Prognostic factors for wellbeing in patients with hyaline fibromatosis syndrome.

BACKGROUND: Hyaline fibromatosis syndrome (HFS) is a congenital disorder characterized by subcutaneous skin nodules, congenital multiple arthrogryposis, gingival hyperplasia, and chronic pain. The intellectual ability of patients with HFS is generally normal. This syndrome arises from variants of ANTXR2. Thus far, about 100 cases have been reported but few of these were reported from Japan. METHODS: This study reports five additional Japanese patients with genetically confirmed HFS, from unrelatd families, and discusses the clinical course and quality of life of these patients. RESULTS: At our last visit the ages of the patients were 3-19 years (the median age was 5 years). All the patients had arthrogryposis, skin nodules, and gingival hyperplasia, and four patients had chronic pain, all of which are distinctive, clinical characteristics of HFS. Four of the patients (80%) had pruritic skin nodules, and three experienced sleep disruptions due to pruritis. The visceral complications are an index of HFS severity. One patient in the present cohort had a mucosal abnormality without any gastrointestinal symptoms. CONCLUSION: Preventive and routine management of pruritis caused by skin nodules should be shared with the patient's family. Even asymptomatic patients might have endoscopic finding, which would be a soft marker that could predict the development of protein losing enteropathy.

Hyaline fibromatosis syndrome: a rare, yet recognizable syndrome.

BACKGROUND: Hyaline fibromatosis syndrome is a rare autosomal recessive disorder caused by ANTXR2 pathogenic variants. The disorder is characterized by the deposition of amorphous hyaline material in connective tissues. The hallmarks of the disease are joint contractures, generalized skin stiffness, hyperpigmented papules over extensor surfaces of joints, fleshy perianal masses, severe diarrhea, and gingival hypertrophy. The severity of the disease varies and prognosis is poor. No specific treatment is yet available. Most patients with the severe form of the condition pass away before the second year of age. In this study, we describe the clinical and molecular findings of a cohort of seven hyaline fibromatosis syndrome patients who were diagnosed and followed up at a single tertiary reference center in Turkey. METHODS: Genomic DNA was extracted by standard salting out method from peripheric blood samples of three patients. In one patient DNA extraction was performed on pathology slides since peripheric blood DNA was not available. All coding exons of the ANTXR2 were amplified and sequenced on ABI Prism 3500 Genetic Analyser. RESULTS: Sanger sequencing was performed in 3 patients and homozygous c.945T>G p.(Cys315Trp), c.1073dup p.(Ala359CysfsTer13), and c.1074del p.(Ala359HisfsTer50) variants were identified in ANTXR2. All patients passed away before the age of five years. CONCLUSIONS: HFS is a rare, progressive disorder with a broad phenotypic spectrum. HFS can be recognized easily with distinctive clinical features. Nevertheless, it has poor prognosis with increased mortality due to severe clinical decompensation.

Hyaline Fibromatosis Syndrome Diagnosed by Whole Genome Sequencing.

Hyaline fibromatosis syndrome is an extremely rare autosomal recessive condition caused by biallelic pathogenic variants in the ANTXR2 gene that leads to abnormal growth of hyalinized fibrous tissue. Severity ranges from life-threatening intractable diarrhea, recurrent infection, and acute pain to milder disease resulting in skin lesions and less severe contractures. Here, we report the case of a 3-month-old female who presented with joint contractures and severe pain followed by failure to thrive. Diagnosis via ultra-rapid whole genome sequencing allowed our team to provide appropriate care and anticipatory guidance for this patient and family.

Hypercalcemia as a rare presentation of hyaline fibromatosis syndrome from different Sudanese families: two case reports.

BACKGROUND: Hyaline fibromatosis syndrome is a rare progressive autosomal recessive connective tissue disorder caused by a mutation in the ANTXR2/CMG2 gene. According to its severity, patients may present with skin nodules or visceral infiltration, which carries a poor prognosis. Hypercalcemia has not been reported as a presenting feature of this syndrome. Stimulation of osteoclasts by inflammatory factors and immobilization--induced hypercalcemia have played role in the pathophysiology. To our knowledge, this is the first report of hypercalcemia-associated hyaline fibromatosis syndrome. CASE PRESENTATION: Here, we describe cases of two Sudanese patients, a boy aged 9 months and a girl aged 3.5 years with hypercalcemia as an associated presenting feature of hyaline fibromatosis syndrome. Other features include gingival hypertrophy, painful joint swellings, and restriction of movement, which was misdiagnosed as juvenile rheumatoid arthritis. Workup showed normal phosphate, normal to mildly elevated parathyroid hormone, low vitamin D 25. Genetic testing confirmed the mutation of the ANTXR2/CMG2 gene. Both patients responded well to medical therapy for hypercalcemia, but one of them with the severe form of juvenile hyaline fibromatosis died due to sepsis, while the other one has maintained normocalcemic status. CONCLUSIONS: These cases highlight the rare presentation of this syndrome and reflect the importance of biopsy and genetic testing in reaching the diagnosis, especially when the clinical presentation can mimic other inflammatory bone disorders. Calcium levels should be checked in such cases.

