Juvenile Hyaline Fibromatosis

Background

This rare disease is characterized by a deposition of hyaline, a collagen-like substance, aberrantly synthesized by the cells of the connective tissue and deposited within many of the organs of the body. Typically, the hyaline is deposited within the skin, gingiva, joints, and bones. It is an autosomal recessive disorder.

OUTLINE

Epidemiology

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/Immunohistochemistry/Electron Microscopy

Differential Diagnosis

Prognosis and Treatment

Commonly Used Terms

EPIDEMIOLOGY CHARACTERIZATION

SYNONYMS Murray-Puretic syndrome
Molluscum fibrosum
Systemic hyalinosis

INCIDENCE Very rare

AGE RANGE-MEDIAN Most are childhood though adult cases have been reported

SEX (M:F)
Equal

PATHOGENESIS CHARACTERIZATION

COLLAGEN SYNTHESIS, ABERRANT

Purification and structural analysis of extracellular matrix of a skin tumor from a patient with juvenile hyaline fibromatosis.

Katagiri K, Takasaki S, Fujiwara S, Kayashima K, Ono T, Shinkai H.

Department of Dermatology, Oita Medical University, Japan.
J Dermatol Sci 1996 Oct;13(1):37-48 Abstract quote
Juvenile hyaline fibromatosis is a rare mesenchymal dysplasia that is inherited in an autosomal recessive fashion. The histological features of the tumor-like lesions are characterized by the deposition of amorphous hyaline material in the extracellular spaces of the dermis and soft tissues.

We have analyzed the hyaline substance in a specimen of a skin tumor obtained from a 4-year-old Japanese girl with juvenile hyaline fibromatosis. It was found to consist mainly of type VI collagen; a small amount of type I collagen was also present. These components were separated by DEAE-cellulose ion-exchange chromatography under reducing conditions.

The ratio of the dry weights of type I and type VI collagen was 1:4. Of the three chains of type VI collagen (alpha 1(VI), alpha 2(VI) and alpha 3(VI)), alpha 3(VI) was the most abundant. Glycosaminoglycans in the tumor tissue comprised dermatan sulfate, chondroitin sulfate and hyaluronan, with dermatan sulfate predominating. In contrast, hyaluronan is the most abundant in normal skin.

Juvenile hyaline fibromatosis: impaired collagen metabolism in human skin fibroblasts.

Breier F, Fang-Kircher S, Wolff K, Jurecka W
Department of Dermatology, Lainz Municipal Hospital, Vienna, Austria.

Arch Dis Child 1997 Nov;77(5):436-40 Abstract quote
Juvenile hyaline fibromatosis (JHF) is inherited as a fatal autosomal recessive disorder characterised by multiple tumorous mucocutaneous proliferations. In this paper a 14 month old girl with JHF is described. For this condition, a malfunction of collagen synthesis is considered as the pathogenetic cause.

Recently published data have revealed an absent band for type III collagen (TIIIC) chain in western blot studies of clinically unaffected JHF skin. Therefore supernatants of skin fibroblast cell cultures, obtained from normal human skin, were analysed for type 1 collagen (TIC) and TIIIC metabolites by radioimmunoassays.

Besides the typical morphological connective tissue changes in the skin lesions, TIC synthesis and degradation were found increased in JHF fibroblasts compared with control fibroblasts. In contrast, TIIIC overall metabolism was significantly reduced by 36% compared with controls.

LABORATORY/RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION

RADIOLOGIC

Juvenile hyalin fibromatosis.

Kitano Y

Arch Dermatol 1976 Jan;112(1):86-8 Abstract quote

A boy had multiple large tumors on the scalp, whitish nodules on the nape and both sides of the neck, hypertrophic gingiva, and severe flexural contractures of hip and knee joints. The histopathologic structure of the tumor was characteristic of juvenile hyalin fibromatosis.

The tumor cells were embedded in an amorphous eosinophillic ground substance. X-ray films revealed numerous osteolytic and osteociastic lesions that are important findings in the study of this disease.

LABORATORY MARKERS

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

GENERAL

Juvenile hyaline fibromatosis: clinical heterogeneity in three patients.

Mancini GM, Stojanov L, Willemsen R, Kleijer WJ, Huijmans JG, van Diggelen OP, de Klerk JB, Vuzevski VD, Oranje AP.

Department of Clinical Genetics, Department of Pathology, Erasmus University, Rotterdam, The Netherlands.
Dermatology 1999;198(1):18-25 Abstract quote
BACKGROUND: Systemic hyalinoses are genetic generalized fibromatoses characterized by an accumulation of hyalin in the dermis. Two distinctive syndromes are recognized in the literature: infantile systemic hyalinosis (ISH) and juvenile hyaline fibromatosis (JHF). ISH and JHF are sometimes difficult to separate since they show significant overlap.

OBSERVATIONS: We report on 3 children from two unrelated families suffering from JHF. The first child is severely handicapped by joint contracture, massive hyperplasia of the gingivae, diffuse skin papules and subcutaneous nodules occupying the scalp, face, perianal area, palms, soles and chest. At the same age, the second child only shows pearly skin papules on the face, groin and perianal area and gingival hyperplasia without joint stiffness or any other subjective complaint. The third patient, a brother of the second child, developed mild skin abnormalities by the end of the first year. The occurrence in siblings and consanguinity in the second family suggests autosomal recessive inheritance. Histological skin examination in the 3 cases showed hyaline deposition in the dermis and abnormal ultrastructure of fibroblasts. Biochemical findings showed mucopolysaccharide abnormalities in both families.

