Autopsy case of Gaucher disease type I in a patient on enzyme replacement therapy. Comments on the dynamics of persistent storage process.

We report a female patient with Gaucher disease (GD) type I on ERT (imiglucerase) for 5 years, which led to a significant general improvement. Aged 59 years she underwent an episode of altitude sickness followed by sepsis, disseminated intravascular coagulation, and multiorgan failure. She succumbed to a cerebral haemorrhage. Autopsy revealed liver cholestatic cirrhosis and multifocal liver carcinoma with immunophenotype compatible with cholangiocarcinoma. Analysis of the storage process revealed its absence or very low levels in the majority of liver and spleen macrophages. Gaucher cells (GCs) were seen only as occasional aggregates of various sizes in these organs. GCs were seen also in the leptomeninx of the cerebellum and as infrequent perivascular clusters in both the grey and white cerebral matters. Bone marrow was heavily infiltrated with GCs, especially in the adipocyte-rich part. GCs in this location displayed varied degrees of cytoplasmic vacuolation unrelated to the lysosomal compartment, caused by droplets of triglyceride, and interpreted as due to resorption of fragments of altered white adipocytes. All these observations point to the relative efficacy of ERT in covering the standard substrate load, which should not be exceeded as it would lead to the evolution of mature GCs. The results are discussed in relation to our recently published hypothesis on GD cell pathology.

We report a

    female
    GENDER

 patient with

    Gaucher disease (GD) type I
    DIAGNOSIS

 on

    ERT (imiglucerase) for 5 years
    MEDICATION

, which led to a

    significant general improvement
    SYMPTOMS

.

    Aged 59 years
    AGE

    she
    GENDER

 underwent an episode of

    altitude sickness
    SYMPTOMS

 followed by

    sepsis
    SYMPTOMS

,

    disseminated intravascular coagulation
    BIOCHEMICAL

, and

    multiorgan failure
    SYMPTOMS

.

    She
    GENDER

 succumbed to a

    cerebral haemorrhage
    SYMPTOMS

.

    Autopsy
    PARACLINICAL

 revealed

    liver cholestatic cirrhosis
    DIAGNOSIS

 and

    multifocal liver carcinoma
    DIAGNOSIS

 with immunophenotype compatible with

    cholangiocarcinoma
    DIAGNOSIS

.

    Analysis of the storage process
    PARACLINICAL

 revealed

    its absence or very low levels in the majority of liver and spleen macrophages
    MICROSCOPIC

.

    Gaucher cells (GCs) were seen only as occasional aggregates of various sizes in these organs
    MICROSCOPIC

.

    GCs were seen also in the leptomeninx of the cerebellum and as infrequent perivascular clusters in both the grey and white cerebral matters
    MICROSCOPIC

.

    Bone marrow was heavily infiltrated with GCs, especially in the adipocyte-rich part
    MICROSCOPIC

.

    GCs in this location
    MICROSCOPIC

 displayed

    varied degrees of cytoplasmic vacuolation unrelated to the lysosomal compartment, caused by droplets of triglyceride
    MICROSCOPIC

, and interpreted as due to

    resorption of fragments of altered white adipocytes
    MICROSCOPIC

. All these observations point to the relative efficacy of

    ERT
    MEDICATION

 in covering the standard substrate load, which should not be exceeded as it would lead to the

    evolution of mature GCs
    MICROSCOPIC

. The results are discussed in relation to our recently published hypothesis on

    GD cell pathology
    DIAGNOSIS

.

Gaucher disease (GD) type I
liver cholestatic cirrhosis
multifocal liver carcinoma
cholangiocarcinoma
GD cell pathology

significant general improvement
altitude sickness
sepsis
multiorgan failure
cerebral haemorrhage


Parkinsonism in Gaucher's disease type 1: ten new cases and a review of the literature.

Parkinsonism has been described in patients with Gaucher's disease (GD). We reviewed the 10 cases of patients with both parkinsonism and GD recorded in the French national GD registry, as well as 49 previously published cases. Relative to the general population, parkinsonism in GD patients (1) was more frequent, (2) occurred at an earlier age, (3) responded less well to levodopa, and (4) was more frequently associated with signs of cortical dysfunction. Enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) were ineffective on GD-associated parkinsonism, suggesting that parkinsonism itself is not an indication for ERT or SRT in this setting.

    Parkinsonism
    DIAGNOSIS

 has been described in patients with

    Gaucher's disease (GD)
    DIAGNOSIS

. We reviewed the 10 cases of patients with both

    parkinsonism
    DIAGNOSIS

 and

    GD
    DIAGNOSIS

 recorded in the French national GD registry, as well as 49 previously published cases. Relative to the general population,

    parkinsonism
    DIAGNOSIS

 in

    GD
    DIAGNOSIS

 patients (1) was more frequent, (2) occurred at an

    earlier age
    AGE

, (3)

    responded less well to levodopa
    NEG_FINDINGS

, and (4) was more frequently associated with

    signs of cortical dysfunction
    SYMPTOMS

.

    Enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) were ineffective on GD-associated parkinsonism
    NEG_FINDINGS

, suggesting that

    parkinsonism
    DIAGNOSIS

 itself is not an indication

    for ERT or SRT
    NEG_FINDINGS

 in this setting.

Parkinsonism
Gaucher's disease (GD)
parkinsonism
GD
parkinsonism
GD
parkinsonism


Partial splenic embolization in a child with Gaucher disease, massive splenomegaly and severe thrombocytopenia.

A 13-month-old boy with Gaucher disease presented with severe thrombocytopenia, anemia and massive splenomegaly. In addition he had significant respiratory compromise caused by abdominal compartment syndrome, requiring mechanical ventilation. Because of the degree of respiratory compromise and his existing bone marrow suppression, splenic artery embolization was chosen as an alternative to splenectomy. Splenic artery embolization was performed using 355-500-microm polyvinyl alcohol particles, with 70% ablation achieved. Within 24 h of the procedure the platelet count had risen to greater than 70,000/mm(3) and to more than 170,000/mm(3) on postoperative day 4. At the 8-month follow-up the splenic size had decreased from 18 cm to 8 cm, with a platelet count of 578,000/mm(3). Partial splenic embolization provides a minimally invasive alternative to splenectomy in patients with Gaucher disease with massive splenomegaly and bone marrow suppression.

A

    13-month-old
    AGE

    boy
    GENDER

 with

    Gaucher disease
    DIAGNOSIS

 presented with

    severe thrombocytopenia
    BIOCHEMICAL

,

    anemia
    BIOCHEMICAL

 and

    massive splenomegaly
    SYMPTOMS

. In addition

    he
    GENDER

 had

    significant respiratory compromise
    SYMPTOMS

 caused by

    abdominal compartment syndrome
    SYMPTOMS

, requiring

    mechanical ventilation
    MEDICATION

. Because of the degree of

    respiratory compromise
    SYMPTOMS

 and his existing

    bone marrow suppression
    SYMPTOMS

,

    splenic artery embolization
    MEDICATION

 was chosen as an

    alternative to splenectomy
    MEDICATION

.

    Splenic artery embolization
    MEDICATION

 was performed using

    355-500-microm polyvinyl alcohol particles
    MEDICATION

, with

    70% ablation achieved
    SYMPTOMS

. Within 24 h of the procedure the

    platelet count had risen to greater than 70,000/mm(3) and to more than 170,000/mm(3)
    BIOCHEMICAL

 on postoperative day 4. At the 8

    -month follow-up
    PARACLINICAL

 the

    splenic size had decreased from 18 cm to 8 cm
    SYMPTOMS

, with a

    platelet count of 578,000/mm(3)
    BIOCHEMICAL

.

    Partial splenic embolization
    MEDICATION

 provides a

    minimally invasive alternative to splenectomy
    MEDICATION

 in patients with

    Gaucher disease
    DIAGNOSIS

 with

    massive splenomegaly
    SYMPTOMS

 and

    bone marrow suppression
    SYMPTOMS

.


Chitotriosidase plasma activity in nephropathic cystinosis.

Chitotriosidase is a fully active chitinase produced and secreted by activated phagocytes. Plasma chitotriosidase activity is a well-established marker of total disease burden in Gaucher disease that has proved useful in monitoring the response to both enzyme replacement and substrate reduction therapies in patients with Gaucher disease. Increased chitotriosidase plasma activity has also been observed in several other lysosomal and non lysosomal disorders. Cystinosis, a rare multisystemic lysosomal storage disease, is characterized by the intralysosomal accumulation of free cystine in many cell types including phagocytes. We here report on plasma chitotriosidase activity in a child with nephropathic cystinosis. Increased plasma chitotriosidase activity (481 nmol/h per ml; normal range 0-150 units) was found on diagnosis and prior to the initiation of oral cysteamine (Cystagon) treatment. Serial estimations of plasma chitotriosidase activity showed that it correlated with leukocyte cystine content and decreased to 100 nmol/h per ml following 14 months' treatment. This novel observation suggests that cystinosis should be included in the differential diagnosis of disorders associated with increased plasma chitotriosidase activity. Furthermore, it suggests that serial estimations of plasma chitotriosidase activity could be of value in monitoring the response to oral cysteamine treatment in cystinosis.

    Chitotriosidase
    BIOCHEMICAL

 is a

    fully active chitinase produced and secreted by activated phagocytes
    BIOCHEMICAL

.

    Plasma chitotriosidase activity
    BIOCHEMICAL

 is a well-established marker of total disease burden in

    Gaucher disease
    DIAGNOSIS

 that has proved useful in monitoring the response to both

    enzyme replacement and substrate reduction therapies
    MEDICATION

 in patients with

    Gaucher disease
    DIAGNOSIS

.

    Increased chitotriosidase plasma activity
    BIOCHEMICAL

 has also been observed in several other

    lysosomal and non lysosomal disorders
    DIAGNOSIS

.

    Cystinosis
    DIAGNOSIS

, a

    rare multisystemic lysosomal storage disease
    DIAGNOSIS

, is characterized by the

    intralysosomal accumulation of free cystine in many cell types including phagocytes
    MICROSCOPIC

. We here report on

    plasma chitotriosidase activity
    BIOCHEMICAL

 in a

    child
    AGE

 with

    nephropathic cystinosis
    DIAGNOSIS

.

    Increased plasma chitotriosidase activity (481 nmol/h per ml; normal range 0-150 units)
    BIOCHEMICAL

 was found on diagnosis and prior to the

    initiation of oral cysteamine (Cystagon) treatment
    MEDICATION

.

    Serial estimations of plasma chitotriosidase activity
    PARACLINICAL

 showed that

    it correlated with leukocyte cystine content and decreased to 100 nmol/h per ml
    BIOCHEMICAL

 following

    14 months' treatment
    MEDICATION

. This novel observation suggests that

    cystinosis
    DIAGNOSIS

 should be included in the

    differential diagnosis
    PARACLINICAL

 of disorders associated with

    increased plasma chitotriosidase activity
    BIOCHEMICAL

. Furthermore, it suggests that

    serial estimations of plasma chitotriosidase activity
    PARACLINICAL

 could be of value in monitoring the response to

    oral cysteamine treatment
    MEDICATION

 in

    cystinosis
    DIAGNOSIS

.


The management of Gaucher disease in developing countries: a successful experience in Southern Brazil.

Gaucher disease (GD) is a genetic disease caused by glucocerebrosidase deficiency. GD is treated by enzyme replacement therapy (ERT) with imiglucerase, a high-cost drug provided by the Brazilian Ministry of Health (BMH). This study reports the implementation of the BMH guidelines for GD in the southernmost state of the country.

We review the clinical and laboratorial data for patients seen at the reference center for GD from Rio Grande do Sul, Brazil (July 2003 to June 2006).

