Clinical Neurogentic Syndromes
What are clinical neurogenetic syndromes?
Clinical neurogenetic syndrome is a broad term for a group of neurologic (brain, spine, and peripheral nerve) disorders. These diseases are life-long conditions that can cause tumors to grow inside the brain, spinal cord, organs, skin, and skeletal bones.
Types of clinical neurogenetic syndromes include the following:
- Tuberous sclerosis (TS)
- Neurofibromatosis (NF): Type I and Type II
- Schwannomatosis
- Sturge-Weber disease
- Von Hippel-Lindau
- Hereditary Hemorrhagic Telangiectasia (HHT)
What causes clinical neurogenetic syndromes?
Clinical neurogenetic syndromes are all conditions that are genetic and may be congenital (present at birth).
Although the true prevalence of tuberous sclerosis is not known, it is estimated that this disease occurs in one in 6,000 births and is an autosomal dominant condition. Autosomal means that both males and females are equally affected and dominant means that only one copy of the gene is necessary to have the disorder. A parent with TS has a 50/50 chance of having a child with TS. Many children born with TS are the first cases in a family, since the majority of TS is caused by a new gene change (mutation), and is not inherited. However, parents of a child with TS may have very subtle symptoms of the disorder, and should be carefully examined. Even if no symptoms are present, the parents are considered at a slightly increased risk to have another child with TS, greater than that of the general population.
Neurofibromatosis (NF) occurs in one in 4,000 persons. NF is an autosomal dominant condition caused by a gene on chromosome 17, which is inherited from a parent with the disease (in half of the cases). A parent with NF has a 50/50 chance of having a child with the disease.
NF may also be the result of a new gene change (mutation). Half of NF cases are caused by a new mutation and are not inherited. Males and females are equally affected, regardless of how the disease occurs.
Schwannomatosis is a genetic disease that causes multiple cutaneous schwannomas, (central nervous system tumors), and other neurological complications, and affects around 1 in 40,000 individuals. There is some type of gene mutation that occurs on chromosome 22 a short distance from the NF2 gene.
The cause of Sturge-Weber disease is unknown and is considered to be sporadic (occurs by chance). Sometimes, other family members will have hemangiomas (a benign growth that consists of blood vessels) to a lesser degree than the person with Sturge-Weber disease. This disease presents in most cases starting in infancy.
Von Hippel-Lindau (VHL) is an autosomal dominant, multisystem disease that occurs in one in 36,000 live births. People with VHL may develop retinal angiomas, hemangioblastomas of the brain and spinal cord, renal cell carcinoma, atypical renal cysts, pheochromocytomas, or abnormal adrenal cysts.
Hereditary Hemorrhagic Telangiectasia, also known as Osler-Weber-Rendu syndrome, is an autosomal dominant disease that affects one in 5000 people. HHT causes abnormal development of blood vessels in the skin, mucous membranes, lungs, liver, and brain.
What are the symptoms of clinical neurogenetic syndromes?
The following are the most common symptoms of clinical neurogenetic syndromes. However, each individual may experience symptoms differently. Symptoms may include:
Tuberous Sclerosis
Growths, called tubers, are often found growing inside of the brain and retinal area of the eye. Tuberous sclerosis affects many organs in the body including the brain, spinal cord, lungs, heart, kidneys, skin, and skeletal bones. Mental retardation, developmental delays, seizures, and learning disabilities are also associated with this disease.
Neurofibromatosis (NF)
There are two distinct types of NF, classified as NF I and NF II.
- Neurofibromatosis I - This is the more common of the two disorders. It is also called Von Recklinghausen's disease. The classic symptom of NF I is light brown patches of pigment on the skin, called café-au-lait spots. Benign (non-cancerous) skin tumors associated with this condition are called neurofibromas. Neurofibromas are often found growing on the nerves and in various organs of the person's body. There is a high rate of brain tumors in patients associated with NF. Ten to 15 percent of individuals with NF will have malignant (cancerous) changes in the neurofibromas. Lisch nodules, which are small tumors on the iris (colored part of the eye), may appear around adolescence, but usually do not cause problems. Hearing loss, headaches, seizures, scoliosis, and facial pain or numbness may also be present. Mental retardation is present in 2 to 5 percent of individuals with neurofibromatosis I, while other persons affected may have learning problems and hyperactivity.
- Neurofibromatosis II - This type of neurofibromatosis accounts for 2 to 5 percent of cases. It is known as bilateral acoustic neurofibromatosis and is less common. This disease is characterized by tumors on the eighth cranial nerve, which can lead to hearing loss, headaches, problems with facial movements, problems with balance, and difficulty walking. Hearing loss may be noted as early as the teenage years. Other clinical signs of NF II may include seizures, neurofibromas (skin nodules), and café-au-lait spots (although this is not as common as in NF I).
Schwannomatosis is a type of NF II
Patients with schwannomatosis may present with multiple schwannomas throughout their body, including the brain, spine and peripheral nerves. Chronic pain, numbness, tingling and weakness are typical symptoms. Patients with this disease can become debilitated from the pain. These Diagnostic critera for schwannomatosis includes: two or more cutaneous schwannomas with no evidence of veistbular tumors and no know NF2 mutation; or one pathologically confirmed non-vestibular schwannoma plus a first degree relative who meets this criteria.
