Bone Marrow Failure and Chromosome Instability Disorders, Leukemia and Lymphoma, Pediatric Oncology, Precision Medicine and Somatic Testing

Bone Marrow Failure Syndromes

Diverse group of disorder characterized by bone marrow failure, usually with ≥1 extra hematopoietic abnormalities (RBCs, WBCs, platelets, etc)

Diamond Blackfan Anemia genes and inheritance

Dominant - 22 genes

X-linked - GATA1 and TSR2

Diamond Blackfan Anemia features

Macrocytic anemia beginning 1st yr of life

Congenital anomalies (heart, GU)

Growth deficiency

Increased risk of AML, MDS, osteosarcoma

The severe form of Diamond Blackfan Anemia causes...

hydrops and fetal demise

Shwachman Diamond Syndrome gene and inheritance

Recessive - DNAJC21, EFL1, SBDS

Dominant - SRP54

Shwachman Diamond Syndrome features

Pancreatic insufficiency with malnutrition

Growth deficiency

Anemia with neutropenia

Increased risk of AML and MDS

Chromosome instability syndromes usually have what inheritance pattern?

Auto recessive

Chromosome instabiliy can lead what medical problems

Immunodeficiency

BMF

Cancer

Neurological decline

Growth issues

Developmental abnormalities signs of chromosome instability disorders

IUGR, SGA, short stature, microcephaly, dysmorphic features

Photosensitivity signs of chromosome instability disorders

Photophobia, skin sensitivity, easy blistering/sunburns

Skin abnormalities signs of chromosome instability disorders

Young onset of sun damage, pigmentation abnormalities

Immunodeficiencies signs of chromosome instability disorders

Frequent infections, laboratory confirmed

Dyskeratosis congenita features

Impaired telomere maintenance resulting in short/very short telomeres (<1st percentile)

High risk for BMF, MDS, AML

Increased risk of squamous cell tumors of H/N and cervix

Development of pulmonary fibrosis

Dyskeratosis congenita classic triad

Lacy reticular pigmentation of upper chest and/or neck

Dysplastic nails

Oral leukoplakia

What is oral leukoplakia?

accumulation of WBC in the cheek, tongue, gums that cannot be scraped off

Gold standard test for dyskeratosis congenita

Flow-FISH for telomere length

Dyskeratosis congenita genes and inheritance and molecular testing

80% will have pathogenic variants in 16 genes

DKC1 (20-25%), TINF2 (12-20%), TERC (5-10%), TERT (1-7%)

All inheritance patterns

Dyskeratosis congenita cancer screening

Annual physical exam/ROS

CBC every 6 mo

Consider annual bone marrow exam

Annual skin exams starting at 5y

Annual nasolaryngoscopy starting at 10y (for H/N cancers)

Annual gynecologic exam starting at 18y or after becoming sexually active (whichever is first)

Tx of dyskeratosis congenita

HCST

Individualized cancer treatment

Prevention for dyskeratosis congenita

Radiation avoidance (if RT needed, shorter interval/lower dose of radiation)

Sun protection

HPV vaccination

Fanconi Anemia features

Growth deficiency (65%)

Abnormal skin pigmentation (40%)

Skeletal malformations (45%)

Microcephaly (20-25%)

GU anomalies (20-25%)

Ocular manifestations (15%)

Progressive BMF withing first decade, 90% by 40y

Increased risk for malignancy

Fanconia anemia growth deficiency manifestations

Prenatal/postnatal short stature

Fanconia anemia skin pigmentation manifestations

Hypopigmentaiton

Cafe au lait macules

Fanconia anemia skeletal manifestations

Upper/lower limbs:

Hypoplastic thumb

Bifid thumb

Hypoplastic radius

Syndactyly

Polydactyly

Fanconia anemia GU manifestations

Kidney anomalies

Uterine anomalies in females

Reduced fertility in males

Fanconia anemia ocular manifestations

Microphthalmia

Cataracts

Ptosis

Fanconi anemia endocrine manifestations

Hypothyroidism

Diabetes

Hyperglycemia/impaired glucose tolerance

Insulin resistance

Fanconi anemia hearing loss type

Conductive due to middle-ear bony anomalies

Cancer risks in Fanconi Anemia

MDS, AML, SCC of H/N and GU tract, skin cancers

When to suspect Fanconi Anemia in cancer clinic

Patient presents with:

BMF

AML in presence of short stature, microcephaly, other congenital anomalies

SCC of H/N or GU tract with neg HPV titers

When to suspect Fanconi Anemia in general genetic/inpatient clinic

Patient presents with:

Radial ray abnormalities

VACTRL

Microcephaly or short stature with other congenital anomalies

Family hx suggestive of HBOC

Gold standard testing for fanconia anemia

Chromosome breakage of lymphocytes using DEB (diepoxybutane)

Fanconi anemia genes and inheritance and molecular testing

>95% will have pathogenic variants in one of 23 genes

FANCA (60-70%), FANCC (14%), FANCG (10%)

