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Chondrodysplasia Punctata 1, X-Linked

Synonyms: Arylsulfatase E Deficiency, CDPX1

, MS, MD, , MD, PhD, , MD, and , MS, CGC.

Author Information

Initial Posting: ; Last Update: November 20, 2014.

Estimated reading time: 19 minutes


Clinical characteristics.

X-linked chondrodysplasia punctata 1 (CDPX1), a congenital disorder of bone and cartilage development, is caused by a deficiency of the Golgi enzyme arylsulfatase E (ARSE). It is characterized by chondrodysplasia punctata (stippled epiphyses), brachytelephalangy (shortening of the distal phalanges), and nasomaxillary hypoplasia. Although most affected males have minimal morbidity and skeletal findings that improve by adulthood, some have significant medical problems including respiratory compromise, cervical spine stenosis and instability, mixed conductive and sensorineural hearing loss, and intellectual disability.


In approximately 25% of individuals with features of CDPX1, routine karyotype analysis reveals deletions or rearrangements of the short arm of the X chromosome (Xp) that include ARSE. Chromosomal microarray (CMA) can be used to evaluate for smaller interstitial deletion syndromes. Sequence analysis of ARSE identifies a pathogenic variant in up to 60% to 75% of males who meet clinical diagnostic criteria.


Treatment of manifestations: Respiratory difficulty can require frequent monitoring, nasal stents, and oxygen. Severe maxillary hypoplasia or maxillary retrognathia may require reconstructive surgery in older individuals. Instability of the cervical spine may require a cervical collar or spinal fusion.

Surveillance: Routine monitoring of hearing, growth, development, and cervical spine instability.

Genetic counseling.

CDPX1 is inherited in an X-linked manner. If the mother of a proband has the ARSE pathogenic variant identified in the proband, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and thus far have not been affected. Males with CDPX1 pass the pathogenic variant to all of their daughters and none of their sons. Carrier testing for at-risk relatives and prenatal testing for at-risk pregnancies are possible if the ARSE pathogenic variant has been identified in the family.


X-linked chondrodysplasia punctata 1 (CDPX1), a congenital disorder of bone and cartilage development, is caused by a deficiency of the enzyme arylsulfatase E (ARSE).

Suggestive Findings

Diagnosis of X-linked chondrodysplasia punctata 1 (CDPX1) should be suspected in a male with the following clinical and radiologic findings:

Clinical findings

  • Chondrodysplasia punctata (CDP) (stippled epiphyses) (see Radiographic findings)
  • Brachytelephalangy (shortening of the distal phalanges)
  • Nasomaxillary hypoplasia in which hypoplasia of the anterior nasal spine results in a characteristic flattened nasal base, reduced nasal tip protrusion with short columella, and in some cases vertical grooves within the alae nasi. The nostrils are crescent-shaped. It may appear as if the child’s nose is pressed flat against a window.

Note: Coagulopathy should be explicitly ruled out by measurement of clotting function (PT and PTT) and clotting factors II, VII, IX, and X (see Differential Diagnosis).

Radiographic findings

  • Stippled epiphyses are observed on skeletal x-rays in infancy, usually in the ankle and distal phalanges, although they can be more generalized to include epiphyses of long bones, vertebrae, hips, costochondral junctions, and hyoid bone. An inverted triangular shape of the distal phalanges with lateral stippling at the apex is characteristic. Stippling is usually symmetric and tends to disappear radiologically after age two to three years when the epiphyses ossify.
  • Calcifications can also occur in the larynx, trachea, and main stem bronchi (structures that do not normally ossify) and cause stenosis.
  • Vertebral abnormalities are common and include dysplastic and hypoplastic vertebrae and coronal or sagittal clefts. Cervical vertebral abnormalities can cause cervical kyphosis, cervical stenosis, and atlantoaxial instability.

Establishing the Diagnosis

The diagnosis of CDPX1 is established in a male proband with the identification of a hemizygous pathogenic variant in ARSE (see Table 1).

Molecular genetic testing approaches can include the following:

Table 1.

