Hyaline fibromatosis syndrome

Alternate names

Juvenile hyaline fibromatosis (former subtype); Puretic syndrome; Infantile systemic hyalinosis (former subtype); Inherited systemic hyalinosis

Definition

Hyaline fibromatosis syndrome (HFS) is a condition characterized by deposits of a clear substance (hyaline) in the skin and in various other body tissues.

Epidemiology

Hyaline fibromatosis syndrome is a rare condition. Its prevalence is unknown.

Cause

Hyaline fibromatosis syndrome is caused by mutations in a gene called ANTXR2. This gene provides instructions for making a protein that is found at the surface of many types of cells. The ANTXR2 protein is believed to interact with components of the extracellular matrix, which is the lattice of proteins and other molecules outside the cell. This matrix strengthens and supports connective tissues, such as skin, bone, cartilage, tendons, and ligaments. The ANTXR2 protein may play a role in the structure of the extracellular matrix. The nature of the hyaline substance that builds up in hyaline fibromatosis syndrome is unknown, but it likely contains extracellular matrix proteins, among other materials.

Gene mutations

• Mutations in the ANTXR2 gene are thought to result in production of an ANTXR2 protein that is unable to get to the surface of cells or that has impaired ability to interact with extracellular matrix components.
• It is unclear what effect these mutations have in cells and tissues.
• Researchers suspect that gene mutations disrupt the formation of the extracellular matrix, allowing a hyaline substance to leak through and build up in various body tissues.
• Alternatively, the mutations could impair the breakdown of excess extracellular matrix proteins, which then accumulate in tissues and lead to the signs and symptoms of hyaline fibromatosis syndrome.
• Researchers are unsure why the severity of hyaline fibromatosis syndrome varies among affected individuals.
• Some studies have indicated that the severity of the condition may be linked to where in the gene the mutation occurs.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

• It typically becomes apparent at birth or in infancy, causing severe pain with movement; progressive joint contractures which limit movement; thickened skin; and hyperpigmented patches over prominences of the joints.
• Other features may include digestive problems; gum enlargement; skin bumps; pearly papules on the face and neck; and masses near the anus (perianal masses).
• Complications can be life threatening.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormal diaphysis morphology(Abnormal shape of shaft of long bone)
• Abnormal hair morphology(Abnormality of the hair)
• Abnormal skull morphology(Abnormality of the skull)
• Abnormality of dental morphology(Abnormality of dental shape)
• Abnormality of the adrenal glands(Adrenal abnormalities)
• Aplasia/Hypoplasia of the thymus(Absent/small thymus)
• Brachydactyly(Short fingers or toes)
• Camptodactyly of finger(Permanent flexion of the finger)
• Chronic diarrhea
• Coarse facial features(Coarse facial appearance)
• Failure to thrive(Faltering weight)
• Feeding difficulties(Feeding problems)
• Gingival overgrowth(Gum enlargement)
• Hyperpigmentation of the skin(Patchy darkened skin)
• Immunodeficiency(Decreased immune function)
• Joint stiffness(Stiff joint)
• Lymphedema(Swelling caused by excess lymph fluid under skin)
• Macrocephaly(Increased size of skull)
• Micromelia(Smaller or shorter than typical limbs)
• Muscular hypotonia(Low or weak muscle tone)
• Osteomalacia(Softening of the bones)
• Osteopenia
• Osteoporosis
• Papule
• Polycystic ovaries
• Recurrent bacterial infections(Bacterial infections, recurrent)
• Recurrent fractures(Increased fracture rate)
• Severe short stature(Dwarfism)
• Short neck(Decreased length of neck)
• Short palm
• Skin ulcer(Open skin sore)
• Steatorrhea(Fat in feces)
• Subcutaneous nodule(Firm lump under the skin)
• Telangiectasia of the skin
• Thickened skin(Thick skin)
• Urticaria(Hives)

30%-79% of people have these symptoms

• Aplasia/Hypoplasia of the skin(Absent/small skin)
• Death in infancy(Infantile death)

5%-29% of people have these symptoms

• Abnormality of the gastrointestinal tract
• Gingival fibromatosis
• Osteolysis(Breakdown of bone)
• Progressive flexion contractures
• Skeletal muscle atrophy(Muscle degeneration)

Diagnosis

Hyaline fibromatosis syndrome (HFS) should be suspected in individuals with the following clinical, laboratory, histopathology, and radiographic features. Clinical features are presented in order of their specificity for clinical diagnosis.

Clinical features

• Hyperpigmented skin over bony prominences. Purplish patches develop over the medial and lateral malleoli of the ankles, metacarpophalangeal joints, spine, and elbows.
• Progressive contractures (e.g., hip, knee and elbow flexion, ankle dorsiflexion, wrist extension with flexion of proximal interphalangeal and distal interphalangeal joints) that may be congenital and/or cause decreased intrauterine movement. Some individuals have only mild contractures.
• Possible pain or excessive crying with passive movement
• Failure to thrive. Postnatal-onset growth deficiency is common. Some children develop chronic diarrhea and protein-losing enteropathy.
• Gingival thickening
• Skin nodules (e.g., pearly papules on the head and neck; skin nodules, papules, and fleshy lesions periorally and perianally)
• Characteristic facies. A depressed nasal bridge, variable ear malformations (large, simple or low-set ears, and preauricular skin tags), and a slightly coarse facial appearance may be present.
• Normal ophthalmologic examination can be used to differentiate HFS from some lysosomal storage disorders.

Laboratory features

• Serum albumin may be low.
• Normal or slightly elevated ESR, anemia, and/or thrombocytosis
• Immunoglobulin levels may be low and cellular immune responses depressed.
• CD3 and CD4 lymphocyte subsets and ANA are unremarkable.

Histopathology

• Skin biopsy. Light microscopy demonstrates hyaline material in the dermis.
• Electron microscopy demonstrates cells filled with fine, fibrillary material with an enlarged endoplasmic reticulum and Golgi apparatus.
• Intestinal biopsy. Villous atrophy, edema, lymphangiectasia, and hyalinosis may be seen in individuals with prominent gastrointestinal symptoms.

Radiographic features

• Skeletal radiographs. Generalized osteopenia, periosteal reaction, and lucent lesions are nonspecific findings that may affect long bones as well as the axial skeleton.
• Upper-gastrointestinal imaging studies may show rapid transit time.
• MRI of the brain is unremarkable.

The diagnosis of HFS is established in a proband with the above suggestive findings and/or biallelic pathogenic variants in ANTXR2 identified by molecular genetic testing.

Treatment

• Possible nasogastric tube, gastrostomy tube feeding, or parenteral nutrition under supervision of a gastroenterologist and nutritionist
• Nutrition tailored for the possibility of malabsorption or lymphangiectasia
• Hydration and albumin infusions for protein-losing enteropathy
• Physiotherapy for joint contractures can be considered although pain may be problematic
• Nonsteroidal anti-inflammatory drugs, opiates, and possibly gabapentin for pain
• Gentle handling; splinting may reduce pain
• Consultation with a pain management specialist as needed
• Lesions that obstruct the airway or interfere with feedings can be excised, but may recur
• Anesthesiologists need to be aware of potential difficulties with endotracheal intubation
• Perianal masses may be resected
• Treatment of skin nodules as recommended by dermatology and/or plastic surgery
• Infections are treated based on the site of infection and causative agent
• Consider family counseling to manage chronic medical condition.[1].

References

‎

NIH genetic and rare disease info

• NIH info on Hyaline fibromatosis syndrome

Hyaline fibromatosis syndrome is a rare disease.

Hyaline fibromatosis syndrome Resources
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