CONCLUSION: Our patients do not only illustrate the different expressions of JHF but also show some overlap with ISH, suggesting a common cause for both disorders. Genetic studies will finally answer this question.

Two siblings with juvenile hyaline fibromatosis: case reports and review of the literature.

Keser G, Karabulut B, Oksel F, Calli C, Ustun EE, Akalin T, Kocanaogullari H, Gumudis G, Doganavsargil E.

Department of Rheumatology, Ege University, Izmir, Turkey.
Clin Rheumatol 1999;18(3):248-52 Abstract quote
In this paper, we describe two siblings with Juvenile Hyaline Fibromatosis (JHF) who were diagnosed at the age of 34 and 29 years respectively. JHF is a very congenital disease, mainly diagnosed in the first few years of life, with less than 40 published cases in literature.

All the main clinical features of this syndrome, which may be summarised as multiple subcutaneous tumours, marked gingival hypertrophy, flexion contractures and osteolytic lesions were present in both of these cases. Clinical, radiological and histological differential diagnosis of JHF were made. Recent information about histopathology, treatment and prognosis of JHF was also reviewed.

Juvenile hyaline fibromatosis.

Larralde M, Santos-Munoz A, Calb I, Magarinos C.

Pediatric Dermatology Division, Ramos Mejia Hospital, Buenos Aires, Argentina
Pediatr Dermatol 2001 Sep-Oct;18(5):400-2 Abstract quote
Juvenile hyaline fibromatosis (JHF) is a rare autosomal recessive disease with onset in infancy or early childhood. It is characterized by papulonodular skin lesions, soft tissue masses, gingival hypertrophy, and flexion contractures of the large joints. The light and electron microscopic features are very distinctive.

Here we report an 8-month-old boy with characteristic stiffness of the knees and elbows and pink confluent papules on the paranasal folds, and periauricular and perianal regions. He also had hard nodules all over the scalp and around the mouth, and severe gingival hypertrophy. Histologic and ultrastructural features were typical of JHF. Clinical features, pathology, and physiology are discussed.

VARIANTS

ADULT

Juvenile hyaline fibromatosis: a report of two unrelated adult sibling cases and a literature review.

Senzaki H, Kiyozuka Y, Uemura Y, Shikata N, Ueda S, Tsubura A.

Department of Pathology, Kansai Medical University, Moriguchi, Japan.
Pathol Int 1998 Mar;48(3):230-6 Abstract quote
Two unrelated adult sibling cases (36- and 32-year-old females) of juvenile hyaline fibromatosis are presented.

The parents of one of these patients were non-consanguineous but natives of a small island, and one elder sister among four siblings was affected with the same disease. The parents of the other patient were consanguineous, and one other sibling suffered from the identical disease. Both patients presented with multiple subcutaneous nodules, which they had had since infancy, and had undergone numerous surgical excisions. Light microscopy examination of skin lesions from both patients showed identical histology; an abundance of a homogenous, amorphous, eosinophilic extracellular matrix in which spindle-shaped cells were embedded. Electron microscopically, the spindle-shaped cells had hypertrophic Golgi apparatus and dilated, rough endoplasmic reticulum. Fine fibrillar and granular material-filled structures, the contents of which were occasionally released into the extracellular matrix, were also seen.

Immunohistochemically, the spindle-shaped cells were vimentin-positive but negative for alpha-smooth muscle actin and S-100 protein, and the hyaline ground substance was positive for type I and type III collagen but negative for type II and type IV collagen and tenascin. Matrix metalloproteinase-1, -2, and -9, and tissue inhibitor of matrix metalloproteinase (TIMP)-2 was positive but TIMP-1 was negative. A review of 39 cases of juvenile hyaline fibromatosis in the literature is also presented. In summary, skin lesions may be the most outstanding symptoms of juvenile hyaline fibromatosis, but joint contracture and gingival hypertrophy precede the skin manifestation.

SKULL CHANGES

Juvenile hyaline fibromatosis with skull-encephalic anomalies: a case report and review of the literature.

Gilaberte Y, Gonzalez-Mediero I, Lopez Barrantes V, Zambrano A.

Department of Dermatology, Hospital Nacional Infantil Nino Jesus, Madrid, Spain.
Dermatology 1993;187(2):144-8 Abstract quote
We report a case of juvenile hyaline fibromatosis. Besides the typical features of this syndrome, skull and encephalic abnormalities, not previously mentioned, are described. Clinical and microscopic characteristics, therapeutic possibilities and different theories concerning histopathogenesis are discussed.

HISTOLOGICAL TYPES CHARACTERIZATION

GENERAL

Fibromatosis hyalinica multiplex (juvenile hyalin fibromatosis). Light microscopic, electron microscopic, immunohistochemical, and biochemical findings.

Remberger K, Krieg T, Kunze D, Weinmann HM, Hubner G.
Cancer 1985 Aug 1;56(3):614-24 Abstract quote
Fibromatosis hyalinica multiplex juvenilis (juvenile hyalin fibromatosis) is a very rare mesenchymal dysplasia, probably inherited as an autosomal-recessive trait.

Two nonrelated cases are reported. Among the clinical features, the most impressive lesions are multiple slowly growing subcutaneous nodules, hypertrophic gingiva, flexural contractures with joint stiffness and radiolucent bone destructions. Light microscopic examination of the nodules reveals tumor-like deposits of an amorphous hyaline ground substance with delicate staining properties situated partly between cellular and vascular areas. Ultrastructural characteristics are cystic, dilated rough endoplasmatic reticulum and cystic Golgi vesicles which contain a fine fibrillar material that is also found in the ground substance.

Immunohistochemical examination shows collagen type I and type III in the hyaline material, but not type II and type IV. Quantitative biochemical investigation reveals a normal ratio of collagen types I and III.