Twenty-five patients were included in this study. At baseline, 19/20 were on ERT (mean dosage of imiglucerase = 51.8 U/kg/infusion), 3/17 presented anemia, and 5/16 thrombocytopenia. The amount of imiglucerase prescribed to these patients was adjusted according to the guidelines in July 2003; out of them, 18 were receiving ERT in the reference center at month 36 (mean dosage of imiglucerase = 27.5 U/kg/infusion), 2/18 presented anemia, and 4/18 presented thrombocytopenia. The analysis of the liver, spleen, and bone data presented some limitations, but the available information suggests that patients did not deteriorate. GD patients who initiated ERT after July 2003 (n = 5) received lower dosage of imiglucerase since the beginning of the treatment; most of them demonstrated clinical and laboratorial response. From baseline to month 36, the consumption of imiglucerase by the reference center showed a significant reduction, which represented savings of USD 3 million to the public health system.

The model of care of GD patients suggested by the BMH guidelines appears to be cost-effective and could be an example for management of rare diseases in underdeveloped countries.

    Gaucher disease (GD)
    DIAGNOSIS

 is a

    genetic disease
    GENETICS

 caused by

    glucocerebrosidase deficiency
    BIOCHEMICAL

.

    GD
    DIAGNOSIS

 is treated by

    enzyme replacement therapy (ERT) with imiglucerase, a high-cost drug
    MEDICATION

 provided by the Brazilian Ministry of Health (BMH). This study reports the implementation of the BMH guidelines for

    GD
    DIAGNOSIS

 in the southernmost state of the country.

We review the clinical and laboratorial data for patients seen at the reference center for

    GD
    DIAGNOSIS

 from Rio Grande do Sul,

    Brazil
    ETHNICITY

 (July 2003 to June 2006).

Twenty-five patients were included in this study. At baseline, 19/20 were

    on ERT (mean dosage of imiglucerase = 51.8 U/kg/infusion)
    MEDICATION

, 3/17 presented

    anemia
    BIOCHEMICAL

, and 5/16

    thrombocytopenia
    BIOCHEMICAL

. The

    amount of imiglucerase
    MEDICATION

 prescribed to these patients was adjusted according to the guidelines in July 2003; out of them, 18 were

    receiving ERT in the reference center at month 36 (mean dosage of imiglucerase = 27.5 U/kg/infusion)
    MEDICATION

, 2/18 presented

    anemia
    BIOCHEMICAL

, and 4/18 presented

    thrombocytopenia
    BIOCHEMICAL

. The

    analysis of the liver, spleen, and bone data
    PARACLINICAL

 presented some limitations, but the available information suggests that patients did

    not deteriorate
    NEG_FINDINGS

.

    GD
    DIAGNOSIS

 patients who initiated

    ERT
    MEDICATION

 after July 2003 (n = 5) received

    lower dosage of imiglucerase since the beginning of the treatment
    MEDICATION

; most of them demonstrated

    clinical and laboratorial response
    SYMPTOMS

. From baseline to month 36, the

    consumption of imiglucerase
    MEDICATION

 by the reference center showed a significant reduction, which represented savings of USD 3 million to the public health system.

The

    model of care
    MEDICATION

 of

    GD
    DIAGNOSIS

 patients suggested by the BMH guidelines appears to be cost-effective and could be an example for management of

    rare diseases
    DIAGNOSIS

 in underdeveloped countries.

Gaucher disease (GD)
GD
GD
GD
GD
GD
rare diseases

glucocerebrosidase deficiency
anemia
thrombocytopenia
anemia
thrombocytopenia


Alternative indications for bisphosphonate therapy.

Bisphosphonates are currently used in the treatment of osteoporosis (postmenopausal and steroid-induced), hypercalcemia of malignancy, Paget's disease of bone, multiple myeloma, and skeletally related events associated with metastatic bone disease in breast, prostate, lung, and other cancers. There are, however, numerous other conditions where a decrease in bone remodeling by bisphosphonates might aid in disease management. The focus of this review will be to discuss a select group of conditions for which bisphosphonate therapy may be efficacious. In this review we present several cases where bisphosphonates have been used as a primary or adjunctive treatment for giant cell lesions of the jaws. Use of bisphosphonate therapy for giant cell tumors of the appendicular skeleton, pediatric osteogenesis imperfecta, fibrous dysplasia, Gaucher's disease, and osteomyelitis will be discussed. Finally, we will review previous in vivo studies on the use of bisphosphonates to augment integration and to treat osteolysis surrounding failing orthopedic implants.

    Bisphosphonates
    MEDICATION

 are currently used in the treatment of

    osteoporosis
    DIAGNOSIS

    (postmenopausal and steroid-induced)
    DIAGNOSIS

,

    hypercalcemia of malignancy
    DIAGNOSIS

,

    Paget's disease of bone
    DIAGNOSIS

,

    multiple myeloma
    DIAGNOSIS

, and

    skeletally related events associated with metastatic bone disease in breast, prostate, lung
    SYMPTOMS

, and other

    cancers
    DIAGNOSIS

. There are, however, numerous other conditions where a

    decrease in bone remodeling
    SYMPTOMS

 by

    bisphosphonates
    MEDICATION

 might aid in disease management. The focus of this review will be to discuss a select group of conditions for which

    bisphosphonate therapy
    MEDICATION

 may be efficacious. In this review we present several cases where

    bisphosphonates
    MEDICATION

 have been used as a primary or

    adjunctive treatment
    MEDICATION

 for

    giant cell lesions of the jaws
    DIAGNOSIS

. Use of

    bisphosphonate therapy
    MEDICATION

 for

    giant cell tumors of the appendicular skeleton
    DIAGNOSIS

,

    pediatric osteogenesis imperfecta
    DIAGNOSIS

,

    fibrous dysplasia
    DIAGNOSIS

,

    Gaucher's disease
    DIAGNOSIS

, and

    osteomyelitis
    DIAGNOSIS

 will be discussed. Finally, we will review previous in vivo studies on the use of

    bisphosphonates to augment integration
    MEDICATION

 and to treat

    osteolysis surrounding failing orthopedic implants
    SYMPTOMS

.

Bisphosphonates
bisphosphonates
bisphosphonate therapy
bisphosphonates
adjunctive treatment
bisphosphonate therapy
bisphosphonates to augment integration


[Voluminous nodular splenomegaly in Gaucher disease: a case report].

Patients affected by type 1 Gaucher disease (an autosomal recessive inheritance lysosome storage disorder) develop nodular splenomegaly in 20 to 30% of cases where imiglucerase therapy proves ineffective. The lack of response to imiglucerase therapy on spleen nodules could be an indication of the existence or development of a malignant spleen. We report a 47-year-old man with Gaucher disease who presented with a voluminous splenic nodule, in whom therapy was delayed. Regular monitoring of patients is the most important factor to predict and therefore prevent morbidity.

Patients affected by

    type 1 Gaucher disease
    DIAGNOSIS

 (an

    autosomal recessive inheritance lysosome storage disorder
    GENETICS

) develop

    nodular splenomegaly
    SYMPTOMS

 in 20 to 30% of cases where

    imiglucerase therapy proves ineffective
    NEG_FINDINGS

. The

    lack of response to imiglucerase therapy on spleen nodules
    NEG_FINDINGS

 could be an indication of the existence or development of a

    malignant spleen
    DIAGNOSIS

. We report a

    47-year-old
    AGE

    man
    GENDER

 with

    Gaucher disease
    DIAGNOSIS

 who presented with a

    voluminous splenic nodule
    SYMPTOMS

, in whom

    therapy was delayed
    NEG_FINDINGS

. Regular monitoring of patients is the most important factor to predict and therefore prevent morbidity.

type 1 Gaucher disease
malignant spleen
Gaucher disease

nodular splenomegaly
voluminous splenic nodule


Osteonecrosis and antiphospholipid syndrome.

Osteonecrosis (ON), or avascular necrosis of bone, has been related to decreased blood flow to the bone. Many local and systemic factors have been implicated in the pathogenesis of ON, involving corticosteroid therapy, systemic lupus erythematosus (SLE), hemoglobinopathies, alcohol abuse, Caisson disease, Gaucher disease, and hypercoagulability states. We describe the case of a previously healthy young male with no history of corticosteroid therapy, who developed ON initially on the femoral head, and later on the humeral head with high levels of anticardiolipin antibodies (aCL), beta-2-glycoprotein 1 antibodies and positive lupus anticoagulant. The association between primary antiphospholipid syndrome (PAPS) and ON is controversial and few cases without other risk factors have been described. A review of ON pathogenesis and its relation with thrombotic microangiopathy because of PAPS is presented.

    Osteonecrosis (ON)
    DIAGNOSIS

, or

    avascular necrosis of bone
    SYMPTOMS

, has been related to

    decreased blood flow to the bone
    SYMPTOMS

. Many local and systemic factors have been implicated in the pathogenesis of ON, involving

    corticosteroid therapy
    MEDICATION

,

    systemic lupus erythematosus (SLE)
    DIAGNOSIS

,

    hemoglobinopathies
    DIAGNOSIS

,

    alcohol abuse
    DIAGNOSIS

,

    Caisson disease
    DIAGNOSIS

,

    Gaucher disease
    DIAGNOSIS

, and

    hypercoagulability states
    BIOCHEMICAL

. We describe the case of a previously healthy

    young
    AGE

    male
    GENDER

 with

    no history of corticosteroid therapy
    NEG_FINDINGS

, who developed

    ON initially on the femoral head, and later on the humeral head
    SYMPTOMS

 with

    high levels of anticardiolipin antibodies (aCL), beta-2-glycoprotein 1 antibodies
    BIOCHEMICAL

 and

    positive lupus anticoagulant
    BIOCHEMICAL

. The association between

    primary antiphospholipid syndrome (PAPS)
    DIAGNOSIS

 and

    ON
    DIAGNOSIS

 is controversial and few cases

    without other risk factors
    NEG_FINDINGS

 have been described. A review of ON pathogenesis and its relation with

    thrombotic microangiopathy
    DIAGNOSIS

 because of

    PAPS
    DIAGNOSIS

 is presented.

no history of corticosteroid therapy
without other risk factors


Recurrent cystic hygroma with hydrops.

A patient whose 5 fetuses, including a set of twins, were affected by cystic hygroma (CH) and hydrops is presented.

A 39-year-old gravida 12 para 7, 2, 2, 8 was followed through her pregnancies. Both patient and her spouse are of Ashkenazi Jewish descent and are non-consanguineous. The spouse has Gaucher disease and is on replacement therapy. The patient is not a carrier of any known allele of Gaucher disease. In 2 pregnancies, an ultrasonogram done at 12 weeks revealed a septated CH in 3 fetuses. We have excluded Noonan syndrome, Fryns syndrome and Gunther's disease as the responsible causes for the recurrent CH and aneuploidy in at least 3 of these fetuses.

The products of conception in 1 pregnancy showed low normal levels of glucocerebrosidase but no known Gaucher mutation.

We present a patient with recurrent CH in 5 fetuses (4 pregnancies) of which 3 fetuses had a normal karyotype. This appears to be an autosomal recessive disorder.

A patient whose

    5 fetuses, including a set of twins, were affected by cystic hygroma (CH)
    FAMILY

 and

    hydrops
    DIAGNOSIS

 is presented.

