I-Cell Disease (Mucolipidosis II)

Summary
I-cell disease is an example of the mucolipidoses, a
group of diseases which show features of both the
mucopolysaccharidoses and the sphingolipidoses. A
clinical description is given of a child suffering from
this condition. The diagnostic criteria are discussed,
as well as some of the necropsy findings.
THE genetic mucolipidoses are a group of diseases
which show the symptoms and signs of both the
mucopolysaccharidoses and the sphingolipidoses
(Table 1). Some of them such as Gm2 gangliosidosis
and infantile sulphatidosis are related to known
enzyme defects, but in others the cause is unknown.
Among the latter some of the affected children have
been described as Hurler's variants as they show
many of the features of Hurler's syndrome, but
excrete normal amounts of urinary mucopolysaccharides.

Case report
M.W. born 29 May 1967.
The child was referred to Booth Hall Children's
Hospital, Manchester, at the age of 2- years. She
had been born at home and was the second child in
the family, the older sibling having developed
normally. The pregnancy and birth were normal.
Multiple deformities had been recognized from birth
and she had been treated for a dislocation of the
right hip. At the time of her referral she could not
sit up herself and made no effort to stand. In general
development was around 8-9 months. Three times
in the past year the child had lost consciousness and
become cyanotic. There was no other past history or
family history of note.

On examination the unusual appearance of the
child was highly suggestive of gargoylism (Figs. 1
and 2). The bridge of the nose was broad and
flattened, the nostrils anteverted, and the tongue
was large. The eylids were puffy, the eybrows prominent,
and the cheeks were highly coloured. The
skin was coarsened. The abdomen was protuberant
and chest expansion was limited. There was flattening
of the left side of the skull and a fairly prominent
lumbo-dorsal kyphosis. There was fair movement in
the legs and feet, but the gluteal muscles appeared
to be weak. The right thumb was flexed in the palm
and could not be extended or abducted. Both hips
were held in about 45° of abduction by contractures,
probably in the abductor muscles. There was no
clouding of the cornea and the optic fundi appeared
normal. Muscle tone was slightly reduced, but the
tendon reflexes were present and equal. The liver
was enlarged one and a half finger's breadth, but the
spleen was not palpable, and there was no evidence
of cardiac involvement.

Over the next 2 years the child was greatly
troubled by chest infections, sometimes severe
enough to be classified as broncho-pneumonia. She
showed some evidence of development, and began
to stand in splints and seemed to benefit from wearing
a spinal jacket. She started to say a few words.
At the age of 2 years 7 months the patient weighed
7-05 kg (third percentile at this age 10-4 kg), and her
height was 70-1 cm (third percentile at this age
83 cm). The GQ on the Griffiths Mental Development
Scale was 27-2. X-ray of the skull showed very
marked asymmetry. On X-ray of the spine and pelvis
there was scoliosis convex to the left, and widening
of the interpedicular spaces in the lumbar spine
(Fig. 3). The posterior borders of the vertebral
bodies in the lumbar spine were concave. The proximal
ends of both the femora were constricted (Fig. 4).
The X-rays of the hands showed that the metacarpal
and the phalangeal medullary cavities were widened.
The cortices were very narrow and thin. The lower
ends of both the ulna and radius were tapered. The
EEG was characterized by a generalized increase of
slow wave activity. There were no epileptic discharges.
There was no excess excretion of mucopolysaccharides
in the urine. Abnormal vacuoles were
found in approximately 30% of mononuclear cells.
No evidence of metachromasia was found. Some
granules in the monocytes were Sudan black positive.


Bone marrow aspirations yielded dry taps. The urine
amino acid chromatogram was normal, as were the
liver function tests. On one occasion the plasma true
glucose was 20 mg/100 ml, but the presence of hypoglycaemia
was not confirmed on a number of other
occasions. Fibroblast cultures were attempted but
were unfortunately unsuccessful. Plans had been
made to repeat these cultures when the child was
admitted to hospital with broncho-pneumonia and
died soon afterwards. Permission for necropsy was
refused.

