Are You Confident of the Diagnosis?

Systemic hyalinoses are genetic generalised fibromatoses. Two distinctive syndromes are recognized in the literature: juvenile hyaline fibromatosis and iInfantile systemic hyalinosis, with significant phenotypic overlaps, characterized by an accumulation of hyaline material in the skin for the former and other organs for the latter.

Juvenile hyaline fibromatosis is a rare autosomal recessive genetic disease characterized by the accumulation of a hyaline substance in skin and joints.

Characteristic findings on physical examination

The clinical expression begins in the first month of the life, but it is often diagnosed later. The skin lesions are small, pink, pearly papules particularly of the perianal, perinasal, and perioral regions. Large subcutaneous nodules are located on the scalp, trunk, and extremeties. The nodular infiltration of the joint capsule limits the mobility, or blocks the joint in bending. Osteoporosis, osteopenia, osteolytic bone lesions and fractures have also been noted. Gingival hypertrophy is almost constant and interferes with feeding.

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Mental development is generally normal. Patients often have pain with movement leading to persistent crying. Low-set ears with preauricular skin tags has been reported.

Expected results of diagnostic studies

The histologic findings characteristic of juvenile hyaline fibromatosis include a benign proliferation of fibroblasts, embedded in an amorphous eosinophilic hyaline substance. The hyaline material is positive with PAS. Analysis by electron microscopy indicates that this substance is produced by fibroblasts.

Diagnosis confirmation

The diagnosis is confirmed by the study of the gene encoding capillary morphogenesis protein type 2 (CMG2), located on chromosome 4q21. This gene’s mutation, recently identified, is the cause of juvenile hyaline fibromatosis and of infantile systemic hyalinosis.

Juvenile hyaline fibromatosis and infantile systemic hyalinosis have many common clinical features: papular or nodular skin lesions, gingival hypertrophy, joint contractures, and osteolytic lesions. Other clinical features are more specific to infantile systemic hyalinosis: thickened skin with hyperpigmentation over prominences, visceral atrophy, chronic diarrhea, recurrent infections, malnutrition with failure to thrive, and reduced life expectancy. Histologic study of these two diseases can be virtually identical.

For some authors, these two diseases are an allelic expression of a single genetic disorder referred to “Systemic hyalinoses”. The different mutations CMG2 explains the phenotypic overlaps.

The differential diagnoses of Infantile hyalinosis inclues infantile myofibromatosis (congenital generalized fibromatosis), lipoid proteinosis (Urbach-Wiethe disease), mucopolysaccharidoses (type 1 [Hurler disease] and type 2 [Hunter’s disease]), and Winchester syndrome.

Who is at Risk for Developing this Disease?

Juvenile hyaline fibromatosis and Infantile systemic hyalinosis is are rare autosomal recessive genetic diseases.

What is the Cause of the Disease?

Both of these conditions are caused by a mutation in the gene encoding capillary morphogenesis protein type 2 (CMG2), located on chromosome 4q21. CGM2 encodes a transmembrane protein activated during the capillary morphogenesis. It connects two extramembrane proteins of extracellular matrix, laminin and collagen IV, via an extramembrane domain called von Willebrand A (VWA). The abnormal CGM2 protein, via laminin and collagen IV, resulted in an alteration of the basement membrane, leading to perivascular hyaline deposits characteristic of these two diseases.

The CGM2 gene has also been referrred to as the ATXR2 gene.

Systemic Implications and Complications

Infantile systemic hyalinosis typically has a more severe course.

Failure to thrive

Reduced life expectancy, often not beyond childhood secondary to infections, and protien losing enteropathy.

Osteopenia/osteoporosis leading to fractures.

Joint contractures.

Increased infections.

Growth retardation.

Osteolytic bone lesions.

Protein losing enteropathy leading to diarrhea.

Treatment Options

Treatment options are summarized in Table I.

Table I.
Medical Surgical Physical
Intralesional Kenalog Excision of subcutaneous nodules Physical therapy to prevent joint contractures
Pain control with NSAIDS Partial gingevectomy may be required  
  Gastric feeding tube may be needed  

NSAIDS, nonsteroidal antiinflammatory drugs.

Optimal Therapeutic Approach for this Disease

There is no cure for these hyalinoses. The treatment is primarily aesthetic and functional. Early excision of subcutaneous nodules is recommended, but local recurrences are common. A few cases of spontaneous regression are also described, but it is not frequent, and surgical removal of lesion is required.

