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Hyalinosis, Inherited Systemic

Synonym: Hyaline Fibromatosis Syndrome

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

Author Information

Initial Posting: ; Last Update: April 11, 2013.

Estimated reading time: 16 minutes


Clinical characteristics.

Inherited systemic hyalinosis is characterized by hyaline deposits in the papillary dermis and other tissues. It typically presents at birth or in infancy with severe pain with movement, progressive joint contractures, and often with severe motor disability, thickened skin, and hyperpigmented macules/patches over bony prominences of the joints. Gingival hypertrophy, skin nodules, pearly papules of the face and neck, and perianal masses are common. Complications of protein-losing enteropathy and failure to thrive can be life threatening. Cognitive development is normal. Many children with the severe form (previously called infantile systemic hyalinosis) die in early childhood; some with a milder phenotype (previously called juvenile hyaline fibromatosis) survive into adulthood.


The diagnosis of inherited systemic hyalinosis is based on clinical findings or results of genetic testing. Skin biopsy may reveal hyaline material accumulation in the dermis or nondiagnostic findings; intestinal biopsy may demonstrate villous atrophy and lymphangiectasia. Skeletal x-rays may reveal osteopenia, periosteal reaction, and lucent lesions. ANTXR2 is the only gene in which mutation is known to cause inherited systemic hyalinosis.


Treatment of manifestations: Nonsteroidal anti-inflammatory drugs (NSAIDs), opiates, and possibly gabapentin for pain; consultation with a pain management specialist as needed; physiotherapy for joint contractures can be considered although pain may be problematic; possible nasogastric tube or gastrostomy tube feeding under supervision of a gastroenterologist and nutritionist; nutrition tailored for the possibility of malabsorption or lymphangiectasia; hydration and albumin infusions for protein-losing enteropathy; infections are treated based on the site of infection and causative agent; lesions that obstruct the airway or interfere with feedings can be excised, but may recur.

Prevention of secondary complications: Anesthesiologists need to be aware of potential difficulties with endotracheal intubation.

Genetic counseling.

Inherited systemic hyalinosis 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. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. If the pathogenic variants in the family are known, prenatal testing for pregnancies at increased risk is possible through laboratories offering either testing for the gene of interest or custom testing.


Clinical Diagnosis

Inherited systemic hyalinosis is characterized by hyaline deposits in the papillary dermis and other tissues associated with the following distinctive clinical findings presented in order of their specificity for clinical diagnosis:

  • Hyperpigmented skin over bony prominences. Characteristic purplish patches develop over the medial and lateral malleoli of the ankles, the metacarpophalangeal joints, spine, and elbows. The degree of hyperpigmentation varies depending on the baseline pigmentation of the skin [Arbour et al 2001].
  • Progressive contractures. Affected individuals can present with congenital contractures. Some mothers report deficient fetal activity during the pregnancy of the affected infant, and many parents note decreased passive and/or active movement of the extremities of their child. Contractures are progressive, and extremities become fixed with the hips and knees flexed and the ankles dorsiflexed. The elbows exhibit flexion contractures, and the wrists are typically positioned in extension with flexion contractures of the proximal interphalangeal and distal interphalangeal joints. Some individuals demonstrate milder features.
  • Pain or excessive crying. Severe pain with passive movement in infancy or early childhood is characteristic. Pathogenesis is unclear.
  • Gingival thickening. Affected individuals develop masses in the gingiva, which enlarge over time.
  • Other skin manifestations. Skin nodules and white to pink pearly papules that are a few millimeters in size are common on the face and neck. Fleshy lesions may appear in the perianal region. These lesions appear to develop and become more numerous over time. The skin is firm to palpation and has been described as thickened.
  • Unusual facies. A depressed nasal bridge, variable ear malformations (large, simple or low-set ears, and preauricular skin tags), and a slightly coarse facial appearance may be present.
  • Failure to thrive. Postnatal-onset growth deficiency is common. Some children develop chronic diarrhea and protein-losing enteropathy.