A

    39-year-old
    AGE

 gravida 12 para 7, 2, 2, 8 was followed through her

    pregnancies
    DIAGNOSIS

. Both patient and

    her
    GENDER

    spouse are of Ashkenazi Jewish descent
    FAMILY

 and are

    non-consanguineous
    FAMILY

. The

    spouse has Gaucher disease
    FAMILY

 and is

    on replacement therapy
    MEDICATION

. The patient is

    not a carrier of any known allele of Gaucher disease
    NEG_FINDINGS

. In 2

    pregnancies
    DIAGNOSIS

, an

    ultrasonogram
    PARACLINICAL

 done at 12 weeks revealed a

    septated CH in 3 fetuses
    SYMPTOMS

. We have excluded

    Noonan syndrome
    NEG_FINDINGS

,

    Fryns syndrome
    NEG_FINDINGS

 and

    Gunther's disease
    DIAGNOSIS

 as the responsible causes for the

    recurrent CH
    DIAGNOSIS

 and

    aneuploidy
    DIAGNOSIS

 in at least 3 of these fetuses.

The

    products of conception
    MEDICATION

 in 1

    pregnancy
    DIAGNOSIS

 showed

    low normal levels of glucocerebrosidase
    NEG_FINDINGS

 but

    no known Gaucher mutation
    NEG_FINDINGS

.

We present a patient with

    recurrent CH
    DIAGNOSIS

 in 5 fetuses (4 pregnancies) of which 3 fetuses had a

    normal karyotype
    NEG_FINDINGS

. This appears to be an

    autosomal recessive disorder
    GENETICS

.

hydrops
pregnancies
pregnancies
Gunther's disease
recurrent CH
aneuploidy
pregnancy
recurrent CH

on replacement therapy
products of conception


Type II Gaucher disease manifesting as haemophagocytic lymphohistiocytosis.

Haemophagocytic lymphohistiocytosis (HLH) is a rare and rapidly progressive disease which, untreated, invariably leads to death. Gaucher disease is a rare lysosomal storage disorder. The acute neuronopathic variant; type II, is also rapidly progressive. We report an infant with Gaucher disease type II manifesting as HLH. Immunoblot revealed a deficiency of Munc 13-4, an intracellular protein responsible for docking of secretory lysosomes. This, and other possible pathogenetic mechanisms to explain the link are discussed.

    Haemophagocytic lymphohistiocytosis (HLH)
    DIAGNOSIS

 is a rare and

    rapidly progressive disease
    DIAGNOSIS

 which, untreated, invariably leads to

    death
    SYMPTOMS

.

    Gaucher disease
    DIAGNOSIS

 is a

    rare lysosomal storage disorder
    DIAGNOSIS

. The

    acute neuronopathic variant; type II
    DIAGNOSIS

, is also

    rapidly progressive
    DIAGNOSIS

. We report an

    infant
    AGE

 with

    Gaucher disease type II
    DIAGNOSIS

 manifesting as

    HLH
    DIAGNOSIS

.

    Immunoblot
    PARACLINICAL

 revealed a

    deficiency of Munc 13-4, an intracellular protein responsible for docking of secretory lysosomes
    BIOCHEMICAL

. This, and other possible pathogenetic mechanisms to explain the link are discussed.


Giant lymphadenopathy infiltrated by gaucher cells mimicking lymphoma.

Gaucher disease (GD) is a lysosomal storage disease characterized by deficiency of beta-glucocerebrosidase, which results in accumulation of glucocerebroside in reticuloendothelial system, bone marrow infiltration, progressive hepatosplenomegaly, and skeletal complications. Herein we report a 5-year-old female with GD receiving enzyme replacement therapy who had giant mesenteric lymphadenopathies.

    Gaucher disease (GD)
    DIAGNOSIS

 is a

    lysosomal storage disease
    DIAGNOSIS

 characterized by

    deficiency of beta-glucocerebrosidase
    BIOCHEMICAL

, which results in

    accumulation of glucocerebroside in reticuloendothelial system
    MICROSCOPIC

,

    bone marrow infiltration
    MICROSCOPIC

,

    progressive hepatosplenomegaly
    SYMPTOMS

, and

    skeletal complications
    SYMPTOMS

. Herein we report a

    5-year-old
    AGE

    female
    GENDER

 with

    GD
    DIAGNOSIS

 receiving

    enzyme replacement therapy
    MEDICATION

 who had

    giant mesenteric lymphadenopathies
    SYMPTOMS

.

Gaucher disease (GD)
lysosomal storage disease
GD

progressive hepatosplenomegaly
skeletal complications
giant mesenteric lymphadenopathies


Familial hypophosphatemic vitamin D-resistant rickets--prevention of spontaneous dental abscesses on primary teeth: a case report.

Familial hypophosphatemic vitamin D-resistant rickets is a hereditary disease generally transmitted as an X-linked dominant trait and characterized by distinctive general clinical signs. Dental features include spontaneous dental abscesses that occur in the absence of a history of trauma or dental decay. The challenge for the dentist is to prevent and treat these lesions. This report describes the case of a young hypophosphatemic boy with abscesses. In this case, the application of fluid resin composites with a self-etching primer bonding system to all primary teeth prevented abscess formation for more than 1 year and thus avoided endodontic treatment or extraction. This constitutes a new approach to the prevention of spontaneous abscesses on primary teeth in children with familial hypophosphatemic rickets.

    Familial hypophosphatemic vitamin D-resistant rickets
    DIAGNOSIS

 is a

    hereditary disease
    GENETICS

 generally

    transmitted as an X-linked dominant trait
    GENETICS

 and characterized by

    distinctive general clinical signs
    SYMPTOMS

. Dental features include

    spontaneous dental abscesses
    SYMPTOMS

 that occur in the

    absence of a history of trauma or dental decay
    NEG_FINDINGS

. The challenge for the dentist is to prevent and treat these lesions. This report describes the case of a

    young
    AGE

    hypophosphatemic
    DIAGNOSIS

    boy
    GENDER

 with

    abscesses
    SYMPTOMS

. In this case, the

    application of fluid resin composites with a self-etching primer bonding system to all primary teeth
    MEDICATION

    prevented abscess formation for more than 1 year
    SYMPTOMS

 and thus

    avoided endodontic treatment or extraction
    NEG_FINDINGS

. This constitutes a new approach to the prevention of

    spontaneous abscesses on primary teeth
    SYMPTOMS

 in

    children
    AGE

 with

    familial hypophosphatemic rickets
    DIAGNOSIS

.


Enzyme replacement therapy for Gaucher's disease in patient treated for non-small cell lung cancer.

Gaucher's disease (GD) is an autosomal recessive lysosomal storage disease resulting in an abnormal accumulation of glucocerebrosides in macrophages. Recent studies have reported that patients with GD are at an increased risk of developing malignancies. Here, a rare case of a patient with Type I GD who developed adenocarcinoma of the lung that was treated with chemotherapy, radiotherapy and biological agents inhibiting receptor tyrosine kinases is presented. The patient developed unusually severe hematological toxicity to chemotherapy as compared to nonsmall cell lung cancer patients without the GD defect. Pancytopenia is already present in GD patients and it is reasonable to expect an increased risk of hematological toxicity in treating solid tumors in these patients. Therefore, it is advisable to consider early glucocerebrosidase replacement therapy in GD patients receiving cytotoxic or targeted therapy for cancer.

    Gaucher's disease (GD)
    DIAGNOSIS

 is an

    autosomal recessive
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 resulting in an

    abnormal accumulation of glucocerebrosides in macrophages
    MICROSCOPIC

. Recent studies have reported that patients with

    GD
    DIAGNOSIS

 are at an increased risk of developing

    malignancies
    DIAGNOSIS

. Here, a rare case of a patient with

    Type I GD
    DIAGNOSIS

 who developed

    adenocarcinoma of the lung
    DIAGNOSIS

 that was treated with

    chemotherapy, radiotherapy
    MEDICATION

 and

    biological agents inhibiting receptor tyrosine kinases
    MEDICATION

 is presented. The patient developed

    unusually severe hematological toxicity to chemotherapy
    SYMPTOMS

 as compared to

    nonsmall cell lung cancer
    DIAGNOSIS

 patients

    without the GD defect
    NEG_FINDINGS

.

    Pancytopenia
    BIOCHEMICAL

 is already present in

    GD
    DIAGNOSIS

 patients and it is reasonable to expect an increased risk of

    hematological toxicity
    SYMPTOMS

 in treating

    solid tumors
    DIAGNOSIS

 in these patients. Therefore, it is advisable to consider

    early glucocerebrosidase replacement therapy
    MEDICATION

 in

    GD
    DIAGNOSIS

 patients receiving

    cytotoxic or targeted therapy for cancer
    MEDICATION

.

Gaucher's disease (GD)
lysosomal storage disease
GD
malignancies
Type I GD
adenocarcinoma of the lung
nonsmall cell lung cancer
GD
solid tumors
GD


Phenotypic continuum of type 2 Gaucher's disease: an intermediate phenotype between perinatal-lethal and classic type 2 Gaucher's disease.

The natural history and clinical presentation of the perinatal-lethal Gaucher's disease, a severe variant of acute type 2 Gaucher's disease, is quite different from classic type 2 Gaucher's disease. Rare reported patients had an overlapping phenotype between these two forms confirming that phenotyping may be difficult. Here we report three patients with an intermediate phenotype. The first two patients showed at birth cholestatic jaundice, hepatosplenomegaly and hematological involvement consistent with hemophagocytosis in one patient, the death occurred from a severe liver involvement in one and lung disease in the second in the absence of neurological symptoms. The third patient displayed ichthyosis and facial dysmorphism but with neurological degeneration course and survival consistent with classic type 2 Gaucher's disease.

The natural history and clinical presentation of the

    perinatal-lethal Gaucher's disease
    DIAGNOSIS

, a

    severe variant of acute type 2 Gaucher's disease
    DIAGNOSIS

, is quite different from

    classic type 2 Gaucher's disease
    DIAGNOSIS

. Rare reported patients had an overlapping phenotype between these two forms confirming that phenotyping may be difficult. Here we report three patients with an intermediate phenotype. The first two patients showed at

    birth
    AGE

    cholestatic jaundice
    SYMPTOMS

,

    hepatosplenomegaly
    SYMPTOMS

 and

    hematological involvement
    MICROSCOPIC

    consistent with hemophagocytosis
    MICROSCOPIC

 in one patient, the

    death
    SYMPTOMS

 occurred from a

    severe liver involvement
    SYMPTOMS

 in one and

    lung disease
    SYMPTOMS

 in the second in the

    absence of neurological symptoms
    NEG_FINDINGS

. The third patient displayed

    ichthyosis
    SYMPTOMS

 and

    facial dysmorphism
    SYMPTOMS

 but with

    neurological degeneration course
    SYMPTOMS

 and

    survival
    SYMPTOMS

 consistent with

    classic type 2 Gaucher's disease
    DIAGNOSIS

.

cholestatic jaundice
hepatosplenomegaly
death
severe liver involvement
lung disease
ichthyosis
facial dysmorphism
neurological degeneration course
survival


A novel genotype c.1228C>G/c.1448C-1498C (L371V/Rec-NciI) in a 3-year-old child with type 1 Gaucher disease.

Gaucher disease (GD) is an autosomal recessive inborn error of metabolism, resulting from a deficiency of the enzyme glucocerebrosidase, causing an accumulation of the glycolipid glucocerebroside within lysosomes of macrophages in the reticuloendothelial system. Three major clinical forms have been assigned and more than 200 gene mutations have been identified. We herein report a Lebanese boy born with a novel combined mutation L371V/Rec-NciI, who presented with moderate-severe type 1 GD. An overview of the clinical and biomarker improvement following enzyme replacement therapy with imiglucerase is described in a follow-up of 30 months. Imiglucerase seems to be efficacious in decreasing the severity of the disease associated with this mutation. However, a high dose may be required to achieve optimal growth, platelet count, and hemoglobin level.

