REVIEW

Revised recommendations for the management of Gaucherdisease in children

Paige Kaplan & Hagit Baris & Linda De Meirleir &

Maja Di Rocco & Amal El-Beshlawy & Martina Huemer &

Ana Maria Martins & Ioana Nascu &

Marianne Rohrbach & Lynne Steinbach & Ian J. Cohen

Received: 18 November 2011 /Accepted: 5 June 2012 /Published online: 8 July 2012# Springer-Verlag 2012

Abstract Gaucher disease is an inherited pan-ethnic disor-der that commonly begins in childhood and is caused bydeficient activity of the lysosomal enzyme glucocerebrosi-dase. Two major phenotypes are recognized: non-neuropathic (type 1) and neuropathic (types 2 and 3). Symp-tomatic children are severely affected and manifest growthretardation, delayed puberty, early-onset osteopenia, signif-icant splenomegaly, hepatomegaly, thrombocytopenia, ane-mia, severe bone pain, acute bone crises, and fractures.Symptomatic children with types 1 or 3 should receiveenzyme replacement therapy, which will prevent debilitatingand often irreversible disease progression and allow those

with non-neuropathic disease to lead normal healthy lives.Children should be monitored every 6 months (physicalexam including growth, spleen and liver volume, neurologicexam, hematologic indices) and have one to two yearlyskeletal assessments (bone density and imaging, preferablywith magnetic resonance, of lumbar vertebrae and lowerlimbs), with specialized cardiovascular monitoring for sometype 3 patients. Response to treatment will determine thefrequency of monitoring and optimal dose of enzyme re-placement. Treatment of children with type 2 (most severe)neuropathic Gaucher disease is supportive. Pre-symptomaticchildren, usually with type 1 Gaucher, increasingly are

P. Kaplan (*)Children’s Hospital of Philadelphia, University of Pennsylvania,9th Floor, Colket Translational Research Building,Civic Center Blvd,Philadelphia, PA 19104, USAe-mail: kaplan@email.chop.edu

H. BarisBeilinson-Schneider Gaucher Clinic, Rabin Medical Center,Sackler Faculty of Medicine, Tel Aviv University,Tel Aviv, Israel

L. De MeirleirPediatric Neurology, UZ Brussels,Brussels, Belgium

M. Di RoccoRare Disease Unit, II Division of Pediatrics, Gaslini Institute,Genoa, Italy

A. El-BeshlawyDepartment of Pediatrics, Cairo University School of Medicine,Cairo, Egypt

M. HuemerDepartment of Pediatrics, LKH Bregenz,Bregenz, Austria

A. M. MartinsCenter of Reference in Inborn Errors of Metabolism,Universidade Federal de Sao Paulo,Sao Paulo, Brazil

I. NascuCenter of Genetic Diseases, Children’s Hospital Emergency Cluj,Cluj, Romania

M. RohrbachDivision of Metabolism, Connective Tissue Unit,University Children’s Hospital,Zurich, Switzerland

L. SteinbachDepartment of Radiology, University of California,San Francisco, CA, USA

I. J. CohenBeilinson-Schneider Gaucher Clinic, Department of PediatricHematology Oncology, Schneider Children’s Medical Center ofIsrael and Sackler Faculty of Medicine, Tel Aviv University,Tel Aviv, Israel

Eur J Pediatr (2013) 172:447–458DOI 10.1007/s00431-012-1771-z

being detected because of affected siblings and screening inhigh-prevalence communities. In this group, annual exami-nations (including bone density) are recommended. How-ever, monitoring of asymptomatic children with affectedsiblings should be guided by the age and severity of mani-festations in the first affected sibling. Treatment is necessaryonly if signs and symptoms develop. Conclusion: Earlydetection and treatment of symptomatic types 1 and 3Gaucher disease with regular monitoring will optimize out-come. Pre-symptomatic children require regular monitoring.Genetic counseling is important.

Keywords Gaucher disease type 1 .Gaucher disease type 2 .

Gaucher disease type 3 . Glucocerebrosidase .

Glucocerebroside . Enzyme replacement therapy . Geneticcounseling . Monitoring . Disease management . Treatmentrecommendations

Introduction

Gaucher disease (GD) is a genetic pan-ethnic disorder af-fecting approximately 1:40,000 to 1:60,000 individualsglobally [17, 28, 49]. In Ashkenazi Jews, it is one of themost common genetic disorders, with a carrier frequency of1:17 [35]. It is inherited in an autosomal recessive mannerand is caused by deficiency of the lysosomal enzyme acidβ-glucosidase (glucocerebrosidase). This leads to accumu-lation of the substrate, glucosylceramide (glucocerebroside),in the lysosomes of macrophages and other cells such asosteoblasts [50]. These lipid-laden “Gaucher cells” accumu-late in various tissues and organs, particularly the spleen,liver, bone marrow (Fig. 1a), lung, and brain.

