum with inability to protrude and fissuring and dental anomalies were also seen.

Figure 2

New cutaneous findings observed. (a) Angular chelitis. (b) Ragged cuticles of nails with onychoschizia. (c) Waxy infiltrated papules over scalp

The nails showed presence of ragged cuticles and onychoschizia [Figure 2b]. On dermoscopy, ragged cuticles over third and fourth fingers of the right hand were observed [Figure 3a]. Scarring alopecia along with grouped infiltrated papules over the scalp was noticed along with supraciliary madarosis [Figure 2c].

Figure 3

Dermoscopy features (Dinolite, polarized, 150×). (a) Ragged nail cuticles. (b) Pits and papules seen on finger tips

Slit-lamp examination revealed dry eye in him too. Video-laryngoscopy showed uniformly thickened vocal cords and X-ray skull features were normal.

Case 3

A 36-year-old man, fourth of the six siblings, presented with hoarseness of voice since birth and vesicular lesions over body since the age of 2 years until 16 years of age, followed by the formation of thick waxy lesions over the joints. There is no history of dysphagia, dyspnea, seizures, or discomfort in summers.

On examination, height was 170.314 cm, with scarring alopecia, moniliform blepharosis, thickened facial skin along with confluent yellowish papules, and atrophic scars on the face giving an appearance of leonine facies. There was infiltration of the lips, thickened tongue along with presence of angular cheilitis. He too had infiltrated skin over the body and hyperkeratotic hyperpigmented plaques over his joints.

On dermoscopy, multiple tiny papules and pits were observed on the tips of the finger pulps of the second, third, and fourth fingers of both hands [Figure 3b]. On slit-lamp examination, dry eye was observed. Video-laryngoscopy showed presence of thickening over the posterior one-third of vocal cords including inter-arytenoid areas. X-ray findings of the skull were suggestive of a radio-opacity in the hippocampus region.

Case 4

A 32-year-old man, sixth of the six siblings, was asymptomatic at birth but started noticing hoarseness of voice by the age of 5 years followed by a similar history of vesicles that healed with scarring, appearance of small numerous yellowish lesions over the face and body and thick warty lesions over the sites of friction. He gave history of seizures since the past 2 years. There were no dysphagia, dyspnea, and discomfort in summers.

He too had short stature (height 150 cm) with moniliform blepharosis, grouped waxy papules on his scalp over the right parieto-occipital area and on the scrotum, and minimally verrucous plaques the knees. Oral cavity showed the presence of infiltrated lips, angular chelitis, dental anomalies, fissured tongue with gross infiltration and an obvious inability to protrude and prominent dental marking along its lateral borders.

On dermoscopic examination, few small papules and pits were seen on the pulps of bilateral third and fourth fingers and dry eyes were seen on slit-lamp and thickened epiglottis and vocal cords on video-larynscopy. X-ray of the skull showed radio-opacity in the pituitary region.

To summarize, Table 1 shows the phenotypic variability in cutaneous features previously described in the literature in these four brothers. Table 2 shows the new features we came across.

Table 1

Summary of clinical features in patients with lipoid proteinosis

Clinical features	Brother 1 (42y)	Brother 2 (40y)	Brother 4 (36y)	Brother 6 (32y)
Hoarseness of voice	Since infancy	6 years of age	Since birth	5 years of age
Vesicular eruptions healed with scarring	+++	++	+	++
Waxy papules	++	+	+	++
Verrucous plaques	+	++	++	++
Moniliform blepharosis	+	++	+++	++
Thickened tongue	+++	++	+	++
Inability to protrude tongue	+++	++	-	+++
Dysphagia	++	-	-	+
Scarring Alopecia	+	+	+	+
Respiratory manifestations	Dyspnea	-	-	-
Neurological manifestations	Epilepsy, Memory loss	-	-	Epilepsy, Memory loss
Severity of C/F	Severe	Milder	Milder	Severe

Table 2

Whats new!

Clinical Features	Brother 1 (42y)	Brother 2 (40y)	Brother 4 (36y)	Brother 6 (32y)
Stunted growth	+++	+++	-	+++
Supraciliary madarosis	+++	+++	+++	+++
Leonine-like Facies	+++	+++	+++	+++
Fissure tongue	++	++	++	++
Angular chelitis	++	++	++	++
Waxy scalp papules	-	++	-	++
Waxy scrotal papules	-	+++	-	-
Fingertip pits and papules	-	-	++	++
Ragged cuticles, onychoschizia	-	++	-	-
Dry Eyes	++	++	++	++

Key: ‘- ‘Absent, ‘+’ Weakly present, ‘++’ Moderately present, ‘+++’ Strongly present

Cases 5 and 6

The remaining two sisters out of the six siblings were also screened and found to be clinically clear of any cutaneous or systemic manifestations.

