R e view 
K E Y 
W ORDS 
fibromatosis, 
congenital, 
tumor, 
papule, 
gingival 
hypertrophy, 
joint 
contracture, 
osteolysis, 
hyaline 
]uvenile hyaline fibromatosis 
Juvenlle 
hyaline jibromatosis 
Y. Kitano 
- - - - ----- - - ----- --- --- --- - SU M M ARY 
Juvenile hyaline fibromatosis is a rare congenital disease with characteristic clinical and histopatho-
logical features. Clinical symptoms develop early in lite, ranging from one month to four years of age. 
Tumors and nodules are the most outstanding symptoms. Whitish papules, hypertrophy of the gingiva 
and flexural contracture of joints are the essential symptoms. X-ray examination often reveals osteolytic 
or destructive bone lesions. Histopathology shows abundant deposition of hyaline substance in the 
tumor. In most cases, those main symptoms are not directly life-threatening, but ultimate prognosis is poor. 
Introduction 
]uvenile hyaline fibromatosis (JHF) is a rare con-
genital disease characterized by tumors of the skin, 
whitish papules, hypertrophy of the gingiva and flexural 
contracture of the joints. The first report was made by 
Murray under the name of "peculiar cases of molluscum 
fibrosum" (1) . In 1903, Whitfield and Robinson menti-
oned the follow-up of the three cases reported by Mu-
rray, and described that those cases did not belong to 
neurofibromatosis but should be placed simply in the 
category of multiple fibromata (2). Since then has been 
no report and the disease was nearly forgotten . In 1962, 
Puretic et al. described the condition under the name 
of "a unique form of mesenchymal dysplasia" (3), and 
then reports of this disease were increasing in number 
until now. This disease is distributed all over the world 
and case reports came from Japan , England, Kenya, 
Lebanon, Poland, Portugal, South Africa, Spain, USA and 
Yugoslavia. Recently, this disease was included in the 
textbooks under the name of 'juvenile hyaline fibro-
matosis ' (4, 5) . 
Etiology 
Family anamnesis shows the herečlitary nature of 
the disease . The patients were bom from apparently 
healthy parents often of consanguineous marriage, and 
sibling cases were occasionally reported. These strongly 
suggested an autosomal recessive trait of inheritance. 
Male and female ratio is 6:4. 
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]uvenile hyaline fibromatosis 
Fig. 1. Large tumors in scalp. 
Clinical symptoms 
The onset of the disease is very early, ranging from 
one month to four years of age. Tumors and nodules Fig. 3. Hypertrophy of gingiva. 
are the most outstanding symptoms. Hypertrophy of 
the gingiva and flexural contracture of the large joints 
of the extremities are also noted early. 
The tumors in the scalp become large, and 
sometimes reach up to 15 cm in diameter (Fig.1). The 
Review 
Fig. 2. Pale-pinkish papules in neck and shoulder. Fig. 4. Club-like enlargement of tips of fingers . 
. 6 ------------------------------- acta dermatovenerologica A.P.A. Vol 8, 99, No 1 
Review 
tumor is dome-shaped or protrudes globally. The 
surface is smooth, and covered with normal skin. When 
the tumor is large, the covering skin is stretched and 
often ulcerated. Semitranslucent pinkish tumor tissue 
can be observed. The newly appeared tumor is rather 
soft and elastic. At first it enlarges rapidly, and after a 
while stops to enlarge. The tumor becomes increasingly 
hard, and after severa! years has cartilage-like con-
sistency. The tumors usually adhere to the skin ancl are 
movable on the unclerlying bone. The tumors can cleve-
lop in any site of the bocly. But the sites of preclilection 
are the scalp, post-auricular folds, the extensor aspects 
of shoulcler, elbow ancl knee joints ancl the perianal 
region. Papules of 2-3 mm size have been clescribecl in 
a half of the cases. These are whitish or pale-pinkish in 
color and have a waxy surface (Fig. 2). The sites of these 
papules are limitecl to the both sicles of ala nasi, post-
auricular region ancl neck. 
The gingiva is so hypertrophic that sometimes the 
teeth are buriecl in it. The hypertrophic gingiva is flesh-
colorecl, semitranslucent ancl granular on the surface 
(Fig. 3). The noclules of perioral region often impair 
opening of the mouth. The perianal area is also unclu-
lated by the noclules and incontinence is notecl. 