Although Gaucher disease manifests along a spectrum,typically it is classified clinically into three subtypes: type 1(non-neuropathic, MIM 230800), type 2 (acute neuropathic,MIM 230900), and type 3 (chronic neuropathic, MIM23100). In Europe, Canada, and the USA, the most preva-lent form (94 %) is GD type 1, characterized by the absenceof primary central nervous system involvement. In other

parts of the world such as Egypt, Japan, Sweden, andPoland, the neuropathic forms can have a higher prevalencethan GD type 1 [37, 64].

The signs and symptoms of non-neuropathic GD in chil-dren include splenomegaly, hepatomegaly, thrombocyto-penia, anemia, failure to thrive, growth retardation,delayed puberty, osteopenia, severe bone pain (acute bonecrises), and fractures [40]. In non-neuropathic GD, oftendescribed incorrectly as an adult disorder, the majority ofpatients manifest symptoms in childhood and are diagnosedbefore age 20 years [10]. Earlier onset correlates with moresevere disease and a high risk of morbid complications [38,47]. Seventy-five percent of untreated symptomatic childrenhave suboptimal growth [39], with 34–42 % being at orbelow the fifth percentile in height [1, 38]. Splenomegaly,hepatomegaly, and bone disease are each found in more than80 % of children at diagnosis [38]. In untreated children,median spleen volumes are more than 20 times the normalsize and median liver volumes are twice the normal size forthe child’s age and weight [1]. Puberty is significantlydelayed in ~60 % of adolescents with untreated GD [42],which can have a considerable psychological impact. Ane-mia and moderate to severe thrombocytopenia, both foundin approximately 40 % of children [38], are caused byhypersplenism. Anemia is a major cause of fatigue [38]and thrombocytopenia increases the tendency for bleeding(including frequent nose bleeds) and bruising [33].

Bone disease is caused by accumulation of Gaucher cells inthe bone marrow, glucocerebrosides in osteoblasts [50], andeffects of cytokines released from these cells. Approximately80 % of children with GD have at least one skeletal abnor-mality at diagnosis [38]. X-ray of the distal femur may showthe characteristic Erlenmeyer flask deformity (Fig. 1b). Somechildren experience chronic bone pain and/or bone crises(acute-onset, prolonged episodes of pain that are dull initiallybut become excruciating, and usually precede osteonecrosisand fractures). Bone mineral density (BMD), mass, and corti-cal bone thickness are abnormally low [47, 59].

GD types 2 and 3 represent a continuum of diseaseinvolvement distinguished mainly by the rate of neurologic

Fig. 1 a MRI showing marrowinfiltration. b X-ray showingErlenmeyer flask deformity

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degeneration—rapid/acute in type 2 and chronic in type 3.Acute neuropathic GD (type 2) is very rare (1:500,000) [17]and is panethnic. Affected children may appear normal atbirth but manifest systemic and neurologic signs by 2 years(often much earlier) and deteriorate rapidly. Most childrendie in infancy, some prenatally, and others after a few years[31]. GD type 3 manifests in early childhood, often withsimilar features to type 1, and has a slowly progressivecourse often leading to death in the second and third deca-des. Neurological signs such as horizontal saccade-initiationfailure, inability to complete vertical gaze, abnormally slowobject tracking, and convergent squint usually develop earlyin childhood but can also develop later. A disease severityscore has been developed for GD type 3 [18] and at leastthree subtypes have been delineated. Patients with type 3ahave progressive neurologic disease with myoclonus anddementia. Patients with type 3b have significant visceraland skeletal disease, similar to severe type 1, but withneurologic signs (mainly horizontal supranuclear gaze pal-sy) that can present before or after somatic signs and symp-toms. Bone disease usually manifests as chest deformitiesand severe kyphoscoliosis without bone pain and crises[64]. Type 3c is characterized by variable neurologic signs(including hydrocephalus), corneal opacities, and cardiacvalvular and aortic calcification leading to congestive heartfailure and arrhythmias.

In symptomatic children with GD types 1 or 3, earlyenzyme replacement therapy can prevent the evolution ofserious, disabling, and irreversible somatic (but not neuro-logic) complications.

Guidelines on the diagnosis and management of non-neuropathic pediatric GD were published in 2004 [3, 29].Recently, a group of international Gaucher experts fromseveral medical specialities met to update these guidelinesand to expand them to include recommendations for chil-dren who are diagnosed pre-symptomatically and those withneuropathic disease.

Diagnosis of Gaucher disease in children

Symptomatic children

The diagnosis of GD in symptomatic children is based onmedical history, physical examination, and laboratory testsconfirmed by enzyme and/or gene assay.