Histopathology of skin biopsy taken from verrucous lesions in all four brothers showed the presence of amorphous eosinophilic hyaline material in the dermis, accentuated around the capillaries, sweat coils in an “onion skin arrangement” [Figure 4a and b on H and E]. These deposits stained positive on PAS [Figure 5a and b] and negative for Congo red stain.

Figure 4

(a) Amorphous eosinophilic hyaline material in the dermis on H and E scanner view. (b) Hyaline material accentuated around the capillaries, sweat coils in an “onion skin arrangement” on H and E at 100×

Figure 5

(a and b): PAS positive deposits in the dermis, highlighted along the capillaries and ducts

Lipoid proteinosis is diagnosed based on its characteristic clinical findings confirmed by histopathology. It is known to display considerable interfamilial and intrafamilial variation.[2]

Hoarseness of voice, which is usually the first presenting symptom, was seen in all our patients. Along with all the classical cutaneous features,[3] some other new interesting features observed in our patients were stunted growth, lateral one-third supraciliary madarosis, waxy papules over the scrotum and scalp, papular deposits on the fingertips with ragged cuticles of nails were seen in ours which have not been mentioned in the literature before which have been highlighted in Table 2.

Mucosal involvement manifesting as immobility of tongue, speech impediment, xerostomia, and dental anomalies, etc.,[13] previously mentioned in the literature were seen in all of our four patients. Infiltration of the pharynx, soft palate, tonsils, and lips lead to recurrent episodes of upper respiratory tract infections, parotitis, and poor dental hygiene. However, clinical features such as angular cheilitis and fissured tongue not described previously were consistently present in all the four brothers.

Extramucocutaneous involvement although uncommon can manifest with ocular, psychiatric, or neurological symptoms. According to literature almost any part of the eye can be affected, usually infiltration of Zeiss, Moll, and Meibomian glands clinically present as madarosis, trichiasis, and distichiasis. Other commonly seen features are focal degeneration of macula and drusen formation in Bruch's membrane. Rare manifestations include glaucoma, lens-related and retinal complications such as cataract, subluxation, impaired color vision, corneal ulcerations, uveitis, epiphora, transient blindness, etc.[4] However, in all our four patients, dry eyes were the consistent eye finding.

Neurological manifestations include long-standing memory impairment, paranoia, rage attacks, mental retardation, and temporal lobe epilepsy.[45] Two out of our four patients reported memory impairment and epilepsy. CT brain with bean-shaped calcifications in the hippocampus, which is pathognomic for this condition. Nevertheless, studies have reported no geno-phenotypic co-relation in severity.

The ECM1 gene encodes for a secretory glycoprotein and plays an important role in the structural and biological function of skin.[67] Mutations in this gene result in a disruption of collagen metabolism with decreased production of fibrous collagen and overproduction of basal membrane collagen. This presents clinically as the deposition of PAS-positive hyaline material in dermis and submucosa.[1]

Hamada et al.[3] in their study have reported a number of mutations in ECM1 gene, however, majority of the mutations reported occur on exon 7 and to a lesser extent on exon 6. This results in variation of clinical severity with exon 7 mutations resulting in milder mucocutaneous phenotype and less severe respiratory symptoms.

Skin lesions in lipoid proteinosis occur in two overlapping stages: Cell-poor subepidermal blisters with secondary acantholysis histopathologically which manifests clinically as spontaneous vesiculation that heals with scarring during early childhood followed by progressive PAS-positive amorphous hyaline material deposition in the dermis, vessel wall, and around eccrine glands presenting clinically as generalized thickened skin.[78]

Lipoid proteinosis is known to run a chronic and benign course with a normal life span but the patient suffers from various functional and cosmetic problems. Treatment options available are limited. Studies have reported the use of drugs that dissolve collagen and scavenge hydroxyl radicals like dimethyl sulfoxide, or help prevent the cross-linking seen in mature collagen by inhibiting key enzyme lysyl oxidase such as d-penicillamine. Retinoids like acitretin modulate the metabolism of basement membrane and reduce the deposition of hyaline material in dermis. Facial lesions can be treated with dermabrasion or chemical peeling with CO2 laser surgery for vocal cords that help in the improvement of hoarseness.[8910]

To conclude, the unique features of stunted growth, waxy scalp papules with scarring alopecia of scalp, angular chelitis, fingertip pits, and papules with ragged cuticles, onychoschizia along with findings of dry eyes in the male siblings, with sparing of the female siblings are highlighted through this case series to provide a greater insight into this uncommon genodermatoses.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.