Flexural contractures of the large joints of the extre-
mities , such as shoulcler, elbow, hip ancl knee are 
essential symptoms. The contracture appears early, ancl 
often as the first symptom. Some patients have never 
walkecl clue to the severe contractures of the hip ancl 
knee joints, which appear within one year after birth. 
The tumor is often noticecl arouncl these joints. Muscle 
atrophy is often clescribecl. Enlargement of the clistal 
portions of the fingers ancl toes occur at a late stage 
(Fig.4). 
There are no essential symptoms involving the 
nervous , respiratory, carcliac, ancl cligestive systems. Few 
reports clescribe mental retardation possibly clue to 
inaclequate eclucation. 
Laboratory examination 
Hypochromic anemia was reportecl in severa! cases. 
Other routine laboratory examinations do not reveal any 
specific abnormality. 
On X-ray examination, osteolytic or clestructive bone 
lesions are often founcl. The lesions are classifiecl in three 
types. 
1) Destruction of bone of large joints of extremities, such 
as humeral heacl (Fig.S). There is no mobility of the 
joint. 
2) Rouncl or oval, punchecl-out osteolytic lesions of the 
skull, ancl long bones of the extremities. 
3) Osteolysis of honeycomb-appearance of the clistal 
phalanges of fingers ancl toes (Fig.6). This change results 
acta dermatovenerologica A.P.A. Vol 8, 99, No 1 
]uvenile hyaline fihromatosis 
finally in complete clestruction of the phalanx. The finger 
takes the shape of club. 
Histopathology 
The histopathologic finclings of JHF are cha-
racteristic. The tumor is locatecl in the clermis. It is fairly 
well circumscribecl from the surrouncling clermal co-
nnective tissue, but cloes not have a capsule. The tumor 
is composecl of tumor cells ancl abunclant grouncl 
substance. The tumor cells have oval or elliptic nuclei 
ancl a fine granular or vesicular cytoplasm, which is 
stainecl pale pink in HE staining. The cells are buriecl in 
the grouncl substance in groups of a few to severa! cells 
ancl the tissue looks like cartilage. The grouncl substance 
is eosinophilic ancl homogeneous with some wavy 
filaments (Fig.7). In the early growing stage there are 
many clilated bloocl vessels. After the tumor stops to 
grow ancl becomes bard (in consistency), the number 
of tumor cells clecreases ancl the amount of fibrous 
elements increases in the grouncl substance. The 
substance is strongly positive to PAS staining ancl 
resistant to amylase cligestion. Alcian blue staining is 
negative and metachromasia is partially seen with 
toluicline blue. Congo reci clicl not stain the substance. 
The epidermis overlying the tumor is atrophic. 
The hypertrophic gingiva shows cleposits of amor-
phous eosinophilic substance with severa! tumor cells 
beneath the oral epithelium. The histopathologic picture 
of the papule is also characteristic. A cleposit of an 
amorphous substance is observecl beneath the epi-
clermis. A few tumor cells, clilatecl bloocl vessels, ancl 
an infiltration of inflammatory cells are seen in the 
grouncl substance. 
Electron microscopic examination of the tumor 
tissue revealecl that the grouncl substance is composecl 
mostly of clelicate filaments (6,7). Uniform fine particles 
are occasionally seen mixecl with the filaments. The 
fibrils with a cross-banclecl structure of 60-100 nm 
perioclicity are occasionally observed (8) (Fig.S). The 
cross-banded structure corresponded to so-called zebra 
bocly, which was recently suggestecl to be composed 
of type VI collagen. Numerous intracytoplasmic granules 
with a limiting membrane characterize tumor cells 
(Fig.9). The granule contains clelicate filaments and fine 
particles similar to those of the ground substance. 
Dilatecl rough encloplasmic reticulum contains fine 
particles of the same electronclensity as the ground 
substance. The Golgi apparatus is well clevelopecl, ancl 
contains the same substance as the granules. A connec-
tion between the Golgi vesicles ancl the granules is seen. 
Electron microscopic observation shows that the ground 
substance is proclucecl by the tumor cells. 