Sturge-Weber disease
The classic symptom of this disease is a port-wine stain located on the face, typically near or around the eye and forehead areas. A port-wine stain is present from birth and is a flat area that varies in color from red to dark purple. The birthmark is caused by the formation of too many tiny blood vessels under the skin. There may also be associated brain abnormalities on the same side of the brain as the face lesion. Neurological changes that occur with this condition may include seizures, muscle weakness, changes in vision, and mental retardation. Glaucoma (a condition that causes increased pressure in the eye) may also be present at birth. Unlike tuberous sclerosis and NF, Sturge-Weber disease does not affect the other organs of the body.
Von Hippel-Lindau disease
Signs and symptoms of VHL depend on the organ/organs targeted by the disease. Tumors in the brain can cause headaches, seizures, visual changes, balance problems, nausea or vomiting, depending on the location with the brain. If the disease involves the eyes, the patient can develop bleeding in the eye and retinal detachment. If the kidney is the targeted organ, the patient may present with bloody urine, pain in the loin, weight loss, anemia, or abdominal mass. Tumors in the adrenal gland may cause flank pain, heart palpitations, increased heart rate, anxiety, headaches, and sweating. Diagnosis is made by the presence of one or more hemangioblastomas with the central nervous system, usually within the cerebellar region of the brain and retina; inconsistent visceral lesions; and frequent family incidence.
Hereditary Hemorrhagic Telangiectasia (HHT)
HHT may affect many different organs, so presenting symptoms of HHT depend on the location of the vascular lesions. Signs and symptoms may include nosebleeds, acute and chronic digestive tract bleeding, coughing up blood, and anemia. If the bleeding vascular lesions are located in the brain, the person may present with headaches and signs and symptoms of a stroke. The diagnosis of HHT is based on4 specific criteria referred to as the Curacao Criteria and include: spontaneous recurrent nose bleeds; multiple telangiectasias in typical locations; proven arteriovenous malformations in the lungs, liver, brain, or spine; and first-degree family member with HHT.
The symptoms of clinical neurogenetic syndromes may resemble other conditions or medical problems. Always consult your physician for a diagnosis.
How are neurogenetic syndromes diagnosed?
Clinical Neurogenetic syndromes are congenital (present at birth), and depending on the specific disease, will manifest itselfself anytime throughout one’s lifespan. Sometimes hormonal changes, including puberty, can trigger tumor growth. The diagnosis is made with a physical examination and diagnostic tests. During the examination, the physician obtains a complete medical history and asks if other family members are known to have any of these conditions. In babies and children, the physician will also ask about developmental milestones, since these disorders can be associated with other neurological problems and may require further medical follow-up.
Diagnostic tests may include:
- blood tests
- genetic testing - diagnostic tests that evaluate for conditions that have a tendency to run in families.
- x-ray - a diagnostic test that uses invisible electromagnetic energy beams to produce images of internal tissues, bones, and organs onto film.
- magnetic resonance imaging (MRI) - a diagnostic procedure that uses a combination of large magnets, radiofrequencies, and a computer to produce detailed images of organs and structures within the body.
- computed tomography scan (Also called a CT or CAT scan.) - a diagnostic imaging procedure that uses a combination of x-rays and computer technology to produce cross-sectional images (often called slices), both horizontally and vertically, of the body. A CT scan shows detailed images of any part of the body, including the bones, muscles, fat, and organs. CT scans are more detailed than general x-rays.
- Cerebral angiograms are used to evaluate blood vessels in the brain.
- electroencephalogram (EEG) - a procedure that records the brain's continuous, electrical activity by means of electrodes attached to the scalp.
- eye examination
- tissue sample of the tumor or skin lesion
Treatment of clinical neurogenetic syndromes:
Specific treatment for clinical neurogenetic syndromes will be determined by your physician based on:
- your age, overall health, and medical history
- extent of the condition
- type of condition
- your tolerance for specific medications, procedures, or therapies
- expectations for the course of the condition
- your opinion or preference
Since clinical neurogenetic syndromes are life-long conditions that are not curable, the focus is on medically managing the symptoms. A person is best treated with an interdisciplinary team that may include the following healthcare providers:
- pediatrician/family practitioner
- neurologist - a physician who specializes in conditions of the brain, nerves, and spinal cord.
- neurosurgeon - a surgeon who specializes in operating on the brain and spinal cord.
- orthopaedic surgeon - a surgeon who specializes in conditions of the muscles, tendons, ligaments, and bone.
- radiologist – a physician that specializes in using radiation to treat tumors
- interventionalist – physicians that specializes in treating vascular and organ lesions and diseases using special x-ray machines and catheters to introduce medicine and devices into vessels or tumors
- nurse
- rehabilitation team (physical, occupational, speech therapy, audiology)
Surgery may be needed to remove tumors that may be cancerous, as well as for cosmetic reasons.
Life-long considerations for a person with clinical neurogenetic syndromes:
Since clinical neurogenetic syndromes are life-long conditions, management includes focusing on preventing or minimizing deformities and maximizing the person's capabilities at home and in the community. Positive reinforcement will encourage the person to strengthen his/her self-esteem and promote independence.
In children, the full extent of the disease is usually not completely understood immediately after birth, but may be revealed as the child grows and develops.
Genetic counseling may be recommended by the physician to provide information on the recurrence risks for these disorders and any available testing.