Discussion
The name 'I-cell disease' was derived from the
striking granular inclusions seen in the cultured
fibroblasts from children suffering from this syndrome.
From the few reported cases it seems likely
that the condition is inherited as an autosomal
recessive. Slow development is recognized early in
life, as well as the hypotonia. Congenital dislocation
of the hips, herniae, and hyperplasia of the gums are
also a feature. Recurrent upper respiratory tract
infection seems to be a characteristic feature, and
often a cause of death when complicated by congestive
heart failure. Development does not seem to
proceed further than sitting and standing without
support, and a few social responses such as smiling
and early vocalization. Unaided walking is not
accomplished, nor is toilet-training or self-feeding.
The affected children do not seem to survive more
than a few years (Leroy et al., 1971).
The appearance of the child becomes strikingly
similar to children with Hurler's syndrome. The
tongue is large, the earlobes fleshy, the forehead
high, the epicanthic folds prominent, the bridge of
the nose flat, the nostrils anteverted, and the upper
lip elongated (Sprangler & Wiedemann, 1970a). In
fact this is the diagnosis likely to be made. Apart
from the facies, dwarfed stature and severe retardation,
there is kyphoscoliosis, limited joint mobility
with claw hands, and sometimes enlargement of the
liver and spleen; but no clouding of the corneae.
The X-ray findings are somewhat similar as well.
There is marked periostieal new bone formation.
The tubular bones of the arms are short and plump.
The metacarpals are irregular and expanded and the
phalanges are bullet-shaped. The distal ends of the
radius and ulna are tilted. The vertebral bodies are
short and rounded and there may be beaking of the
last dorsal and first lumbar vertebrae. The ribs are
broad and the cranial vault is thickened. However,
the mucopolysaccharide excretion in the urine is
normal.
The peripheral lymphocytes and monocytes are
vacuolated and finely vacuolated cells are present in
the bone marrow. Cultured fibroblasts contain
coarse, regular, refringent inclusions staining blue
with toluidine blue, which are PAS and Sudan black
positive (Sprangler & Wiedemann, 1970b). Special
staining may also reveal metachromasia, indicating
that they contain mucopolysaccharides as well as
lipids (Matalon et al., 1968).
At necropsy foam cells are found in the endocardium,
lungs, spleen, liver, kidneys, adrenals and
aorta. Electron microscopy does not reveal the lipid
inclusions (zebra bodies) typical of Hurler's syndrome.
The lipid content of the tissues is generally
normal, ecept for some increase in total values
(Leroy et al., 1971). Liver acid P-galactosidase
activity has been found to be decreased, with hyperactivity
of a number of other enzymes (Tondeur
et al., 1971). Although the findings so far suggest a
storage disease involving both lipids and mucopolysaccharides
no definite cause can yet be suggested.
The differentiation from Hurler's syndrome is
made by the normal urinary excretion of mucopolysaccharides.
A somewhat similar clinical picture
occurs in mucolipidosis I or lipomucopolysaccharidosis,
but the features of gargoylism are not so marked
and the course of the disease is much more protracted.
Gm,-gangliosidosis, type I, has also been
referred to as pseudo-Hurler's syndrome because of
the appearance of the affected child, but the diagnosis
of this disease is confirmed by the abnormal
ganglioside pattern on thin layer chromatography of
brain extracts.


References
LEROY, J.G., SPRANGLER, J.W., FEINGOLD, M., OPITZ, J.M.
& CROCKER, A.C. (1971) I-cell disease: a clinical picture.
Pediatrics, 79, 360.
MATALON, R., CIFONELLI, J.A., ZELLWEGER, H. & DORFMAN,
A. (1968) Lipid abnormalities in a variant of the Hurler's
syndrome. Proceedings of the National Academy of Science,
59, 1097.
SPRANGLER, J.W. & WIEDEMANN, H-R. (1970a) The genetic
mucolipidoses. Neuropddiatrie, 2, 3.
SPRANGLER, J.W. & WIEDERMANN, H-R. (1970b) The genetic
mucolipidoses. Humangenetik, 9, 113.
TONDEUR, M., VAMAS-HURWITZ, E., MOCKEL-POHL, S.,
DERENME, J.P., CREMER, N. & LOEB, H. (1971) Clinical,
biochemical, and ultrastructural studies in a case of
chondrodystrophy presenting the I-cell phenotype in
tissue culture. Pediatrics, 79, 366

Information obtained from:
IINEIL GORDONM.D., F.R.C.P.

Hemophagocytic Lymphohistiocytosis (HLH)

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder of the immune system primarily affecting young infants and children. Although physicians have written about the disorder over the years, it has been only in the last few years that it has received more widespread attention. The prevalence of HLH is 1.2 in every 1,000,000 children under the age of 15.