Summary of Molecular Genetic Testing Used in Chondrodysplasia Punctata 1, X-Linked

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
Affected MalesCarrier Females
Detecting sequence variants 260%-75% 3, 4, 5>50%-65% 6
Detecting (multi)exon and whole-gene deletions 20% 6
Deletion/duplication analysis 710% 8Unknown
Unknown 9NA

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants.


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.


Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.


Includes the variant detection frequency using deletion/duplication analysis


Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.


Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Males initially suspected on sequence analysis of having a deletion in whom the deletion is subsequently confirmed by deletion/duplication analysis


Non-genetic phenocopies contribute to some cases in which ARSE sequence analysis does not identify a pathogenic variant [Eash et al 2003, Chitayat et al 2008, Nino et al 2008, Matos-Miranda et al 2013, Huarte et al 2014].

Clinical Characteristics

Clinical Description

Affected males. The most consistent clinical features of X-linked chondrodysplasia punctata 1 (CDPX1) in affected males are CDP, brachytelephalangy, and nasomaxillary hypoplasia. Of note, a child with brachytelephalangy, nasomaxillary hypoplasia, and tracheobronchial calcifications did not have CDP at age 14 months [Casarin et al 2009].

Most affected males have minimal morbidity, and skeletal findings improve by adulthood; however, some have significant medical problems including airway stenosis and cervical spine instability.

Growth measurements tend to be normal at birth; short stature usually develops postnatally but only some affected adults have small stature. The shortening of the distal phalanges may become less apparent with age such that older individuals may show brachytelephalangy only in some digits.

Affected individuals have been thought to have a normal life span; however, recent descriptions have identified persons with more severe morbidity and mortality. These complications include the following:

  • Respiratory compromise caused by severe nasal hypoplasia or extensive punctate calcifications along the tracheobronchial tree requiring choanal stents, tracheostomy, or tracheal reconstruction [Wolpoe et al 2004]
  • Abnormal ossification of the cervical vertebrae that leads to cervical spine stenosis and/or instability and can result in spinal cord compression [Garnier et al 2007, Vogel & Menezes 2012]

These complications have led to early death in some cases [Brunetti-Pierri et al 2003, Garnier et al 2007, Nino et al 2008].

In a retrospective review of clinical features associated with CDPX1 and proven pathogenic variants in ARSE, the following were observed [Nino et al 2008, Matos-Miranda et al 2013]. Note: These studies may have an ascertainment bias towards more severely affected children.

  • Significant respiratory abnormalities (30%-50%)
  • Mixed conductive and sensorineural hearing loss (~25%)
  • Significant cervical spine abnormalities (~25%)
  • Delayed cognitive development (16%-20%)

Less frequently seen findings included the following:

  • Ophthalmologic abnormalities (cataracts, optic disc atrophy, small optic nerves)
  • Cardiac abnormalities (PDA, VSD, ASD)
  • Gastroesophageal reflux
  • Feeding difficulties

Heterozygotes. Affected carrier females have not been described, presumably because they have sufficient levels of ARSE enzyme activity expressed from both X chromosomes. Some carrier females may have smaller than expected stature [Sheffield et al 1998, Brunetti-Pierri et al 2003].

Genotype-Phenotype Correlations

The absence of common ARSE pathogenic variants precludes identifying correlations between genotype and phenotype.

The severity of the phenotype differed significantly between two brothers with the missense ARSE allele p.Ile40Ser, demonstrating variable intrafamilial disease expression [Nino et al 2008].

Thus far, affected individuals with intragenic deletions do not appear to be more severely affected than those with missense alleles. Matos-Miranda et al [2013] determined that all identified missense alleles were located close to the ARSE active site and resulted in enzyme inactivity, suggesting that most missense alleles abrogate enzyme activity.


Penetrance appears to be complete; however, in one report, the pathogenic ARSE variant p.Gly137Ala was identified in a proband and his maternal grandfather, the latter of whom was considered asymptomatic [Sheffield et al 1998]. This missense substitution involving a conserved amino acid was identified in a second unrelated, clinically affected proband [Nino et al 2008], implicating it as pathogenic. In a second, similar case [Casarin et al 2009] a deletion of exons 7-10 was identified in a proband and his asymptomatic maternal grandfather. Considering that physical features of CDPX1 improve with age, it is uncertain whether such cases represent non-penetrance.