History should encompass abdominal swelling and dis-comfort, early satiety for food, fatigue, bruising or bleedingtendency, growth deceleration and/or retardation, bone pain,and poor school performance. Family history should includeinquiries about the presence of siblings with the disease,consanguinity, ethnicity, and close relatives with hyper-splenism, splenectomy, and the presence of diseases

associated with GD such as early onset Parkinson-like dis-ease and Alzheimer disease [25, 36, 62].

Physical examinations assess growth, abdomen, skin(pallor, bruises, and petechiae), musculoskeletal and neuro-logical systems, heart, and lungs. Palpation of the abdomenshould start in the inguinal area so as not to overlook theedge of a massively enlarged spleen and liver. The absenceof neurological signs in early childhood does not rule outneurological disease because eye signs can also developlater in childhood.

A blood count should be performed and is likely to showanemia, thrombocytopenia, and, possibly, leucopenia. Un-related factor XI deficiency, common in Ashkenazi Jews,may also be present.

The definitive diagnosis is made by measurement of acidβ-glucosidase activity levels in total white cells, mononu-clear cells, fibroblasts, or dried blood spots on filter paper[6, 53], and/or molecular assay of the gene. Bone marrowaspiration and/or biopsy are invasive and are not requiredfor diagnosis [12]. Determination of the subtype in GD type3 is important to guide monitoring of disease progression.

Asymptomatic children

Increasingly, children are being diagnosed with GD pre-symptomatically (through enzyme testing or molecularanalysis) by genetic screening of their parents, prenatal/neonatal diagnosis in the Ashkenazi Jewish community,or because of relatives with GD. Newborn screening forlysosomal disorders will reveal other asymptomatic children.

Molecular analysis and genetic counseling

Molecular analysis of the acid β-glucosidase (GBA) gene isrecommended in every child with confirmed GD (includingthose diagnosed presymptomatically by enzyme testing) tohelp differentiate non-neuropathic (type 1) from chronicneuropathic (type 3), which can be clinically similar in earlychildhood. Although genotype–phenotype correlations arenot absolute, at least one N370S mutation protects againstneuropathic disease, whereas at least one L444P mutationtends to increase disease severity. The majority of patientsdiagnosed by Ashkenazi Jewish community screening willhave N370S mutations. Homozygosity or compound hetero-zygosity for L444P and D409H is usually associated with aneuropathic phenotype; evidence in Brazilian patients alsosuggests that a G377S mutation can be associated withneuropathic disease [6, 27, 61]. Knowledge of the genotypecan be used for family screening and prenatal diagnosis.

Parents should be offered genetic counseling by a pro-vider with experience in Gaucher disease. For those diag-nosed through community screening, counseling should be

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given prior to pregnancy. Couples who are both carriersshould be advised that every child that they conceive to-gether will have a 25 % risk of having Gaucher disease. Fora couple who both carry N370S mutations, counseling aboutthe wide range of symptoms and ages at onset is extremelyimportant [74].

Baseline assessments in confirmed cases

A thorough baseline assessment is essential for all childrendiagnosed with Gaucher disease, even those diagnosed pre-symptomatically (Table 1). This includes blood tests, meas-urements of spleen and liver volume, and assessment ofbone disease.

Blood tests

Laboratory testing should include a complete blood count,liver and kidney function tests, and other biomarkers.Possible abnormalities include high immunoglobulin levels[70], low cholesterol levels, especially HDL cholesterol[15], prolonged prothrombin time (PT) and partial thrombo-plastin time (PTT) (found in 30 % of patients), and elevated

biomarkers (chitotriosidase, CCL18, tartrate-resistant acidphosphatase [TRAP], and angiotensin converting enzyme[ACE]). About 6 % of individuals do not express chitotrio-sidase (an enzyme secreted by activated macrophages thathydrolyses the trisaccharide derived from chitin) due to anull mutation in the gene; in some parts of the world such asTaiwan, this encompasses approximately 30 % of the pop-ulation [8]. In those GD patients, measurement of the alter-nate biomarkers ACE and TRAP or CCL18 is useful forongoing monitoring of disease manifestations and efficacyof therapeutic intervention [8, 34].

Before starting treatment, it is recommended that a base-line serum sample (3 mL) be obtained for storage in a bank(−70 °C) for future reference. This is invaluable to measureantibodies in case of an adverse reaction to enzyme treat-ment or for other tests/studies that may become relevantlater.

Spleen, liver, and bone assessments

Spleen and liver volume and infiltration should be measuredwith magnetic resonance imaging (MRI). If MRI is notavailable, ultrasonography (less accurate) can give someindication of organ size.