    Gaucher disease (GD)
    DIAGNOSIS

 is an

    autosomal recessive inborn error of metabolism
    GENETICS

, resulting from a

    deficiency of the enzyme glucocerebrosidase
    BIOCHEMICAL

, causing an

    accumulation of the glycolipid glucocerebroside within lysosomes of macrophages in the reticuloendothelial system
    MICROSCOPIC

. Three major clinical forms have been assigned and more than 200

    gene mutations
    GENETICS

 have been identified. We herein report a

    Lebanese
    ETHNICITY

    boy
    GENDER

 born with a

    novel combined mutation L371V/Rec-NciI
    GENETICS

, who presented with

    moderate-severe type 1 GD
    DIAGNOSIS

. An overview of the clinical and biomarker improvement following

    enzyme replacement therapy with imiglucerase
    MEDICATION

 is described in a follow-up of 30 months.

    Imiglucerase
    MEDICATION

 seems to be efficacious in decreasing the severity of the disease associated with this mutation. However, a high dose may be required to achieve

    optimal growth, platelet count, and hemoglobin level
    BIOCHEMICAL

.

Gaucher disease (GD)
moderate-severe type 1 GD


Gaucher disease: A 10 year old girl with anemia and huge spelenomegaly (a case report).

Gaucher's disease is a rare lipid storage disorder, affecting one in 40,000-200,000 people and results from a genetic deficiency of the enzyme glucocerebrosidase (glucosylceramidase). We report a 10-year old Iranian girl with chief complaint of anemia from 8 years ago, managed for iron deficiency anemia. The patient had hepatomegaly associated with huge splenomegaly which was confirmed by sonography. No skeletal disorder was found. Bone marrow aspiration revealed typical Gaucher cells. Low level of beta-glucocerebrosidase enzyme activity confirmed the Gaucher disease. The patient is now under treatment with CEREZIME, a recombinant DNA modified form of glucocerebrosidase with good condition.

    Gaucher's disease
    DIAGNOSIS

 is a

    rare lipid storage disorder
    DIAGNOSIS

, affecting one in 40,000-200,000 people and results from a

    genetic deficiency of the enzyme glucocerebrosidase (glucosylceramidase)
    GENETICS

. We report a

    10-year old
    AGE

    Iranian
    ETHNICITY

    girl
    GENDER

 with chief complaint of

    anemia
    BIOCHEMICAL

 from 8 years ago, managed for

    iron deficiency anemia
    BIOCHEMICAL

. The patient had

    hepatomegaly
    SYMPTOMS

 associated with

    huge splenomegaly
    SYMPTOMS

 which was confirmed by

    sonography
    PARACLINICAL

.

    No skeletal disorder was found
    NEG_FINDINGS

.

    Bone marrow aspiration
    PARACLINICAL

 revealed

    typical Gaucher cells
    MICROSCOPIC

.

    Low level of beta-glucocerebrosidase enzyme activity
    BIOCHEMICAL

 confirmed the

    Gaucher disease
    DIAGNOSIS

. The patient is now under

    treatment with CEREZIME, a recombinant DNA modified form of glucocerebrosidase
    MEDICATION

 with good condition.

Gaucher's disease
rare lipid storage disorder
Gaucher disease


Functional retinal changes in Gaucher disease.

In Gaucher disease, sphingolipid glucosylceramide is accumulated in cells of the reticulo-endothelial system. This leads to the formation of "Gaucher cells," which are enlarged macrophages. In the eye, circumscript preretinal deposits are a pathognomonic feature. We describe the case of a 23-year-old woman with no subjective complaints but a reduced ERG response, leading to the suspicion that in addition to circumscript deposition diffuse accumulation of metabolic endproducts might be present in the retina in Gaucher patients.

In

    Gaucher disease
    DIAGNOSIS

,

    sphingolipid glucosylceramide is accumulated in cells of the reticulo-endothelial system
    MICROSCOPIC

. This leads to the

    formation of "Gaucher cells," which are enlarged macrophages
    MICROSCOPIC

. In the eye,

    circumscript preretinal deposits
    MICROSCOPIC

 are a pathognomonic feature. We describe the case of a

    23-year-old
    AGE

    woman
    GENDER

 with

    no subjective complaints
    NEG_FINDINGS

 but a

    reduced ERG response
    SYMPTOMS

, leading to the suspicion that in addition to

    circumscript deposition
    MICROSCOPIC

    diffuse accumulation of metabolic endproducts
    MICROSCOPIC

 might be present

    in the retina
    MICROSCOPIC

 in

    Gaucher
    DIAGNOSIS

 patients.


Splenomegaly as a primary manifestation of Gaucher disease in a young adult woman.

Gaucher disease is the most common lysosomal storage disease. It is caused by the defective activity of acid β-glucosidase, which results in the accumulation of lipid glucocerebroside in macrophages throughout the body. In this case report we describe the case of a young adult woman with splenomegaly as the primary manifestation of this pathology. This is a case of type 1 Gaucher disease because there is a lack of primary neurological involvement but we have, instead, an age-independent involvement of the visceral organs. It is very important to classify or characterize these patients in a precise manner and to make a complete diagnosis with the help of the many diagnostic resources now at our disposal, especially with genetics, radiology and new techniques of advanced microscopy, also because Gaucher disease requires a long and complex management from early life to adulthood.

    Gaucher disease
    DIAGNOSIS

 is the most common

    lysosomal storage disease
    DIAGNOSIS

. It is caused by the

    defective activity of acid β-glucosidase
    BIOCHEMICAL

, which results in the

    accumulation of lipid glucocerebroside in macrophages throughout the body
    MICROSCOPIC

. In this case report we describe the case of a

    young adult
    AGE

    woman
    GENDER

 with

    splenomegaly
    SYMPTOMS

 as the primary manifestation of this pathology. This is a case of

    type 1 Gaucher disease
    DIAGNOSIS

 because there is a

    lack of primary neurological involvement
    NEG_FINDINGS

 but we have, instead, an

    age-independent involvement of the visceral organs
    SYMPTOMS

. It is very important to classify or characterize these patients in a precise manner and to make a complete diagnosis with the help of the many diagnostic resources now at our disposal, especially with genetics,

    radiology
    PARACLINICAL

 and new techniques of

    advanced microscopy
    PARACLINICAL

, also because

    Gaucher disease
    DIAGNOSIS

 requires a

    long and complex management
    MEDICATION

 from

    early life to adulthood
    AGE

.

Gaucher disease
lysosomal storage disease
type 1 Gaucher disease
Gaucher disease


Creating genetics-based infusion centers: a case study of two models.

In 1993, the first effective enzyme replacement therapy for a genetic disease, Ceredase (Genzyme Corporation, Cambridge, MA), was approved for use in patients with Gaucher disease. Over the next 13 years, enzyme replacement therapy became clinically available for the treatment of Fabry disease, mucopolysaccharidosis Type I, mucopolysaccharidosis Type II, mucopolysaccharidosis Type VI, and glycogen storage disease Type II. The development of enzyme replacement therapy to treat lysosomal storage diseases has resulted in an increasing number of genetic patients undergoing weekly or biweekly intravenous enzyme replacement therapy and an expanded role of the genetics team to include comprehensive care involving therapeutic intervention for lysosomal storage diseases. This article describes the development of two outpatient genetics-based infusion centers: the Northshore Genetics Infusion Clinic as part of the Children's Hospital of Wisconsin Lysosomal Diseases Treatment Center in conjunction with the Medical College of Wisconsin and the Emory Lysosomal Storage Disease Center for Genetic Infusions in the Emory University Department of Human Genetics.

In 1993, the first

    effective enzyme replacement therapy for a genetic disease
    MEDICATION

,

    Ceredase (
    MEDICATION

Genzyme Corporation, Cambridge, MA), was approved for use in patients with

    Gaucher disease
    DIAGNOSIS

. Over the next 13 years,

    enzyme replacement therapy
    MEDICATION

 became clinically available for the treatment of

    Fabry disease
    DIAGNOSIS

,

    mucopolysaccharidosis Type I
    DIAGNOSIS

,

    mucopolysaccharidosis Type II
    DIAGNOSIS

,

    mucopolysaccharidosis Type VI
    DIAGNOSIS

, and

    glycogen storage disease Type II
    DIAGNOSIS

. The development of

    enzyme replacement therapy
    MEDICATION

 to treat

    lysosomal storage diseases
    DIAGNOSIS

 has resulted in an increasing number of genetic patients undergoing

    weekly or biweekly intravenous enzyme replacement therapy
    MEDICATION

 and an expanded role of the genetics team to include

    comprehensive care involving therapeutic intervention
    MEDICATION

 for

    lysosomal storage diseases
    DIAGNOSIS

. This article describes the development of two

    outpatient genetics-based infusion centers
    MEDICATION

: the

    Northshore Genetics Infusion Clinic as part of the Children's Hospital of Wisconsin Lysosomal Diseases Treatment Center
    MEDICATION

 in conjunction with the Medical College of Wisconsin and the Emory

    Lysosomal Storage Disease Center for Genetic Infusions
    DIAGNOSIS

 in the Emory University Department of Human Genetics.


Gaucher's disease type III C: Unusual cause of intracardiac calcification.

We report a case of intracardiac calcification associated with oculomotor apraxia and corneal deposits in a 12-year-old girl, who presented with dyspnea on exertion, sinusitis, and epistaxis since the age of 6 years. Unusual presentation with multiorgan involvement prompted us to evaluate her in terms of metabolic/storage disorder. The bone marrow aspirate confirmed the diagnosis of Gaucher's disease.

We report a case of

    intracardiac calcification
    SYMPTOMS

 associated with

    oculomotor apraxia
    SYMPTOMS

 and

    corneal deposits
    SYMPTOMS

 in a

    12-year-old
    AGE

    girl
    GENDER

, who presented with

    dyspnea on exertion
    SYMPTOMS

,

    sinusitis
    SYMPTOMS

, and

    epistaxis
    SYMPTOMS

    since the age of 6 years
    AGE

. Unusual presentation with

    multiorgan involvement
    SYMPTOMS

 prompted us to evaluate

    her
    GENDER

 in terms of

    metabolic/storage disorder
    DIAGNOSIS

. The

    bone marrow aspirate
    PARACLINICAL

 confirmed the diagnosis of

    Gaucher's disease
    DIAGNOSIS

.

intracardiac calcification
oculomotor apraxia
corneal deposits
dyspnea on exertion
sinusitis
epistaxis
multiorgan involvement

metabolic/storage disorder
Gaucher's disease


Mitochondriopathy: a rare aetiology of restrictive cardiomyopathy.

When diagnosing a restrictive hypertrophied cardiomyopathy, most echocardiographists consider cardiac amyloidosis as a possible cause, especially after the appearance of 'granular' sparkling echoes on a transthoracic echocardiography. However, other infiltrative diseases (i.e. metabolic myopathies, Gaucher, Hunter's, and Hurler's diseases) or storage cardiomyopathies (haemochromatosis, Fabry's disease, glycogen storage, and Niemann-Pick disease) should be considered. In this paper, we report on another unusual cause of restrictive cardiomyopathy of which all cardiologists should be aware.

When diagnosing a

    restrictive hypertrophied cardiomyopathy
    DIAGNOSIS

, most

    echocardiographists
    PARACLINICAL

 consider

    cardiac amyloidosis
    DIAGNOSIS

 as a possible cause, especially after the appearance of

    'granular' sparkling echoes
    SYMPTOMS

 on a

    transthoracic echocardiography
    PARACLINICAL

. However, other

    infiltrative diseases
    DIAGNOSIS

 (i.e.

    metabolic myopathies
    DIAGNOSIS

,

    Gaucher, Hunter's, and Hurler's diseases
    DIAGNOSIS

) or

    storage cardiomyopathies
    DIAGNOSIS

 (

    haemochromatosis, Fabry's disease, glycogen storage, and Niemann-Pick disease)
    DIAGNOSIS

 should be considered. In this paper, we report on another unusual cause of

    restrictive cardiomyopathy
    DIAGNOSIS

 of which all

    cardiologists
    PARACLINICAL

 should be aware.


