What are the other Names for this Condition? (Also known as/Synonyms)

• Inherited Systemic Hyalinosis
• ISH (Infantile Systemic Hyalinosis)

What is Infantile Systemic Hyalinosis? (Definition/Background Information)

• Infantile Systemic Hyalinosis (ISH) is a highly infrequent genetic disorder affecting newborn and infant children. It occurs due to the deposition of a collagen-like substance (called amorphous hyaline) in the tissues, muscles, and organs of the body
• This results in the numerous signs and symptoms of ISH affecting the entire body. The parts involved may include the skin, lymph nodes, heart and skeletal muscles, thyroid, gastrointestinal tract, spleen, and adrenal glands
• Due to the deposition of hyaline (a process called hyalinosis), it leads to the formation of multiple subcutaneous and deep-seated nodules. These benign tumors can severely disrupt the function of various body organs and the joints
• The cause of Infantile Systemic Hyalinosis is due to gene mutations that disrupt the function of certain proteins in the body. Parents who are closely-related to each other (blood relatives) have a very high risk for ISH
• The condition is intractable and presents serious treatment challenges. Healthcare providers generally treat the signs and symptoms of Infantile Systemic Hyalinosis, which may involve administration of medication, fluids, physiotherapy for weak joints and bones, and surgical excision and tumor removal
• Even though the mental and intellectual growth of the child is unaffected, the prognosis of Infantile Systemic Hyalinosis is frequently poor; many children do not survive beyond age 3 years

Who gets Infantile Systemic Hyalinosis? (Age and Sex Distribution)

• Infantile Systemic Hyalinosis is congenital condition affecting newborns and infants. It is manifested at birth or immediately following birth, and is present throughout the child’s life
• Both male and female are affected by the condition
• No racial or ethnic group preference is noted
• ISH is an extremely rare disorder with an incident rate reported at less than 1 per million population. Currently, only about 25 cases have been recorded in the medical literature

What are the Risk Factors for Infantile Systemic Hyalinosis? (Predisposing Factors)

The risk factors of Infantile Systemic Hyalinosis include:

• Individual with a positive family history of the condition
• Consanguineous union (or marriages among close blood-relations) greatly increases the risk for this autosomal recessive disorder
• ISH may be present with juvenile hyalinosis fibromatosis, which is another rare genetic abnormality. Both conditions are known to have the same genetic origin

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Infantile Systemic Hyalinosis? (Etiology)

Following are the factors that may be responsible for development of Infantile Systemic Hyalinosis:

• It is a genetic disorder that is inherited in an autosomal recessive manner; children with ISH, often have parents who are closely related by blood
• Scientific research indicates that it develops due to CMG2 or ANTXR2 gene mutations that codes for a protein on chromosome 4 (at 4q21.21)
• This results in disruption of the basement membrane (thin layer separating the epithelium at various locations) leading to abnormal collection of hyaline material (a type of glassy material) at the affected regions/tissues
• This abnormal collection of these extracellular components results in the formation of benign tumors (single or multiple) beneath the cutaneous layers, giving rise to a set of associated signs and symptoms

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children, born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Infantile Systemic Hyalinosis?

The symptoms of Infantile Systemic Hyalinosis, which is a progressive disorder, may be several and affect various parts of the body. The combination of symptoms may also vary from one individual to another.

Infantile Systemic Hyalinosis signs and symptoms may include:

• The skin is affected causing the following:
  • Numerous painful skin lesions in the form of papules on head and neck region and scalp; red spots on scalp, including skin scaling
  • The nodular skin lesions are mostly seen on skin immediately covering the bones, such as on the ankles and knees, knuckles and elbows, etc.
  • Lesions around the anus, looking like genital warts
  • The skin lesions are about 2-3 cm in size
  • Presence of thick skin, which makes it hard and inflexible
  • Skin creases on skin folds (such as in the groin) and joints
  • Increased skin pigmentation (usually deep brown skin) over finger and hand joints
• The nodules are known to destroy the tissue and body components where they form, due to the deposition of hyaline material into the soft tissues and organs of the body
• Other head and neck related symptoms include:
  • Facial hair
  • Watery discharge from eyes
  • Large-sized head
  • Overgrowth of gums in the mouth, causing gingival hyperplasia
• When the bones and joints are affected, it can cause:
  • Limited and painful joint movement; hands and feet coordination difficulties
  • Deformity of the knee and elbow joints due to joint contracture
  • Osteoporosis of the affected bones, bone depletion causing weak bones
  • Frequent fractures due to weak bones
• Chronic infections and severe diarrhea is typically noted in many children