CDPX1 refers specifically to a deficiency of ARSE enzyme activity.

Brachytelephalangic chondrodysplasia punctata (BCDP) is a descriptive term associated with CDPX1 and its non-genetic phenocopies.


The prevalence of CDPX1 is unknown; in one study it was estimated to be 1:500,000 [Malou et al 2001], but it is likely more common.

CDPX1 is pan ethnic.

Differential Diagnosis

Brachytelephalangic Chondrodysplasia Punctata (BCDP)

Stippled calcifications are observed in a wide variety of disorders including single gene disorders, chromosomal abnormalities, and intrauterine infections, maternal illnesses, or drug exposurl; for a review see Patel et al [1999]. A number of those disorders with radiographic stippling are also associated with shortening of the distal phalanges.

Genetic conditions associated with BCDP

  • Keutel syndrome (OMIM 245150). This autosomal recessive disorder has features that overlap with X-linked chondrodysplasia punctata 1 (CDPX1), but with more diffuse and progressive calcification of cartilage including nose, auricles, and respiratory tract. Peripheral pulmonic stenosis is also observed. Biallelic pathogenic variants in MGP (encoding the vitamin K-dependent matrix Gla protein) cause Keutel syndrome [Munroe et al 1999, Weaver et al 2014].
  • Deficiency of vitamin K epoxide reductase subunit 1 (VKORC1) and gamma-glutamyl carboxylase (GGCX). Mutation of VKORC1 causes both warfarin resistance (OMIM 122700) and multiple coagulation factor deficiency type 2 (OMIM 607473), an autosomal recessive disorder that also may include BCDP [Pauli et al 1987, Rost et al 2004]. Mutation of GGCX causes multiple coagulation factor deficiency type 1 (OMIM 277450), an autosomal recessive disorder that also includes BCDP [Brenner et al 1990].
  • Xp contiguous deletion syndromes. See Genetically Related Disorders.
  • Multiple sulfatase deficiency (OMIM 272200) is a rare autosomal recessive disorder characterized by impaired activity of all known sulfatases including ARSE [Cosma et al 2003].

Teratogenic conditions associated with BCDP. Both male and female infants with BCDP have been described. In the case of an affected male, no specific clinical features distinguished CDPX1 from these non-genetic conditions [Nino et al 2008, Matos-Miranda et al 2013].

Note: Prenatal exposure to warfarin, fetal vitamin K deficiency, and vitamin K epoxide reductase deficiency has been associated with brain malformation [Menger et al 1997, van Driel et al 2002, Puetz et al 2004, Brunetti-Pierri et al 2007]. However, brain abnormalities have not been reported to date in persons with ARSE pathogenic variants.

Maternal autoimmune disease. BCDP was reported in infants born to mothers with systemic lupus erythematosus (SLE), Sjogren syndrome, mixed connective tissue disease, scleroderma, and unclassified autoimmune disorders [Kozlowski et al 2004, Kirkland et al 2006, Shanske et al 2007, Chitayat et al 2008, Nino et al 2008, Schulz et al 2010, Tim-aroon et al 2011, Nayak et al 2012, Huarte et al 2014]. It was proposed that antibodies against ARSE or a component of the biochemical pathway are causative.

Non-Brachytelephalangic CDP / Other CDP Conditions Clinically Distinguishable from BCDP

X-linked chondrodysplasia punctata 2 (CDPX2) [Herman et al 2002] and CHILD syndrome (congenital hemidysplasia, ichthyosis, and limb defects) [König et al 2000] are a result of defects in cholesterol synthesis; they are X-linked dominant and typically lethal in males:

  • CDPX2 (Conradi-Hünermann syndrome, Happle syndrome) is caused by defects in sterol 8-isomerase (encoded by EBP). Affected females have asymmetric rhizomesomelia, sectorial cataracts, patchy alopecia, ichthyosis, and atrophoderma. Rare males with a 47,XXY karyotype or mosaic for pathogenic variants in EBP have been reported [Aughton et al 2003].
  • CHILD syndrome (see NSDHL-Related Disorders) results from defects in the NAD(P)-dependent steroid dehydrogenase-like enzyme. Affected females have unilateral distribution of ichthyosis, limb defects, CDP, and visceral anomalies.

