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Lipoid Proteinosis

Synonyms: Hyalinosis Cutis et Mucosae, Urbach-Wiethe Disease

, MSc, , MSc, and , MD, PhD.

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Estimated reading time: 17 minutes

Summary

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.

Diagnosis

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.

Figure 1.

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

Neuroimaging

Establishing the Diagnosis

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

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.

Table 1.

Molecular Genetic Testing Used in Lipoid Proteinosis

Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method
ECM1Sequence analysis 3More than 95% 4
Gene-targeted deletion/duplication analysis 5Unknown 6
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Nearly 50% of all pathogenic variants occur in exons 6 and 7 in all populations [Chan et al 2007].

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

No data on detection rate of gene-targeted deletion/duplication analysis are available. Gross deletions have been reported in two cases [Hamada et al 2002, Lee et al 2015a].

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 Characteristics

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].

Differential Diagnosis

Erythropoietic protoporphyria (EPP) is characterized by cutaneous photosensitivity (usually beginning in infancy or childhood) that results in tingling, burning, pain, and itching within minutes of sun/light exposure and may be accompanied by swelling and redness. Blistering is uncommon. Symptoms (which may seem out of proportion to the visible skin lesions) may persist for hours or days after the initial phototoxic reaction. Photosensitivity usually remains for life. Multiple episodes of acute photosensitivity may lead to chronic changes of sun-exposed skin (lichenification, leathery pseudo-vesicles, grooving around the lips) and loss of lunulae of the nails. Approximately 20%-30% of individuals with EPP have some degree of liver dysfunction, which is typically mild with slight elevation of the liver enzymes. Up to 5% may develop more advanced liver disease variably accompanied by motor neuropathy similar to that seen in the acute porphyrias. Except for the small minority with advanced liver disease, life expectancy is not reduced. The early vesicular lesions in LP can resemble those in EPP. EPP is caused by biallelic pathogenic variants in FECH and inherited in an autosomal recessive manner.

Pseudoxanthoma elasticum (PXE) is a systemic disorder that affects the elastic tissue of the skin, the eye, and the cardiovascular and gastrointestinal systems. Individuals most commonly present with yellowish papules in the skin and/or with angioid streaks of the retina found on routine eye examination or associated with retinal hemorrhage. Occasionally, individuals may present with vascular signs and symptoms, including nephrogenic hypertension, intermittent claudication, angina, gastrointestinal bleeding, myocardial infarct, and stroke. The most frequent cause of morbidity and disability in PXE is reduced vision from macular hemorrhage and disciform scarring of the macula. Some of the skin changes seen on the neck in LP are reminiscent of those in PXE. PXE is caused by biallelic pathogenic variants in ABCC6 and inherited in an autosomal recessive manner.

Management

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Lipoid proteinosis (LP) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • 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.
  • Heterozygotes (carriers) are typically asymptomatic but may have variable findings. Youssefian et al [2015] reported voice hoarseness in cold seasons and thickening of the frenulum and a firm tongue in family members heterozygous for the c.507delT pathogenic variant in ECM1.

Offspring of a proband. Unless an individual with lipoid proteinosis has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in ECM1.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of an ECM1pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the ECM1 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the ECM1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for lipoid proteinosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Lipoid Proteinosis: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
ECM11q21​.2Extracellular matrix protein 1ECM1 databaseECM1ECM1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Lipoid Proteinosis (View All in OMIM)

247100LIPOID PROTEINOSIS OF URBACH AND WIETHE
602201EXTRACELLULAR MATRIX PROTEIN 1; ECM1

Molecular Pathogenesis

Lipoid proteinosis is caused by ECM1 loss-of-function variants as originally described in six consanguineous families [Hamada et al 2002].

Gene structure. ECM1 has at least four splice variants: ECM1a, ECM1b, ECM1c, and a short splicing variant. For a detailed summary of gene and protein information, see Table A, Gene.

ECM1a, the most widely expressed splice variant in various tissues including skin, liver, small intestines, lung, ovary, prostate, testis, skeletal muscle, pancreas, kidney, placenta, and heart, is a transcript from the full-length 10-exon gene, whereas ECM1b lacks exon 7 and ECM1c contains an additional exon 5a sequence within intron 5.

ECM1b has a much more restricted expression pattern, being detectable only in tonsils and keratinocytes.

The full pattern of ECM1c expression has yet to be determined; however, in skin it accounts for approximately 15% of total ECM1 RNA [Smits et al 1997, Smits et al 2000, Horev et al 2005].