[Gaucher disease type I diagnosed at 63 years old presenting with thrombocytopenia].

A 63-year-old man who was incidentally found to have thrombocytopenia at a periodic physical examination visited our hospital. The spleen was palpable 3 finger-breadths below the navel level, and the liver was palpable 1 finger-breadth below the right costal margin. Peripheral blood examination showed WBC 2,900/microl, Hb 13.4 g/dl, and platelets 54 X 10(3)/ microl. Gaucher cells were recognized in the bone marrow by aspiration, and serum levels of total acid phosphatase and angiotensin converting enzyme were increased. Glucocerebrosidase activity was lower than the control level in bone marrow stroma cells, and modification of glucocerebrosidase genotype N188S was shown, which had been identified in the past. Furthermore, neurological examination was normal. Based on these results, we diagnosed the patient with Gaucher disease type I, and started enzyme replacement therapy. Gaucher disease is rare in Japanese, approximately 100 cases having been reported; diagnosis at older age is also relatively rare and, as far as we know, the oldest age reported in Japanese was 57 years old. Gaucher disease should be considered a differential diagnosis when thrombocytopenia and splenomegaly are found in elderly patients, although it is relatively rare.

A

    63-year-old
    AGE

    man
    GENDER

 who was incidentally found to have

    thrombocytopenia
    BIOCHEMICAL

 at a

    periodic physical examination
    PARACLINICAL

 visited our hospital. The

    spleen was palpable 3 finger-breadths below the navel level
    SYMPTOMS

, and the

    liver was palpable 1 finger-breadth below the right costal margin
    SYMPTOMS

.

    Peripheral blood examination
    PARACLINICAL

 showed

    WBC 2,900/microl, Hb 13.4 g/dl
    BIOCHEMICAL

, and

    platelets 54 X 10(3)/ microl
    BIOCHEMICAL

.

    Gaucher cells were recognized in the bone marrow
    MICROSCOPIC

 by

    aspiration
    PARACLINICAL

, and

    serum levels of total acid phosphatase and angiotensin converting enzyme were increased
    BIOCHEMICAL

.

    Glucocerebrosidase activity was lower than the control level in bone marrow stroma cells
    BIOCHEMICAL

, and

    modification of glucocerebrosidase genotype N188S was shown
    GENETICS

, which had been identified in the past. Furthermore,

    neurological examination was normal
    NEG_FINDINGS

. Based on these results, we diagnosed the patient with

    Gaucher disease type I
    DIAGNOSIS

, and started

    enzyme replacement therapy
    MEDICATION

.

    Gaucher disease
    DIAGNOSIS

 is rare in

    Japanese
    ETHNICITY

, approximately 100 cases having been reported; diagnosis at

    older age
    AGE

 is also relatively rare and, as far as we know, the oldest age reported in

    Japanese
    ETHNICITY

 was

    57 years old
    AGE

.

    Gaucher disease
    DIAGNOSIS

 should be considered a

    differential diagnosis
    PARACLINICAL

 when

    thrombocytopenia
    BIOCHEMICAL

 and

    splenomegaly
    SYMPTOMS

 are found in

    elderly
    AGE

 patients, although it is relatively rare.

Gaucher disease type I
Gaucher disease
Gaucher disease


Pulmonary extramedullary hematopoiesis.

Extramedullary hematopoiesis (EMH) is the formation and development of blood cells outside of the bone marrow. Of particular interest to chest physicians and radiologists is the occurrence of EMH in the lungs and pleura. There have been several reports of patients presenting with pulmonary EMH published in the literature and the majority are due to a secondary process, such as myeloproliferative disorders, hemolytic anemias, hereditary spherocytosis, and Gaucher disease. We present a case report of pulmonary EMH and a review of the literature concentrating on the etiology, clinical presentation, pathophysiology, diagnosis, and therapy for this uncommon disorder.

    Extramedullary hematopoiesis (EMH)
    MICROSCOPIC

 is the

    formation and development of blood cells outside of the bone marrow
    MICROSCOPIC

. Of particular interest to

    chest physicians
    PARACLINICAL

 and

    radiologists
    PARACLINICAL

 is the occurrence of

    EMH in the lungs and pleura
    MICROSCOPIC

. There have been several reports of patients presenting with

    pulmonary EMH
    MICROSCOPIC

 published in the literature and the majority are due to a secondary process, such as

    myeloproliferative disorders
    DIAGNOSIS

,

    hemolytic anemias
    DIAGNOSIS

,

    hereditary spherocytosis
    DIAGNOSIS

, and

    Gaucher disease
    DIAGNOSIS

. We present a case report of

    pulmonary EMH
    DIAGNOSIS

 and a review of the literature concentrating on the etiology, clinical presentation, pathophysiology, diagnosis, and therapy for this

    uncommon disorder
    DIAGNOSIS

.

myeloproliferative disorders
hemolytic anemias
hereditary spherocytosis
Gaucher disease
pulmonary EMH
uncommon disorder


[Gaucher disease: importance of early diagnosis and therapy].

Gaucher disease is the most common lysosomal storage disorder caused by deficiency of the lysosomal enzyme glucocerebrosidase. By the end of 2006, the total enrollment in the international Gaucher Disease Registry included 4584 patients, 34 of them were Hungarian. The disease has three main types: non neuropathic (Type 1), acute neuropathic (Type 2), and chronic neuropathic (Type 3). The non-neuropathic type has the highest prevalence and also the greatest variability. The first symptoms occur before 10 years of age in more than 50% of the patients. Early onset of the clinical symptoms and signs predispose patients to severe phenotype and irreversible complications. Safe and efficient enzyme substitution therapy has been available from 1991 and applied since 1992 in Hungary. Optimal dose and early therapy are effective in stopping disease progression, leading to the regression of visceral and haematological abnormalities, preventing irreversible bone deformities, and providing a better quality of life. The authors present here three patients with Gaucher disease diagnosed in early childhood. They highlight the importance of early diagnosis and treatment before the development of severe co-morbidities or irreversible complications. They also analyse the challenges for pediatricians in establishing correct diagnosis of Gaucher disease in time.

    Gaucher disease
    DIAGNOSIS

 is the most common

    lysosomal storage disorder
    DIAGNOSIS

 caused by

    deficiency of the lysosomal enzyme glucocerebrosidase
    BIOCHEMICAL

. By the end of 2006, the total enrollment in the international

    Gaucher Disease
    DIAGNOSIS

 Registry included 4584 patients, 34 of them were

    Hungarian
    ETHNICITY

. The disease has three main types:

    non neuropathic (Type 1)
    DIAGNOSIS

,

    acute neuropathic (Type 2)
    DIAGNOSIS

, and

    chronic neuropathic (Type 3)
    DIAGNOSIS

. The

    non-neuropathic type
    DIAGNOSIS

 has the highest prevalence and also the greatest variability. The first symptoms occur

    before 10 years of age
    AGE

 in more than 50% of the patients.

    Early onset of the clinical symptoms and signs
    SYMPTOMS

 predispose patients to

    severe phenotype
    SYMPTOMS

 and

    irreversible complications
    SYMPTOMS

.

    Safe and efficient enzyme substitution therapy
    MEDICATION

 has been available from 1991 and applied since 1992 in

    Hungary
    ETHNICITY

.

    Optimal dose and early therapy
    MEDICATION

 are effective in

    stopping disease progression
    SYMPTOMS

, leading to the

    regression of visceral and haematological abnormalities
    SYMPTOMS

,

    preventing irreversible bone deformities
    SYMPTOMS

, and providing a

    better quality of life
    SYMPTOMS

. The authors present here three patients with

    Gaucher disease
    DIAGNOSIS

 diagnosed in

    early childhood
    AGE

. They highlight the importance of early diagnosis and treatment before the development of

    severe co-morbidities
    SYMPTOMS

 or

    irreversible complications
    SYMPTOMS

. They also analyse the challenges for

    pediatricians
    PARACLINICAL

 in establishing correct diagnosis of

    Gaucher disease
    DIAGNOSIS

 in time.

Gaucher disease
lysosomal storage disorder
Gaucher Disease
non neuropathic (Type 1)
acute neuropathic (Type 2)
chronic neuropathic (Type 3)
non-neuropathic type
Gaucher disease
Gaucher disease


Pseudo-Gaucher cells in multiple myeloma.

A case of multiple myeloma is reported in which the bone marrow contained sheets of histiocytes with light microscopic features mimicking Gaucher cells. The patient had no clinical evidence of inherited Gaucher's disease. These pseudo-Gaucher cells obscured neoplastic plasma cells causing diagnostic difficulty.

A case of

    multiple myeloma
    DIAGNOSIS

 is reported in which

    the bone marrow contained sheets of histiocytes with light microscopic features mimicking Gaucher cells
    MICROSCOPIC

. The patient had

    no clinical evidence of inherited Gaucher's disease
    NEG_FINDINGS

. These

    pseudo-Gaucher cells obscured neoplastic plasma cells
    MICROSCOPIC

 causing diagnostic difficulty.


Functional antibody deficiency in a patient with type I Gaucher disease.

Gaucher disease (GD), the most common lysosomal storage disorder, demonstrates an autosomal recessive pattern of inheritance. The genetic defect in GD leads to decreased production of the lysosomal enzyme glucosylceramide hydrolase, thereby resulting in the deposition of glucosylceramide sphingolipids within multiple organ systems. Although the precise mechanisms remain unclear, GD is usually associated with chronic antigenic stimulation and hyperimmunoglobulinaemia. We report a novel case of type I GD coexisting with relatively low serum immunoglobulins, impaired antibody production, and recurrent bacterial infections in a 62-year-old male. The patient had been diagnosed with GD 30 years previously and had subsequently started enzyme replacement therapy. Since being diagnosed with GD, the patient had suffered from repeated episodes of acute bronchitis and a recent severe bout of community-acquired pneumonia that required a lengthy hospitalization. On our initial evaluation, the patient had laboratory testing that demonstrated: decreased serum IgG, IgG2, and IgA levels; reduced absolute CD3(+)/CD4(+), CD3(+)/CD8(+), and lymphocyte counts; low IgG titres to pneumococcal polysaccharide vaccine; and decreased anti-tetanus antibodies. Lymphocyte function analysis demonstrated a normal response to phytohaemagglutinin, and decreased responses to concanavalin A and pokeweed mitogen. Repeat testing after 6 months revealed normal serum immunoglobulin levels and mitogenic responses. Although the explanation for our observed transient hypogammaglobulinaemia remains unclear, this patient's clinical constellation (i.e. repeated infections, hypogammaglobulinaemia and lymphopenia, decreased post-vaccination titres, and impaired responses to some mitogens) shares overlapping features with common variable immunodeficiency (CVID).