Juvenile hyaline fibromatosis. A histologic and histochemical study.

Mayer-da-Silva A, Poiares-Baptista A, Guerra Rodrigo F, Teresa-Lopes M.

Department of Dermatology, University Medical School of Lisbon, Hospital de Santa Maria, Portugal.
Arch Pathol Lab Med 1988 Sep;112(9):928-31 Abstract quote
Histochemical and routine light microscopic studies were performed in nodular skin lesions excised from one patient with juvenile hyaline fibromatosis.

The lesions had different times of evolution. Recent lesions showed a high density of fibroblastlike cells embedded in an amorphous matrix of glycoproteins, hyaluronic acid, and small amounts of chondroitin sulfates A and C and of dermatan sulfate. The progressive enlargement of the lesions was due to an increase in the amount of intercellular matrix produced by the cells that progressively displayed a pattern of peripheral stratification. In the older lesions, the matrix was mainly composed by chondroitin sulfates A and C.

We suggest that juvenile hyaline fibromatosis represents a disease of the connective tissue with progressive abnormal differentiation to chondroid tissue.

VARIANTS

CALCOSPHERULES

Calcospherules associated with juvenile hyaline fibromatosis.

Ko CJ, Barr RJ.
Am J Dermatopathol 2003 Feb;25(1):53-6 Abstract quote
Juvenile hyaline fibromatosis is a rare autosomal recessive genodermatosis that manifests with 1 to 5 cm skin tumors, gingival hyperplasia, osteolytic bone lesions, and joint contractures. The skin tumors are most often located on the head and periarticular extremities.

A case of juvenile hyaline fibromatosis with typical skin tumors that on biopsy exhibited basophilic calcospherules is presented. Although noted in a single case, these structures may be a novel, yet helpful, diagnostic marker.

SPECIAL STAINS/IMMUNOPEROXIDASE/
OTHER CHARACTERIZATION

SPECIAL STAINS PAS positive and Alcian blue positive
Negative for Congo red, elastic, or collagen stains

IMMUNOPEROXIDASE

Juvenile Hyaline Fibromatosis: Morphologic, Immunohistochemical, and Ultrastructural Study of Three Siblings

Abdul Haleem, F.R.C.Path.; Hindi N. Al-Hindi, M.D.; Muna Al Juboury, F.R.C.Path.; Hussa Al Husseini, M.R.C.Path.; Abdulaziz Al Ajlan, M.R.C.Path.
Am J Dermatopathol 2002; 24(3):218-224 Abstract quote

Juvenile hyaline fibromatosis (JHF) is a rare hereditary disease characterized by the deposition of hyaline ground substance, which is described as fibrillogranular material on electron microscopy. Approximately 65 cases have been reported to date in the English language literature.

We add 3 new cases of children presenting with multiple subcutaneous nodules. We have described the light microscopic, electron microscopic, and immunohistochemical features of these nodules. The characteristic chondroid appearance on light microscopy is imparted by large peripheral vesicles in the stromal cell cytoplasm. Ultrastructurally, the fibroblasts have shown evidence of defective synthesis of collagen, which is then deposited as fibrillogranular material in the matrix. Immunohistochemical studies have shown CD68+ macrophages and multinucleated histiocytic giant cells in all five specimens from our 3 cases. As far as we know, the presence of giant cells has not been reported in the literature.

The main purposes of this report are to highlight the presence of macrophages as a constant constituent of the stromal cells in JHF and to review the literature on this subject.

ELECTRON MICROSCOPY

Systemic hyalinosis (juvenile hyaline fibromatosis). Ultrastructure of the hyaline with particular reference to the cross-banded structure.

Ishikawa H, Maeda H, Takamatsu H, Saito Y.
Arch Dermatol Res 1979 Jun 25;265(2):195-206 Abstract quote
Systematic hyalinosis (juvenile hyaline fibromatosis) is characterized by hyalinized skin lesions. Electron microscopic examination of a hyalinized skin tumor from a 19-year-old man with this syndrome revealed that the hyaline was composed of ruthenium red-positive ultrastructures (granules, filaments, and a kind of cross-banded structure), indicating the presence of glycosamino-glycan or glycoprotein, and a small number of thin collagen fibrils.

Using a new ruthenium red staining method combined with an enzymatic digestion procedure, it was demonstrated that the cross-banded structure and granules consisted of chondroitin sulfate-proteoglycan and/or glycoprotein, and that the cross-banded structure is probably a noncollageneous aggregate of the granules attached to the parallel-arranged filaments of hyaluronic acid-like nature.

Juvenile hyaline fibromatosis: ultrastructural study.

Winik BC, Boente MC, Asial R.

Laboratorio de Microscopia electronica del Noroeste Argentino, CONICET, Tucuman, Argentina.
Am J Dermatopathol 1998 Aug;20(4):373-8 Abstract quote
Juvenile hyaline fibromatosis is a multisystemic disorder characterized by a triad of cephalic fibrous outgrowths, gingival hyperplasia, and flexion contractures. The aim of this study was to find new ultrastructural features that could be useful for differentiating this entity from other types of fibromatosis.

Mucosal lesions processed for light and electron microscopy by routine techniques showed hyperactive-appearing spindle-shaped fibroblasts and dysplastic mesenchymal cells. Dilated rough endoplasmic reticulum, prominent Golgi complexes, and multivesicular bodies as well as single membrane vesicles filled with fibrillogranular material were seen within the cytoplasm of dysplastic mesenchymal cells. Many fibrillogranular vesicles contained smaller vesicles. There were also invaginations of the cell membrane that contained fibrillogranular material similar to that seen in the single membrane vesicles, suggesting engulfment of an extracellular substance.