Table 1 Revised minimal recommendations for assessments in children with non-neuropathic Gaucher disease (modified from Charrow et al. [9])

Assessment All patientsat baselinea

Non-symptomaticpatients not receivingenzyme therapy

Patients receivingenzyme therapynot yet meetingtherapeutic goals

Patients on enzymetherapy who are achievingtherapeutic goals

At time of dosechange or significantclinical complication

Every 12months

Every 24months

Every 6months

Every 12months

Every 6–12months

Every 12–24months

Physical examination including growth(height, weight)

X X X X X

Hematology Hemoglobin X X X X X

Platelets X X X X X

PT and PTT in patientswith bleeding symptoms

X X X

Biochemistry Chitotriosidase/CCL18/TRAP/ACE

X X X X X

Visceral Spleen volumeb X X X X

Liver volumeb X X X X

Skeletal MRI (sagittal T1-weightedscan of spine; T1-weightedscan of head of femur)

X X X X

DXA (spine and total bodyZ-scorec)

X X Xc X

Pain X X X X

Quality of life SF-36d, PedsQL [65],or KidscreenR [58]

X X X X

a For the assessments that are normal at baseline there is no need to do follow-up within 6 months againb Spleen and liver volume preferably to be measured by MRI. Ultrasonography can be used if MRI is not available or to get an approximateassessment of sizec Annually until normal; then every 3 years in treated patients. Requires comparison with normal data for age and genderd The Short-Form 36 (SF-36) Health Survey is of limited value in very young patients [3]

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Bone assessments ideally should include bone mineraldensity, best measured with dual-energy X-ray absorption(DXA) of the total body, lumbar spine and/or hips, and MRIof lumbar spine and femurs.

Treatment guidelines

Enzyme replacement therapy

Every child and adolescent with symptomatic GD (Table 2)should be treated with regular intravenous infusions ofenzyme replacement therapy. The dose should be individu-alized according to the clinical and molecular status of thepatient. The recombinant enzyme is available in over 80countries, including all of Europe. As it is very expensive,reimbursement procedures, schedules, and doses for initialtreatment differ from region to region. When possible, se-verely affected children should receive 60 U/kg per 2 weeks.For moderately affected children, at least 30 U/kg should begiven, and if treatment goals are not met, the dose should beincreased (Table 3). The child’s weight should be checked ateach assessment and the appropriate number of units perkilogram prescribed. A permanent indwelling venous cath-eter is not necessary unless there is recurring difficulty inaccessing the vein or if the child is extremely fearful despitepre-treatment with a topical anesthetic such as lidocaine.

Enzyme replacement results in the breakdown of storedglucosylceramide and improvement or normalization ofvisceral, growth, and bone manifestations. Most of the literature

Table 2 Indications for initiating enzyme replacement therapy insymptomatic children

One or more of the following

• Diagnosis of symptomatic disease in the first two decades of life

• Severe anemia (Hb <8 mg/dl)

• Severe thrombocytopenia (<60,000 cells/mL)

• Leukocyte count <3,000 cells/mL

• Symptomatic bone disease (prior bone crisis and osteonecrosis)

• Active bone disease (can be asymptomatic)

• Decreased growth velocity and/or growth retardation

• Pubertal delay

• Sibling with severe disease requiring enzyme replacement therapy

• Genotype known to cause severe disease (e.g., presence of L444Por D409H mutations)

• Height <5th percentile or significantly decreased growth velocity

• BMD Z-score below −2.0 [59]

• Spleen volume >2.0 MN and liver volume of >2.0 MN

Table 3 Therapeutic goals for children (adapted from Pastores et al. [54])

Anemia Increase hemoglobin levels within 12 to 24 months to >11.0 g/dL

Eliminate blood transfusion dependency

Reduce fatigue and dyspnea

Maintain improved hemoglobin values achieved after the first 12 to 24 months of therapy

Thrombocytopenia Increase platelet counts during the 1st year of treatment sufficiently to prevent spontaneousand surgical bleeding

Moderate baseline thrombocytopenia: the platelet count should increase by 1.5- to 2.0-fold by 1 yearand approach low-normal level by 2 years of treatment

Severe baseline thrombocytopenia: the platelet count should increase by 1.5-fold by 1 year of treatmentand continue to increase slightly during years 2 to 5 (doubling by year 2), but normalization is not expected

Avoid splenectomy

Maintain stable platelet counts to eliminate risks of bleeding after a maximal response has been achieved

Hepatomegaly Reduce and maintain the liver volume to 1.0 to 1.5 times normal

Reduce the liver volume by 20 to 30 % within 1–2 years and by 30 to 40 % by years 3–5 of treatment

Splenomegaly Reduce and maintain spleen volume to <2–8-fold normal

Reduce the spleen volume by 30 to 50 % within 1 year and by 50 to 60 % by years 2–5 of treatment

Alleviate symptoms due to splenomegaly: abdominal distension, early satiety, new splenic infarction

Eliminate hypersplenism

Bones Lessen or eliminate bone pain within 1 to 2 years of treatment

Prevent bone crises

Prevent osteonecrosis and subchondral joint collapse

Improve bone mineral density; increase cortical and trabecular BMD by 2 years of treatment