In 1985, physicians from all over the world who were interested in studying the histiocyte and disorders related to this cell created the Histiocyte Society. Thanks to their research, in part financed by the Histiocytosis Association of America (HAA) and national subgroups, we now have a better understanding of the disease, as well as dramatically improved treatments. With growing knowledge, there is also increased awareness of the disease among nonspecialized physicians.

The disease usually presents with fever and sometimes other symptoms of an infection. In many cases, a pathogen (viral, bacterial, etc.) can be identified. The human body contains many cells including T-cells and histiocytes that fight infection. The activation of these cells causes an inflammatory reaction in the body. Normally, when the pathogen has been eliminated, the inflammatory reaction is turned off, and the immune system returns to its steady state. In HLH patients, due to defect of the immune system, the inflammatory reaction persists and causes the symptoms of HLH.

What is the cause of this severe immune dysregulation?
We currently know that HLH occurs either on the basis of a genetic defect or as a secondary form with underlying diseases such as infections, cancer, or rheumatic diseases. In the primary form, also known as familial hemophagocytic lymphohistiocytosis (FHL or FHLH), defective genes are inherited from both the mother and the father (autosomal recessive inheritance). FHL is diagnosed if there is more than one affected child in the family and/or a gene defect has been determined. FHL should be suspected if the symptoms do not disappear with treatment or if symptoms recur when therapy has been stopped. The onset of FHL is usually early in life, and a persistent cure can only be achieved with BMT (bone marrow transplantation). It is important to know that infections can trigger both the familial and the secondary disease.

So far, 3 gene defects have been identified, which account for approximately 50% to 80% of the familial cases, depending on the population that has been analyzed. Two of the genes, PRF1 and UNC13D, are responsible for the synthesis of proteins, perforin, and MUNC13-4 that are involved in the killing process of infectious pathogens. They are believed to also have a function in switching off immune responses. The precise mechanism, however, is not fully understood. A third defect affecting the Syntaxin 11 (STX11) gene has so far only been detected in patients of Turkish origin. The function of the mutated protein remains to be elucidated. There remains a considerable percentage of FHL patients with no known underlying gene defect.

In cases of secondary HLH, a condition of temporary immunodeficiency seems to contribute to the development of the disease.

Symptoms
Typical symptoms of HLH besides persistent fever are pallor (paleness), jaundice, liver and spleen enlargement, and neurological symptoms, such as irritability or even seizures. The involvement of the bone marrow, the site of blood cell production, can lead to severe decline of the blood cell counts (red and white blood cells and platelets). On bone marrow examination, histiocytes that are “eating” other blood cells (also known as phagocytosis) can be detected. Although the disease was named after this phenomenon, it can be absent at the onset or even throughout the course of the disease.

Because symptoms can vary widely, it is sometimes difficult for the physician to make a diagnosis of HLH early in the course of the disease without the help of specialized laboratory tests. To facilitate a rapid and accurate diagnosis, the Histiocyte Society has created diagnostic guidelines and recommendations concerning the treatment of HLH. This is known as the HLH-2004 treatment protocol.

How is HLH diagnosed?
It is sometimes difficult to establish the diagnosis of HLH, and the combination of the clinical picture and certain laboratory test criteria is required. A test that has been found very useful in substantiating a clinical diagnosis of HLH is absent or low NK (natural killer)-cell function. This is found in 90% of patients with FHL, as well as in many cases of secondary disease. Results of NK-cell function testing are generally reliable if the blood sample is properly shipped and tested in less than 24 hours. NK function cannot be determined prenatally, and it may not be reliably studied until a child is several weeks old. Notably, this test does not discriminate between familial and secondary disease.

Detection of perforin by staining of lymphocytes and analysis by flow cytometry is a highly reliable method for predicting the likelihood of the PRF1 gene mutation as the cause of FHL in a given patient. This test can also be used with reasonable predictive potential to screen parents and siblings to determine whether they might be carriers of PRF1 mutations. This test is not available prenatally.

Another test recently described analyzes the expression of a molecule on the surface of NK-cells (CD107) by flow cytometry that marks NK-cell degranulation. Reduced expression can predict mutations in the UNC13D gene. This test also requires specially prepared blood samples and cannot be used prenatally.