The stroma contained both normal and serrated collagen fibrils, microfibrils, and two types of fibrillogranular material, one of them with a characteristic banding pattern.

Our clinical and histopathologic findings resemble those previously described in cases of infantile systemic hyalinosis and juvenile hyaline fibromatosis. So many features of these two conditions overlap that it is difficult not to consider them as parts of a spectrum of the same disorder.

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

INFANTILE SYSTEMIC HYALINOSIS

Infantile systemic hyalinosis: report of four cases of a disease, fatal in infancy, apparently different from juvenile systemic hyalinosis.

Landing BH, Nadorra R.
Pediatr Pathol 1986;6(1):55-79 Abstract quote
Four female Mexican-American infants, two siblings, had widespread deposit of hyaline material in skin, gastrointestinal tract, adrenals, urinary bladder, ovaries, skeletal muscles, thymus, parathyroids, and other loci.

Clinical features included thickness and focal nodularity of skin, relatively short limbs and neck, gum hypertrophy, hypotonia and reduced movement, joint contractures, osteoporosis, growth failure, diarrhea, and recurrent infections. Clinical onset was in the first week, and all 4 patients died by age 20 months.

Infantile systemic hyalinosis appears to be a specific, presumably autosomal recessive, genetic disease, differing from the disorder called systemic hyalinosis, juvenile hyaline fibromatosis, or Puretic syndrome. The biochemical defect and the pathogenetic mechanisms responsible for the pathologic and clinical features of this condition remain to be established.

Infantile systemic hyalinosis: newly recognized disorder of collagen?

Glover MT, Lake BD, Atherton DJ.

Department of Dermatology, Hospital for Sick Children, London, England.
Pediatrics 1991 Feb;87(2):228-34 Abstract quote
Four infants with stiff skin and painful joint contractures in the first few months of life are described. Other features included small papules, particularly on the face and trunk, perianal nodules, hyperpigmentation over the metacarpophalangeal joints and over the malleoli, gingival hyperplasia, persistent diarrhea, and failure to thrive. Two of these infants died before the age of 18 months. In each case hyaline material was found in the papillary dermis. Ultrastructurally, there was a distinctive fibrillogranular appearance in which a banding pattern could be observed.

This material was also found within membrane-bound vacuoles in macrophages and fibroblasts. It had an appearance and localization identical with that of collagen type VI.

These features are similar to those reported in juvenile hyaline fibromatosis. It is believed that these infants have a closely related, but nonetheless distinctive, inherited disorder of collagen.

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSTIC FACTORS Most die within childhood or infancy
Rare reports of long survival

A 19-year follow-up of multiple juvenile hyaline fibromatosis.

Woyke S, Domagala W, Markiewicz C.
J Pediatr Surg 1984 Jun;19(3):302-4 Abstract quote
Nineteen years observation of two siblings with multiple juvenile hyaline fibromatosis is presented. This entity was described 14 years ago. It is concluded that this disease can be effectively controlled by surgical excision of all newly discovered subcutaneous tumors.

Juvenile hyaline fibromatosis. A 15-year follow-up.

Quintal D, Jackson R.
Arch Dermatol 1985 Aug;121(8):1062-3 Abstract quote
A 37-year-old man was seen because of juvenile hyaline fibromatosis that had been present since he was 2 to 3 years old. His case illustrates the progressive nature of the disease, and during the years attempts to treat the condition were as mutilating in some cases as the disease itself.

Juvenile hyaline fibromatosis: a report of two severe cases.

Bedford CD, Sills JA, Sommelet-Olive D, Boman F, Beltramo F, Cornu G
Royal Liverpool Children's Hospital, England.
J Pediatr 1991 Sep;119(3):404-10 Abstract quote
Two unrelated children with a severe form of juvenile hyaline fibromatosis are described. In addition to painful flexion contractures of all of the large joints, oral and skin lesions, and typical radiologic appearance of osteolytic defects, both girls had marked growth retardation and recurrent infections.

Both children died in early infancy of overwhelming infection.

Juvenile hyaline fibromatosis. Case report with five years' follow-up.

Miyake I, Tokumaru H, Sugino H, Tanno M, Yamamoto T.

Department of Plastic Surgery, School of Medicine, Juntendo University, Saitama, Japan.

Am J Dermatopathol 1995 Dec;17(6):584-90 Abstract quote
Juvenile hyaline fibromatosis (JHF) is a rare hereditary disorder named by Drescher et al. in 1969. As recently as 1985, only 30 cases had been reported worldwide. We report the case of a 9-year-old girl who was diagnosed with JHF at age 3 and has been closely followed since.

She initially had slowly growing multiple soft tumors over her entire body as well as hypertrophic gingiva and mild bone deformities. She was originally misdiagnosed with infantile myofibromatosis at age 3. However, at age 6, because of the light and electron microscopic findings of the tumors, she was diagnosed as having JHF. Currently, at age 9, she has nodular lesions developing over her body as well as bone changes that are progressing with no evidence of regression.

MALIGNANCY

Juvenile hyaline fibromatosis complicated with oral squamous cell carcinoma: a case report.

Kawasaki G, Yanamoto S, Mizuno A, Fujita S.

First Department of Oral and Maxillofacial Surgery, Nagasaki University School of Dentistry, Japan.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001 Feb;91(2):200-4 Abstract quote
A 45-year-old woman was referred because of swelling of the palate, gingival hypertrophy, and multiple cutaneous tumors. She had many cutaneous tumors, which covered most of her body, and she also displayed contractures of the major joints. Maxillary and mandibular gingival hypertrophy, malposition of the teeth, and swelling of the hard palate were the oral findings.