Most are auto recessive

FANCB is X-linked

Few reported de novo RAD51 variants causing auto dom FA

Consideration for sample selection with FA

Somatic reversions can cause false negatives in blood

If clinical suspicion is high, test skin fibroblast

Fanconi Anemia heterozygous risk genes

BRCA2, BRIP1, PALB2, RAD51C

Inc risk for BOPP cancers

Fanconi Anemia cancer screening

Annual bone marrow exam

CBC every 3-4 months

ENT eval at 10y for H/N malignancies

Annual gyn eval starting at 13y

Annual skin exam

Tx of Fanconi Anemia

Surgical resection of solid tumors (especially if they dont respond well to tumors)

HSCT (only curative therapy for heme manifestations)

Prevention for Fanconi Anemia

Radiation avoidance

Sun protection

HPV vaccination

Ataxia telangiectasia features

Progressive cerebellar ataxia in childhood (onset 1-4y)

Gait and truncal ataxia (causes lack of coordination, difficulty walking straight, poor balance)

Slurred speech

Oculomotor apraxia (inability to move eyes horizontally, abnormal and uncontrolled eye movements)

Telangiectasias mostly in eyes by age 5y (dont cause irritation or vision problems)

Ataxia telangiectasia associated cancer risks

Increased cancer risk of 25% lifetime risk

Children (Lymphomas: B-cell NHL and HL; Leukemias: T-cell ALL)

Adults (several types of solid tumors)

What are patients with ataxia telangiectasia extremely susceptible to?

Ionizing radiation

Ataxia telangiectasia gene and inheritance

Gene: ATM

Inheritance: Auto rec

Heterozygous risk for solid tumors

Ataxia telangiectasia cancer screening

Annual ROS/physical exam

Annual skin exam

Breast MRI starting at 25y

Abdominal US in adulthood

Ataxia telangiectasia cancer tx

Individualized, dose-adjusted protocols

Avoid radiation tx if homozygous

Prevention for ataxia telangiectasia

Radiation avoidance

Sun protection

Bloom Syndrome features

Severe pre/postnatal growth deficiency

Immunodeficiency

Sensitivity to sunlight (butterfly rash on face)

Insulin resistance

Increased risk for cancers

Bloom Syndrome cancer risks

Most cancers dx prior to 40y (avg 20-30y)

Hematologic malignancies (26%) - lymphoma > leukemia

Solid tumors: Skin, CRC, Oropharyngeal, breast, Wilms (rare)

Life expectancy of individuals with Bloom syndrome

30-40s

Cancer most common cause of death

Bloom syndrome cancer risk considerations

Sensitive to common chemos and RT

Reduce dose and short course of chemo, RT should be avoided

When to suspect Bloom Syndrome

Individuals very small for their age with sparse adipose tissue and normal intelligence

Lymphoma work-ups

Sun sensitivity with rash

Bloom Syndrome cytogenetic testing

Sister chromatid exchange

Bloom Syndrome gene and inheritance and molecular testing

Gene: BLM gene

Inheritance: Auto rec

Very rare, increased freq in AJ population

Bloom Syndrome cancer screening

Annual ROS/physical exam

Yearly colonoscopy starting at 10-12y (colon polyp risk in homozygotes only)

Breast MRI starting at 18y

Some guidelines may recommend WBMRI

Prevention for Bloom Syndrome

Radiation avoidance

Sun protection

HPV vaccination

Nijmengen Breakage Syndrome features

Progressive microcephaly

Growth deficiency

Recurrent respiratory infections (pneumonia/bronchitis)

Increased risk for cancer

Premature ovarian failure

Developmental delay (early milestones met, but decline to mild/moderate delay)

Cancer risk in Nijmegen Breakage Syndrome

40% risk of cancer by 20y

Most common is lymphoma

Solid tumors (most by 15y) : Medulloblastoma, glioma, rhabdomyosarcoma, ovarian germ cell tumor

Nijmegen Breakage Syndrome gene and inheritance

Gene: NBN

Inheritance: AR

Nijmegen Breakage Syndrome cancer screening

Annual ROS/physical exam

NO imaging or screening for solid tumors

Nijmegen Breakage Syndrome cancer tx

Protocols adapted to individual tolerance

Prevention for Nijmegen Breakage Syndrome

Radiation avoidance

Sun protection

HPV vaccination

Rothmund-Thomson Syndrome general features

Sun sensitivity

Skeletal

Teeth

Growth

Hair

Eyes

Increased cancer risk

Rothmund-Thomson Syndrome sun sensitivity manifestations

Begins as red, swollen, blistering rash between 3mo-2y

Rash becomes chronic and progresses to poikiloderma (sun damaged skin)

Rothmund-Thomson Syndrome skeletal manifestations

Radial anomalies

Shortened radii

Hypoplastic thumbs

Hypoplastic/absent patella

Low bone mineral density

Rothmund-Thomson Syndrome teeth manifestations

Hypoplastic teeth

Microdontia

Supernumerary teeth

Congenitally missing teeth

Increased dental caries

Rothmund-Thomson Syndrome growth manifestations

LBW and length

Usually below 5th percentile throughout life

Rothmund-Thomson Syndrome hair manifestations

Sparse scalp hair or complete alopecia

May have sparse eyelashes or eyebrows

Rothmund-Thomson Syndrome eye manifestations

Juvenile cataracts

Rothmund-Thomson Syndrome cancer risks

Most common cancer is osteosarcoma (30%)