Rhizomelic chondrodysplasia punctata is an autosomal recessive disorder caused by a deficiency of the peroxisomal step of ether phospholipid synthesis [Braverman et al 2002] (see Rhizomelic Chondrodysplasia Punctata Type 1).

Tibial-metacarpal type CDP (CDP-TM) (OMIM 118651) is inherited in an autosomal dominant manner; the gene in which mutation is causative is unknown [Savarirayan et al 2004].

Humeral-metacarpal type CDP may include brachytelephalangy as well as hypoplasia of the humeri and metacarpals [Fryburg & Kelly 1996]. All instances have been sporadic.

Toriello-type CDP is a rare and presumably autosomal recessive disorder with multiple dysmorphic features, colobomata, short stature, and stippling of the proximal humeral epiphyses [Toriello et al 1993].

Smith-Lemli-Opitz syndrome, resulting from a defect in conversion of 7-dehydrocholesterol to cholesterol, can also present with stippled calcifications.

Peroxisome biogenesis disorders (PBD), Zellweger syndrome spectrum can have stippling in the knees and hips.

Stippling is occasionally present in GM1 gangliosidosis, mucolipidosis II, mucopolysaccharidosis type III [Irving et al 2008], trisomy 18, and trisomy 21.

Nasomaxillary Dysplasia

Binder phenotype (OMIM 155050), a term describing nasomaxillary dysplasia similar to that observed in CDPX1, does not represent a single nosologic entity. A subset of individuals with Binder syndrome may have pathogenic variants in ARSE; this has yet to be determined [Carach et al 2002, Cuillier et al 2005, Chummun et al 2012].


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with X-linked chondrodysplasia punctata 1 (CDPX1), the following evaluations are recommended:

  • Full skeletal survey
  • Flexion, neutral, and extension lateral views of the C-spine in every patient. If clinical evidence suggests cervical myelopathy or if significant instability is demonstrated radiographically, a cervical MRI should be performed. Special consideration should be given to performing this study in flexion and extension positions as spinal cord compression may only occur with these movements (i.e., a normal neutral cervical MRI does not rule out dynamic compression).
  • Growth measures
  • Developmental assessment
  • Hearing assessment
  • Assessment of upper and lower airways if stridor is present
  • Polysomnography
  • Ophthalmologic evaluation
  • Cardiac ultrasound examination
  • Brain imaging studies
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Management is supportive.

Respiratory difficulty can require frequent monitoring, nasal stents, and oxygen.

Severe maxillary hypoplasia or maxillary retrognathia may require reconstructive surgery in older individuals [Carach et al 2002].

Instability of the cervical spine may require a cervical collar or spinal fusion; cervical spine stenosis may require decompression.

Surveillance of the following is according to recommended pediatric practice, with closer follow-up recommended if abnormalities are identified:

  • Hearing
  • Growth
  • Development
  • Thoracic and lumbar spine (for scoliosis)

Evaluation of Relatives at Risk

It is appropriate to evaluate the older and younger at-risk relatives of an individual with CDPX1 in order to identify as early as possible those who would benefit from early screening for hearing loss. If the ARSE pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.

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

Therapies Under Investigation

Search in the US and 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

X-linked chondrodysplasia punctata 1 (CDPX1) is inherited in an X-linked manner.

Risk to Family Members

Parents of the proband

Sibs of the proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother of the proband has an ARSE pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the pathogenic variant will be affected; female sibs who inherit the pathogenic variant will be carriers and have thus far not been affected.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the ARSE pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of a proband. Males with CDPX1 will pass the ARSE pathogenic variant to all of their daughters and none of their sons.

Other family members. The proband's maternal aunts may be at risk of being carriers and the aunts’ offspring, depending on their gender, may be at risk of being carriers or of being affected.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Carrier (Heterozygote) Detection

Identification of female heterozygotes requires either (a) prior identification of the ARSE pathogenic variant in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no pathogenic variant is identified, by deletion/duplication analysis.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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 ARSE pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for CDPX1 are possible.