The histopathologic features of the cutaneous and gingival tumors were consistent with hyaline fibromatosis, and the swelling of the palate proved to be a squamous cell carcinoma. The carcinoma was treated with tegafur/uracil and seemed to respond to this therapy.

Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Weedon D. Weedon's Skin Pathology. Churchill Livingstone. 1997.
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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Last Updated 2/7/2003

PATHOGENESIS	CHARACTERIZATION
COLLAGEN SYNTHESIS, ABERRANT
Purification and structural analysis of extracellular matrix of a skin tumor from a patient with juvenile hyaline fibromatosis. Katagiri K, Takasaki S, Fujiwara S, Kayashima K, Ono T, Shinkai H. Department of Dermatology, Oita Medical University, Japan.	J Dermatol Sci 1996 Oct;13(1):37-48 Abstract quote Juvenile hyaline fibromatosis is a rare mesenchymal dysplasia that is inherited in an autosomal recessive fashion. The histological features of the tumor-like lesions are characterized by the deposition of amorphous hyaline material in the extracellular spaces of the dermis and soft tissues. We have analyzed the hyaline substance in a specimen of a skin tumor obtained from a 4-year-old Japanese girl with juvenile hyaline fibromatosis. It was found to consist mainly of type VI collagen; a small amount of type I collagen was also present. These components were separated by DEAE-cellulose ion-exchange chromatography under reducing conditions. The ratio of the dry weights of type I and type VI collagen was 1:4. Of the three chains of type VI collagen (alpha 1(VI), alpha 2(VI) and alpha 3(VI)), alpha 3(VI) was the most abundant. Glycosaminoglycans in the tumor tissue comprised dermatan sulfate, chondroitin sulfate and hyaluronan, with dermatan sulfate predominating. In contrast, hyaluronan is the most abundant in normal skin.
Juvenile hyaline fibromatosis: impaired collagen metabolism in human skin fibroblasts. Breier F, Fang-Kircher S, Wolff K, Jurecka W Department of Dermatology, Lainz Municipal Hospital, Vienna, Austria.	Arch Dis Child 1997 Nov;77(5):436-40 Abstract quote Juvenile hyaline fibromatosis (JHF) is inherited as a fatal autosomal recessive disorder characterised by multiple tumorous mucocutaneous proliferations. In this paper a 14 month old girl with JHF is described. For this condition, a malfunction of collagen synthesis is considered as the pathogenetic cause. Recently published data have revealed an absent band for type III collagen (TIIIC) chain in western blot studies of clinically unaffected JHF skin. Therefore supernatants of skin fibroblast cell cultures, obtained from normal human skin, were analysed for type 1 collagen (TIC) and TIIIC metabolites by radioimmunoassays. Besides the typical morphological connective tissue changes in the skin lesions, TIC synthesis and degradation were found increased in JHF fibroblasts compared with control fibroblasts. In contrast, TIIIC overall metabolism was significantly reduced by 36% compared with controls.

