Hyaline fibromatosis syndrome is an autosomal recessive condition characterized by abnormal growth of hyalinized fibrous tissue usually affecting subcutaneous regions on the scalp, ears, neck, face, hands, and feet. The lesions appear as pearly papules or fleshy nodules. ... Hyaline fibromatosis syndrome is an autosomal recessive condition characterized by abnormal growth of hyalinized fibrous tissue usually affecting subcutaneous regions on the scalp, ears, neck, face, hands, and feet. The lesions appear as pearly papules or fleshy nodules. The severity is variable. Some individuals present in infancy and have additional visceral or systemic involvement, which can lead to early death. These patients may show intractable diarrhea and increased susceptibility to infection. Other patients have later onset of a milder disorder affecting only the face and digits. Additional features include gingival hypertrophy, progressive joint contractures resulting in severe limitation of mobility, osteopenia, and osteoporosis. Histologic analysis of skin lesions shows proliferation of spindle-shaped cells forming strands in a homogeneous and hyaline eosinophilic extracellular material in the dermis (summary by Denadai et al., 2012).
Puretic et al. (1962) described what they considered to be a novel connective tissue disorder. In addition to the proband, a brother and sister were probably affected, having died in infancy with painful flexural contractures of the elbows, ... Puretic et al. (1962) described what they considered to be a novel connective tissue disorder. In addition to the proband, a brother and sister were probably affected, having died in infancy with painful flexural contractures of the elbows, shoulder joints and knees, which developed at about 3 months of age. The proband also showed deformity of the face and skull, stunted growth, osteolysis of terminal phalanges, multiple large subcutaneous nodes, some calcified, dysseborrheic, sclerodermiform and atrophic changes of the skin, recurrent suppurative infections of the skin, eyes, nose and ears, and gingival fibromatosis. Ishikawa and Hori (1964) described a 2.5-year-old Japanese infant whose sib had died at 8 months, probably of the same condition. 'Systemic hyalinosis' was suggested as a designation. Kitano et al. (1972) reported the disorder in 2 sibs, and observed that cells from affected areas contained a metachromatic substance. Kitano (1976) reported an affected boy who was born of consanguineous parents. He had large tumors on the scalp and whitish nodules on the nape and sides of the neck. Hypertrophic gingivae and tumors at both commissures of the lips were illustrated. Histopathologic studies showed that the tumor cells were embedded in an amorphous eosinophilic ground substance. X-ray films showed numerous osteolytic and osteoclastic lesions of the skeleton. Aldred and Crawford (1987) gave a comprehensive review of 23 cases of juvenile hyaline fibromatosis from 17 families. Landing and Nadorra (1986) described a condition, which they called infantile systemic hyalinosis, in 4 female Mexican-American infants, including 2 sibs. The main features were early thickening and focal nodularity of the skin leading to reduced movement and joint contractures, gum hypertrophy, and osteoporosis. The infants failed to thrive and had diarrhea and recurrent infections. All had onset in the first week of life and died before age 20 months. Pathologic examination showed widespread deposits of hyaline material in skin, skeletal muscle, gastrointestinal tract, endocrine glands, and other locations. The condition was probably first described by Nezelof et al. (1978). Landing and Nadorra (1986) suggested that this infantile systemic disorder was distinct from juvenile systemic hyalinosis, which they considered to be the same as juvenile hyaline fibromatosis. Aldred and Crawford (1987) gave a comprehensive review of 23 cases from 17 families. Gorlin et al. (1990) emphasized the occurrence of flexion contractures and gingival fibromatosis. Bedford et al. (1991) described 2 severely affected unrelated children with painful flexion contractures of all the large joints, perianal granulomas, and recurrent infections from which both died at 19 months and 