Juvenile Hyaline Fibromatosis: Report of a Case with a Novel ANTXR2 Gene Mutation.

BACKGROUND Juvenile hyaline fibromatosis is a rare autosomal recessive disorder with unknown prevalence characterized by abnormal development of hyalinized fibrous tissue usually in the skin, mucosa, bone, and often the internal organs. Here, we report the case of a 7-year-old girl from a family with ANTXR2 mutation confirming JHF. CASE REPORT The girl presented with multiple painless soft-tissue swellings affecting the ears, forehead, and scalp. Excisional biopsies of the masses reported positive immunohistochemical staining for collagen type VI in the extracellular matrix area, which indicated collagen VI accumulation. Genetic analysis was performed using whole-exome sequencing. The variants were further validated using Sanger sequencing in trio-based approach. We identified a novel mutation, c.1273_1293delinsTCTTGTGGGTTTGGCT in exon 15 of ANTXR2 gene, leading to a frameshift of the amino acid from codon 425 to all the rest of the amino acid chain (p.Pro425Serfs). The change of an encoded protein interrupted lysosome-mediated degradation of collagen VI. This finding was compatible with her parents whose genetic tests were both positive for the same heterogenous deletion/insertion mutation. The patient was treated with surgical excision of the tumor masses, which had to be repeated several times due to recurrences. CONCLUSIONS This novel mutation in exon 15 of the ANTXR2 gene may help improve understanding of genotype-phenotype correlations for this syndrome and provide the basis for diagnostic testing. A multidisciplinary team approach including genetic molecular testing is required for an accurate diagnosis and management of JHF for conducting genetic counseling for affected families as a part of holistic management.

Atypical Presentation of Juvenile Hyaline Fibromatosis of Hands.

Juvenile hyaline fibromatosis is a rare disorder characterized by an extracellular accumulation of hyaline deposit. In the extremities, lesions may remain quiescent or gradually increase in size, eventually resulting in skin ulceration. There is no curative treatment. Surgery may allow some recovery of function, but recurrence is possible. We report a case of juvenile hyaline fibromatosis in both hands of a 25-year-old man who required multiple surgical procedures to address problems with function, pain, and appearance.

Hyaline fibromatosis syndrome: a case presenting with gingival enlargement as the only clinical manifestation and a report of two new mutations in the ANTXR2 gene.

BACKGROUND: Hyaline fibromatosis syndrome (HFS) is a rare autosomal recessive disorder caused by mutations in the gene for anthrax toxin receptor-2 (ANTXR2). The clinical features of HFS include skin thickening with nodules, papules and plaques, gingival enlargement, joint stiffness and contractures, and systemic manifestations. Notably, in all patients with HFS reported in the literature, gingival enlargement has never occurred alone. CASE PRESENTATION: A case of a child with gingival enlargement as the only clinical manifestation, who was later diagnosed with HFS, is described. In this case, the absence of skin and joint lesions and other characteristic clinical presentations gave rise to a diagnostic problem. This uncommon condition was clinically indistinguishable from other diseases or conditions that presented with diffuse gingival enlargement. A definitive diagnosis of HFS was reached through genetic analysis. Trio whole exome sequencing revealed compound heterozygous mutations of ANTXR2 in this patient and two new mutations were reported. CONCLUSIONS: The findings of this case serve as an important reminder to clinicians. When dental practitioners encounter gingival manifestations of HFS without accompanied skin or joint involvement, there is a need to pay attention to the differential diagnosis and increase awareness of HFS.

Juvenile hyaline fibromatosis: A clinicopathological study of five cases.