Attain normal or ideal peak skeletal mass

Growth Achieve normal height according to population standards within 3 years of treatment

Achieve normal onset of puberty

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on the effects of enzyme replacement therapy refers to resultsobtained with alglucerase (Ceredase®, Genzyme Corpora-tion)—macrophage-targeted placentally-derived human gluco-cerebrosidase, which became available in 1991—and itsrecombinant successor, imiglucerase (Cerezyme®, GenzymeCorporation), available since 1994. An alternate form of recom-binant human glucocerebrosidase, velaglucerase alfa (VPRIV®,Shire plc), became available in 2010 [22, 71]. A third recombi-nant form of human glucocerebrosidase, taliglucerase alfa(Pfizer/Protalix BioTherapeutics, Inc.) received approval fromthe US FDA in May 2012 [72].

Enzyme replacement therapy in children typically results indramatic reduction of spleen and liver size and resolution ofanemia and thrombocytopenia. Longitudinal data from 884alglucerase/imiglucerase-treated children enrolled in theICGG Gaucher Registry shows that most of the hematologicbenefits and approximately half of the organomegaly benefitsoccur during the first year of treatment, with continued orsustained improvement in all parameters for at least 8 yearsof treatment [1] (Figs. 2 and 3). This analysis also demonstrat-ed an improvement in median height Z-scores of 1.9 unitswithin 8 years of treatment with alglucerase/imiglucerase [1](Fig. 4). The graphs shown in Figs. 2, 3 and 4 can be used to

gauge each patient’s response to therapy in the same way thatgrowth charts are used.

Children with GDwho begin imiglucerase therapy in the firstdecade of life have a normal onset of puberty, whereas puberty isdelayed in patients who do not begin therapy until their teens [1,39]. Because most bone mass is accrued during puberty andreaches a peak by 30 years, failure to achieve peak bone mass inthe critical age period, together with osteonecrosis, places un-treated Gaucher patients at risk of fractures, including micro-fractures. Enzyme replacement improves BMD, bone mass, andcortical bone thickness [1, 11, 22, 51], with the greatest improve-ments in BMD seen in younger patients treated with imiglucer-ase [1, 4, 51, 69]. Imiglucerase also suppresses most acute bonecrises [1] and prevents bone pain [20] and fractures [13]. Thus,by improving BMD and reducing bone crises, enzyme replace-ment therapymay prevent serious skeletal complications such asjoint and vertebral collapse, and fractures.

Elevated levels of disease biomarkers such as chitotriosidase,ACE, TRAP, and CCL18 return to near-normal values withenzyme replacement [56, 63]. Hyperimmunoglobulinemia [70]and increased ferritin [30, 60, 68, 73] are also reduced by treat-ment. With sustained imiglucerase therapy, IgA and IgM levelsimprove or normalize, but IgG levels are less responsive [70].

5th Percentile

50th Percentile

75th Percentile

95th Percentile

90

120

150

180

210

240

270

Years on ERT

60

25th Percentile

3010 32 54 86 7

33

Pla

tele

tC

ou

nt

(x10

/mm

)

Percentile Platelet counts (x 103/mm3)

at first infusion

Platelet counts (x 103/mm3) at 8 years

Numberof

Patients

95 168 247 730

75 130 209 576

50 98 171 384

25 73 137 192

5 57 111 38

No

rmal

ized

Hem

og

lob

in (

g/d

L)

-1

0

1

2

3

Years on ERT

5th Percentile

25th Percentile

50th Percentile

95th Percentile75th Percentile

-2

10 32 54 86 7

PercentileNormalized hemoglobin

(g/dL) at first infusion

Normalized hemoglobin

(g/dL) at 8 years

Numberof

Patients

95 1.1 2.1 732

75 0.4 1.9 578

50 -0.3 1.7 386

25 -1.1 1.4 193

5 -1.8 1.1 39

Fig. 2 Changes in platelet counts and hemoglobin levels counts withyears of imiglucerase/alglucerase. Reproduced with permission fromAndersson et al. [1]. Data are from 884 pediatric patients enrolled inthe ICGG Gaucher Registry as of January 6, 2006 who had intactspleens and were receiving imiglucerase. Platelet data were availablefrom 768 patients (7,991 observations); normalized hemoglobin data

from 771 patients (8,022 observations). Normalized hemoglobin levelswere analyzed as grams per deciliter below the lower limit of thereference range, defined on the basis of the following normal, age-and gender-adjusted values: birth to 6 months, <10.1 g/dL; 6 months to2 years, <9.5 g/dL; >2 to 12 years, <10.5 g/dL; 12 years, male, <12 g/dL; >12 years, female, <11 g/dL