Intralesional injections of corticosteroids (triamcinolone. 10mg/cc) are sometimes helpful in reducing the size of the papules and nodules . Partial gingivectomy is considered in case of gingival hypertrophy. Finally, physiotherapy should be proposed to limit the joint contractures.

Patient Management

Patients need to be taken care of by a team of physicians in the following specialties: pediatrics, genetics, dental, dermatology, physical therapy, and pediatric surgery. Infants may present to the dermatologist who subsequently makes the diagnosis. Referral to the appropriate subspecialists is critical.

Intralesional kenalog 10mg/cc has not been shown to be that helpful in reducing the papules or nodules. Excision of problematic nodules is often performed. It is important to start physical therapy early to try to avert joint contractures, or at least minimize this complication.

Unusual Clinical Scenarios to Consider in Patient Management

As there are less than 40 cases in total reported in the literature, this rare entity is highly unusual in and of itself.

What is the Evidence?

Habibeddine, S, Khadir, K, Azzouzi, S, Skalli, S, Lakhdar, H. “Fibromatose hyaline juvénile : Atteinte de 2 jumeaux”. Ann Dermatol Venereol. vol. 130. 2003. pp. 43-6. Juvenile hyaline fibromatosis review and report of two individuals.)

Mancini, GM, Stojanov, L, Willemsen, R, Kleijer, WJ, Huijmans, HG, van Diggelen, OP. “Juvenile hyaline fibromatosis: clinical heterogenity in three patients”. Dermatology. vol. 198. 1999. pp. 18-25. (Case report of three individuals with juvenile hyaline fibromatosis and the different phenotypic expression.)

Criado, GR, Gonzalez-Meneses, A, Canadas, M, Rafel, E, Yanes, F, De Terreros, IG. “Infantile systemic hyalinosis: a clinicopathological study”. Am J Med Genet A.. vol. 129. 2004. pp. 282-5. (Review and discussion of the characteristics of infantile systemic hyalinosis.)

Al-Najjadah, I, Bang, RL, Ghoneim, IE, Kanjoor, JR. “Infantile systemic hyalinosis”. J Craniofac Surg. vol. 14. 2003. pp. 719-23. (Review of infantile systemic hyalinosis from the craniofacial perspective.)

Rahman, N, Dunstan, M, Teare, MD, Hanks, S, Edkins, SJ, Hughes, J. “The gene for juvenile hyaline fibromatosis maps to chromosome 4q21”. Am J Hum Genet. vol. 71. 2002. pp. 975-80. (Discovery of the gene mutation responsible for juvenile hyaline fibromatosis.)

Hanks, S, Adams, S, Douglas, J, Arbour, L, Atherton, DJ, Balci, S. “Mutations in the gene encoding capillary morphogenesis protein 2 cause juvenile hyaline fibromatosis and infantile systemic hyalinosis”. Am J Hum Genet. vol. 73. pp. 791-800. (Study looking at how the gene mutations may change the phenotypic expression of the disease.)

Dowling, O, Difeo, A, Ramirez, MC, Tukel, T, Narla, G, Bonafe, L. “Mutations in capillary morphogenesis gene-2 result in the allelic disorders juvenile hyaline fibromatosis and infantile systemic hyalinosis”. Am J Hum Genet.. vol. 73. 2003. pp. 957-66. (Study looking at the gene mutations seen in these two disorders.)

Dereure, O. “Mutation du gène codant pour la protéine de morphogénèse capillaire de type 2 dans la fibrohyalinose juvénile et dans la hyalinose systémique infantile”. Ann Dermatol Venereol. vol. 131. 2004. pp. 1118(Case report of the hyalinosis with emphasis on the material depositied around capalliries.)

Urbina, F, Sazunic, I, Murray, G. “Infantile systemic hyalinosis or juvenile hyaline fibromatosis?”. Pediatr Dermatol. vol. 21. 2004 . pp. 154-9. (Discussion of the phenotypic differences and similiarities of the two conditions.)

Thauvin-Robinet, C, Faivre, L, Beer, F, Justrabo, E, Nivelon-Chevalier, A, Huet, F. “Infantile systemic hyalinosis : a case with atypical prolonged survival”. Acta Paediatr. vol. 90. 2001. pp. 705-6. (Case of a child that had prolonged survival with the diagnosis of infantile systemic hyalonosis.)

Shin, HT, Paller, A, Hoganson, G, Willner, JP, Chang, MW, Orlow, SJ. “Infantile systemic hyalinosis”. J Am Acad Dermatol. vol. 50. 2004. pp. S61-4. (Case report and review of the literature.)