    Gaucher disease (GD)
    DIAGNOSIS

, the most common

    lysosomal storage disorder
    DIAGNOSIS

, demonstrates an

    autosomal recessive pattern of inheritance
    GENETICS

. The

    genetic defect
    GENETICS

 in

    GD
    DIAGNOSIS

 leads to

    decreased production of the lysosomal enzyme glucosylceramide hydrolase
    BIOCHEMICAL

, thereby resulting in the

    deposition of glucosylceramide sphingolipids within multiple organ systems
    MICROSCOPIC

. Although the precise mechanisms remain unclear,

    GD
    DIAGNOSIS

 is usually associated with

    chronic antigenic stimulation
    SYMPTOMS

 and

    hyperimmunoglobulinaemia
    BIOCHEMICAL

. We report a novel case of

    type I GD
    DIAGNOSIS

 coexisting with

    relatively low serum immunoglobulins
    BIOCHEMICAL

,

    impaired antibody production
    BIOCHEMICAL

, and

    recurrent bacterial infections
    SYMPTOMS

 in a

    62-year-old
    AGE

    male
    GENDER

. The patient had been diagnosed with

    GD
    DIAGNOSIS

 30 years previously and had subsequently started

    enzyme replacement therapy
    MEDICATION

. Since being diagnosed with

    GD
    DIAGNOSIS

, the patient had suffered from

    repeated episodes of acute bronchitis
    SYMPTOMS

 and a

    recent severe bout of community-acquired pneumonia
    SYMPTOMS

 that required a

    lengthy hospitalization
    MEDICATION

. On our initial evaluation, the patient had

    laboratory testing
    PARACLINICAL

 that demonstrated:

    decreased serum IgG, IgG2, and IgA levels
    BIOCHEMICAL

;

    reduced absolute CD3(+)/CD4(+), CD3(+)/CD8(+), and lymphocyte counts
    BIOCHEMICAL

;

    low IgG titres to pneumococcal polysaccharide vaccine
    BIOCHEMICAL

; and

    decreased anti-tetanus antibodies
    BIOCHEMICAL

.

    Lymphocyte function analysis
    PARACLINICAL

 demonstrated a

    normal response to phytohaemagglutinin,
    NEG_FINDINGS

 and

    decreased responses to concanavalin A and pokeweed mitogen
    NEG_FINDINGS

.

    Repeat testing after 6 months
    PARACLINICAL

 revealed

    normal serum immunoglobulin levels and mitogenic responses
    NEG_FINDINGS

. Although the explanation for our observed

    transient hypogammaglobulinaemia
    BIOCHEMICAL

 remains unclear, this patient's clinical constellation (i.e.

    repeated infections
    SYMPTOMS

,

    hypogammaglobulinaemia and lymphopenia
    BIOCHEMICAL

,

    decreased post-vaccination titres
    BIOCHEMICAL

, and

    impaired responses to some mitogens
    BIOCHEMICAL

) shares overlapping features with

    common variable immunodeficiency (CVID)
    DIAGNOSIS

.

Gaucher disease (GD)
lysosomal storage disorder
GD
GD
type I GD
GD
GD
common variable immunodeficiency (CVID)

enzyme replacement therapy
lengthy hospitalization


Gaucher's disease: report of 4 cases.

Review of records for last 5 years has shown 4 cases of Type I Gaucher's disease in our institute. The cases were diagnosed on bone marrow aspiration, examination of splenectomy specimen, liver biopsy and post mortem in one case. The age range was 2 years to 22 years. Male to female ratio was 3:1. Splenectomy was performed in one case and one case received enzyme replacement therapy with high dose, low frequency regimen for six months without any favorable effect. All were Hindus. Family history of similarly affected and treated twin brother was available in one case. The predominant clinical presentation was pancytopenia and splenohepatomegaly with splenomegaly greater than hepatomegaly. Remarkable constitutional inferiority was noted in one case, which succumbed to death following acute illness and bleeding diathesis. Post mortem performed showed infiltration of spleen and liver with Gaucher cells, fibrosis and myeloid metaplasia in liver and lung.

Review of records for last 5 years has shown 4 cases of

    Type I Gaucher's disease
    DIAGNOSIS

 in our institute. The cases were diagnosed on

    bone marrow aspiration
    PARACLINICAL

,

    examination of splenectomy specimen
    PARACLINICAL

,

    liver biopsy
    PARACLINICAL

 and

    post mortem
    PARACLINICAL

 in one case. The

    age range was 2 years to 22 years
    AGE

.

    Male
    GENDER

 to

    female
    GENDER

 ratio was 3:1.

    Splenectomy
    MEDICATION

 was performed in one case and one case received

    enzyme replacement therapy with high dose, low frequency regimen for six months
    MEDICATION

    without any favorable effect
    NEG_FINDINGS

. All were

    Hindus
    ETHNICITY

.

    Family history of similarly affected and treated twin brother was available
    FAMILY

 in one case. The predominant clinical presentation was

    pancytopenia
    BIOCHEMICAL

 and

    splenohepatomegaly
    SYMPTOMS

 with

    splenomegaly greater than hepatomegaly
    SYMPTOMS

.

    Remarkable constitutional inferiority
    SYMPTOMS

 was noted in one case, which succumbed to

    death
    SYMPTOMS

 following

    acute illness
    SYMPTOMS

 and

    bleeding diathesis
    SYMPTOMS

.

    Post mortem
    PARACLINICAL

 performed showed

    infiltration of spleen and liver with Gaucher cells, fibrosis and myeloid metaplasia in liver and lung
    MICROSCOPIC

.

splenohepatomegaly
splenomegaly greater than hepatomegaly
Remarkable constitutional inferiority
death
acute illness
bleeding diathesis


Laparoscopic subtotal splenectomy.

Since 1979, we have been studying subtotal splenectomy. This procedure was used in over 200 patients to treat splenic trauma, portal hypertension, myeloid metaplasia due to myelofibrosis, Gaucher disease, chronic lymphocytic leukemia, retarded growth, and sexual development associated with splenomegaly, and disorders of the pancreatic tail. On the basis of our clinic experience with laparoscopic splenectomy with and without splenic autotransplantation, open subtotal splenectomy, and after a training period with laparoscopic conservative splenic operations on animals, this communication presents laparoscopic subtotal splenectomy as a new treatment of severe pain due to ischemia of the spleen.

Two patients with severe splenic pain due to ischemia provoked by vascular obstruction of the spleen were successfully treated by laparoscopic subtotal splenectomy, with preservation of the upper splenic pole supplied only by the gastrosplenic vessels.

This procedure was safely conducted with minor bleeding and no technical difficulties or complications. The postoperative follow-up of 5 and 21 months has been uneventful and the pain disappeared since the first postoperative day.

It is feasible and safe to perform subtotal splenectomy by laparoscopy. This procedure seems to be a good treatment for pain due to splenic ischemia.

Since 1979, we have been studying

    subtotal splenectomy
    MEDICATION

. This procedure was used in over 200 patients to treat

    splenic trauma
    SYMPTOMS

,

    portal hypertension
    SYMPTOMS

,

    myeloid metaplasia due to myelofibrosis
    DIAGNOSIS

,

    Gaucher disease
    DIAGNOSIS

,

    chronic lymphocytic leukemia
    DIAGNOSIS

,

    retarded growth, and sexual development
    SYMPTOMS

 associated with

    splenomegaly
    SYMPTOMS

, and

    disorders of the pancreatic tail
    DIAGNOSIS

. On the basis of our clinic experience with

    laparoscopic splenectomy with and without splenic autotransplantation
    MEDICATION

,

    open subtotal splenectomy
    MEDICATION

, and after a training period with

    laparoscopic conservative splenic operations
    MEDICATION

 on animals, this communication presents

    laparoscopic subtotal splenectomy
    MEDICATION

 as a new treatment of

    severe pain due to ischemia of the spleen
    SYMPTOMS

.

Two patients with

    severe splenic pain
    SYMPTOMS

 due to

    ischemia
    SYMPTOMS

 provoked by

    vascular obstruction of the spleen
    SYMPTOMS

 were successfully treated by

    laparoscopic subtotal splenectomy
    MEDICATION

, with

    preservation of the upper splenic pole supplied only by the gastrosplenic vessels
    MEDICATION

.

This procedure was safely conducted with

    minor bleeding
    SYMPTOMS

 and

    no technical difficulties or complications
    NEG_FINDINGS

. The postoperative

    follow-up
    PARACLINICAL

 of 5 and 21 months has been

    uneventful
    SYMPTOMS

 and the

    pain disappeared
    SYMPTOMS

 since the first postoperative day.

It is feasible and safe to perform

    subtotal splenectomy
    MEDICATION

 by

    laparoscopy
    MEDICATION

. This procedure seems to be a good treatment for

    pain due to splenic ischemia
    SYMPTOMS

.

myeloid metaplasia due to myelofibrosis
Gaucher disease
chronic lymphocytic leukemia
disorders of the pancreatic tail


[A 56-year-old patient with Gaucher's disease sustaining a pathologic subcapital fracture of the humerus].

We present a case of a pathologic humerus fracture in a patient with the initial diagnosis of Gaucher's disease, which is the most frequent form of lipidosis transmitted as an autosomal recessive trait. It often results in orthopaedic complications with pain, osteonecrosis, fractures and joint infractions. If there is cause for suspicion, beta-glucocerebrosidase in white blood cells should be measured because of the important consequences for treatment. Therapy with a modified enzyme is effective in managing the disease.

We present a case of a

    pathologic humerus fracture
    SYMPTOMS

 in a patient with the initial diagnosis of

    Gaucher's disease
    DIAGNOSIS

, which is the most frequent form of

    lipidosis
    DIAGNOSIS

    transmitted as an autosomal recessive trait
    GENETICS

. It often results in

    orthopaedic complications
    SYMPTOMS

 with

    pain
    SYMPTOMS

,

    osteonecrosis
    SYMPTOMS

,

    fractures
    SYMPTOMS

 and

    joint infractions
    SYMPTOMS

. If there is cause for suspicion,

    beta-glucocerebrosidase in white blood cells
    BIOCHEMICAL

 should be measured because of the important consequences for treatment.

    Therapy with a modified enzyme
    MEDICATION

 is effective in managing the disease.

pathologic humerus fracture
orthopaedic complications
pain
osteonecrosis
fractures
joint infractions


[Current development and usefulness of biomarkers for Gaucher disease follow up].

Gaucher's disease is due to glucocerebrosidase deficiency which is responsible for the accumulation of non degraded glucosylceramide within the lysosomes of macrophages: these "Gaucher cells", overloaded and alternatively activated, release in patient's plasma numerous compounds (cytokines, chemokines, hydrolases...) some of which contribute to the various tissue damages. Some of these compounds are surrogate biomarkers which contribute to the evaluation of disease severity, progression and stabilisation or regression during treatment. To date, the most interesting biomarkers are chitotriosidase and the chemokine CCL18/PARC, especially in chitotriosidase deficient patients. These biomarkers together with the clinical evaluation help to therapeutic choice (treatment by enzyme replacement therapy or substrate reduction therapy) and initiation decision, response follow-up and dose adjustments. Biomarkers should be assessed every 12 months together with clinical evaluation in patients not receiving specific treatments. An assessment every 3 months is recommended during the first year of treatment. Then when clinical goals have been achieved, the frequency can be reduced to every 12 months if the therapeutic scheme is not modified.

    Gaucher's disease
    DIAGNOSIS

 is due to

    glucocerebrosidase deficiency
    BIOCHEMICAL

 which is responsible for the

    accumulation of non degraded glucosylceramide within the lysosomes of macrophages
    MICROSCOPIC

:

    these "Gaucher cells", overloaded and alternatively activated, release in patient's plasma numerous compounds (cytokines, chemokines, hydrolases
    MICROSCOPIC

...) some of which contribute to the various

    tissue damages
    SYMPTOMS

. Some of these compounds are surrogate biomarkers which contribute to the evaluation of disease severity, progression and stabilisation or regression during treatment. To date, the most interesting biomarkers are

    chitotriosidase
    BIOCHEMICAL

 and the

    chemokine CCL18/PARC
    BIOCHEMICAL

, especially in

    chitotriosidase deficient
    BIOCHEMICAL

 patients. These biomarkers together with the clinical evaluation help to therapeutic choice (

    treatment by enzyme replacement therapy or substrate reduction therapy)
    MEDICATION

 and initiation decision,

    response follow-up
    PARACLINICAL

 and

    dose adjustments
    MEDICATION

. Biomarkers should be

    assessed every 12 months
    PARACLINICAL

 together with

    clinical evaluation
    PARACLINICAL

 in patients

    not receiving specific treatments
    NEG_FINDINGS

. An

    assessment every 3 months
    PARACLINICAL

 is recommended during the first year of treatment. Then when clinical goals have been achieved, the frequency can be reduced to every 12 months if the therapeutic scheme is not modified.

glucocerebrosidase deficiency
chitotriosidase
chemokine CCL18/PARC
chitotriosidase deficient


Imiglucerase treatment in Gaucher's disease.