Genetic testing is recommended in cases of suspected FHL and confirms the diagnosis. Usually a blood sample is used. Even in the event of death, salvaged tissue can be tested. Once the genetic defect of a patient is known, the parents and siblings can be easily tested to determine if they are carriers for this specific defect. In such cases, prenatal diagnosis is possible as well.

How is HLH treated?
Without treatment, FHL is usually rapidly fatal with a median survival of about 2 months. The current treatment protocol, HLH 2004, provides recommendations for HLH therapy with a combination of immunosuppressive drugs and chemotherapy. The protocol has been accepted internationally and is used in many countries worldwide. In order to prevent early death or severe persisting organ damage, therapy must be initiated in a timely manner. In FHL cases, only temporary remission will be achieved. For a definite cure, the patient must undergo BMT.

With the former HLH-94 protocol and the now active HLH-2004 protocol, high remission rates and cure rates with BMT have been reported.

Secondary HLH sometimes resolves spontaneously or after treatment of the underlying disease. In some cases, modified immunochemotherapy can be applied, while in others, full immunochemotherapy is required.

Source: Histiocytosis Association of America

Cerebellar Pilocytic Astrocytoma

What is a cerebellar pilocytic astrocytoma?
(grade I pilocytic astrocytoma of the cerebellum)
(grade II fibrillary astrocytoma of the cerebellum)

A cerebellar low-grade glioma is a tumor arising from a type of cell of the central nervous system known as a glial cell. These tumors originate from a specific type of glial cell known as an astrocyte. Astrocytes make up the supportive network of the brain. These cells are named for their star-like appearance.

As you read further below, you will find general information about cerebellar low-grade glioma. If you would like to view summary information about brain tumors first, see the overview on brain tumors.

Cerebellar low-grade gliomas are astrocytomas that arise in the location of the brain known as the cerebellum. The cerebellum is the center of the brain that controls balance and coordination. Of patients with cerebellar low-grade gliomas, 80-85 percent have what is called grade I pilocytic astrocytomas, and the remaining 15-20 percent have what is called grade II fibrillary astrocytomas. These cerebellar astrocytomas account for 10-20 percent of all childhood brain tumors. They tend to occur before the age of 10 years, most commonly between the ages of 6 and 9.

What causes cerebellar low-grade gliomas?
Children with certain genetic syndromes, including neurofibromatosis type I and tuberous sclerosis, are at higher risk of developing tumors of glial origin, including cerebellar low-grade gliomas. The vast majority of children with cerebellar low-grade gliomas however, develop these tumors spontaneously, meaning there is no identifiable cause.

What are the symptoms of a cerebellar low-grade glioma?
Due to the relative slow growth rate of cerebellar low-grade gliomas, children with these tumors tend to present to the doctor with symptoms that have been occurring for many months. Some children, however, have a more sudden onset of symptoms. The following are the most common symptoms of a cerebellar low-grade glioma, however, each child may experience symptoms differently. Common symptoms may include:

Oh more that 90 percent of patients present with symptoms of increased pressure within the brain. These symptoms include:
*headache (generally upon awakening in the morning)
*vomiting
*fatigue
*Oh the majority of children have evidence of difficulty with balance and coordination

The symptoms of a brain tumor may resemble other conditions or medical problems. Always consult your child's physician for a diagnosis.

How is a cerebellar low-grade glioma diagnosed?
Diagnostic procedures for a cerebellar low-grade glioma may include:
*physical examination - the child may demonstrate difficulty walking and coordinating movements of the hands and/or legs
*computerized 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. CT scans are more detailed than general x-rays. For cerebellar low-grade gliomas, a CT scan of the brain is usually done.
*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. For cerebellar low-grade gliomas, an MRI of the brain is usually done. In rare cases when cerebellar low-grade gliomas spread to the spine, an MRI of the spine may also be ordered.
*biopsy - in many cases, a tissue sample from the tumor will be taken through a needle during a simple surgical procedure performed by a surgeon to confirm the diagnosis

What are the treatments for a cerebellar low-grade glioma?
Specific treatment for a cerebellar low-grade glioma will be determined by your child's physician based on:
*your child's age, overall health, and medical history
*type, location, and size of the tumor
*extent of the disease
*your child's tolerance for specific medications, procedures, or therapies
*how your child's doctors expects the disease to progress
*your opinion or preference

