Lipoid Proteinosis

Clinical characteristics.

Lipoid proteinosis (LP) is characterized by deposition of hyaline-like material in various tissues resulting in a hoarse voice from early infancy, vesicles and hemorrhagic crusts in the mouth and on the face and extremities, verrucous and keratotic cutaneous lesions on extensor surfaces (especially the elbows), and moniliform blepharosis (multiple beaded papules along the eyelid margins and inner canthus). Extracutaneous manifestations may include epilepsy, neuropsychiatric disorders, and spontaneous CNS hemorrhage. Males and females are affected equally. Generally, the disease course is chronic and fluctuating. Affected individuals have a normal life span unless they experience laryngeal obstruction.

Diagnosis/testing.

The diagnosis of lipoid proteinosis is established in a proband with characteristic clinical findings and either identification of biallelic ECM1 pathogenic variants on molecular genetic testing or characteristic histologic and/or immuno-labeling findings on skin biopsy.

Management.

Treatment of manifestations: There are no proven treatments for the skin lesions. Microlaryngoscopic excision of laryngeal deposits can improve airway access and voice quality. Significant airway obstruction may require tracheostomy to ensure a safe airway. Seizures should be assessed and managed by a neurologist, using antiepileptic drugs (AEDs).

Surveillance: Routine follow up of children to monitor general health as well as psychomotor, emotional, and cognitive development. Monitoring of the airway and vocal cords by an otolaryngologist.

Genetic counseling.

LP is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible when the ECM1 pathogenic variants in the family are known.

Suggestive Findings

Lipoid proteinosis (LP), which is characterized by deposition of hyaline-like material in the larynx, oral cavity, skin, and internal organs, should be suspected in individuals with the following clinical manifestations and findings on neuroimaging.

Clinical manifestations (in order of their importance for diagnosis):

• Hoarse voice. The first manifestation in almost all individuals is a weak cry or hoarse voice (due to infiltration and deposition of hyaline-like material in the vocal cords) appearing during the first year of life, and often in early infancy. Hoarseness usually persists lifelong [Savage et al 1988].
• Moniliform blepharosis, a pathognomonic sign, is the presence of multiple beaded papules along the eyelid margins and inner canthus (Figure 1d, e) [Belliveau et al 2015].The papular infiltration can be quite subtle in some individuals.
• Cutaneous findings (appearing in two overlapping stages):
  • First, vesicles and hemorrhagic crusts, often caused by minor trauma or friction, appear in the mouth and on the face and extremities (Figure1a). Vesicles can be one of the earliest clinical manifestations in up to 50% of affected neonates.
  • Later, with increasing hyaline deposition in the dermis, the skin becomes diffusely thickened and appears waxy with a yellowish discoloration; papules, nodules, and plaques appear on the face and lips (Figure1d). Verrucous and keratotic cutaneous lesions may develop on extensor surfaces, especially the elbows (Figure1f) [Hamada 2002].
• Central nervous system and neuropsychiatric manifestations commonly include epilepsy (predominantly temporal lobe variant) and behavioral manifestations (memory impairment, paranoia, aggressive behavior, hallucinations, and absence of fear) [Siebert et al 2003, Thornton et al 2008] in association with calcification of the temporal lobes or hippocampi (Figure1h).
• Ear-nose-throat. Infiltration of the mucosae of the pharynx, tongue, soft palate, tonsils, and lips may lead to upper respiratory tract infections as well as recurrent episodes of parotitis (caused by stenosis of the parotid duct), submandibular gland inflammation, and poor dental health. The tongue may be short; thickening of the frenulum may result in difficulty protruding the tongue (Figure1c) [Chan et al 2007].
• Hair and nails. Patchy alopecia of the scalp, beard, eyelashes, and eyebrows as well as nail dystrophy are present in some [Hamada 2002].
  Note: Clinical findings may vary among affected individuals within the same family or population isolate, including presence of neurologic abnormalities in the absence of skin manifestations [Youssefian et al 2015].

Figure 1.

Clinical appearances of lipoid proteinosis a. Vesicles and hemorrhagic crusts and scars on the face

Neuroimaging

• Brain CT. Brain CT readily detects mineral deposits (i.e., intracranial calcifications); in some it reveals circumscribed, horn-shaped bilateral symmetric calcifications.
• Brain MRI. Although brain MRI can provide better anatomic details than CT, it is less sensitive in detecting calcification (Figure1h) [Siebert et al 2003, Chan et al 2004, Thornton et al 2008, Gonçalves et al 2010].

Establishing the Diagnosis

The diagnosis of lipoid proteinosis is established in a proband with characteristic clinical findings and EITHER of the following:

• Identification of biallelic ECM1 pathogenic variants on molecular genetic testing [Hamada et al 2002] (see Table 1)
• Characteristic histologic findings and/or immunolabeling on skin biopsy (see Skin biopsy)

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Single-gene testing. Sequence analysis of ECM1 is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
• A multigene panel that includes ECM1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes ECM1) fails to confirm a diagnosis in an individual with features of lipoid proteinosis. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Skin biopsy

• Hematoxylin and eosin (H&E) staining shows hyperkeratosis and accumulation of hyaline-like material in the dermis.
• Periodic acid-Schiff (PAS)-diastase staining shows PAS-positive, diastase-resistant basement membrane thickening and reduplication at the dermal-epidermal junction around blood vessels [Moy et al 1987].
• Immuno-labeling using polyclonal anti-ECM1 antibody shows reduced levels of ECM1 protein, providing a means of rapid diagnosis especially in the early stages of the disease [Chan et al 2004].