The short splicing variant includes 71 bp from the 3’ end of intron 1 and part of exon 2 to give a truncated 57-amino acid protein with unknown function.

Pathogenic variants. Over 50 ECM1 pathogenic variants have been reported. Although these include missense variants, the majority of inactivating variants are nonsense, frameshift, splice site variants, and large deletions.

Slightly more than half of all pathogenic variants are located within or in the boundaries of exons 6 or 7 [Hamada et al 2003]. Commonly identified pathogenic variants:

Table 2.

ECM1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
c.826C>Tp.Gln276TerNM_004425​.3
NP_004416​.2
c.506dupC
(501insC)
p.Pro140ProfsTer3
c.727C>Tp.Arg243Ter
c.507delTp.Pro169ProfsTer8
c.658T>Gp.Cys220Gly
c.93_94delGCinsTTp.Gln32Ter

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

Normal gene product. Extracellular matrix protein 1(ECM1) is a secretory glycoprotein consisting of three major isoforms, ECM1a (540 amino acids), ECM1b (415 amino acids), and ECM1c (559 amino acids).

ECM1 contains a signal peptide of 19 amino acids followed by four functional domains: a cysteine-free N-terminus, two tandem repeats, and a C-terminus. The latter three domains contain 29 cysteine (C) residues, arranged as CC-(X7–10)-C motif (X: any amino acid) that is capable of forming protein double loops facilitating protein-protein interactions. ECM1 contains three double-loop domains within latter three domains. The CC-(X7–10)-C motif may enable ECM1 to serve as a transporter protein or to be involved in binding growth or differentiation factors. ECM1 also contains a calcium-binding domain, which is present in the ECM1a and ECM1c isoforms but not in ECM1b [Smits et al 1997, Smits et al 2000, Horev et al 2005].

Abnormal gene product. All reported pathogenic variants are loss-of-function variants and may lead to absence of ECM1 protein or production of non-functional protein [Chan et al 2007].

Cancer and Benign Tumors

No correlation between increased cancer incidence and lipoid proteinosis has been reported; however, recently evidence linking expression of ECM1 with aspects of malignancy has emerged as ECM1 is overexpressed in some carcinomas [Wang et al 2003]. ECM1 has been shown to have an important role in growth, angiogenesis, metastasis, and epithelial-stromal interactions [Lee et al 2015b].

In contrast, a recent study suggests that ECM1 is a tumor suppressor candidate gene [Gao et al 2014].

References

Literature Cited

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Chapter Notes

Author Notes

Jouni Uitto, MD, PhD, has been Professor of Dermatology and Cutaneous Biology, and Biochemistry and Molecular Biology, and Chair of the Department of Dermatology and Cutaneous Biology at The Sidney Kimmel Medical College at Thomas Jefferson University, in Philadelphia, Pennsylvania, since 1986. He is also Director of the Jefferson Institute of Molecular Medicine at Thomas Jefferson University. He received his MD and PhD degrees from the University of Helsinki, Finland, and completed his residency training in dermatology at Washington University School of Medicine, St Louis, Missouri. Dr Uitto is internationally recognized for his research on connective tissue biology and molecular genetics in relation to cutaneous diseases. Dr Uitto’s publications include 665 original articles in peer-reviewed journals, 314 textbook chapters and review articles, and 965 abstracts on presentations in national and international meetings. Dr Uitto has been the recipient of numerous national and international awards, including honorary doctorate degrees from the University of Kuopio, University of Oulu, and University of Turku, all in Finland, as well as honorary professorship at China Medical University, Shenyang, Hebei United University, Tangshan, and The Fourth Military Medical University, Xi’an, all in China. Dr Uitto has held office in several scientific and professional societies, including as President of the Society for Investigative Dermatology and President and Chairman of the Board of Trustees of Dermatology Foundation. Dr Uitto is also Section Editor of the Journal of Investigative Dermatology and Associate Editor of the American Journal of Pathology; he is on the editorial boards of numerous peer-reviewed journals.

Hassan Vahidnezhad and Leila Youssefian are PhD candidates in medical genetics working on genodermatoses at Sidney Kimmel Medical college of Thomas Jefferson University in Philadelphia, Pennsylvania.

Leila Youssefian and Hassan Vahidnezhad contributed equally to this work.

Acknowledgments

Carol Kelly assisted in manuscript preparation.

Revision History

  • 21 January 2016 (bp) Review posted live
  • 28 July 2015 (ju) Original submission
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