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
Juvenile hyaline fibromatosis: clinical heterogeneity in three patients. Mancini GM, Stojanov L, Willemsen R, Kleijer WJ, Huijmans JG, van Diggelen OP, de Klerk JB, Vuzevski VD, Oranje AP. Department of Clinical Genetics, Department of Pathology, Erasmus University, Rotterdam, The Netherlands.	Dermatology 1999;198(1):18-25 Abstract quote BACKGROUND: Systemic hyalinoses are genetic generalized fibromatoses characterized by an accumulation of hyalin in the dermis. Two distinctive syndromes are recognized in the literature: infantile systemic hyalinosis (ISH) and juvenile hyaline fibromatosis (JHF). ISH and JHF are sometimes difficult to separate since they show significant overlap. OBSERVATIONS: We report on 3 children from two unrelated families suffering from JHF. The first child is severely handicapped by joint contracture, massive hyperplasia of the gingivae, diffuse skin papules and subcutaneous nodules occupying the scalp, face, perianal area, palms, soles and chest. At the same age, the second child only shows pearly skin papules on the face, groin and perianal area and gingival hyperplasia without joint stiffness or any other subjective complaint. The third patient, a brother of the second child, developed mild skin abnormalities by the end of the first year. The occurrence in siblings and consanguinity in the second family suggests autosomal recessive inheritance. Histological skin examination in the 3 cases showed hyaline deposition in the dermis and abnormal ultrastructure of fibroblasts. Biochemical findings showed mucopolysaccharide abnormalities in both families. CONCLUSION: Our patients do not only illustrate the different expressions of JHF but also show some overlap with ISH, suggesting a common cause for both disorders. Genetic studies will finally answer this question.
Two siblings with juvenile hyaline fibromatosis: case reports and review of the literature. Keser G, Karabulut B, Oksel F, Calli C, Ustun EE, Akalin T, Kocanaogullari H, Gumudis G, Doganavsargil E. Department of Rheumatology, Ege University, Izmir, Turkey.	Clin Rheumatol 1999;18(3):248-52 Abstract quote In this paper, we describe two siblings with Juvenile Hyaline Fibromatosis (JHF) who were diagnosed at the age of 34 and 29 years respectively. JHF is a very congenital disease, mainly diagnosed in the first few years of life, with less than 40 published cases in literature. All the main clinical features of this syndrome, which may be summarised as multiple subcutaneous tumours, marked gingival hypertrophy, flexion contractures and osteolytic lesions were present in both of these cases. Clinical, radiological and histological differential diagnosis of JHF were made. Recent information about histopathology, treatment and prognosis of JHF was also reviewed.
Juvenile hyaline fibromatosis. Larralde M, Santos-Munoz A, Calb I, Magarinos C. Pediatric Dermatology Division, Ramos Mejia Hospital, Buenos Aires, Argentina	Pediatr Dermatol 2001 Sep-Oct;18(5):400-2 Abstract quote Juvenile hyaline fibromatosis (JHF) is a rare autosomal recessive disease with onset in infancy or early childhood. It is characterized by papulonodular skin lesions, soft tissue masses, gingival hypertrophy, and flexion contractures of the large joints. The light and electron microscopic features are very distinctive. Here we report an 8-month-old boy with characteristic stiffness of the knees and elbows and pink confluent papules on the paranasal folds, and periauricular and perianal regions. He also had hard nodules all over the scalp and around the mouth, and severe gingival hypertrophy. Histologic and ultrastructural features were typical of JHF. Clinical features, pathology, and physiology are discussed.
VARIANTS
ADULT
Juvenile hyaline fibromatosis: a report of two unrelated adult sibling cases and a literature review. Senzaki H, Kiyozuka Y, Uemura Y, Shikata N, Ueda S, Tsubura A. Department of Pathology, Kansai Medical University, Moriguchi, Japan.	Pathol Int 1998 Mar;48(3):230-6 Abstract quote Two unrelated adult sibling cases (36- and 32-year-old females) of juvenile hyaline fibromatosis are presented. The parents of one of these patients were non-consanguineous but natives of a small island, and one elder sister among four siblings was affected with the same disease. The parents of the other patient were consanguineous, and one other sibling suffered from the identical disease. Both patients presented with multiple subcutaneous nodules, which they had had since infancy, and had undergone numerous surgical excisions. Light microscopy examination of skin lesions from both patients showed identical histology; an abundance of a homogenous, amorphous, eosinophilic extracellular matrix in which spindle-shaped cells were embedded. Electron microscopically, the spindle-shaped cells had hypertrophic Golgi apparatus and dilated, rough endoplasmic reticulum. Fine fibrillar and granular material-filled structures, the contents of which were occasionally released into the extracellular matrix, were also seen. Immunohistochemically, the spindle-shaped cells were vimentin-positive but negative for alpha-smooth muscle actin and S-100 protein, and the hyaline ground substance was positive for type I and type III collagen but negative for type II and type IV collagen and tenascin. Matrix metalloproteinase-1, -2, and -9, and tissue inhibitor of matrix metalloproteinase (TIMP)-2 was positive but TIMP-1 was negative. A review of 39 cases of juvenile hyaline fibromatosis in the literature is also presented. In summary, skin lesions may be the most outstanding symptoms of juvenile hyaline fibromatosis, but joint contracture and gingival hypertrophy precede the skin manifestation.
SKULL CHANGES
Juvenile hyaline fibromatosis with skull-encephalic anomalies: a case report and review of the literature. Gilaberte Y, Gonzalez-Mediero I, Lopez Barrantes V, Zambrano A. Department of Dermatology, Hospital Nacional Infantil Nino Jesus, Madrid, Spain.	Dermatology 1993;187(2):144-8 Abstract quote We report a case of juvenile hyaline fibromatosis. Besides the typical features of this syndrome, skull and encephalic abnormalities, not previously mentioned, are described. Clinical and microscopic characteristics, therapeutic possibilities and different theories concerning histopathogenesis are discussed.

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
Fibromatosis hyalinica multiplex (juvenile hyalin fibromatosis). Light microscopic, electron microscopic, immunohistochemical, and biochemical findings. Remberger K, Krieg T, Kunze D, Weinmann HM, Hubner G.	Cancer 1985 Aug 1;56(3):614-24 Abstract quote Fibromatosis hyalinica multiplex juvenilis (juvenile hyalin fibromatosis) is a very rare mesenchymal dysplasia, probably inherited as an autosomal-recessive trait. Two nonrelated cases are reported. Among the clinical features, the most impressive lesions are multiple slowly growing subcutaneous nodules, hypertrophic gingiva, flexural contractures with joint stiffness and radiolucent bone destructions. Light microscopic examination of the nodules reveals tumor-like deposits of an amorphous hyaline ground substance with delicate staining properties situated partly between cellular and vascular areas. Ultrastructural characteristics are cystic, dilated rough endoplasmatic reticulum and cystic Golgi vesicles which contain a fine fibrillar material that is also found in the ground substance. Immunohistochemical examination shows collagen type I and type III in the hyaline material, but not type II and type IV. Quantitative biochemical investigation reveals a normal ratio of collagen types I and III.
Juvenile hyaline fibromatosis. A histologic and histochemical study. Mayer-da-Silva A, Poiares-Baptista A, Guerra Rodrigo F, Teresa-Lopes M. Department of Dermatology, University Medical School of Lisbon, Hospital de Santa Maria, Portugal.	Arch Pathol Lab Med 1988 Sep;112(9):928-31 Abstract quote Histochemical and routine light microscopic studies were performed in nodular skin lesions excised from one patient with juvenile hyaline fibromatosis. The lesions had different times of evolution. Recent lesions showed a high density of fibroblastlike cells embedded in an amorphous matrix of glycoproteins, hyaluronic acid, and small amounts of chondroitin sulfates A and C and of dermatan sulfate. The progressive enlargement of the lesions was due to an increase in the amount of intercellular matrix produced by the cells that progressively displayed a pattern of peripheral stratification. In the older lesions, the matrix was mainly composed by chondroitin sulfates A and C. We suggest that juvenile hyaline fibromatosis represents a disease of the connective tissue with progressive abnormal differentiation to chondroid tissue.
VARIANTS
CALCOSPHERULES
Calcospherules associated with juvenile hyaline fibromatosis. Ko CJ, Barr RJ.	Am J Dermatopathol 2003 Feb;25(1):53-6 Abstract quote Juvenile hyaline fibromatosis is a rare autosomal recessive genodermatosis that manifests with 1 to 5 cm skin tumors, gingival hyperplasia, osteolytic bone lesions, and joint contractures. The skin tumors are most often located on the head and periarticular extremities. A case of juvenile hyaline fibromatosis with typical skin tumors that on biopsy exhibited basophilic calcospherules is presented. Although noted in a single case, these structures may be a novel, yet helpful, diagnostic marker.