Note: Disease grading based on organ involvement has been reported [Nofal et al 2009, Denadai et al 2012].


Skin biopsy. Light microscopy demonstrates hyaline material in the dermis.

Note: This finding may not be evident in the early stages of the disease [Arbour et al 2001]. The hyaline material appears as an amorphous eosinophilic substance that is periodic acid-Schiff (PAS) positive. It is thought to contain glycoproteins and collagen. The spindle-shaped fibroblasts dispersed in abundant amounts of hyaline material render a "chondroid appearance."

Electron microscopy demonstrates cells filled with fine, fibrillary material with an enlarged endoplasmic reticulum and Golgi apparatus.

Intestinal biopsy and imaging. Findings in biopsy specimens from individuals with prominent gastrointestinal symptoms include villous atrophy, edema, lymphangiectasia, and hyalinosis. Rapid transit time has been reported in real-time upper-gastrointestinal imaging studies.

Skeletal radiographs. Radiographic abnormalities include generalized osteopenia, periosteal reaction, and lucent lesions. These nonspecific findings may affect long bones as well as the axial skeleton and can support a clinical suspicion of inherited systemic hyalinosis.

Molecular Genetic Testing

Gene. ANTXR2, the capillary morphogenesis gene-2, is the only gene in which pathogenic variants are currently known to cause inherited systemic hyalinosis.

Table 1.

Molecular Genetic Testing Used in Inherited Systemic Hyalinosis

Gene 1Test MethodVariants Detected 2Variant Detection Frequency by Test Method 3
ANTXR2Sequence analysis 4Sequence variants90% 5
Deletion/duplication analysis 6Multiexon deletion or insertionUnknown 7

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a variant that is present in the indicated gene


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.


Multiple pathogenic variants have been identified [Dowling et al 2003, Hanks et al 2003, El-Kamah et al 2010, Denadai et al 2012] (see Molecular Genetics).


Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Testing Strategy

To confirm/establish the diagnosis in a proband

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family.

Clinical Characteristics

Clinical Description

Inherited systemic hyalinosis, named for the characteristic hyaline deposits in the papillary dermis and other tissues of affected individuals, exhibits a broad spectrum of clinical severity [Mancini et al 1999, Urbina et al 2004]. Severely affected children often succumb in the first years of life; this severe phenotype was originally termed infantile systemic hyalinosis. Milder forms of the disease were originally described as juvenile hyaline fibromatosis (JHF); however, it has become clear that both the severe and mild forms occur on a continuum of clinical findings [Rahman et al 2002, Dowling et al 2003, Hanks et al 2003]. Thus, the term inherited systemic hyalinosis encompasses the entire spectrum of disease.

Inherited systemic hyalinosis presents at birth or in infancy with severe pain with movement, progressive joint contractures, skin that is firm to palpation, and characteristic hyperpigmented macules/patches over bony prominences of the joints, especially the ankles, wrists, and metacarpal-phalangeal joints [Stucki et al 2001].

The degree of hyperpigmentation varies depending on the baseline pigmentation of the skin [Arbour et al 2001].

Pearly papules develop on the head and neck. Skin nodules, papules, and fleshy lesions develop especially periorally and perianally.

The gingivae are thickened and may reveal focal masses. Dental abnormalities include malpositioned teeth, curved dental roots, or other dental abnormalities.

Cognitive function is preserved; however, cases of delayed development have been reported [Nischal et al 2004].

Excessive diaphoresis is common.

Hepatomegaly may be present.

Susceptibility to fractures may be increased.

Failure to thrive is associated with difficulty in feeding and severe intractable protein-losing diarrhea, likely accompanying hyalinosis of the intestine.

Recurrent infections may develop.

Individuals with severe disease succumb to infection or complications of protein-losing enteropathy.

Some individuals demonstrate a milder phenotype (previously described as JHF), which may be of later onset. Although joint contractures, skin hyperpigmentation, and lesions occur with the milder phenotype, the presentation is variable, the pain is less severe, the disability may be less pronounced, and affected individuals may live into adulthood. Pain may lessen with age. Short stature, limb shortening, and brachydactyly may be present. Intractable diarrhea is rare in milder forms of the disorder.