Gaucher's disease is an inherited lysosomal storage disorder with a deficiency of the enzyme glucocerbrosidase that manifests with clinical features of anemia, hepato-splenomegaly, skeletal destruction and organ dysfunction due to the accumulation of glucocerbrosides. There are several types of Gaucher's disease with varying prognosis and clinical progression of disease. We describe two cases followed at the Aga Khan University, Karachi, Pakistan, with different forms of the disorder. The enzyme Imiglucerase (Cerezyme, Genzyme) has been used to treat Type 1 Gaucher disease while the neuronopathic type has been resistant to therapy. We used Imiglucerase 60 microg/kg every 2 weeks in one patient with Type 1 Gaucher disease and followed hepatic, splenic volumes and blood counts. Treatment with Imiglucerase resulted in a decrease in splenic size, reduced requirements for transfusions and an improvement in cardiopulmonary symptoms.

    Gaucher's disease
    DIAGNOSIS

 is an

    inherited
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 with a

    deficiency of the enzyme glucocerbrosidase
    BIOCHEMICAL

 that manifests with clinical features of

    anemia
    BIOCHEMICAL

,

    hepato-splenomegaly
    SYMPTOMS

,

    skeletal destruction
    SYMPTOMS

 and

    organ dysfunction
    SYMPTOMS

 due to the

    accumulation of glucocerbrosides
    MICROSCOPIC

. There are several types of

    Gaucher's disease
    DIAGNOSIS

 with varying prognosis and clinical progression of disease. We describe two cases followed at the Aga Khan University, Karachi,

    Pakistan
    ETHNICITY

, with different forms of the disorder. The

    enzyme Imiglucerase (Cerezyme, Genzyme)
    MEDICATION

 has been used to treat

    Type 1 Gaucher disease
    DIAGNOSIS

 while the

    neuronopathic type
    DIAGNOSIS

 has been

    resistant to therapy
    NEG_FINDINGS

. We used

    Imiglucerase 60 microg/kg every 2 weeks
    MEDICATION

 in one patient with

    Type 1 Gaucher disease
    DIAGNOSIS

 and

    followed hepatic, splenic volumes and blood counts
    PARACLINICAL

. Treatment with

    Imiglucerase
    MEDICATION

 resulted in a

    decrease in splenic size
    SYMPTOMS

,

    reduced requirements for transfusions
    MEDICATION

 and an

    improvement in cardiopulmonary symptoms
    SYMPTOMS

.

Gaucher's disease
lysosomal storage disorder
Gaucher's disease
Type 1 Gaucher disease
neuronopathic type
Type 1 Gaucher disease

hepato-splenomegaly
skeletal destruction
organ dysfunction
decrease in splenic size
improvement in cardiopulmonary symptoms

enzyme Imiglucerase (Cerezyme, Genzyme)
Imiglucerase 60 microg/kg every 2 weeks
Imiglucerase
reduced requirements for transfusions


[Biochemical and molecular diagnosis of Gaucher disease in Tunisia].

Our study was carried out at a family from the Sahel (Tunisia). The father (index case) and his two children (son and daughter). The father beta-glucocerebrosidase (GCB) activity showing a deficit. These biochemical analyses are supplemented by molecular studies: enzymatic digestion and the direct sequencing. Two mutations were analysed, the p.Asn 370 Ser and the p.Leu 444 Pro. The DNA sequencing confirmed the presence of the homozygous genotype of this p.Asn 370 Ser in the father DNA and the heterozygous one in the two children DNA. It has no detection of the 55 pb deletion in exon 9 among all the specimens of DNA treated. The mutation p.Asn 370 Ser is associated with Gaucher disease type 1 correlated of a total absence of neurological involvements.

Our study was carried out at a family from the

    Sahel
    ETHNICITY

 (

    Tunisia
    ETHNICITY

). The

    father
    GENDER

 (index case) and

    his two children (son and daughter)
    FAMILY

. The

    father beta-glucocerebrosidase (GCB) activity showing a deficit
    BIOCHEMICAL

. These

    biochemical analyses
    PARACLINICAL

 are supplemented by

    molecular studies
    PARACLINICAL

:

    enzymatic digestion and the direct sequencing
    PARACLINICAL

. Two mutations were analysed

    , the p.Asn 370 Ser and the p.Leu 444 Pro
    GENETICS

. The

    DNA sequencing
    PARACLINICAL

 confirmed the

    presence of the homozygous genotype of this p.Asn 370 Ser in the father DNA and the heterozygous one in the two children DNA
    GENETICS

. It has

    no detection of the 55 pb deletion in exon 9 among all the specimens of DNA treated
    NEG_FINDINGS

. The

    mutation p.Asn 370 Ser
    GENETICS

 is associated with

    Gaucher disease type 1
    DIAGNOSIS

 correlated of a

    total absence of neurological involvements
    NEG_FINDINGS

.


Subdural empyema in a case of Gaucher disease: a rare presentation.

Subdural empyema is a surgical emergency; if not recognized and managed early, it may prove fatal. In most of the cases, condition is preceded by paranasal sinusitis, otitis media or trauma. The authors report a previously undescribed case of spontaneous subdural empyema associated with Gaucher disease that had a good outcome following burr hole evacuation of subdural empyema and parenteral antibiotics. Patients with Gaucher disease may be vulnerable to severe bacterial infections, due to defective function of phagocytic cells and hypersplenism.

    Subdural empyema
    DIAGNOSIS

 is a surgical emergency; if not recognized and managed early, it may prove fatal. In most of the cases, condition is preceded by

    paranasal sinusitis
    DIAGNOSIS

,

    otitis media
    DIAGNOSIS

 or

    trauma
    SYMPTOMS

. The authors report a previously undescribed case of

    spontaneous subdural empyema
    DIAGNOSIS

 associated with

    Gaucher disease
    DIAGNOSIS

 that had a good outcome following

    burr hole evacuation of subdural empyema
    MEDICATION

 and

    parenteral antibiotics
    MEDICATION

. Patients with

    Gaucher disease
    DIAGNOSIS

 may be vulnerable to

    severe bacterial infections
    SYMPTOMS

, due to

    defective function of phagocytic cells
    BIOCHEMICAL

 and

    hypersplenism
    BIOCHEMICAL

.

Subdural empyema
paranasal sinusitis
otitis media
spontaneous subdural empyema
Gaucher disease
Gaucher disease

defective function of phagocytic cells
hypersplenism


Pathological fractures; a consideration with metachondromatosis and differential diagnoses. Osteochondromatosis and Gauchers disease.

Metachondromatosis is a condition that causes gross conical metaphyseal expansion (sometimes irregular), cortical thinning, exostoses. Metachondromatous lesions occur mainly in the extremities and are roughly symmetrical. The lesions can involve the bones of the hand and all long bones in the arms and legs. The distribution in this case additionally involved the acromion process and ischia. The bone changes, although dramatic, can be confused with other types of metaphyseal dysplasia such as Gaucher disease and multiple exostoses.

This paper will review the literature with regard to Metachondromatosis, Gaucher disease and Osteochondromatosis due to their similarities. The case study serves as an example of these findings and documents a history of fractures secondary to the obvious bone changes.

Clinical manifestations of these conditions and how they may present to the manual therapist are discussed. With respect to Metachondromatosis, the manual therapist needs to be mindful of pathological fractures that can occur with little trauma. Manual therapists are cautioned against using long bones as levers for spinal manipulation in these patients.

    Metachondromatosis
    DIAGNOSIS

 is a condition that causes

    gross conical metaphyseal expansion (sometimes irregular)
    SYMPTOMS

,

    cortical thinning
    SYMPTOMS

,

    exostoses
    SYMPTOMS

.

    Metachondromatous lesions
    SYMPTOMS

 occur mainly

    in the extremities
    SYMPTOMS

 and are

    roughly symmetrical
    SYMPTOMS

. The

    lesions can involve the bones of the hand and all long bones in the arms and legs
    SYMPTOMS

. The distribution in this case

    additionally involved the acromion process and ischia
    SYMPTOMS

. The

    bone changes
    SYMPTOMS

, although dramatic, can be confused with other types of

    metaphyseal dysplasia
    DIAGNOSIS

 such as

    Gaucher disease
    DIAGNOSIS

 and

    multiple exostoses
    SYMPTOMS

.

This paper will review the literature with regard to

    Metachondromatosis
    DIAGNOSIS

,

    Gaucher disease
    DIAGNOSIS

 and

    Osteochondromatosis
    DIAGNOSIS

 due to their similarities. The case study serves as an example of these findings and documents a

    history of fractures secondary to the obvious bone changes
    SYMPTOMS

.

Clinical manifestations of these conditions and how they may present to the manual therapist are discussed. With respect to

    Metachondromatosis
    DIAGNOSIS

, the

    manual therapist
    PARACLINICAL

 needs to be mindful of

    pathological fractures
    SYMPTOMS

 that can occur with

    little trauma
    NEG_FINDINGS

.

    Manual therapists
    PARACLINICAL

 are cautioned

    against using long bones as levers for spinal manipulation
    NEG_FINDINGS

 in these patients.

Metachondromatosis
metaphyseal dysplasia
Gaucher disease
Metachondromatosis
Gaucher disease
Osteochondromatosis
Metachondromatosis


Non-neuronopathic Gaucher disease due to saposin C deficiency.

Gaucher disease is generally caused by a deficiency of the lysosomal enzyme glucocerebrosidase. The degradation of glycosphingolipids requires also the participation of sphingolipid activator proteins. The prosaposin PSAP gene codes for a single protein which undergoes post-translational cleavage to yield four proteins named saposins A, B, C and D. Saposin (SAP-) C is required for glucosylceramide degradation, and its deficiency results in a variant form of Gaucher disease. In this report, we present clinical, biochemical, and molecular findings in a 36-year-old man and his 30-year-old sister with non-neuronopathic Gaucher disease due to SAP-C deficiency. Very high levels of chitotriosidase activity, chemokine CCL18, and increased concentration of glucosylceramide in plasma and normal beta-glucosidase activity in skin fibroblasts were observed in the patients. A molecular genetics study of the PSAP gene enabled the identification of one missense mutation, p.L349P, located in the SAP-C domain and another mutation, p.M1L, located in the initiation codon of the prosaposin precursor protein. The presented findings describe the first cases where the non-neuronopathic Gaucher disease has been definitely demonstrated to be a consequence of SAP-C deficiency. Three previously described cases in the literature displayed a Gaucher type 3 phenotype.

    Gaucher disease
    DIAGNOSIS

 is generally caused by a

    deficiency of the lysosomal enzyme glucocerebrosidase
    BIOCHEMICAL

. The

    degradation of glycosphingolipids
    MICROSCOPIC

 requires also the participation of

    sphingolipid activator proteins
    BIOCHEMICAL

. The

    prosaposin PSAP gene
    GENETICS

 codes for a single protein which undergoes

    post-translational cleavage
    GENETICS

 to yield four proteins named saposins A, B, C and D.

    Saposin (SAP-) C
    BIOCHEMICAL

 is required for

    glucosylceramide degradation
    BIOCHEMICAL

, and its

    deficiency
    BIOCHEMICAL

 results in a

    variant form of Gaucher disease
    DIAGNOSIS

. In this report, we present clinical, biochemical, and molecular findings in a

    36-year-old
    AGE

    man
    GENDER

 and

    his
    GENDER

    30-year-old
    AGE

    sister
    FAMILY

 with

    non-neuronopathic Gaucher disease
    DIAGNOSIS

 due to

    SAP-C deficiency
    BIOCHEMICAL

.

