A Case of Bone Marrow Failure
And Treatment Dilemmas
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
PMHx: Full term infant – 5 lb No surgeries, no hospitalizations Meds: None Allergies: None
German ø Jewish
German ø Jewish
MVA
68
72 HBP
70 Heart Attack
48
49
44
Lung CA – smoked cigs dx – 41 years d. 43 years
46
d. 16 years boating accident
14
16
18
24
21
18 Premature birth wt Intellectual impairment
14
4 Intellectual Impairment 02 supplement
12 Bone Marrow Failure
16
18
Key Female, Male deceased cancer bone marrow failure
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
Labs
Date
3/8/05
WBC
4.9
ANC
2793
Hgb
9.2
Hct
26.8
Plt
22
3/11/05 1.7
3/14/05 7.1 3/21/05 1.9 4/1/05 2.6
901
5893 779 624
9.9
9.7 8.9 8.5
29.3
28.0 26.6 25.1
17
23 16 13
4/15/05 2.3
897
8.1
23.9
30
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
DKC
Rare disorder Characterized by…
cutaneous reticulated hyperpigmentation nail dystrophy premalignant leukoplakia of the oral mucosa progressive pancytopenia
Frequency
Most likely underdiagnosed and underreported Approximately 180 cases reported in the literature
Clinical history
Mucocutaneous features develop typically between age 5 to 15 years Median age of onset of peripheral cytopenia is age 10 years
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 leukoplakia may become verrucous and ulceration may occur
Mucosal findings
Physical Findings
Nail findings
progressive nail dystrophy begins with ridging and longitudinal fissures progressive atrophy thinning and distortion
scalp alopecia hyperhidrosis hyperkeratosis of palms and soles adermatoglyphia
Other findings
Increased incidence of malignancy
Squamous cell carcinoma of skin, nasopharynx, esophagus, rectum, vagina, cervix
Pulmonary complications
Fibrosis Abnormalities in the microvascular Presents challenge during BMT
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
DC family registry
92 families (as of 1992) 86% of affected patients were male
Confirming that the major mutation is Xlinked
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.
Genetics
Autosomal Dominant X-linked forms Autosomal Recessive
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
AD DKC
Clinical picture is milder than in the Xlinked form Patients may show signs of bone marrow failure, but lack the mucocutaneous findings Appears to be anticipation in this form of the disease
German ø Jewish
German ø Jewish
MVA
68
72 HBP
70 Heart Attack
48
49
44
Lung CA – smoked cigs dx – 41 years d. 43 years
46
d. 16 years boating accident
14
16
18
24
21
18 Premature birth wt Intellectual impairment
14
4 Intellectual Impairment 02 supplement
12 Bone Marrow Failure
16
18
Key Female, Male deceased cancer bone marrow failure
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
Treatment of Bone Marrow Failure
Androgens Immunosuppression Hemopoietic growth factors Bone Marrow Transplant
Bone Marrow Transplant and DKC
Only curative measure for bone marrow failure related to DKC Limited experience
Retrospective report of 5 patients with aplastic anemia related to DKC Between 1979 and 1993 All male patients Ages 4-13
Patients
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
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
Report of 2 children with DKC and severe aplastic anemia Underwent successful MUD HSCT Over 1 year out with minimal transplant related mortality
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
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