Juvenile hyaline fibromatosis (JHF) is an extremely rare autosomal recessive disease that typically presents in infancy or early childhood. Largely due to the rarity, JHF is still not widely recognized by clinicians and pathologists in China. It is not uncommonly to misdiagnose the disease as other types of disorders. In this study, we present our experience with five cases of JHF to enhance the recognition of this rare but distinctive entity. There were 4 males and 1 female, with age at presentation ranging from 5 to 44 years. All patients presented with multiple subcutaneous nodular lesions of varying size in various parts of the body since birth or early childhood. Three patients also had joint involvement. Pathologically, the lesions were poorly circumscribed, located mainly in the dermis and subcutis. All five cases were characterized by abundant homogeneous hyaline-like matrix that differs sharply from the adjacent connective tissue, which stained strongly with periodic acid-Schiff (PAS) and was diastase resistant. Embedded within the eosinophilic glassy matrix were cords or small clusters of plump spindled to epithelioid cells, frequently with clear cytoplasm. Familiarity with the characteristic features of JHF is not only important in avoiding misdiagnosis but also essential for clinical management and prognostic evaluation.

Clinical Significance of Serum Soluble TNF Receptor I/II Ratio for the Differential Diagnosis of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome From Other Autoinflammatory Diseases.

Objectives: Genetic analysis of TNFRSF1A can confirm the diagnosis of tumor necrosis factor receptor-associated periodic syndrome (TRAPS), but interpretation of the pathogenesis of variants of unknown significance is sometimes required. The aim of this study was to evaluate the clinical significance of serum soluble tumor necrosis factor receptor type I (sTNFR-I)/II ratio to differentiate TRAPS from other autoinflammatory diseases. Methods: Serum sTNFR-I and sTNFR-II levels were measured using an enzyme-linked immunosorbent assay in patients with TRAPS (n = 5), familial Mediterranean fever (FMF) (n = 14), systemic juvenile idiopathic arthritis (s-JIA) (n = 90), and Kawasaki disease (KD) (n = 37) in the active and inactive phase, along with healthy controls (HCs) (n = 18). Results: In the active phase, the serum sTNFR-I/II ratio in patients with s-JIA, KD, and FMF was significantly elevated compared with that in HCs, whereas it was not elevated in patients with TRAPS. In the inactive phase, the serum sTNFR-I/II ratio in patients with s-JIA and FMF was significantly higher compared with that in HCs, and the ratio was lower in TRAPS patients than in patients with s-JIA and FMF. Conclusions: Low serum sTNFR-I/II ratio in the active and inactive phase might be useful for the differential diagnosis of TRAPS and other autoinflammatory diseases.

Hyaline fibromatosis syndrome: A case report.

Hyaline fibromatosis syndrome (HFS) is a rare monogenic disease inherited in an autosomal recessive pattern and characterized by hyaline deposits on the skin, mucosa, and multiple organs; osteoporosis; and joint contractures. This progressive condition is caused by mutations in the gene encoding the anthrax toxin receptor 2 protein (ANTXR2). HFS is a disabling disease, and patients suffer from progressive pain and disfiguring symptoms. There are few published case reports detailing oral findings in patients with this condition. The present case report describes a 4-year-old female patient who showed severe manifestations of HFS, emphasizing the oral manifestations, the histopathologic aspects of HFS, the molecular pathogenesis, and the interdisciplinary management of patients affected by this condition.

Juvenile hyaline fibromatosis: an unusual clinical presentation.

Juvenile hyaline fibromatosis is a recessive autosomal hereditary disorder characterized by abnormal growth of hyalinized fibrous tissue. Its clinical presentation is marked by tumors of the skin, bone lesions, joint contractures, and gingival hyperplasia. We report a localized form of juvenile hyaline fibromatosis, a rare disease with several cases reported in the worldwide literature. A 23-year-old man presented with multiple tumors, joint contractures, and osteolytic bone lesions, but without gingival hyperplasia in one year of follow-up. Although, the onset of this condition is commonly in early childhood with progression, his unusual clinical presentation began at eight years of age with late progression in adolescence.

Juvenile hyaline fibromatosis in siblings.

BACKGROUND: Juvenile Hyaline Fibromatosis is a rare autosomal recessive connective tissue disorder. CASE CHARACTERISTICS: Three year old girl with multiple facial nodules, gingival hypertrophy and multiple joint contractures. Her sibling, male child also had similar findings which was progressive and he died at 2 years. OUTCOME: Nodule biopsy showed extensively hyalinised dermis with PAS positivity. MESSAGE: Juvenile Hyaline Fibromatosis is a differential diagnosis for children presenting with multiple nodular lesions.

[Identification of novel compound heterozygous mutations in the ANTXR2 gene in a Chinese patient with juvenile hyaline fibromatosis].