452 Eur J Pediatr (2013) 172:447–458

Years on ERT

Sp

leen

Volu

me

inM

ult

iple

so

fN

orm

al

0

10

15

20

25

30

35

40

45

50

5

5th Percentile

50th Percentile75th Percentile

95th Percentile

25th Percentile

10 32 54 86 7

Percentile Spleen volume (MN)

at first infusion

Spleen volume (MN)

at 8 years

Numberof

Patients

95 45 9.3 435

75 33 6.9 344

50 23 4.8 229

25 17 3.4 115

5 12 2.5 23

0.5

1.5

2.0

2.5

3.0

Years on ERTL

iver

Volu

me

inM

ult

iple

so

fN

orm

al

1.0

5th Percentile

50th Percentile

75th Percentile

95th Percentile

25th Percentile

10 32 54 86 7

Percentile Liver volume (MN)

at first infusion

Liver volume (MN)

at 8 years

Numberof

Patients

95 2.7 1.3 399

75 2.3 1.1 315

50 2.0 1.1 210

25 1.7 0.8 105

5 1.5 0.7 21

Fig. 3 Changes in spleen and liver volume with years of imiglucerase/alglucerase. Reproduced with permission from Andersson et al. [1].Data are from 884 pediatric patients enrolled in the ICGG GaucherRegistry as of January 6, 2006 who had intact spleens and were

receiving imiglucerase. Spleen volume data were available from 458patients (1,593 observations); liver data from 420 patients (1,524observations). MN denotes multiples of normal

25th Percentile

50th Percentile

75th Percentile

5th Percentile

Hei

gh

tZ

-sco

re

-4

-3

-2

-1

0

1

2

Years on ERT

95th Percentile

0 32 54 86 7

1

Percentile Height Z-score at first infusion

Height Z-score at 8 years

Numberof Patients

95 0.5 1.0 667

75 -0.4 0.3 527

50 -1.4 -0.3 351

25 -2.5 -1.0 176

5 -3.4 -1.5 35

DX

AZ

-sco

re

-2

-1

0

1

2

3

-3

Years on ERT

10 11 1296 7 8541 2 30

5th Percentile

50th Percentile

75th Percentile

95th Percentile

25th Percentile

Percentile DXA Z-scoreat first infusion

DXA Z-score at 12 years

Numberof Patients

95 1.22 1.87 121

75 0.49 1.13 95

50 -0.35 0.29 64

25 -1.19 -0.55 32

5 -1.93 -1.29 6

Fig. 4 Changes in height and BMD Z-scores with years of alglucerase/imiglucerase therapy. Reproduced with permission from Andersson etal. [1]. Data are from 884 pediatric patients enrolled in the ICGGGaucher Registry as of January 6, 2006 who had intact spleens and

were receiving imiglucerase. Height Z-scores were available from 702patients (5,602 measurements); bone mineral density Z-score from 127patients (244 observations)

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Approximately 7 % of patients have had recurrent adverseevents during or up to several days following an infusion [5].These hypersensitivity or non-allergic adverse events can beprevented by slowing and extending the infusion time and/orby pretreatment with antihistamines or corticosteroids. Based onextended experience with imiglucerase, a ramping schedule thatstarts with a very slow infusion rate and gradually increases hasprevented adverse reactions. Usually, children with GD areassessed and receive their (initial) courses of treatment in thehospital environment, where there is close monitoring.However, if there have been no adverse reactions to enzymereplacement therapy, treatment in the home environment after6–12 months has become an option in some countries and canincrease compliance and improve quality of life for patients andtheir families. The duration of hospital-based infusions beforeswitching patients to home infusion should be individualized foreach patient, but if no infusion related adverse events haveoccurred for 6–12 months, subsequent development of IgEantibodies is unlikely.

Treatment of acute bone crises

Bone crises can cause excruciating pain for up to severalweeks and are often resistant to intensive narcotic programs.Diagnosis can be made by MRI [16] or Technetium bonescans [41]. High-dose oral prednisone 1 gm/m2 for 2 daysfollowed by smaller doses of prednisone has been shown toalleviate the pain within several hours [14] and has no long-term side effects [16]. Non-steroidal anti-inflammatorydrugs may be used to treat non-specific pain. Radiographsare usually nondiagnostic in an acute crisis but may even-tually show periosteal elevation several weeks later [14].

Treatment of patients with neuropathic disease

There is no evidence that enzyme replacement therapy, even athigh doses, can prevent or slow neurological progression inpatients with type 2 or type 3 GD [7, 57]. Enzyme replacementtherapy is not recommended for type 2 GD. Managementshould be focused on supportive care [66]. Partial splenecto-my (surgical or thromboembolism) can alleviate some symp-toms in type 2 patients [55]. For children with type 3 GD,enzyme replacement therapy is recommended at a minimumdose of 60 U/kg per 2 weeks to ameliorate the severe visceralmanifestations [66]. Enzyme replacement therapy for patientswith type 3 GD is not approved in all countries. In theEuropean Union and Canada, imiglucerase is indicated foruse in patients with a confirmed diagnosis of type 3 GD whoexhibit clinically significant anemia, thrombocytopenia, bonedisease, hepatomegaly, or splenomegaly. In many othercountries, imiglucerase is not specifically indicated for type3 GD. At this time, velaglucerase alfa is approved for use onlyin type 1 GD patients.