Newborn babies and infants, who present with ISH, may additionally display the following:

• Excessive crying while being picked up, or during feeding
• Minimal limb movements
• Abdominal swelling
• Short stature
• Failure to thrive

The child may have a normal delivery and normal weight at birth; also, normal mental health and intellectual growth is frequently seen.

How is Infantile Systemic Hyalinosis Diagnosed?

The following methods may be adopted to diagnose Infantile Systemic Hyalinosis:

• A thorough physical examination and a complete medical history
• X-ray of the affected region
• CT scans and MRI scans of the affected region to assess the extent of tumor growth and destruction of surrounding tissues, muscles, and bones
• Molecular testing to identify the gene causing ISH may help in the diagnosis
• Tissue or skin biopsy: In this procedure, the physician removes a sample of the accessible tissue and sends it to the laboratory for a histopathological examination. The pathologist examines the biopsy under a microscope and arrives at a definitive diagnosis after a thorough evaluation of the clinical and microscopic findings, as well as by correlating the results of special studies on tissues (if required)
• A differential diagnosis may be necessary to eliminate the following conditions:
  • Collagen deposition disorder
  • Lipoid proteinosis (Urbach-Wiethe disease)
  • Mucopolysaccharidosis
  • Stiff skin syndrome
  • Winchester syndrome

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Infantile Systemic Hyalinosis?

The complications of Infantile Systemic Hyalinosis may include the following:

• The major complication of ISH is that increased numbers and large sizes of subcutaneous and deep-seated tumors (benign tissue masses) can lead to the destruction of organs and cause physical deformities. It can lead to severe pain and functional impairment of the organs
• Bacterial infection causing pneumonia may be frequently observed; this, can be fatal
• Multiple sepsis
• The gastrointestinal tract is affected leading to protein-losing enteropathy. This can result in severe diarrhea
• No growth/weight gain is observed; cachexia
• Deep tissue tumors and the involvement of the underlying bones can make surgical excision and tumor removal very difficult
• Recurrence of the tumor after surgical excision is observed in many cases

How is Infantile Systemic Hyalinosis Treated?

The treatment of Infantile Systemic Hyalinosis is very difficult, because currently, the healthcare providers do not know how to manage hyalinosis (deposition of hyaline into the tissues and organs). Also, no specific guidelines exist to treat ISH. The disorder is treated symptomatically, using some of the following measures:

• Administration of fluids for diarrhea
• Antibiotics for infection
• Medications for other conditions such as to improve joint movement
• Extensive physiotherapy for joint movement issues, including physical therapy to enable the child to be mobile and walk
• Nutritional support
• The treatment of the nodules involves surgical excision, especially when it presents pain or other complications. Complete excision and tumor removal should be performed, if possible, to decrease the chance of tumor recurrence
• Long-term follow-up with healthcare visits and multiple surgeries may be necessary

How can Infantile Systemic Hyalinosis be Prevented?

• Currently, there are no specific methods or guidelines to prevent Infantile Systemic Hyalinosis, since it is a genetic condition
• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as ISH

What is the Prognosis of Infantile Systemic Hyalinosis? (Outcomes/Resolutions)

• Infantile Systemic Hyalinosis is a genetic disorder and the prognosis of the condition is dictated by the number of tumors present, their locations, the degree of organ destruction, functional impairment, and overall health status
• Many children do not live beyond early childhood and the 3-year mortality rate is very high (more than 90%). The leading cause of death is chest infection or chronic diarrhea
• Children, who survive into adulthood, are severely disabled with limited joint movement and other complications

Additional and Relevant Useful Information for Infantile Systemic Hyalinosis:

Infantile Systemic Hyalinosis and juvenile hyaline fibromatosis are both caused by similar set of genetic mutations. Previously, the two conditions were considered as being distinct and separate, but now they are thought to be closely-related and belonging to the same genetic family.