SPECIAL STAINS/IMMUNOPEROXIDASE/ OTHER	CHARACTERIZATION
SPECIAL STAINS	PAS positive and Alcian blue positive Negative for Congo red, elastic, or collagen stains
IMMUNOPEROXIDASE
Juvenile Hyaline Fibromatosis: Morphologic, Immunohistochemical, and Ultrastructural Study of Three Siblings Abdul Haleem, F.R.C.Path.; Hindi N. Al-Hindi, M.D.; Muna Al Juboury, F.R.C.Path.; Hussa Al Husseini, M.R.C.Path.; Abdulaziz Al Ajlan, M.R.C.Path.	Am J Dermatopathol 2002; 24(3):218-224 Abstract quote Juvenile hyaline fibromatosis (JHF) is a rare hereditary disease characterized by the deposition of hyaline ground substance, which is described as fibrillogranular material on electron microscopy. Approximately 65 cases have been reported to date in the English language literature. We add 3 new cases of children presenting with multiple subcutaneous nodules. We have described the light microscopic, electron microscopic, and immunohistochemical features of these nodules. The characteristic chondroid appearance on light microscopy is imparted by large peripheral vesicles in the stromal cell cytoplasm. Ultrastructurally, the fibroblasts have shown evidence of defective synthesis of collagen, which is then deposited as fibrillogranular material in the matrix. Immunohistochemical studies have shown CD68+ macrophages and multinucleated histiocytic giant cells in all five specimens from our 3 cases. As far as we know, the presence of giant cells has not been reported in the literature. The main purposes of this report are to highlight the presence of macrophages as a constant constituent of the stromal cells in JHF and to review the literature on this subject.
ELECTRON MICROSCOPY
Systemic hyalinosis (juvenile hyaline fibromatosis). Ultrastructure of the hyaline with particular reference to the cross-banded structure. Ishikawa H, Maeda H, Takamatsu H, Saito Y.	Arch Dermatol Res 1979 Jun 25;265(2):195-206 Abstract quote Systematic hyalinosis (juvenile hyaline fibromatosis) is characterized by hyalinized skin lesions. Electron microscopic examination of a hyalinized skin tumor from a 19-year-old man with this syndrome revealed that the hyaline was composed of ruthenium red-positive ultrastructures (granules, filaments, and a kind of cross-banded structure), indicating the presence of glycosamino-glycan or glycoprotein, and a small number of thin collagen fibrils. Using a new ruthenium red staining method combined with an enzymatic digestion procedure, it was demonstrated that the cross-banded structure and granules consisted of chondroitin sulfate-proteoglycan and/or glycoprotein, and that the cross-banded structure is probably a noncollageneous aggregate of the granules attached to the parallel-arranged filaments of hyaluronic acid-like nature.
Juvenile hyaline fibromatosis: ultrastructural study. Winik BC, Boente MC, Asial R. Laboratorio de Microscopia electronica del Noroeste Argentino, CONICET, Tucuman, Argentina.	Am J Dermatopathol 1998 Aug;20(4):373-8 Abstract quote Juvenile hyaline fibromatosis is a multisystemic disorder characterized by a triad of cephalic fibrous outgrowths, gingival hyperplasia, and flexion contractures. The aim of this study was to find new ultrastructural features that could be useful for differentiating this entity from other types of fibromatosis. Mucosal lesions processed for light and electron microscopy by routine techniques showed hyperactive-appearing spindle-shaped fibroblasts and dysplastic mesenchymal cells. Dilated rough endoplasmic reticulum, prominent Golgi complexes, and multivesicular bodies as well as single membrane vesicles filled with fibrillogranular material were seen within the cytoplasm of dysplastic mesenchymal cells. Many fibrillogranular vesicles contained smaller vesicles. There were also invaginations of the cell membrane that contained fibrillogranular material similar to that seen in the single membrane vesicles, suggesting engulfment of an extracellular substance. The stroma contained both normal and serrated collagen fibrils, microfibrils, and two types of fibrillogranular material, one of them with a characteristic banding pattern. Our clinical and histopathologic findings resemble those previously described in cases of infantile systemic hyalinosis and juvenile hyaline fibromatosis. So many features of these two conditions overlap that it is difficult not to consider them as parts of a spectrum of the same disorder.