OBJECTIVE: To identify pathogenic mutations of ANTXR2 gene in a patient with juvenile hyaline fibromatosis. METHODS: Genomic DNA was extracted from peripheral venous blood sample from the patient. All coding exons (exons 1-17) and splicing sites of the ANTXR2 gene were amplified with PCR. Potential mutations were detected with direct sequencing of the PCR products. 100 unrelated healthy subjects were used as the controls. CLUSTALX (1.81) was employed to analyze cross-species conservation of the mutant amino acid. Impact of the mutations was analyzed with software including SIFT, PolyPhen-2 and MutationTaster. RESULTS: A compound heterozygous mutation c.1074delT/c.1153G>C, was identified, among which c.1153G>C has not been reported previously and was predicted to be probably damaging. Both mutations were not found among the 100 healthy controls. CONCLUSION: The patient's condition may be attributed to the compound heterozygous mutations of c.1074delT and c.1153G>C of the ANTXR2 gene. Above results has facilitated molecular diagnosis for this patient.

Pulmonary hyalinosis in captive sugar gliders ( Petaurus breviceps).

Pulmonary hyalinosis is an idiopathic, typically incidental lesion of old dogs, characterized by multifocal aggregates of epithelioid and multinucleate macrophages that surround periodic acid-Schiff (PAS)-positive hyaline material in airways. Lung lesions resembling pulmonary hyalinosis were observed in 6 captive adult sugar gliders ( Petaurus breviceps; 5 females and 1 male) in a retrospective review of 18 autopsied animals. Clinical signs for 3 of the sugar gliders included lethargy, tachypnea, and dyspnea. At autopsy, 5 of 6 animals had comorbid lesions that were the primary cause of death. Gross pulmonary lesions were characterized by mildly firm, discolored, vaguely nodular areas of parenchyma. Histologic examination of the lung revealed granulomatous inflammation with intracellular and extracellular amphophilic hyaline bodies within alveoli and airways. Hyaline bodies were positive for PAS and oil red O staining, blue via crystal violet staining, and displayed birefringence under polarized light, similar to findings in dogs with pulmonary hyalinosis.

Infantile Systemic Hyalinosis Complicated with Right Atrial Thrombus and Pericardial Effusion in an Infant.

Infantile systemic hyalinosis (ISH) is a rare multisystem fatal autosomal recessive disorder that involves widespread deposition of hyaline on connective tissues and certain internal organs. The major manifestations include painful articular contractures, hyperpigmentation, subcutaneous nodules, gingival hypertrophy, failure to thrive secondary to protein-losing enteropathy, and osteolytic bone lesions. In this paper, we report a 12-month-old girl with ISH presenting with recurrent diarrhea, failure to thrive, and refractory infections. A molecular study identified a homozygous missense mutation, c.134T > C; p.L45P, in exon 1 of the anthrax toxin receptor 2 (ANTRX2) gene. Our patient passed through an eventful course that included septic shock, central line infections, right atrial thrombosis, and pericardial effusion. She incurred acute bronchiolitis due to respiratory syncytial virus infection, which led to her death. In conclusion, this case report highlights that severe and life-threatening morbidities and complications can be encountered in ISH, to which some management options can be applied.

Systemic Hyalinosis With Heterozygous CMG2 Mutations: A Case Report and Review of Literature.

Juvenile hyaline fibromatosis (JHF) is a rare autosomal recessive disorder characterized by hyalinizing fibrosis of the skin and internal organs. Clinical features include multiple papular skin lesions, gingival hyperplasia, joint contractures, and osteolytic bone lesions. The systemic variant of JHF, known as infantile systemic hyalinosis (ISH), has an early onset and poor prognosis. Histological examination of cutaneous lesions shows bland-appearing fibroblasts within amorphous eosinophilic hyaline depositions. JHF and infantile systemic hyalinosis form a clinical spectrum with higher mortality that is typically observed in systemic cases. Here, the authors present a case of systemic hyalinosis with a heterozygous mutation in CMG2 that resulted in improved survival.

Unusual cause for gum hypertrophy and skin nodules in a child.

Juvenile hyaline fibromatosis (JHF) is a rare progressive autosomal recessive disease that is characterised by papulonodular skin lesions, soft tissue masses, joint contractures, gingival hypertrophy and osteolytic bone lesions. We present an 18-month-old boy with JHF. This case demonstrates that JHF should be considered in the differential diagnosis when multiple subcutaneous nodules are observed in the face, head and neck. Gum hypertrophy with palatal nodules is unusual in JHF.