At least two individuals clinically diagnosed as having JHF developed squamous cell carcinoma [Kawasaki et al 2001, Shimizu et al 2005]; the ANTXR2 mutation status in these individuals is unknown.

Other studies

  • MRI of the brain is unremarkable.
  • Ophthalmologic examination does not reveal any characteristic findings and can be used to differentiate inherited systemic hyalinosis from some lysosomal storage disorders.
  • Myopathic changes on muscle biopsy may be evident [Zolkipli et al 2003].
  • Laboratory studies may demonstrate a normal or slightly elevated ESR, anemia, and/or thrombocytosis.
  • Immunoglobulin levels may be low and cellular immune responses depressed.
  • CD3 and CD4 lymphocyte subsets and ANA are unremarkable.

Pathology. Only a few post-mortem examinations have been reported. Hyaline deposition has been documented in the dermis, the small and large intestine, skeletal muscle, lymph nodes, thymus, spleen, thyroid, adrenals, and myocardium. Interstitial parenchymal fibrosis of the pancreas, skeletal muscle, lung, and liver was observed [Criado et al 2004].

Genotype-Phenotype Correlations

Hanks et al [2003] reported on genotype/phenotype correlations in 17 families with features of either infantile systemic hyalinosis or JHF:

  • Those with at least one insertion/deletion in ANTXR2 resulting in a translational frameshift had a severe phenotype (infantile systemic hyalinosis).
  • All individuals with pathogenic variants situated in the von Willebrand domain had infantile systemic hyalinosis, suggesting that disruption of the protein-binding domain leads to serious clinical consequences.
  • In-frame and missense variants in the cytoplasmic domain were associated with a milder phenotype, with survival to adulthood without recurrent infections, diarrhea, or multiorgan failure. Skeletal manifestations, however, were variably present.


Before the molecular basis of inherited systemic hyalinosis was understood, severe and milder forms of the disorder were described as separate conditions (infantile systemic hyalinosis and juvenile hyaline fibromatosis, respectively). Recent data indicate that both severe and mild forms of inherited systemic hyalinosis are caused by pathogenic variants in ANTXR2.


Inherited systemic hyalinosis is rare, but it has been recognized in families of various ethnic backgrounds on multiple continents [Félix et al 2004]. One report described multiple cases in the Arab population [Al-Mayouf et al 2005], reflecting the presence of consanguinity.

Differential Diagnosis

The following conditions exhibit some features similar to inherited systemic hyalinosis; however, inherited systemic hyalinosis can be distinguished by the characteristic associated pain, hyperpigmented skin lesions, and perianal and perioral masses:

  • Farber disease (Farber lipogranulomatosis) is a lysosomal storage disease caused by deficiency of the enzyme acid ceramidase. Affected individuals typically present with painful joint contractures and progressive hoarseness. Skin nodules develop, especially over bony prominences. However, most of the reported cases have neurologic involvement, which helps distinguish Farber disease from inherited systemic hyalinosis. Furthermore, individuals with Farber disease do not have the hyperpigmented patches seen in inherited systemic hyalinosis. The diagnosis of Farber disease can be made by assessing activity of the enzyme ceramidase in fibroblasts.
  • I-cell disease (mucolipidosis II) is a storage disorder associated with ineffective transport of enzymes into the lysosome accompanying a defect in the enzyme lysosomal phosphotransferase. Affected individuals develop gingival thickening and dysostosis multiplex. The facies are coarse and joint contractures develop over time. The distinctive skin findings of inherited systemic hyalinosis can help differentiate these disorders. Diagnosis is confirmed by enzyme analysis.
  • Non-accidental trauma. Periosteal reaction or fractures on skeletal radiographs in systemic hyalinosis have been mistaken for non-accidental trauma. The hyperpigmented skin lesions may mistakenly be considered post-traumatic, and the perianal masses can resemble condylomata, prompting a workup for an infectious etiology.
  • Pseudo-Hurler polydystrophy (mucolipidosis IIIA) is caused by pathogenic variants in GNPTAB, the gene encoding N-acetylglucosamine-1-phophotransferase. The phenotype varies in severity; principal features include contractures and dysostosis multiplex. The skin findings of systemic hyalinosis distinguish the two conditions.
  • Multicentric osteolysis nodulosis and arthropathy (MONA) is characterized by short stature and osteolysis of the interphalangeal and metacarpal-phalangeal joints. MONA lacks the distinctive dermatologic features of inherited systemic hyalinosis.
    Note: In addition to MONA, this phenotype has been reported in the literature as Torg syndrome, Winchester-Torg (or Torg-Winchester) syndrome, and nodulosis-arthropathy-osteolysis (NAO) syndrome. All of these conditions have been shown to be caused by biallelic pathogenic variants in MMP2 with no discernible genotype-phenotype correlation.
  • Congenital generalized fibromatosis (infantile myofibromatosis) (OMIM 228550) is associated with solitary, multiple, or generalized nodules composed of cells with features of differentiated fibroblasts and smooth muscle cells. Autosomal dominant inheritance has been suggested [Zand et al 2004].
  • Stiff skin syndrome (OMIM 184900) is characterized by thickened skin and flexion contractures, with early lethality in some cases. Mucopolysaccharide deposition has been found in the skin but mucopolysacchariduria has not been detected.
  • Lipoid proteinosis of Urbach and Wiethe (hyaline cutis et mucosae) presents with hoarseness, followed by the development of papules around the eyelids. Other findings include facial papules, tongue enlargement, dental hypoplasia, and skin lesions (vesicles and crusted bullae evolving into waxy plaques) that are distinct from those in inherited systemic hyalinosis. Many cases have been reported from South Africa. Pathogenic variants in ECM1, the gene encoding extracellular matrix protein 1, have been identified in some affected individuals.
  • Caffey disease (infantile cortical hyperostosis) presents with irritability, poor feeding, fever, and soft tissue swelling. Radiographic hyperostoses are characteristic and can help differentiate Caffey disease from inherited systemic hyalinosis. Some individuals exhibit pathogenic variants in COL1A1, the gene encoding collagen alpha-1(I) chain.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with inherited systemic hyalinosis, the following evaluations should be considered:

  • Complete nutritional evaluation, including evaluation for intestinal malabsorption
  • Evaluation for immune deficiency
  • Because hyalinosis of the heart has been reported, consideration of echocardiogram
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations


  • Nonsteroidal anti-inflammatory drugs (NSAIDs) and opiates help control pain. Agents such as gabapentin should be considered.
  • Gentle handling may reduce pain that is worsened with movement. Splinting of affected joints may provide comfort.
  • When passive movement of joint contractures is painful, physiotherapy should be carried out with care; in some cases physiotherapy is not tolerated because of pain.
  • Consultation with a pain management specialist may be helpful. Palliative care may be an option in severe cases.

Failure to thrive

  • Early consideration should be given to nasogastric tube or gastrostomy tube feeding.
  • Nutrition should be tailored for the possibility for malabsorption or lymphangiectasia.
  • A nutritionist should follow affected individuals.

Protein-losing enteropathy

  • Chronic diarrhea and protein-losing enteropathy with subsequent edema are treated with hydration and albumin infusions; an effective long-term treatment is lacking.
  • The effectiveness of dietary therapies with intestinal lymphangiectasia is not known.

Skin nodules, gingival thickening, and lesions of the mouth. Lesions that obstruct the airway or interfere with oral intake are particularly problematic; surgical excision is an option that has been used, but lesions may recur.

Dermatitis. Intertriginous, perianal, and neck areas appear to be particularly prone to dermatitis and should be treated appropriately.

Perianal masses may be excised, but may recur.

Joint contractures. Contractures are typically progressive. Treatment of contractures with physiotherapy should be performed with care because of pain.

Immune system/Infections

  • Infections are treated based on the site of infection and causative agent.
  • An immunology evaluation should be considered given the possibility of impaired cellular immune responses and immunoglobulin levels [Klebanova & Schwindt 2009].