2 years. The parents of 1 of the children were consanguineous. Stucki et al. (2001) described a brother and sister who presented with infantile systemic hyalinosis at ages 3.5 and 2 months, respectively. Both patients had skin lesions and painful joint contractures. Electron microscopic studies showed increased amorphous mucoid or hyaline material in the skin, with a striking perivascular deposition suggestive of an intravascular origin. The authors concluded that their findings supported the hypothesis of autosomal recessive inheritance of this condition. Rahman et al. (2002) reported 2 Indian families in which 4 individuals had hyaline fibromatosis. The families were presumably unrelated, but originated from the same small village. The patients presented in early childhood with progressive development of multiple subcutaneous swellings and nodules on the scalp, face, extremities, and trunk. Large nodules on the hands and feet coincided with underlying articular cartilage. Other features included gingival fibromatosis and progressive severe joint contractures. Radiographs showed osteopenia or osteolysis, and skin biopsy showed excessive hyaline deposition. El-Kamah et al. (2010) reported 3 Egyptian sibs, born of consanguineous parents, with severe infantile-onset hyaline fibromatosis. The first child died of respiratory distress at age 3 days. The second child had multiple cutaneous swellings, painful joint contractures, gingival hypertrophy, repeated chest infections, and intractable diarrhea. He died at age 4 years of cardiac arrest. The third child had painful joint contractures and died at age 2 years from diarrhea. Genetic analysis identified a homozygous truncating mutation in the ANTXR2 gene (1074delT; 608041.0008). Denadai et al. (2012) reported a pair of sibs and 3 other unrelated patients, all of Brazilian origin, with hyaline fibromatosis syndrome. The sibs developed pearly skin papules on the face and neck and cutaneous nodules on the ears, scalp, and fingers at ages 3 and 8 months, respectively. The girl had recurrent diarrhea and failure to thrive in the first 2 years of life. Her brother developed numerous skin lesions all over the body, including some that coalesced to form plaques in the neck and gluteal regions. Both also had gingival hyperplasia and joint contractures. Two of the other patients also had severe failure to thrive, diarrhea, joint contractures followed by skin lesions, and gingival hyperplasia. The last patient was a 20-year-old man who was wheelchair-bound due to postural deformity and severe contractures of multiple joints. He had a history of pearly and nodular skin lesions, gingival hyperplasia, and joint contractures from the first months of life. Radiographs of the patients showed osteolytic bone lesions. Duodenal biopsy of 1 patient with diarrhea showed deposition of hyalinized material. Histologic analysis of the skin lesions showed proliferation of spindle cells without atypical features forming strands in a homogeneous and hyaline eosinophilic material within the dermis. The material was PAS-positive and diastase-resistant. Some of the lesions had ulcerated. Denadai et al. (2012) concluded that it is difficult to classify patients with this disorder into an infantile or juvenile form, and suggested using the term hyaline fibromatosis syndrome (HFS), which reflects variable severity. Denadai et al. (2012) proposed a 4-grade grading system of the disorder to reflect increasing severity, with grade 4 resulting in early death due to severe clinical decompensation. The authors emphasized that adequate healthcare in the newborn period is critical for survival.
Hanks et al. (2003) and Dowling et al. (2003) identified mutations in the CMG2 gene as the cause of both infantile-onset and juvenile-onset hyaline fibromatosis (608041.0001-608041.0007), indicating that these disorders are allelic and part of the same phenotypic ... Hanks et al. (2003) and Dowling et al. (2003) identified mutations in the CMG2 gene as the cause of both infantile-onset and juvenile-onset hyaline fibromatosis (608041.0001-608041.0007), indicating that these disorders are allelic and part of the same phenotypic spectrum.
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:...