Biochemical analysis of the tumor tissue showecl 
that the tumor glycosaminoglycans consist of chonclro-
7 
]uvenile hyaline fibromatosis 
Fig. 5. Destruction of humeral head. 
itin sulfate, dermatan sulfate and hyaluronic acid. The 
proportion of each glycosaminoglycan varied from re-
port to report. Characterization of collagen showed that 
the hyaline substance mainly consisted of type VI 
collagen (9). 
The findings of histopathology, electron microscopy 
and biochemical analysis suggest that the tumor cells 
proliferate at first and produce the ground substance. 
The substance is secreted and the cells are embedded 
into the substance. The ground substance consists of 
collagen, probably type VI, and glycosaminoglycans. 
Autopsy was done in one case (6). There were 
deposits ofhyaline substance in the tongue, esophagus, 
stomach, small intestine, thymus , spleen and lymph 
nodes as well. 
Diagnosis and 
dlfferential diagnosis 
Tumors, especially the large tumors on the scalp, 
whitish papules, hypertrophy of the gingiva and flexural 
contracture of the large joints of the extremities are 
8 
Fig. 6. Osteolysis of distal phalanges. Some have 
honeycomb-appearance. 
Fig. 7. Histopathology of tumor. The tumor cells 
are buried in the eosinophilic homogenous ground 
substance. (H.E.staining, x200) 
--,- """""',=,· # ,, ~ 
Review 
acta dermatovenerologica A.P.A. Vol 8, 99, No 1 
Review 
Fig. 8. Electron microscopy of tumor tissue. The 
ground substance is composed of fine fibrils 
which occasionally show a cross-banded 
structure of 60-100 nm periodicity. (x3,000) 
Fig. 9. lntracytoplasmic granules of tumor celi. 
The granule has a limiting membrane and 
contains delicate filaments and fine granules. 
(x3,000) 
acta dermatovenerologica A.P.A. Vol 8, 99, No 1 
]uvenile hyaline fibromatosis 
characteristic symptoms of JHF. Early onset is also 
impo1tant. Histopathology of the tumor tissue confirms 
the diagnosis. 
So-called juvenile fibromatosis, such as congenital 
generalized fibromatosis , juvenile aponeurotic fibroma, 
calcifying fibroma and infantile myofibromatosis, are 
to be differentiated. The tumors in this disease may 
contain hyalinized portions or cartilage-like substance. 
But these histological structures do not permeate the 
whole tumor tissue. In hyalinosis cutis et mucosae, 
deposition of hyalinoid substance is observed around 
blood vessels of the upper dermis. 
There are severa! cases reported under the diagnosis 
of infantile systemic hyalinosis (ISH) (10,11). These 
cases showed stiff skin and painful joint contractures in 
the first few months after birth. Other features were small 
papules, perianal nodules, hyperpigmentation over the 
metacarpophalangeal joints and the malleoli, gingival 
hyperplasia, persistent diarrhea, and failure to thrive. 
Most patients were dead by the age of 20 months. 
Hyaline material was found in the papillary dermis. 
Ultrastructurally, the hyaline material had fibrillogranular 
appearance in which a banding pattern could be 
observed. There are striking similarities in clinical 
features and histological findings betweenJHF and ISH 
and it is proposed that JHF and ISH represent different 
expressions of the same disorder (11,12). 
Winchester syndrome is characterized by short 
stature, coarse facial features, peripheral corneal 
opacities and joint stiffness and contractures. Cutaneous 
changes are diffuse thickening, hypertrichosis and 
hyperpigmentation. Radiological examination reveals 
destructive changes at the epiphyseal articular margins 
of the hands, wrists, feet and ankles. The histological 
findings of gum and skin biopsies showed an abun-
dance of fibrillogranular material (13). The multiple large 
tumors and nodules were not reported in Winchester 
syndrome. 
Treatment and prognosis 
When the tumor becomes large, disfiguring and 
causes functional disturbance, excision is indicated. 
Sometimes, intratumoral injection of corticosteroid is 
effective when the tumor is stili soft and fast growing in 
the stage of early development (6). Radiation therapy is 
not effective (3). Hypertrophic gingiva can also be 
excised, but recurs in a short period (13,14,15). Ortho-
pedic surge1y, including capsulotomy, was performed 
to make the contracted knee joints movable. After a few 
months of rehabilitation, the patient could stand and 
walk with the aid of long leg braces. But the contracture 
recurred soon (7). 