Other. Given the chronic nature of this disorder in an individual with normal intelligence, family counseling should be considered in order to develop coping strategies for both the patient and the immediate family.

Prevention of Secondary Complications

Anesthesiologists should be aware of the diagnosis given the difficulty of endotracheal intubation and management in some affected individuals as a result of anatomy and gingival thickening [Pollard et al 2008, Qasem et al 2012]. Significant complication with anesthesia has been reported [El-Kamah & Mostafa 2009].


Routine nutritional assessment is appropriate.

Periodic assessment for gastrointestinal malabsorption may aid in optimizing nutritional status.

Agents/Circumstances to Avoid

The role of surgery in management of lesions is unclear since lesions appear to recur.

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 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

Systemic hyalinosis is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being unaffected and a carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with systemic hyalinosis are obligate heterozygotes (carriers) for a pathogenic variant.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier (Heterozygote) Detection

Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified.

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 Premimplantation Genetic Diagnosis

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

Ultrasound examination/imaging. The utility of prenatal ultrasound examination is unclear; however, in a pregnancy at risk, detection of decreased fetal activity and contractures could suggest recurrence.


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.

  • American Chronic Pain Association: Growing Pains
    Growing Pains is a support group for chronically ill youth.
    PO Box 346
    Putnam Valley NY 10579
    Phone: 800-533-3231
  • Centre for Pediatric Pain Research
    IWK Health Centre
    5850/5980 University Avenue
    PO Box 9700
    Halifax Nova Scotia B3K 6R8
  • MISS Foundation
    International organization which provides immediate and ongoing support to grieving families after the death of a baby or young child from any cause
    PO Box 5333
    Peoria AZ 85385-5333
    Phone: 888-455-6477 (toll-free); 623-979-1000
    Fax: 623-979-1001

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.

Hyalinosis, Inherited Systemic: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
ANTXR24q21​.21Anthrax toxin receptor 2ANTXR2 databaseANTXR2ANTXR2

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 Hyalinosis, Inherited Systemic (View All in OMIM)


Gene structure. At least two transcripts are annotated for ANTXR2. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Several pathogenic variants have been reported representing a variety of ethnic groups [Dowling et al 2003, Hanks et al 2003, El-Kamah et al 2010, Denadai et al 2012]:

Multiple affected individuals have had pathogenic variants involving the polycytosine tract in the region encoding the cytoplasmic domain, suggesting that this may be a hot spot for mutation.

Large intragenic multiexon insertion and deletion in ANTXR2 have been reported [Shieh et al 2006, Denadai et al 2012].

Normal gene product. Anthrax toxin receptor 2 is a protein of 488 amino acids including a cytoplasmic, transmembrane, and extracellular domain. The extracellular latter domain contains a von Willebrand factor type A domain. ANTXR2 is expressed in numerous tissues including heart, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon, and leukocytes. It is minimally or not expressed in the brain. It is induced during capillary morphogenesis and binds laminin and collagen IV via the von Willebrand domain. It is hypothesized that anthrax toxin receptor 2 plays an important role in basement membrane matrix homeostasis. Anthrax toxin receptor 2 has significant homology to tumor endothelium marker 8 (TEM8), which also acts as an anthrax receptor [Scobie et al 2003]. Antxr2 knockout mice had impaired parturition and myometrial histologic changes [Peters et al 2012]

Abnormal gene product. Abnormalities in the anthrax toxin receptor 2 protein affect anthrax toxin receptor 2-laminin interaction, likely affecting basement membrane homeostasis [Dowling et al 2003, Hanks et al 2003]. Abnormal protein may be retained in the endoplasmic reticulum [Deuquet et al 2011], and cellular studies using proteasome inhibitors are underway.


Literature Cited

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Chapter Notes

Revision History

  • 11 April 2013 (me) Comprehensive update posted live
  • 27 February 2008 (me) Review posted live
  • 5 May 2004 (la) Original submission
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