Lipoid proteinosis’ weak, hoarse cry is crying for targeted therapeutic intervention

By Warren R. Heymann, MD, FAAD
Nov. 6, 2024
Vol. 6, No. 45

Having recently participated in the excellent conference devoted to antisemitism in medicine organized by Heather Milbar at the University of Pennsylvania, I reacquainted myself with Erich Urbach, who described lipoid proteinosis (LP, Urbach-Wiethe disease) with the otolaryngologist Camillo Wiethe in 1929. Following the Anschluss in 1938, under duress, Urbach and his family fled Austria, ultimately settling at the University of Pennsylvania, where he became Chief of the Allergy Service at the Jewish Hospital of Philadelphia. (1)

One of the peculiarities of dermatology is learning the intricacies of diseases you may never encounter. A reasonable question is, “Why bother?” The answers are simple: 1) you will never secure a rare diagnosis if you are not aware of it; 2) learning of the disease may apply to other disorders. This commentary focuses on newer literature devoted to LP.

LP is a rare autosomal recessive genodermatosis, with fewer than 500 reported cases. Twenty percent of LP probands’ parents are from consanguineous unions. (2) LP is characterized by the deposition of amorphous hyaline material (PAS +, diastase-resistant) in various tissues, including the mucosa, visceral organs, and skin. (3,4)

The earliest manifestation is usually a weak or hoarse cry in early life due to hyaline-like deposits on the vocal cords. Hoarseness may persist throughout life.

Cutaneous features of LP usually begin with vesicles or bullae and hemorrhagic crusts on sites of friction or trauma, most notably the face and around the mouth. These lesions heal with prominent pox-like or acneiform scarring. Over time, the skin can appear thick and waxy with a yellowish hue. Moniliform blepharosis, (“beaded” papules) along the eyelid margin, is a pathognomonic finding identified in about 50% of patients. Other cutaneous manifestations include papules, nodules, plaques on the face and lips, and verrucous and hyperkeratotic lesions at sites of trauma or friction. (4) Scarring alopecia has been reported. (3) Dermoscopy demonstrates pale, yellowish, structureless globules. (5)

A stiff sublingual frenulum, restricted tongue movement, macroglossia, vegetative lesions, fissures at the lateral commissures, and oral mucosal ulcerations may occur. (4,6) Salivary gland involvement causes hyposalivation, which leads to poor oral hygiene. (7)

According to Yang et al., “Other systems may also be involved, including the gastrointestinal (dysphagia, yellowish nodules, gastrointestinal bleeding), genitourinary (renal cysts), respiratory (airway obstruction), endocrine (insulin resistance, short stature), neuropsychological (migraine, seizures, intracranial mesiotemporal calcifications), and psychiatric (cognitive dysfunction, memory impairment, schizophrenia, depression, anxiety disorder) systems.” (6) Although life expectancy is usually normal, ongoing support for quality-of-life issues is necessary. (4)

Based on clinical, histopathologic, and other laboratory studies, LP can be differentiated from erythropoietic protoporphyria, epidermolysis bullosa, hydroa vacciniforme, incontinentia pigmenti, scars from herpes simplex infection, and acne-related scars. (6)

LP is caused by a homozygous or compound heterozygous loss-of-function mutation of extracellular matrix protein 1 (ECM1) located on chromosome 1q21. More than 40 variant ECM1 mutations have been reported, most of which are nonsense or missense mutations located in exons 6 and 7. Although there is clinical variability between different LP patients, the genotype-phenotype correlations remain unclear. (2)

Given the rarity of LP, there is no definitive therapeutic protocol. Bueno-Molina et al performed a systemic review of data from 44 patients with histologically-confirmed LP patients. Treatment modalities ranged from systemic therapies (acitretin, etretinate, dimethyl sulfoxide, corticosteroids, penicillamine) to surgical or laser procedures. Low-dose oral acitretin could potentially manage LP, exhibiting fewer side effects than other therapeutic agents. (8) Plasma exeresis (PE) is an aesthetic procedure that works by ionizing the gases in the space between the instrument’s tip and the treated tissue; the microsurgical device transfers concentrated heat to the skin. (9) Because of its minimal ablation power, PE was utilized and successfully treated moniliform blepharosis in a 30-year-old man with LP. (10) A multidisciplinary approach to LP is essential. (11) Further research is needed to establish more comprehensive and evidence-based treatment guidelines. (8)

Point to Remember: Lipoid proteinosis was described almost a century ago. Although the genetics of the disease have been deciphered due to mutations in ECM-1, these discoveries have yet to translate into precise therapeutic interventions. Acitretin remains the systemic treatment of choice.

Our experts’ viewpoint

Rocío C. Bueno-Molina MD
Juan-Carlos Hernández-Rodríguez, MD, PhD
Department of Dermatology
Virgen del Rocío University Hospital, Seville, Spain

Lately, we have been inundated with information on ‘everyday dermatology’ and we are constantly witnessing the numerous therapeutic advances being developed for treating prevalent dermatologic conditions. However, we have always had the itch to go further, to look beyond the obvious. Please, do not misunderstand us; all these advances are reasons to feel even more proud of our fascinating specialty, which is increasingly on the up and up. But we firmly believe that we all deserve the same opportunities, even those who are one in a million.

