Coy Heldermon

1
Splenomegaly and cytopeniaPlease wait for the
path

• Coy Heldermon

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Pt 1 infant (from another hospital)

• June increased abdominal girth
• Dec anemia noted
• Jan cough and shortness of breath
• Feb hepatosplenomegaly and petechia on exam
  admitted for evaluation
• U/S and CT confirm normal flow in enlarged liver
  and spleen NL echo, viral serologies, BMP,
  LFTs, LDH
• WBC 8.4, nl dif, no blasts, Hgb 9 MCV 70, Plt 60k

3

• Cefepime started for presumed pneumonia
• BM bx 2/20
• portacath placement 2/21
• IT AraC for presumed pre B ALL 2/22 (unclear on
  what this is based)

4

• Path 2/23 no evidence of leukemia, increased
  macrophages/histiocytes
• Flow NL
• Immunoglobulins NL

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Pt 2 Adult

• 29 yo referred for thrombocytopenia
• Pt also c/o abdominal bloating and pain, early
  satiety, constipation and limited range of motion
  in both shoulders but denies bruising or
  bleeding. Splenomegaly since childhood.
• No significant PMH
• PE remarkable for very slim appearance, prominent
  gums, spleen and liver 15 cm below costal
  margin, diminished sensation over left upper leg.
• WBC 3.7 Hgb 15.7 Plt 33

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BM biopsy

• Normocellular with erythroid hyperplasia and
  involvement by lysosomal storage disease. 40-50
  Gaucher cells

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Tissue paper cytoplasm Gauchers cell
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• 1882 First description by Philippe Charles
  Ernest Gaucher of pt with hepato-splenomegaly.
• Prevalence 150k births most ethnicities
• 1450 births in Ashkenazi populations (1 in 15
  carrier frequency)
• Autosomal Recessive Ch 1q21 - mutation of the
  gene for beta-glucocerebrosidase

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• Glucocerebroside

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Gaucher Disease

• Type 1 Typically adult onset
  hepatosplenomegaly, osteoporosis, bone
  pain/necrosis, anemia, thrombocytopenia,
  leukopenia, bruising, bleeding, bone
  infarcts/fractures, lung impairment, brown skin
  coloring, pingueculae associated most with
  N370S mutations
• Type II acute infantile neuropathic form -
  onset by 6 moa hepato-splenomegaly, progressive
  brain damage, eye movement disorders, seizures,
  limb rigidity, and poor suckling death by age 2
  associated most with L444P mutation
• Type III chronic neuropathic form child to
  adult onset hepatosplenomegaly, seizures, poor
  motor and ocular coordination, bone changes,
  cytopenias. Death in early adulthood.

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Testing

• Enzyme assay and mutation analysis
• ACE, Chitotriosidase, Tartrate resistant Acid
  Phosphatase markers of disease severity
  Chitotriosidase seems to be best correlated and
  with least variance.
• Annual physical, CBC
• Initial and periodic volumetric liver/spleen
  assessment, dexa scan/femoral MRI

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Testing Centers

• Baylor College of Medicine Medical Genetics
  Laboratorieshttp//www.bcmgeneticlabs.orgPhone
  1-800-411-GENE (4363)Fax [phone]E-mail
  genetictest_at_bcm.edu Baylor College of Medicine
  Medical Genetics Laboratories2450 Holcombe Grand
  Blvd. - Receiving Dock Houston, TX 77021-2024
• Childrens Hospital and Regional Medical Center
  Biochemical and Molecular Genetics
  Laboratorieshttp//www.seattlechildrens.org/geneti
  cslabPhone 206-987-2102E-maillisa.sniderman-king
  _at_seattlechildrens.org Childrens Hospital and
  Regional Medical Center Laboratory, A-69014800
  Sand Point Way NE Seattle, WA 98105
• Emory University, Department of Human Genetics
  Emory Genetics Laboratory www.geneticslab.emory.ed
  uPhone 1-800-366-1502Fax [phone]E-mail
  lab_at_genetics.emory.edu Emory Genetics
  Laboratory2165 N. Decatur Road Decatur, GA 30033
• Genzyme Genetics Molecular Diagnostic Laboratory
  www.genzymegenetics.comPhone 800-848-4436Fax
  505-438-2270 Genzyme Genetics2000 Vivigen WayS
  anta Fe, NM 87505
• Mayo Clinic College of Medicine Biochemical
  Genetics Laboratory www.mayomedicallaboratories.co
  mPhone 507-266-8158Fax [phone]E-mail
  Biochemicalgenetics _at_mayo.edu Mayo Medical
  Laboratories3050 Superior Drive NW Rochester, MN
  55901-1995
• Mount Sinai School of Medicine Biochemical and
  Molecular Diagnostic Laboratorieswww.mssm.edu/gauc
  her Phone [phone] Fax [phone] Mount
  Sinai School of Medicine Genetics and Genomic
  Sciences Atran Laboratory Building Room
  AB2-321428 Madison Avenue New York, NY 10029Attn
  Genetic Testing
• New York University School of Medicine NYU
  Neurogenetics Laboratory Phone [phone]Fax
  212-263-1018 NYU Neurogenetics Laboratory400 East
  34 th St , RR213New York, NY 10016

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Treatment

• Bone marrow transplant curative in type I
  disease though high morbidity
• Supportive care for symptoms including joint
  replacements, organ transplants/excisions,
  anti-epileptics and transfusions, etc.
• Enzyme replacement for Type I and III disease
  (beneficial for visceral disease but does not
  cross BBB to help Type II or III CNS disease)
  with Imiglucerase or Cerezyme produced by
  Genzyme.

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Imiglucerase

• The amino acid sequence of imiglucerase differs
  from human placental beta-glucocerebrosidase by
  one amino acid at position 495, where histidine
  is substituted for arginine.  
• The CHO-expressed imiglucerase glycoprotein
  undergoes further processing during manufacture
  using enzymes to modify its glycosylation pattern
  (attached carbohydrate side chains). Mannose
  terminators on glycosylations.

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Indications for treatment

• One or more of the following
• Anemia
• Thrombocytopenia
• Bone disease
• Hepatomegaly or splenomegaly

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Dosing

• 2.5 U/kg TIW 60 U/kg q 2 weeks IV infusion
• Serum half life 12 minutes so CIVI may be
  better way to dose but not trialed.
• Meta analysis of doses and organomegaly response
  indicate 15U/kg q 2 weeks may have similar
  efficacy in children.
• Cost 4/U 17,000/dose at 60U/kg for 70kg pt.
• Dose reconstituted in sterile water and diluted
  in NS prior to each dose, stable at room
  temperature for up to 12 hours or at 4C for 24
  hours. Comes in 200 and 400 unit vials.

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Side effects

• 15 develop antibody within first year of
  treatment - half of these develop
  hypersensitivity reaction may need
  pre-treatment with antihistamine and/or steroid
• Hypersensitivity also occurs despite no
  measurable antibody to enzyme.
• Anaphylactoid reaction in lt 1 of patients.
• Pulmonary HTN/pneumonia lt 1 of patients
• Injection site reactions are possible.
• Nausea, belly pain, emesis, diarrhea, rash,
  aches, fatigue, fever, dizziness, edema,
  tachycardia - lt 1.5 each

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• National Gaucher Foundation2227 Idlewood Road,
  Suite 12Tucker, GA   30084ngf_at_gaucherdisease.org
  http//www.gaucherdisease.org
• Tel [phone]Fax [phone]