Clinical Description

Lipoid proteinosis (LP) is characterized by deposition of hyaline-like material that results in a hoarse voice from early infancy, vesicles and hemorrhagic crusts in the mouth and on the face and extremities induced by minor trauma, verrucous and keratotic cutaneous lesions on extensor surfaces (especially the elbows), and moniliform blepharosis (multiple beaded papules along the eyelid margins and inner canthus).

Generally, LP follows a chronic and fluctuating course. Males and females are affected equally. Affected individuals have a normal life span unless they experience laryngeal obstruction.

A hoarse voice, often evident at birth or in early infancy as a weak cry, is present in essentially all individuals with LP and usually persists lifelong and can progress to severe dysphonia and/or complete aphonia [Savage et al 1988]. In addition, involvement of the mucosae of the pharynx, soft palate, tonsils, and lips may lead to pulmonary manifestations, especially upper-respiratory tract infection. In some cases, infiltration of the laryngeal mucosa may lead to breathing difficulties.

Recurrent episodes of parotitis caused by stenosis of the parotid duct and submandibular gland inflammation are reported. Infiltration of the tongue may destroy the dorsal papillae, causing the tongue to have a smooth surface.

Dental health is often poor [Savage et al 1988, Chan et al 2007].

The skin lesions usually progress during the first few years of life in two overlapping stages:

• During childhood the skin may be easily damaged by minor trauma or friction, resulting in blisters and scar formation. Pock-like or acneiform scars, vesicles, and hemorrhagic crust are particularly evident on the face and extremities (Figure1a).
• At later stages with increasing hyaline-like deposition within the dermis, skin becomes diffusely thickened and appears waxy with yellowish discoloration; papules, nodules, and plaques appear on the face and the lips (Figure1d).

Hyperkeratotic and verrucous lesions may appear in regions exposed to mechanical trauma, such as the hands, elbows, knees, buttocks, and axillae (Figure 1b, f, g) [Hamada 2002].

Patchy and diffuse alopecia of the scalp, beard, eyelashes, and eyebrows may be present; however, alopecia is not a significant finding in most. Nail dystrophy has been reported [Hamada 2002].

Extracutaneous manifestations may include the following:

• Epilepsy. Seizure onset may be in childhood or adulthood. Temporal lobe epilepsy is the most common type, with both partial and (less frequently) secondarily generalized seizures observed. Seizures may be therapy-resistant [Claeys et al 2007].
• Neuropsychiatric disorders can include impairment of day-to-day memory (but not distant memory), paranoia, aggressive behavior and rage, hallucinations, absence of fear, and lack of normal sense of distrust or danger. Neuropsychiatric disorders can appear in childhood and are progressive. Individuals with lipoid proteinosis perform poorly on facial recognition of positive and negative emotions. These neuropsychiatric manifestations sometimes occur in association with calcification in the temporal lobes in the region of the amygdalae (Figure1h) [Siebert et al 2003, Thornton et al 2008].
• Spontaneous CNS hemorrhage (including small deep brain hemorrhages and large brain hematomata) has been reported and can lead to hemiparesis and hemiplegia [Siebert et al 2003, Messina et al 2012, Teive et al 2013].
• Gastrointestinal bleeding. Multiple yellowish nodules can be found throughout the esophagus, stomach, duodenum, and colon, and are usually asymptomatic [Custódio Lima et al 2014]; however, small intestinal bleeding has been observed in one individual [Caccamo et al 1994].

Genotype-Phenotype Correlations

No apparent ECM1 genotype-phenotype correlations are evident [Hamada et al 2003]. A wide range of clinical manifestations and disease progression (termed variable expressivity) occurs in individuals with the same ECM1 pathogenic variants even within the same family or population isolate [Youssefian et al 2015].

Prevalence

Fewer than 500 individuals with lipoid proteinosis (LP) have been reported worldwide.

LP tends to be more common in countries with extensive consanguinity and/or in areas (e.g., South Africa) in which a founder variant has been postulated [Van Hougenhouck-Tulleken et al 2004, Chan et al 2007].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with lipoid proteinosis (LP), the following are recommended:

• Consultation with a dermatologist (or pediatric dermatologist)
• Consultation with an otolaryngologist if vocal cord infiltration leads to airway obstruction, recurrent upper respiratory infections, and/or impaired speech
• Evaluation for evidence of seizures if clinical findings are suggestive
• Evaluation for neuropsychiatric manifestations
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

There is no curative therapy for LP.

Microlaryngoscopic excision of laryngeal deposits improves airway access and voice quality [Harper et al 1983].

Tracheostomy on occasion is required to ensure a safe airway in patients with significant airway obstruction [Richards & Bull 1973].

Seizures should be assessed and managed by a neurologist, using antiepileptic drugs (AEDs).

Treatments of unproven efficacy. Although several reports have described variable success in treatment of skin and vocal cord lesions with dermabrasion, carbon dioxide laser surgery, D-penicillamine, dimethyl sulfoxide (DMSO), corticosteroids, etretinate, acitretin, carbon dioxide laser, and surgical intervention, they are not widely used and their efficacy is unproven. Click here (pdf) for further details.

Surveillance

The following are appropriate:

• Routine follow up of children to monitor general health as well as psychomotor, emotional, and cognitive development
• Monitoring of the airway and vocal cords by an otolaryngologist

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.