Monitoring disease progression and treatment efficacy

Table 1 summarizes the recommended baseline and follow-up assessments for patients on treatment and patients whoare not on treatment. Treatment goals are shown in Table 3.With regard to quality of life assessments, note that these areimportant for parents/caregivers as well as for patients.

Monitoring symptomatic children

Physical examinations and hematologic assessments, includingbiomarkers, should be performedat diagnosis and every 6monthsthereafter. When treatment goals are met, the number and fre-quency of laboratory assessments can be decreased, but historyand physical exams still should be performed every 6 months.

Visceral assessments

In symptomatic children, volumetric MRI should be done every12–24 months, depending on the severity of organomegaly.When stable/normal volumes have been achieved, the MRI canbe done less frequently. Volumetric measures are reported asmultiples of normal (MN) size predicted for body weight. Inyounger children, oral or intravenous sedation is often necessaryduring the MRI. Because of the radiation dose involved, com-puterized tomography (CT) is no longer acceptable for routinemonitoring. Because of lack of sensitivity, ultrasound is notrecommended, unless MRI is unavailable. When ultrasound isused, it should not inform decisions to change drug doses, sinceorgan volumes can only be estimated, even by an experiencedradiologist [9, 21]. Manual measurements of the distance belowcostal margin in centimeters are also not very accurate.

Skeletal assessments

Bone disease can cause significant morbidity and long-termdisability [26]. The extent of bone disease does not alwayscorrelate with the spleen/liver enlargement, anemia, or throm-bocytopenia, so bone evaluations are required regardless ofinvolvement of other systems. Untreated children and youngadults between 10 and 20 years of age have significantly moresevere skeletal disease [38] and lower bone density than youngerchildren [59], reflecting the progressive nature of untreateddisease in childhood. Although not all children experienceosteonecrosis, osteopenia, and/or bone crises, these diseasemanifestations can have significant long-term sequelae, suchas joint collapse, fractures, and chronic pain. Splenectomy, acommon treatment in the pre-enzyme replacement era, has theunfortunate side effect of making the bone disease worse be-cause there is more accumulation of macrophages, chemokines,and cytokines [2].

Evaluating and monitoring the impact of skeletal diseasemust be comprehensive, and the treating physician should

454 Eur J Pediatr (2013) 172:447–458

regularly inquire about bone crises and bone pain. Physicalexamination should assess height, range of motion of joints,scoliosis, and deformities. Bone mineral density is best mea-sured with dual-energy X-ray absorption (DXA) of the totalbody, lumbar spine, and/or hips [69]. In children, bone mineraldensity must be expressed as an age- and gender-matchedZ-score, requiring appropriate software for data analysis.

In general, X-rays are not sufficiently sensitive to moni-tor disease progression, show changes too late and, if usedroutinely, expose the patient to excessive ionizing radiation.

MRI is the most widely used and accepted method formonitoring skeletal and marrow disease in GD and can be donewith sedation in very young children. MRI of the spine andfemur (the “gold standard”) gives information about abnormalremodelling, marrow infiltration, osteonecrosis, and osteoscle-rosis. InterpretingMRI during childhood requires knowledge ofthe conversion of hematopoietic (red) to fatty (yellow) marrowin the femur [52, 67] so that discrepancies from normal devel-opment can be observed. The infiltration of fatty marrow byGaucher cells can be observed with the Dixon quantitativechemical shift imaging (Dixon-QCSI), a special MRI tech-nique; however, norms for children have not been establishedand the technique is not available in most centers. The bonemarrow burden score obtained with MRI is a reproduciblesemiquantitative scoring system [48].

Growth velocity (height and weight) should be assessedevery 6 months in patients on treatment. MRI should bedone at baseline (time of diagnosis) and every subsequent12 months in patients on treatment as well as at the time ofany dose change. DXA should be performed in treatedchildren at baseline and then every 12–24 months until itis normal or if there is a dose change; then every 3 years(preferably in the same center with the same machine).

Monitoring asymptomatic children

Like symptomatic children, asymptomatic children who arediagnosed with GD because of affected siblings should bemonitored at least every 6 months. Since affected siblingsusually have a similar disease course, additional monitoringshould be guided by the age and severity of manifestationsin the older affected sibling(s).

Children diagnosed by community screening pose a man-agement dilemma, especially if they have an unknown ge-notype or one that predicts a more attenuated disease course.Such children could manifest symptoms of GD at any age oreven remain asymptomatic for their entire lives. At mini-mum, annual examinations are recommended. The frequen-cy of monitoring for infants detected in newborn screeningprograms will be determined by the genotype: for those witha “severe” genotype, assessments should be done every6 months; for those with a more benign genotype, includingN370S, assessments should be done annually.