This is why, upon our patient’s arrival at the office, we embarked on gathering all available evidence on lipoid proteinosis, to try to offer him the best therapeutic alternative. However, when a dermatologist decides to investigate a disease with 400 described cases in the world, trying to find high-methodological quality scientific studies is like crying for the moon. In our case, all studies were case reports and case series with little standardization. And perhaps that is one of the main takeaways: When it comes to rare diseases, where large-scale studies are practically impossible, it is imperative that case reports follow some rules to assure consistency, reliability, and reproducibility.

Lipoid proteinosis, also known as Urbach-Wiethe disease, is a very rare genodermatosis caused by loss of function mutations in the extracellular matrix protein 1 gene (ECM1), resulting in the deposition of PAS-positive hyaline-like material on the skin, mucosa, and central nervous system. Classically, onset occurs in childhood with a hoarse cry, while skin lesions can manifest years later. They consist of thickening of the skin, yellowish infiltrated papules, and verrucous hyperkeratosis of the elbows, knees, and knuckles.

Although this rare disease does not shorten life expectancy, it does have a significant impact on the quality of life of those living with it. On the one hand, it causes permanent and disfiguring scars, often in highly visible areas like the face. On the other hand, as seen in our patient, it may require the placement of a permanent tracheostomy due to dyspnea. Not to mention that this nightmare begins during the vulnerable stages of childhood or adolescence, critical periods where personality and self-esteem are forged.

Dr. Heymann’s insightful commentary highlights that this disease was described almost a century ago. Despite advances in understanding its pathophysiology and the discovery of genes involved in its development, there is still a long way to go in terms of its therapeutic approach.

For the time being, there is no targeted therapy, and acitretin is the systemic treatment with the most substantial evidence within the scientific literature, with approximately 63% of the patients described (17 out of 27) experiencing overall improvement in both skin and voice, with minimal side effects. In our experience, we have also achieved excellent results with a treatment regimen of 0.5 mg/kg/day of acitretin. Promising results have been achieved with the fractional ablative CO2 laser in the aesthetic management of eyelid papules and facial scars. In our humble opinion, both treatments could complement each other effectively.

However, much more research is still needed to develop a targeted therapy or to establish clinical practice guidelines.

1. Hoenig LJ, Lipsker D, Parish LC. Eponyms that honor Jewish dermatologists: A celebration and a remembrance, Part three: Jewish physicians who practiced during the Holocaust and in its aftermath. Clin Dermatol. 2024 Feb 9:S0738-081X(24)00028-2. doi: 10.1016/j.clindermatol.2024.01.014. Epub ahead of print. PMID: 38340908.

2. Liu YL, Zhang ZY, Chen XM. A Sporadic Family of Lipoid Proteinosis with Novel ECM1 Gene Mutations. Clin Cosmet Investig Dermatol. 2024 Apr 18;17:885-889. doi: 10.2147/CCID.S452127. PMID: 38651074; PMCID: PMC11034508.

3. Hashmi FN, Huma S, Singireddy H, Zareen N, Suvvari TK, Ansari MH, Sultana N, Hasibuzzaman MA. Lipoid proteinosis: A rare genodermatosis with multisystemic manifestations-A case report. Clin Case Rep. 2024 Feb 6;12(2):e8512. doi: 10.1002/ccr3.8512. PMID: 38328486; PMCID: PMC10847059.

4. LeWitt TM, Paller AS, Bell A, Zhou XA. Lipoid Proteinosis. 2023 Jun 18. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–. PMID: 33760528.

5. Ray A, Agrawal I, Singh BS, Kar BR. Novel features in dermoscopy of lipoid proteinosis. Indian J Dermatol Venereol Leprol. 2023 Jan-Frebuary;89(1):116-118. doi: 10.25259/IJDVL_1027_2021. PMID: 36331838.

6. Yang Z, Xu Z, Ma L. Multiple facial atrophic scars in childhood. Pediatr Dermatol. 2024 May-Jun;41(3):537-539. doi: 10.1111/pde.15542. Epub 2024 Feb 8. PMID: 38332461.

7. Jahanimoghadam F, Hasheminejad J. Oral Manifestations and Dental Management Considerations of Lipoid Proteinosis: A Case Report and Review of Literature. J Dent (Shiraz). 2022 Sep;23(3):321-326. doi: 10.30476/DENTJODS.2021.89748.1435. PMID: 36506885; PMCID: PMC9719597.

8. Bueno-Molina RC, Hernández-Rodríguez JC, Cabrera-Fuentes R, Cabrera-Pérez R, Conejo-Mir Sánchez J, Pereyra-Rodríguez JJ. Advances in treatment for lipoid proteinosis (Urbach-Wiethe disease): a case report and systematic review. Clin Exp Dermatol. 2024 May 21;49(6):547-555. doi: 10.1093/ced/llae039. PMID: 38308656.

9. Sotiris TG, Nittari G, Sagaro GG, Amenta F. A Descriptive Study on the Applications of Plasma Exeresis in Dermatology. J Clin Aesthet Dermatol. 2021 Mar;14(3):E58-E62. Epub 2021 Mar 1. PMID: 33841619; PMCID: PMC8021407.

10. Araghi F, Moravvej Farshi H. A New Method to Remove Eyelid Lesions in Lipoid Proteinosis. Dermatol Surg. 2024 Jun 1;50(6):594-595. doi: 10.1097/DSS.0000000000004143. Epub 2024 Mar 26. PMID: 38530982.

11. Fenech MT, Yeo D. Lipoid proteinosis; a rare pathology, requiring multidisciplinary input. BMJ Case Rep. 2023 Nov 6;16(11):e257108. doi: 10.1136/bcr-2023-257108. PMID: 37931963; PMCID: PMC10632804.

---