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.

  • CDPX1 Family Support Group
    This site, developed with support from the National Institute on Deafness and Other Communication Disorders, provides information about newborn hearing screening and hearing loss.
  • Human Growth Foundation (HGF)
    997 Glen Cove Avenue
    Suite 5
    Glen Head NY 11545
    Phone: 800-451-6434 (toll-free)
    Fax: 516-671-4055
  • Little People of America, Inc. (LPA)
    250 El Camino Real
    Suite 201
    Tustin CA 92780
    Phone: 888-572-2001 (toll-free); 714-368-3689
    Fax: 714-368-3367
  • MAGIC Foundation
    4200 Cantera Drive #106
    Warrenville IL 60555
    Phone: 800-362-4423 (Toll-free Parent Help Line); 630-836-8200
    Fax: 630-836-8181
  • International Skeletal Dysplasia Registry
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998

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.

Chondrodysplasia Punctata 1, X-Linked: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
ARSEXp22​.33Arylsulfatase EARSE @ LOVDARSEARSE

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 Chondrodysplasia Punctata 1, X-Linked (View All in OMIM)


Gene structure. ARSE spans 29.5 kb of genomic DNA and contains 11 exons and ten introns. It encodes a 2.2-kb full-length transcript. ARSE is located in Xp22.3, close to the pseudoautosomal boundary within a cluster of evolutionarily related sulfatase genes that include ARSD, ARSF, ARSG, and ARSC (STS), which encodes steroid sulfatase. These genes escape X-chromosome inactivation and have a pseudogene on the Y chromosome [Sardiello et al 2005]. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Several polymorphic variations occur in the coding region.

Pathogenic variants. See Table 2. Eighteen unique pathogenic variants, two partial deletions, and three complete gene deletions have been identified to date in 30 probands. A few recurrent pathogenic variants were reported in two unrelated probands: p.Gly137Ala, p.Thr481Met, and p.Pro578Ser. The nonsense variant p.Trp581Ter was reported in five probands. The Gly137 residue was also mutated to Val (p.Gly137Val) in another individual [Franco et al 1995, Sheffield et al 1998, Brunetti-Pierri et al 2003, Garnier et al 2007, Nino et al 2008].

Table 2.

Selected ARSE Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences

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

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.

Normal gene product. The protein encoded by ARSE comprises 589 amino acid residues. Sulfatase enzymes hydrolyze sulfate ester bonds in glycosaminoglycans, sulfolipids, steroid sulfates, and other compounds. All sulfatases undergo a post-translational processing event by the enzyme SUMF1, in which a C-alpha-formylglycine (FGly), the catalytic residue in the active site, is generated from a cysteine [Cosma et al 2003]. The ARSE protein has been studied in an in vitro expression system in COS7 cells, where it localized to Golgi membranes [Daniele et al 1998]. Although its physiologic substrate has not yet been identified, ARSE enzyme hydrolyzes the fluorogenic artificial substrate, 4-methylumbelliferyl (4-MU) sulfate. It is active at neutral pH, heat labile, and inactive toward steroid sulfates [Daniele et al 1998]. ARSE enzyme activity is inhibited in vitro by warfarin, an anticoagulant that inhibits VKORC1, and therefore the regeneration of active vitamin K [Rost et al 2004]. Given the well-documented phenotypic similarities between CDPX1 and warfarin embryopathy, it was proposed that ARSE was the vitamin K-dependent protein inhibited by warfarin. Alternatively, ARSE could act downstream of a vitamin K-dependent metabolic pathway.

Abnormal gene product. Several missense alleles were experimentally evaluated and shown to have reduced function [Daniele et al 1998, Brunetti-Pierri et al 2003, Matos-Miranda et al 2013].


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Chapter Notes

Revision History

  • 20 November 2014 (me) Comprehensive update posted live
  • 3 November 2011 (me) Comprehensive update posted live
  • 22 April 2008 (me) Review posted live
  • 16 November 2007 (nb) Original submission
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