Visceral and skeletal assessments

Ultrasound exams are acceptable for monitoring organome-galy in asymptomatic children only until clinical deteriorationmakes enzyme replacement therapy an option. MRI of bonesshould be done every 12 to 24 months (if available) and as ispractical, considering the need for sedation. DXA should bedone every 12 months, especially if MRI is not done.

Monitoring of neuropathic disease

Monitoring of patients with type 3 GD is dictated by thesubtype. For type 3a, the emphasis is on neurological involve-ment; for type 3b there is more emphasis on internal organs,hematological, and skeletal complications; and for type 3c, closecardiovascular follow-up is required. In addition to the standardtests performed in non-neuropathic GD patients, the followingtests should be performed: neurological examination includingeye movements, additional neuro-ophthalmological investiga-tions, testing of peripheral hearing, brain imaging, EEG, andneuro-psychometry. Avalidatedmodified severity score tomon-itor the clinical course is a useful tool [19]. In addition, type 3cpatients should also have periodic chest X-ray and echocardio-gram for calcification evaluation, cardiac CT angiography orcoronary artery catheterization evaluation for calcifications (andpossible atherosclerosis), and a periodic pulmonary evaluationfor interstitial lung disease.

Alternative treatment modalities

Miglustat (Zavesca®, Actelion Pharmaceuticals US) is anoral treatment for adult patients with GD type 1 that reducesthe production of the substrate glucosylceramide and otherglycosphingolipids. Miglustat is approved for symptomaticadult type 1 GD patients with mild to moderate clinicalmanifestations for whom enzyme therapy is not an option;however, it is not approved to treat children with GD.Isolated case reports in children with type 3 suggest it mighthelp decrease seizure frequency [44]. Side effects includeperipheral neuropathy and diarrhea [32].

An alternative oral substrate reduction therapy, eliglustattartrate (Genzyme, a Sanofi company, Cambridge, USA), spe-cifically inhibits production of glucosylceramide and is beingevaluated in clinical trials of adults with type 1 GD. A phase 2study showed statistically significant improvements in keysigns, including hemoglobin level, platelet count, spleen andliver volumes, and lumbar spine bone mineral density [45, 46].A pediatric investigational plan is under development to estab-lish the safety and efficacy of eliglustat in children with GD.

Significant morbidity and mortality limit the use of hemato-poietic stem cell transplantation (HSCT) in patients with GDtype 1. As enzyme replacement therapy is a highly efficacious

Eur J Pediatr (2013) 172:447–458 455

treatment for the hematological, visceral ,and skeletal manifes-tations of GD, this remains the first line of therapy. However,HSCT could have the theoretic advantage over enzyme therapyin stabilizing the neurological aspects of GD [24]. Studies ofgene therapy in animal models of GD show promise, but thisresearch is still preclinical [23, 43].

Conclusion

Gaucher disease usually manifests in childhood. To preventdevelopment of serious, irreversible disease, children withsymptomatic and pre-symptomatic Gaucher disease requirethorough, regularmulti-modalitymonitoring. Symptomatic chil-dren require enzyme replacement therapy. These revised guide-lines widen the spectrum of children with GD who should bemonitored at regular intervals to include those with neuropathicdisease and those who are diagnosed presymptomatically. En-hanced understanding of the natural history of childhood GDand long-term data on recombinant enzyme therapy outcomeshave led us to recommend more measurements of bone health(bone density measurements because of high prevalence of lowbone density) and growth, and to specify when dose modifica-tion should be considered.

Acknowledgments The meeting to formulate these recommendationswas funded by an unrestricted grant from the Genzyme Corporation. Gen-zyme also provided medical writing support from Frans van Huizen, Ph.D.and Lisa Underhill, MS, of Genzyme Global Medical Affairs. Genzyme hadno formative role in developing these management guidelines or in thedecision to submit the manuscript for publication. All views expressed andtreatment recommendations are solely those of the authors.

Conflict of interest disclosures Paige Kaplan has received grants andhonoraria from Genzyme. Hagit N. Baris has received grants and honorariafrom Genzyme. Linda De Merlier has received honoraria from Genzyme.Maja Di Rocco has received honoraria from Genzyme and Actelion. AmalEl Beshlawy has recieved honoraria from Genzyme. Martina Huemer hasreceived speaker honoraria from Genzyme. AnaMaria Martins has receivedsupport to attend congress and honoraria as a consultant from Genzyme.Ioana Nascu has received honoraria from Genzyme. M. Rohrbach hasreceived unrestricted grants and/or honoraria from Actelion, Genzyme, andShire. Lynne Steinbach has received honoraria fromGenzyme. Ian J. Cohenhas received a grant and honoraria from Genzyme.

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