A Case of Bone Marrow Failure

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A Case of Bone Marrow Failure

• And Treatment Dilemmas

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• 11 yo caucasian male
• 1 month history of intermittent fevers, fatigue
  and decreased appetite
• Intermittent knee pain
• No weight loss or night sweats
• Seen in OSH ER and found to have pancytopenia

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• PMHx Full term infant 5 lb
• No surgeries, no hospitalizations
• Meds None
• Allergies None

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German ø Jewish
German ø Jewish
MVA
68
72 ?HBP
70 Heart Attack
49
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Lung CA smoked cigs dx 41 years d. 43 years
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d. 16 years boating accident
48
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16
18
24
21
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18 Premature ?birth wt Intellectual impairment
4 Intellectual Impairment 02 supplement
12 Bone Marrow Failure
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Physical Exam

• Gen pale, thin boy
• Skin pretibial bruising, no pigment changes
• Dysplastic, brittle toenails
• HEENT nl
• Lungs CTA
• CV RRR with 1/6 SEM
• Abd soft, ND, liver down 1 cm
• GU Tanner 1
• No LAD
• Neuro exam normal

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Labs
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Other Labs

• ESR 64
• Hepatitis B, Hepatitis C, EBV, CMV neg
• PNH screen negative
• Fanconi screen - negative
• Bone Marrow markedly hypocellular marrow with
  limited normal hematopoiesis
• Cytogenetics no abnormalities

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DKC

• Rare disorder
• Characterized by
• cutaneous reticulated hyperpigmentation
• nail dystrophy
• premalignant leukoplakia of the oral mucosa
• progressive pancytopenia

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Frequency

• Most likely underdiagnosed and underreported
• Approximately 180 cases reported in the literature

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Clinical history

• Mucocutaneous features develop typically between
  age 5 to 15 years
• Median age of onset of peripheral cytopenia is
  age 10 years

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Physical findings

• Cutaneous
• abnormal skin pigmentation with tan-grey
  hyperpigmented or hypopigmented macules and
  patches in a mottled or reticulated pattern
• typical distribution - upper trunk neck and face
• Mucosal findings
• mucosal leukoplakia
• may become verrucous and ulceration may occur

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Physical Findings

• Nail findings
• progressive nail dystrophy
• begins with ridging and longitudinal fissures
• progressive atrophy thinning and distortion
• Other findings
• scalp alopecia
• hyperhidrosis
• hyperkeratosis of palms and soles
• adermatoglyphia

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• Increased incidence of malignancy
• Squamous cell carcinoma of skin, nasopharynx,
  esophagus, rectum, vagina, cervix

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Pulmonary complications

• Fibrosis
• Abnormalities in the microvascular
• Presents challenge during BMT

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Bone marrow failure

• Usually occurring in second decade of life
• Main cause of mortality
• Median survival following diagnosis with aplastic
  anemia is approximately 4 years

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DC family registry

• 92 families (as of 1992)
• 86 of affected patients were male
• Confirming that the major mutation is X-linked

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Mortality

• 70 of patients die from bone marrow failure or
  complications at a median age of 16 years
• 11 died from sudden pulmonary complications
• 11 died of pulmonary disease in the BMT setting
• 7 died from malignancy.

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Genetics

• Autosomal Dominant
• X-linked forms
• Autosomal Recessive

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Autosomal dominant DKC

• Caused by mutations in the TERC gene
• Encodes the RNA component of the telomerase
  complex
• Mutations have also been found in the TERT gene
• Encodes the catalytic part of the enzyme
  telomarase
• Responsible for elongating and maintaining
  telomeres

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AD DKC

• Clinical picture is milder than in the X-linked
  form
• Patients may show signs of bone marrow failure,
  but lack the mucocutaneous findings
• Appears to be anticipation in this form of the
  disease

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German ø Jewish
German ø Jewish
MVA
68
72 ?HBP
70 Heart Attack
49
44
Lung CA smoked cigs dx 41 years d. 43 years
46
d. 16 years boating accident
48
14
16
18
24
21
14
18 Premature ?birth wt Intellectual impairment
4 Intellectual Impairment 02 supplement
12 Bone Marrow Failure
16
18
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X-linked DKC

• DKC1 encodes dyskerin
• a nucleolar protein that associates with a class
  of small nucleolar RNA molecules
• active pseudouridine synthase
• also forms part of the telomerase complex
• Impaired telomerase activity and defective rRNA
  production most likely both play a role in the
  X-linked form of the disease

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Treatment of Bone Marrow Failure

• Androgens
• Immunosuppression
• Hemopoietic growth factors
• Bone Marrow Transplant

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Bone Marrow Transplant and DKC

• Only curative measure for bone marrow failure
  related to DKC
• Limited experience

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• Retrospective report of 5 patients with aplastic
  anemia related to DKC
• Between 1979 and 1993
• All male patients
• Ages 4-13

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Patients
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Complications

• 4 out of 5 patients had vascular lesions and
  fibrosis involvement of various organs
• High frequency of bronchopulmonary complications
• Pts appear to be susceptible to early and late
  endothelial damage syndromes
• VOD, TMAS, TTP

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How to minimize affects of BMT

• Minimize endothelial damage
• Use of heparin or prostaglandin E1
• Modification of conditioning regimen
• Avoidance of radiation
• Improved supportive Care
• Surveillance of the unusual complications

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• Report of 2 children with DKC and severe aplastic
  anemia
• Underwent successful MUD HSCT
• Over 1 year out with minimal transplant related
  mortality

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Conditioning Regimen

• Fludarabine 30mg/m2/day from day 10 to day 5
• Cyclophosphamide 60mg/kg/day from day 6 to day
  5
• ATGAM from day 4 to day 1
• GVHD prophylaxis cyclosporine and prednisone

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What to do?

• Cure means BMT
• HLA -typed he and his family
• Conditioning regimen of Campath, Fludarabine, and
  Melphalan
• Started on oral cyclosporine
• Considering use of androgens
• Increased immunosuppression and/or
• Erythropoeitin and neupogen