Skin cancers (BCC, SCC, melanoma) (5%)

May develop 2nd primary (often lymphoma)

Rothmund-Thomson Syndrome gene and inheritance

Genes: RECQL4 (60%), ANAPC1 (10%), 30% unknown

Inheritance: AR

Very rare

Rothmund-Thomson Syndrome cancer screening

Annual ROS/physical exam

Consider annual WBMRI in individuals with RECQL4 variants

Annual derm exam

Rothmund-Thomson Syndrome cancer tx

Standard therapy

Prevention for Rothmund-Thomson Syndrome

Radiation avoidance

Sun protection

HPV vaccination

Xeroderma Pigmentosum (XP) features

Acute sun sensitivity

Sunlight-induced ocular involvement

Increased risk of skin cancer

Neurodegeneration

XP sun sensitivity manifestations

Severe sunburn with blistering

Persistent erythema on minimal sun exposure

XP sunlight-induced ocular manifestations

Photophobia

Sever keratitis

Atrophy of eyelids

XP neurodegeneration manifestations

Acquired microcephaly

Diminshed deep tendon reflex

Progressive SNHL

Progressive cognitive impairment

Ataxia

XP cancer risk

Skin cancer (65%) may occur in 1st decade of life if proper UV avoidance is not begun early

BCC/SCC avg onset at 9y

Melanoma avg onset at 22y

Solid tumors reported but not as common

XP gene and inheritance

Genes: Pathogenic variants in 1 of 9 different genes

XPA (30%), XPC (27%), POLH (23%)

Inheritance: AR

Prevalence of XP

1:1,000,000 in US

Some populations with founder variants/high rates of consanguinity have higher prevalence

XP cancer screening

Quarterly derm exams

Ophthalmology exam every 6-12mo

CBC every 6-12mo

Annual bone marrow assessment

XP cancer tx

Mohs surgery (remove skin cancers)

Chemo and immunotherapy (targeted PD-L1 inhibitors)

RT

Prevention for XP

Radiation avoidance

Sun protection

HPV vaccination

Hematopoiesis

Process of blood cell production (continuous process throughout life to replace old blood cells)

Three major types of blood cells

1) Erythrocytes

2) Leukocytes

3) Thrombocytes

Medullary hematopoiesis

Blood cell production in bone marrow

Most common

Extramedullary hematopoiesis

Blood cell production in the liver and spleen

Less common

Leukemia

Cancer of the WBCs and arises from the bone marrow

Myeloid and Lymphoid

Myeloid leukemias

Affects the myeloid cells (myeloid progenitor cells)

Acute Myeloid Leukemia (AML)

Chronic Myeloid Leukemia (CML)

Lymphoid leukemias

Affect the B- and T-lymphoid cells

Acute Lymphoblastic Leukemia (ALL)

Chronic Lymphoblastic Leukemia (CLL)

Leukemia symptoms

Low RBC and platelets

High WBC and WBC look abnormal

Immunodeficiency

Anemia

Fatigue

Easy bleeding and bruising

Treatment of leukemia

Chemotherapy

Radiation therapy (RT)

Targeted therapy (based on somatic testing results)

Bone marrow/stem cell transplant

Induction therapy

Intense chemotherapy and radiation give at time of diagnosis with the goal of achieving initial remission

Consolidation therapy

Chemotherapy treatment after cancer is in initial remission, aims to eradicate lingering and undetectable cancer cells

Maintenance therapy

Low dose therapy to prevent relapse or recurrence

Risk factors of leukemia

1) Smoking (specifically AML)

2) Exposure to high levels of radiation

3) Prior cancer tx with chemo or RT

4) Family hx

5) Genetic syndrome/predisposition

6) Exposure to cancer-causing agents

Myelodysplastic Disease (MDS)

One or more type of WBC or RBC are dysplastic and have low count

High risk (1 in 3) or progressing to an acute AML

What cancer does MDS increase risk of developing

AML

What is the only way to cure MDS

Bone Marrow Transplant

Risk Assessment Red Flags in Personal History to be suspicious for genetic etiology/syndrome

1) Hematologic malignancy (AML or MDS <50y)

2) Solid tumor <50y

3) Childhood cancers

4) Thrombocytopenia, ITP, platelet defect/bleeding or clotting concern

5) Bone marrow failure/aplastic anemia

6) Hx of BMT

Risk Assessment Red Flags in Family History to be suspicious for genetic etiology/syndrome

1) Premature greying or hair loss

2) Pulmonary fibrosis

3) Liver disease

4) Immunodeficiency

5) Hearing loss

6) Skeletal anomalies

7) Cafe au lait spots

8) Heart defects

9) Eczema