DiagnosisClinical DiagnosisInherited 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 seem 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].TestingSkin 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 TestingGene. ANTXR2, the capillary morphogenesis gene-2, is the only gene in which mutations are currently known to cause inherited systemic hyalinosis. Clinical testing Table 1. Summary of Molecular Genetic Testing Used in Inherited Systemic HyalinosisView in own windowGene 1Test MethodMutations DetectedMutation Detection Frequency by Test Method 2Test AvailabilityANTXR2Sequence analysis Sequence variants 3 90% 4 ClinicalDeletion / duplication analysis 5Multiexonic deletion or insertionUnknown 61. See Table A. Genes and Databases for chromosome locus and protein name.2. The ability of the test method used to detect a mutation that is present in the indicated gene3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.4. Multiple mutations have been identified [Dowling et al 2003, Hanks et al 2003, El-Kamah et al 2010, Denadai et al 2012] (see Molecular Genetics).5. Testing that identifies deletions/duplications not readily 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. 6. Shieh et al [2006], Denadai et al [2012]Testing Strategy To confirm/establish the diagnosis in a probandSequence analysis of ANTXR2 should be pursued first.If no disease causing mutation is identified or if only a single heterozygous disease causing mutation is identified through sequence analysis, deletion/duplication analysis can be considered. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations 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 disease-causing mutations in the family Genetically Related (Allelic) DisordersNo phenotypes other than those discussed in this GeneReview are known to be associated with ANTXR2 mutations.
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....
Natural HistoryInherited 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].
Hanks et al [2003] reported on genotype/phenotype correlations in 17 families with features of either infantile systemic hyalinosis or JHF:...
Genotype-Phenotype CorrelationsHanks 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 mutations 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 mutations 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.
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:...
Differential DiagnosisThe 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) [OMIM 228000] 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 mutations 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. Winchester syndrome is characterized by short stature and osteolysis of the interphalangeal and metacarpal-phalangeal joints. Winchester syndrome has been proposed to be allelic with nodulosis-arthropathy-osteolysis syndrome (NAO), a disorder resulting from mutations in MMP2, the gene encoding matrix metalloproteinase-2. Torg syndrome has also been clinically classified as the same disorder as NAO. All three disorders lack the distinctive dermatologic features of inherited systemic hyalinosis [OMIM 259600]. 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) [OMIM 247100] 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. Mutations in ECM1, the gene encoding extracellular matrix protein 1, have been observed 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 mutations in COL1A1, the gene encoding collagen alpha-1(I) chain. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs in an individual diagnosed with inherited systemic hyalinosis, the following evaluations should be considered:...
ManagementEvaluations Following Initial DiagnosisTo 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 echocardiogramMedical genetics consultationTreatment of ManifestationsPain 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 thriveEarly 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 enteropathyChronic 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 seem 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/InfectionsInfections 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 ComplicationsAnesthesiologists 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].SurveillanceRoutine nutritional assessment is appropriate.Periodic assessment for gastrointestinal malabsorption may aid in optimizing nutritional status.Agents/Circumstances to AvoidThe role of surgery in management of lesions is unclear since lesions seem to recur. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDANTXR24q21.21Anthrax toxin receptor 2ANTXR2 homepage - Mendelian genesANTXR2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Hyalinosis, Inherited Systemic (View All in OMIM) View in own window 228600HYALINE FIBROMATOSIS SYNDROME; HFS 608041ANTHRAX TOXIN RECEPTOR 2; ANTXR2Normal allelic variants. At least two transcripts are annotated for ANTXR2 (see Table A, Gene Symbol). Pathologic allelic variants. Several mutations 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]: The milder phenotype, consistent with a diagnosis of juvenile hyaline fibromatosis, is more likely caused by mutations in the cytoplasmic domain (in-frame and missense) [Hanks et al 2003]. The more severe phenotype, consistent with early onset and death in infancy or early childhood, is more likely to be caused by missense and truncating mutations in the extracellular domain, although truncating mutations in the transmembrane and cytoplasmic domains may also result in the severe phenotype. Homozygous and compound heterozygote mutations have been reported [Dowling et al 2003, Hanks et al 2003, El-Kamah et al 2010, Denadai et al 2012]. Multiple affected individuals have had mutations 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.