Treatment may include (alone or in combination):
*surgery - the initial treatment is surgery, and complete tumor removal is associated with a very high rate of cure. In cases when the tumor recurs after initial surgical removal, or if the tumor re-grows after partial surgical removal, the recommended treatment would be a second attempt at surgical removal/de-bulking of the tumor.
*radiation and chemotherapy - in cases of residual/recurrent disease, where maximal surgical removal has been achieved, alternative treatment options include chemotherapy and radiation therapy:
*chemotherapy - a drug treatment that works by interfering with the cancer cell's ability to grow or reproduce. Different groups of chemotherapy drugs work in different ways to fight cancer cells and shrink tumors. Often, a combination of chemotherapy drugs is used to fight a specific cancer. Certain chemotherapy drugs may be given in a specific order depending on the type of cancer it is being used to treat.A number of combinations of chemotherapy drugs are being tested to treat cerebellar low-grade gliomas, including vincristine with carboplatin, and vincristine with CCNU, procarbazine and thioguanine. While chemotherapy can be quite effective in treating certain cancers, the agents do not differentiate normal healthy cells from cancer cells. Because of this, there can be many adverse side effects during treatment. Being able to anticipate these side effects can help the care team, parents, and child prepare, and, in some cases, prevent these symptoms from occurring, if possible. Chemotherapy is systemic treatment, meaning it is introduced to the bloodstream and travels throughout the body to kill cancer cells.

Chemotherapy can be given:
*as a pill to swallow
*as an injection into the muscle or fat tissue
*intravenously (directly to the bloodstream; also called IV)
*intrathecally - chemotherapy given directly into the spinal column with a needle
*radiation therapy - using high-energy rays (radiation) from a specialized machine to damage or *kill cancer cells and shrink tumors. Radiation therapy to the tumor bed is also being used for recurrent disease.

The effectiveness of these methods of treatment is still being studied. There is some evidence to suggest that the use of chemotherapy and/or radiation therapy may increase long-term survival in children with incompletely removal tumors.

How are side effects of treatment managed?
Children with cerebellar low-grade gliomas may have side effects related to the tumor itself and its treatment. Symptoms at the time of diagnosis related to increased pressure within the brain, such as headache, vomiting and lethargy, are often relieved by surgical removal of the tumor. Effects on coordination and balance are also often improved with surgical removal of the tumor that is compressing structures that control these functions. Dexamethasone, an oral steroid, is often used, especially in the post-operative period, to assist in controlling these systems as well as any additional tissue swelling that may occur post-operatively.

Common side effects related to chemotherapy include nausea, vomiting and decreased blood counts (i.e. anemia). Anti-emetics (anti-nausea) medications are administered with the chemotherapy to control symptoms of nausea and vomiting. Occasionally, children receiving chemotherapy will require transfusion of red blood cells and/or platelets to replace these cells, since chemotherapy temporarily decreases the body's ability to produce red blood cells and platelets. White blood cells are reduced with chemotherapy, however these cells are not transfused. Occasionally, children will receive a medication to assist the body in producing white blood cells. Radiation therapy may cause swelling related to tissue inflammation. This inflammation may lead to symptoms of headache or difficulty with coordination. These symptoms, if significant, may be treated with the oral medication dexamethasone.

What is the expected outcome after treatment for cerebellar low-grade glioma?
Grade I cerebellar gliomas are associated with a 10-year survival rate of 70-100 percent after surgical removal alone. Grade II cerebellar gliomas are more likely to recur after surgical removal. Recurrent disease may necessitate the use of chemotherapy and/or radiation therapy. Inability to achieve a complete surgical removal and the presence of recurrent disease decreases prognosis and long-term survival.

What about progressive or recurrent disease?
The recommended treatment for progressive or recurrent cerebellar low-grade glioma is reattempt at surgical removal. In cases of progressive/recurrent disease, where maximal surgical removal has been achieved, chemotherapy and/or radiation therapy will be recommended. The Dana-Farber Cancer Institute is one of nine institutes in the nation belonging to the Pediatric Brain Tumor Consortium. The consortium is dedicated to the development of new and innovative treatments for children with progressive/recurrent brain tumors not responsive to standard therapies. Children with progressive/recurrent low-grade glioma of the cerebellum would be eligible for a number of experimental therapies available through the consortium.

(http://www.childrenshospital.org/)