    Very high levels of chitotriosidase activity, chemokine CCL18
    BIOCHEMICAL

, and

    increased concentration of glucosylceramide in plasma
    BIOCHEMICAL

 and

    normal beta-glucosidase activity in skin fibroblasts
    NEG_FINDINGS

 were observed in the patients. A

    molecular genetics study of the PSAP gene
    PARACLINICAL

 enabled the identification of one

    missense mutation, p.L349P, located in the SAP-C domain and another mutation, p.M1L, located in the initiation codon of the prosaposin precursor protein
    GENETICS

. The presented findings describe the first cases where the

    non-neuronopathic Gaucher disease
    DIAGNOSIS

 has been definitely demonstrated to be a consequence of

    SAP-C deficiency
    BIOCHEMICAL

. Three previously described cases in the literature displayed a

    Gaucher type 3
    DIAGNOSIS

 phenotype.

Gaucher disease
variant form of Gaucher disease
non-neuronopathic Gaucher disease
non-neuronopathic Gaucher disease
Gaucher type 3


Congenital Gaucher disease with nonimmune hydrops/erythroblastosis, infantile arterial calcification, and neonatal hepatitis/fibrosis. Clinicopathologic report with enzymatic and genetic analysis.

The findings in a stillborn female fetus of 31 weeks' gestation with congenital Gaucher disease, nonimmune hydrops/erythroblastosis, infantile arterial calcification, and neonatal hepatitis/fibrosis are presented, the first report of this complete constellation. Prior reports describe two similar patients. One lacked the hepatocellular features of giant cell hepatitis although manifesting hepatic fibrosis; the second lacked hepatic pathology. The diagnosis of Gaucher disease herein was established by microscopic examination of the proband, enzymatic analysis of trophoblast, and enzymatic and genetic study of the parents. The father was heterozygous for a recombinant glucocerebrosidase gene; the mother demonstrated a unique frame shift mutation. Thus the fetus is a compound heterozygote for a null and a severe mutation. Studies of parental DNA were negative for the D409H mutation of type IIIc Gaucher disease. Genetic studies were not performed of the ENPP1 gene, mutations of which are associated with idiopathic infantile arterial calcification.

The findings in a

    stillborn female
    AGE

    fetus
    AGE

 of

    31 weeks' gestation
    AGE

 with

    congenital Gaucher disease
    DIAGNOSIS

,

    nonimmune hydrops/erythroblastosis
    DIAGNOSIS

,

    infantile arterial calcification
    SYMPTOMS

, and

    neonatal hepatitis/fibrosis
    SYMPTOMS

 are presented, the first report of this complete constellation. Prior reports describe two similar patients. One

    lacked the hepatocellular features of giant cell hepatitis
    NEG_FINDINGS

 although manifesting

    hepatic fibrosis
    SYMPTOMS

; the second

    lacked hepatic pathology
    NEG_FINDINGS

. The diagnosis of

    Gaucher disease
    DIAGNOSIS

 herein was established by

    microscopic examination of the proband
    PARACLINICAL

,

    enzymatic analysis of trophoblast
    PARACLINICAL

, and

    enzymatic and genetic study of the parents
    PARACLINICAL

. The

    father was heterozygous for a recombinant glucocerebrosidase gene
    FAMILY

; the

    mother demonstrated a unique frame shift mutation
    FAMILY

. Thus the

    fetus
    AGE

 is a

    compound heterozygote for a null and a severe mutation
    GENETICS

.

    Studies of parental DNA were negative for the D409H mutation of type IIIc Gaucher disease
    NEG_FINDINGS

.

    Genetic studies were not performed of the ENPP1 gene
    NEG_FINDINGS

,

    mutations of
    GENETICS

 which are associated with

    idiopathic infantile arterial calcification
    DIAGNOSIS

.

infantile arterial calcification
neonatal hepatitis/fibrosis
hepatic fibrosis


Effect of treatment on biclonal gammopathy associated with Gaucher disease.

The non-random association of Gaucher disease with polyclonal and monoclonal gammopathy has been known since 1950. The effect of treatment on monoclonal gammopathy is not well documented. We report on the long-term evolution of a biclonal gammopathy in a patient with type I Gaucher disease who was treated with splenectomy and enzyme replacement therapy. A 44-year-old man presented with hepatomegaly and massive splenomegaly. Bone marrow aspirate contained typical Gaucher cells and beta-glucosidase was low in peripheral blood leukocytes. Mutations N370S and R120W were detected. Serum protein electrophoresis disclosed two spikes in gammaglobulins. Immunofixation identified two monoclonal components: IgG kappa and IgA kappa. Gammaglobulin concentration was 31.6 g/L. A splenectomy was performed on September 2003 because of massive splenomegaly (9500 g). Two months after the splenectomy, gammaglobulin concentration was 25.2 g/L. Enzyme replacement therapy (Cerezyme 45 UI/kg every two weeks) was prescribed from April 2004 because of significant hepatomegaly and cholestasis. In April 2007 (3 years after the beginning of treatment), serum electrophoresis showed the persistence of two spikes with gammaglobulin concentration at 20.5 g/L. Simultaneously, chitotriosidase activity decreased from 6181 to 2877 nkat/L. Our observation and previous reports suggest that enzyme replacement therapy is more effective in polyclonal hypergammaglobulinaemia than in monoclonal gammopathy.

The non-random association of

    Gaucher disease
    DIAGNOSIS

 with

    polyclonal and monoclonal gammopathy
    DIAGNOSIS

 has been known since 1950. The effect of treatment on

    monoclonal gammopathy
    DIAGNOSIS

 is not well documented. We report on the long-term evolution of a

    biclonal gammopathy
    DIAGNOSIS

 in a patient with

    type I Gaucher disease
    DIAGNOSIS

 who was treated with

    splenectomy
    MEDICATION

    and enzyme replacement therapy
    MEDICATION

. A

    44-year-old
    AGE

    man
    GENDER

 presented with

    hepatomegaly
    SYMPTOMS

 and

    massive splenomegaly
    SYMPTOMS

.

    Bone marrow aspirate
    PARACLINICAL

 contained

    typical Gaucher cells
    MICROSCOPIC

 and

    beta-glucosidase was low in peripheral blood leukocytes
    BIOCHEMICAL

.

    Mutations N370S and R120W
    GENETICS

 were detected.

    Serum protein electrophoresis
    PARACLINICAL

 disclosed

    two spikes in gammaglobulins
    BIOCHEMICAL

.

    Immunofixation
    PARACLINICAL

 identified

    two monoclonal components: IgG kappa and IgA kappa
    BIOCHEMICAL

. Gammaglobulin concentration was 31.6 g/L. A

    splenectomy
    MEDICATION

 was performed on September 2003 because of

    massive splenomegaly (9500 g)
    SYMPTOMS

. Two months after the

    splenectomy
    MEDICATION

, gammaglobulin concentration was 25.2 g/L.

    Enzyme replacement therapy (Cerezyme 45 UI/kg every two weeks)
    MEDICATION

 was prescribed from April 2004 because of

    significant hepatomegaly
    SYMPTOMS

 and

    cholestasis
    SYMPTOMS

. In April 2007 (3 years after the beginning of treatment),

    serum electrophoresis
    PARACLINICAL

 showed the persistence of two spikes with gammaglobulin concentration at 20.5 g/L. Simultaneously, chitotriosidase activity decreased from 6181 to 2877 nkat/L. Our observation and previous reports suggest that

    enzyme replacement therapy
    MEDICATION

 is more effective in

    polyclonal hypergammaglobulinaemia
    DIAGNOSIS

 than in

    monoclonal gammopathy
    DIAGNOSIS

.

Gaucher disease
polyclonal and monoclonal gammopathy
monoclonal gammopathy
biclonal gammopathy
type I Gaucher disease
polyclonal hypergammaglobulinaemia
monoclonal gammopathy

hepatomegaly
massive splenomegaly
massive splenomegaly (9500 g)
significant hepatomegaly
cholestasis


[Gaucher disease].

We describe, with a brief thematic review, the case of a 47-year-old woman that was hospitalized to study a clinical picture characterized by massive splenomegaly with asthenia, postprandial fullness, weight loss and edema in the left lower extremity, in which Gaucher disease was diagnosed.

We describe, with a brief thematic review, the case of a

    47-year-old
    AGE

    woman
    GENDER

 that was hospitalized to study a clinical picture characterized by

    massive splenomegaly
    SYMPTOMS

 with

    asthenia
    SYMPTOMS

,

    postprandial fullness
    SYMPTOMS

,

    weight loss
    SYMPTOMS

 and

    edema in the left lower extremity
    SYMPTOMS

, in which

    Gaucher disease
    DIAGNOSIS

 was diagnosed.

massive splenomegaly
asthenia
postprandial fullness
weight loss
edema in the left lower extremity


Pseudo-Gaucher cells in Hb E disease and thalassemia intermedia.

Pseudo-Gaucher cells are morphologic curiosities described in a number of conditions. We report their presence in a bone marrow biopsy and a spleen from 2 patients with hemoglobin E disease and thalassemia intermedia, respectively. The pathogenesis of these cells and their multiple known associations are discussed.

    Pseudo-Gaucher cells
    MICROSCOPIC

 are

    morphologic curiosities
    MICROSCOPIC

 described in a number of conditions. We report their

    presence in a bone marrow biopsy and a spleen
    MICROSCOPIC

 from 2 patients with

    hemoglobin E disease
    DIAGNOSIS

 and

    thalassemia intermedia
    DIAGNOSIS

, respectively. The pathogenesis of these cells and their multiple known associations are discussed.

hemoglobin E disease
thalassemia intermedia


Movement and mood disorder in two brothers with Gaucher disease.

Gaucher disease (GD) is a lysosomal storage disorder with a wide spectrum of phenotypic presentations. We report the case histories of two adult brothers with GD who developed both parkinsonism and psychiatric symptoms. Direct sequencing and real-time polymerase chain reaction were used to establish that the patients were homozygous for mutation L444P. While parkinsonism has been described previously in GD, these patients had atypical features, including a complicated mood disorder. The comorbidity of GD and a mood disorder is a new finding, as psychiatric manifestations of GD have been described rarely. The etiology of the mental illness could be related to the processes contributing to the development of parkinsonism.

    Gaucher disease (GD)
    DIAGNOSIS

 is a

    lysosomal storage disorder
    DIAGNOSIS

 with a wide spectrum of phenotypic presentations. We report the case histories of two

    adult
    AGE

    brothers
    GENDER

 with

    GD
    DIAGNOSIS

 who developed both

    parkinsonism
    SYMPTOMS

 and

    psychiatric symptoms
    SYMPTOMS

.

    Direct sequencing and real-time polymerase chain reaction
    PARACLINICAL

 were used to establish that the patients were homozygous for mutation L444P. While

    parkinsonism
    DIAGNOSIS

 has been described previously in

    GD
    DIAGNOSIS

, these patients had

    atypical features
    SYMPTOMS

, including a

    complicated mood disorder
    DIAGNOSIS

. The

    comorbidity of GD and a mood disorder
    DIAGNOSIS

 is a new finding, as

    psychiatric manifestations
    SYMPTOMS

 of

    GD
    DIAGNOSIS

 have been described rarely. The etiology of the

    mental illness
    DIAGNOSIS

 could be related to the processes contributing to the development of

    parkinsonism
    DIAGNOSIS

.

Gaucher disease (GD)
lysosomal storage disorder
GD
parkinsonism
GD
complicated mood disorder
comorbidity of GD and a mood disorder
GD
mental illness
parkinsonism

parkinsonism
psychiatric symptoms
atypical features
psychiatric manifestations