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Hand, Upper Limb, and Peripheral Nerve Surgery Service, Georges-Pompidou European Hospital, Paris, FranceMedical School, University of Paris, Paris, FranceClinique Blomet (Research Unit), Paris, France
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.
Juvenile hyaline fibromatosis (JHF) is a rare, progressive, autosomal recessive disorder without ethnic predilection that arises from mutation of the CMG/ANTXR2 gene, located in chromosome 4q21.
Infantile systemic hyalinosis is distinguished from JHF by hyaline deposits in multiple organs, recurrent infections, protein-losing enteropathy, and death within the first 2 years of life owing to severe thoracic infections.
The diagnosis of JHF is difficult and often delayed because of the existence of multiple and different genotypic and phenotypic intermediary possibilities. Two distinct forms of JHF have been postulated: a localized form with slow progression, and a diffuse form with large and rapidly growing tumors. The initial symptoms are often papular and nodular skin lesions, joint contractures, and gingival hyperplasia.
Evolution and severity are variable, as is the impact on the quality of life. Progression of the lesions is inevitable.
Most skin tumors involve the head and back with a tendency to enlarge and ulcerate. Skin lesions involving the hand are rare and locally aggressive despite their benign nature, causing substantial painful disability.
Hyaline fibromatosis syndrome (juvenile hyaline fibromatosis): whole-body MR findings in two siblings with different subcutaneous nodules distribution.
We report a case of JHF affecting the extremities, leading to notable disability, and for which surgery was performed to excise the lesions. The patient provided consent to report this case.
Case Report
The patient was a 25-year-old man, the first of 3 children, born of unrelated parents in France. He was right-handed and a nonsmoker. There was no family history of fibrous disorders. Juvenile hyaline fibromatosis was diagnosed at age 4 years. He gradually lost the ability to walk because of bilateral knee deformity and clubfoot. At age 17 years, lower-limb corrective surgeries involving distal femoral extension osteotomy and percutaneous Achilles tenotomy were performed to improve ambulation.
The first skin lesions appeared on the face and back in childhood. Papular and nodular skin lesions, appeared progressively in the extremities, causing substantial aesthetic and functional disability. Evolution of the various skin lesion was variable, with some progressing more quickly than others. Difficulty fitting footwear and plantar pain required resection of the nodules from the feet at age 18 years. In the hands, multiple excisions were performed at ages 18, 22, and 23 years (Fig. 1A, B , Table 1). At each procedure, careful dissection of the neurovascular structures was performed to assess their integrity and release them from compression.
Figure 1Third procedure. Fingertip nodules resection of A first and second rays (left hand) and B third ray (right hand).
Histologic examination of the excised specimen revealed JHF each time (Fig. 2A ). The tumor was composed of abundant hyaline extracellular matrix embedding spindle or oval cells, which were isolated or organized in sheets. The density of the cells was heterogeneous, from scanty (Fig. 2B) to moderate (Fig. 2B). No atypia, necrosis, or mitosis was observed.
Figure 2A Macroscopic view of JHF nodule. B, C Abundant hyaline extracellular matrix embedding spindle and oval cells at B very low density or C at a moderate density. (Hematoxylin-eosin stain; bar = 50 μm.)
Successive radiographic assessment of the hands showed osteopenia and revealed both erosive and sclerotic lesions, predominantly at the distal interphalangeal joints (Fig. 3).
Figure 3Last follow-up x-rays: erosive and sclerotic lesions predominant at the distal interphalangeal joints. The distal radioulnar joint of the left hand is severely damaged.
At the last follow-up (2 years after the last procedure), we observed no recurrence at the site of the previously resected nodules. The evolution of the other lesions and masses did not result in a loss of functional capacity, and thus did not require surgery. Despite the contractures of different hand joints related to JHF, the patient maintained functional grip and pinch capacity. He was able to continue work as a consultant.
Juvenile hyaline fibromatosis had progressed in the lower extremities and the patient was confined to a wheelchair. Nevertheless, the satisfactory evolution of the hands (Fig. 4) allowed him to perform upper-limb muscular-strengthening activities, enabling him to maintain a social life and some ambulation.
Figure 4Last follow-up views of dorsal and palmar hand.
Juvenile hyaline fibromatosis, which was first reported in 1873, is a rare autosomal recessive condition caused by sequence variations in gene-encoding capillary morphogenesis protein-2 (CMG2 or ANTXR2) on chromosome 4q21.
This gene codes for a protein involved in basement membrane matrix assembly, collagen type VI homeostasis, and morphogenesis of endothelial cells. Pathogenesis is not yet fully understood, but Lyra et al
suggested that this abnormal collagen metabolism leads to instability and intracellular accumulation, and may explain the clinical manifestations of JHF. Penetrance is variable. The literature is poor; a total of fewer than 70 cases were reported. There is no sex predominance.
Patients are usually normal at birth. The disease commonly affects children aged 2 to 5 years. Characteristically, there are papular and nodular skin lesions, gingival hypertrophy, and joint contractures owing to amorphous hyaline deposit.
The affected areas are usually the head, back, and perianal region. Involvement of the limbs is less common and can be disabling, eventually resulting in a loss of ambulatory ability in early adulthood. Involvement of other organs is less severe than in infantile systemic hyalinosis. The brain is not involved and cognitive development is normal.
Hyaline material deposition is persistent and progressive, and the skin lesions progressively enlarge, eventually resulting in ulceration and infection. However, lesions can remain quiescent for several years. There is no risk for malignant transformation.
Radiographic bone assessment may reveal osteopenia and periosteal reaction (erosive and sclerotic).
Histopathology is required to establish the diagnosis and is characterized by the presence of amorphous hyaline material, eosinophilic substance, and fibroblast proliferation. Cellularity is variable and inversely proportional to the intensity of hyaline deposit. Cells are periodic acid Schiff–positive and diastase-resistant. Staining for amyloid substance is negative.
Hyaline fibromatosis syndrome (juvenile hyaline fibromatosis): whole-body MR findings in two siblings with different subcutaneous nodules distribution.
No therapy is curative or halts the progression of JHF. Oral d-penicillamine may be administered to improve joint mobility in combination with physiotherapy, with variable success.
The approach to treatment is palliative, consisting of excision of cutaneous and mucosal lesions if practical and safe. Intralesional steroid injection may reduce the size and volume of early lesions. Physiotherapy and proper nutrition may help to minimize osteoarticular, muscular, and nutritional repercussions. We recommend early surgical resection, but recurrences are possible.
In our experience, this condition does not affect the structure of the vessels, nerves, and tendons. We believe that the symptoms result from compression related to the accumulation of hyaline products in the extracellular space and may result in venous engorgement, dysesthesia, or even paralysis. The dermis and epidermis are not affected in JHF, and we did not experience difficulty in closing the surgical sites. The purplish appearance of the scars may be caused by a defect in subdermal microcirculation related to extravascular hyaline-fibroblastic deposits.
Genetic counseling includes informing the parents that the next child has a 25% chance of being affected.
Early diagnosis, familial genetic counseling, and multidisciplinary follow-up, including the hand surgeon, is important to managing this rare condition.
References
Denadai R.
Raposo-Amaral C.E.
Bertola D.
et al.
Identification of 2 novel ANTXR2 mutations in patients with hyaline fibromatosis syndrome and proposal of a modified grading system.
Hyaline fibromatosis syndrome (juvenile hyaline fibromatosis): whole-body MR findings in two siblings with different subcutaneous nodules distribution.
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