9 
R eview ]uvenile hyaline fibromatosis 
In JHF, neurological abnormality is not found, and 
mental deve lopment is essentially n o t retarded. 
Disfiguring tumors and joint contracture deprive the 
patients of the normal social life. The patients with ISH 
and two severe cases reported by Bedford at al. were 
dead before the age of 24 months (10,11 ,16). The 
reported longest survivor was 51 years old. A patient 
reported in 1972 and followed by myself is 39 years old 
by now (6). He is disabled by contractures of joints of 
extremities, but his interna! organs, including heart, 
lung, !iver and kidney do not show functional dis-
turbance. 
REFERENC ES 
AUTHOR'S 
ADDRESS 
1. Murray J. On three peculiar cases of molluscum fibrosum in children. Med Chir Trans 1873; 38: 235-53. 
2. Whitfield A, Robinson AH. A further report on the remarkable series of cases of molluscum fibrosum 
in children communicated to the society by Dr.]ohn Murray in 1873. Med Chir Trans 1903; 86: 293-301. 
3. Puretič Š, Puretič B, Fiser-Herman M, Adamčič M. A unique form of mesenchymal dysplasia. Br J 
Dermatol 1962; 74: 8-19. 
4. Enzinger FM, Weiss SM. Fibrous tumors of infancy and childhood. In: Soft Tissue Tumors, 3rd Ed. 
Mosby 1995: 231- 68. 
5. Heenan PJ. Tumors of the fibrous tissue involving the skin. In: Elder D, Elenitsas R, Jaworsky C, 
Johnson B, Eds. Lever's Histopathology of the Skin, 8th Ed. Lippincott-Raven, 1997: 847-87. 
6. Kitano Y, Horiki M, Aoki T, Sagami S. 'Iwo cases of juvenile hyaline fibromatosis. Arch Dermatol 1972; 
106: 877-83. 
7. Kitano Y. ]uvenile hyaline fibromatosis. Arch Dermatol 1976; 112: 86-8. 
8. Ishikawa H, Maeda H, Takamatsu H, Saito Y. Systemic hyalinosis (juvenile hyaline fibromatosis)-
Ultrastructure of the hyaline with particular reference to the cross-banded structure. Arch Dermatol Res 
1979; 265: 195-206. 
9. Katagiri K, Takasaki S, Fujiwara S, Kayashima K, Ono T, Shinkai H. Purification and structural analysis 
of extracellular matrix of a skin tumor from a patient with juvenile hyaline fibromatosis. J Dermatol Sci 
1996; 13: 37-48. 
10. Landing BH, Nadorra R. Infantile systemic hyalinosis: report of four cases of a disease, fatal in 
infancy, apparently different from juvenile systemic hyalinosis. Pediatr Pathol 1986; 6: 5 5-79. 
11. Glover MT, Lake BD, Atherton DJ. Infantile systemic hyalinosis: Newly recognized disorder of collagen? 
Pediatr 1991; 87: 228-34. 
12. Shehab ZP, Raafat F, Proops DW. ]uvenile hyaline fibromatosis. IntJ Pediatr Otorhinolaryngol 1995; 
33: 179-86. 
13. Dunger DB, Dicks-Mireaux C, O'Driscoll P, Lake B, Ersser R, Shaw DG, Grant DB. 'Iwo cases of 
Winchester Syndrome: with increased urinary oligosaccharide excretion. Eur J Pediatr 1987; 146: 615-9. 
14. Finlay AY, Ferguson SD, Bolt PJA. ]uvenile hyaline fibromatosis. Br J Dermatol 1983; 108: 609-16. 
15. Aldred MJ, Crawford PJM. ]uvenile hyaline fibromatosis. Oral Surg Oral Pathol 1987; 63: 71-7. 
16. Bedford CD, Sillis JA, Sommelet-Olive D, Boman F, Beltrama F, Comu G. ]uvenile hyaline fibromatosis: 
A report of two severe cases. J Pediatr 1991; 119: 404-10. 
Yukio Kitano MD, projessor oj dermatology, Department oj Dermatology, 
Hyogo College oj Medicine, 1-1 Mukogawa-cho Nishinomiya, Hyogo 663-
8501, Japan 
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