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
INFANTILE SYSTEMIC HYALINOSIS
Infantile systemic hyalinosis: report of four cases of a disease, fatal in infancy, apparently different from juvenile systemic hyalinosis. Landing BH, Nadorra R.	Pediatr Pathol 1986;6(1):55-79 Abstract quote Four female Mexican-American infants, two siblings, had widespread deposit of hyaline material in skin, gastrointestinal tract, adrenals, urinary bladder, ovaries, skeletal muscles, thymus, parathyroids, and other loci. Clinical features included thickness and focal nodularity of skin, relatively short limbs and neck, gum hypertrophy, hypotonia and reduced movement, joint contractures, osteoporosis, growth failure, diarrhea, and recurrent infections. Clinical onset was in the first week, and all 4 patients died by age 20 months. Infantile systemic hyalinosis appears to be a specific, presumably autosomal recessive, genetic disease, differing from the disorder called systemic hyalinosis, juvenile hyaline fibromatosis, or Puretic syndrome. The biochemical defect and the pathogenetic mechanisms responsible for the pathologic and clinical features of this condition remain to be established.
Infantile systemic hyalinosis: newly recognized disorder of collagen? Glover MT, Lake BD, Atherton DJ. Department of Dermatology, Hospital for Sick Children, London, England.	Pediatrics 1991 Feb;87(2):228-34 Abstract quote Four infants with stiff skin and painful joint contractures in the first few months of life are described. Other features included small papules, particularly on the face and trunk, perianal nodules, hyperpigmentation over the metacarpophalangeal joints and over the malleoli, gingival hyperplasia, persistent diarrhea, and failure to thrive. Two of these infants died before the age of 18 months. In each case hyaline material was found in the papillary dermis. Ultrastructurally, there was a distinctive fibrillogranular appearance in which a banding pattern could be observed. This material was also found within membrane-bound vacuoles in macrophages and fibroblasts. It had an appearance and localization identical with that of collagen type VI. These features are similar to those reported in juvenile hyaline fibromatosis. It is believed that these infants have a closely related, but nonetheless distinctive, inherited disorder of collagen.

Epidemiology
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Differential Diagnosis
Prognosis and Treatment
Commonly Used Terms

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	Murray-Puretic syndrome Molluscum fibrosum Systemic hyalinosis
INCIDENCE	Very rare
AGE RANGE-MEDIAN	Most are childhood though adult cases have been reported
SEX (M:F)	Equal

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
Juvenile hyalin fibromatosis. Kitano Y	Arch Dermatol 1976 Jan;112(1):86-8 Abstract quote A boy had multiple large tumors on the scalp, whitish nodules on the nape and both sides of the neck, hypertrophic gingiva, and severe flexural contractures of hip and knee joints. The histopathologic structure of the tumor was characteristic of juvenile hyalin fibromatosis. The tumor cells were embedded in an amorphous eosinophillic ground substance. X-ray films revealed numerous osteolytic and osteociastic lesions that are important findings in the study of this disease.
LABORATORY MARKERS

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS	Most die within childhood or infancy Rare reports of long survival
A 19-year follow-up of multiple juvenile hyaline fibromatosis. Woyke S, Domagala W, Markiewicz C.	J Pediatr Surg 1984 Jun;19(3):302-4 Abstract quote Nineteen years observation of two siblings with multiple juvenile hyaline fibromatosis is presented. This entity was described 14 years ago. It is concluded that this disease can be effectively controlled by surgical excision of all newly discovered subcutaneous tumors.
Juvenile hyaline fibromatosis. A 15-year follow-up. Quintal D, Jackson R.	Arch Dermatol 1985 Aug;121(8):1062-3 Abstract quote A 37-year-old man was seen because of juvenile hyaline fibromatosis that had been present since he was 2 to 3 years old. His case illustrates the progressive nature of the disease, and during the years attempts to treat the condition were as mutilating in some cases as the disease itself.
Juvenile hyaline fibromatosis: a report of two severe cases. Bedford CD, Sills JA, Sommelet-Olive D, Boman F, Beltramo F, Cornu G Royal Liverpool Children's Hospital, England.	J Pediatr 1991 Sep;119(3):404-10 Abstract quote Two unrelated children with a severe form of juvenile hyaline fibromatosis are described. In addition to painful flexion contractures of all of the large joints, oral and skin lesions, and typical radiologic appearance of osteolytic defects, both girls had marked growth retardation and recurrent infections. Both children died in early infancy of overwhelming infection.
Juvenile hyaline fibromatosis. Case report with five years' follow-up. Miyake I, Tokumaru H, Sugino H, Tanno M, Yamamoto T. Department of Plastic Surgery, School of Medicine, Juntendo University, Saitama, Japan.	Am J Dermatopathol 1995 Dec;17(6):584-90 Abstract quote Juvenile hyaline fibromatosis (JHF) is a rare hereditary disorder named by Drescher et al. in 1969. As recently as 1985, only 30 cases had been reported worldwide. We report the case of a 9-year-old girl who was diagnosed with JHF at age 3 and has been closely followed since. She initially had slowly growing multiple soft tumors over her entire body as well as hypertrophic gingiva and mild bone deformities. She was originally misdiagnosed with infantile myofibromatosis at age 3. However, at age 6, because of the light and electron microscopic findings of the tumors, she was diagnosed as having JHF. Currently, at age 9, she has nodular lesions developing over her body as well as bone changes that are progressing with no evidence of regression.
MALIGNANCY
Juvenile hyaline fibromatosis complicated with oral squamous cell carcinoma: a case report. Kawasaki G, Yanamoto S, Mizuno A, Fujita S. First Department of Oral and Maxillofacial Surgery, Nagasaki University School of Dentistry, Japan.	Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001 Feb;91(2):200-4 Abstract quote A 45-year-old woman was referred because of swelling of the palate, gingival hypertrophy, and multiple cutaneous tumors. She had many cutaneous tumors, which covered most of her body, and she also displayed contractures of the major joints. Maxillary and mandibular gingival hypertrophy, malposition of the teeth, and swelling of the hard palate were the oral findings. The histopathologic features of the cutaneous and gingival tumors were consistent with hyaline fibromatosis, and the swelling of the palate proved to be a squamous cell carcinoma. The carcinoma was treated with tegafur/uracil and seemed to respond to this therapy.