Recessive Cancer syndromes

Question 1

How is the dx of Fanconi anemia established

Answer 1

in a proband with either of the following:
1. increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes w DEB and MMC
2. identification of biallelic PVs in one of the 21 genes known to cause AR FA, or a heterozygous PV in RAD51, or a hemizygous PV in FANCB known to cause XLR FA

Question 2

What molecular testing should be ordered for pts with suspected FA

Answer 2

Sequence analysis of FANCA can be performed first
THEN multigene panel w other genes may be considered next if single gene testing does not identify a FANCA PV

Question 3

What are the physical features seen in pts with Fanconi Anemia

Answer 3

occur in ~75% of individuals
growth deficiency, short stature, low birth weight, generalized hyperpigmentation, cafe au lait macules, hypopigmentation, skeletal malformations (thumbs, radii, hands, ulnae), skeletal malformations of the lower limbs (syndactyly, abnormal toes, club feet, congenital hip dislocation), microcephaly, microphthalmia, cataracts, strabismus, ptosis, genitourinary tract anomalies (renal: horseshoe, ectopic, pelvic, hypoplastic, absent kidney; males: hypospadias, cryptorchidism, reduced fertility; females: bicornate or uterus malposition, small ovaries); endocrine disorders (hypothyroidism, diabetes, hyperglycemia/impaired glucose tolerance, insulin resistance), hearing loss, CHD, gastro (atresias, imperforate anus, tracheoesophageal fistula, annular pancreas), DD/ID seen in 10%
bone marrow failure: risk of developing any hematologic abnormality is 90% by 40yo, thrombocytopenia or leukopenia precede anemia, pancytopenia worsens over time

Question 4

What are the cancer risks associated with Fanconi anemia

Answer 4

relative risk for AML: 500-fold increase, most individuals dx by 15-35 (13% risk by age 50)
increased risk of developing myelodysplastic syndrome is associated w monosomy 7 and most 7q dels

head and neck squamous cell carcinoma are the most common type; occur at an earlier age, most in the oral cavity, present at an advanced stage and respond poorly to therapy
at increased risk for secondary cancers in the GU tract and skin
those receiving androgen tx therapy for bone marrow failure are at increased risk for liver tumors

Question 5

What are phenotype genotype correlations in fanconi anemia

Answer 5

BRCA2: Biallelic PVs are associated w early onset AML and sold tumors; 97% probability of malignancy by 6yo including AML, medulloblastoma, and Wilms tumor
FANCB: early onset bone marrow failure and severe congenital abnormalities
FANCG: associated w severe marrow failure and a higher incidence of leukemia
PALB2: solid tumors are associated w PVs

Question 6

What are the tx recommendations for someone with Fanconi anemia

Answer 6

growth deficiency tx per endocrinologist
limb abnormalities and other orthopedic manifestations tx w surgeon, OT/PT
ocular abnormalities tx by specialist
renal malformations, genital malformations, hypothyroidism, hearing loss, and cardiac anomalies should be tx by their respective specialists
dermatologic manifestations should be tx w sunscreen and rash guards
early intervention for DD, IEPs for school age children

androgens improve the red cell and platelet counts in ~50% of individuals; side effects include liver toxicity and virilization, if no response is seen in 3-4mo, androgens should be discontinued
granulocyte-colony stimulating factor (G-CSF) improves the neutrophil count in some individuals
HSCT is the only curative therapy for hematologic manifestations, including aplastic anemia, myelodysplastic syndrome, and acute leukemia
solid tumors: early detection and sx removal remain the mainstay therapy; tx is challenging due to increased toxicity associated w chemo and radiation

Question 7

What vaccine should be given to pts with Fanconi anemia early

Answer 7

HPV vaccine should be initiated at 9yo to reduce the risk of gynecologic cancer in females, possibly reduce the risk of oral cancer in all individuals

Question 8

What is the recommended surveillance for individuals with Fanconi Anemia

Answer 8

ophthalmologist exam annually for strabismus/cataracts
endocrine manifestations: annually measure TSH and free T4, 25-hydroxy vitamin D, 2hr glucose tolerance test, insulin levels
hearing eval at dx and serially if exposed to chemo agents
developmental assessment annually throughout childhood
blood counts q3-4mo for pancytopenia
annual bone marrow bx w FISH and cytogenetics to assess for myelodysplasia
liver function tests q3-6mo on androgen therapy and u/s q6-12 on therapy to assess for liver disfunction
gyno exam for genital lesions annually @13yo, pap smear annually @18, bx of malignant lesions to assess for cancers
dental/oral exam q6mo @9-10yo, q2-3mo if have a hx of premalignant or malignant lesions; nasolaryngoscopy annually @10yo
skin cancer eval q6-12 mo
BRCA-related FA needs abdominal u/s and brain MRI starting at dx

THOSE WHO HAVE FA DUE TO A PV IN A BREAST CA SUSCEPTIBILITY GENE ALSO NEED TO UNDERGO NCCN SURVEILLANCE FOR THAT CONDITION

Question 9

How is Fanconi Anemia inherited

Answer 9

AR, AD (RAD51- all are de novo), XLR (FANCB)

Question 10

How can you test for chromosome breakage in a pregnancy

Answer 10

perform cyto testing in the presence of DEB/MMC (Stain) to eval for increased chromosome breakage in fetal cells obtained by CVS/Amnio. Molecular testing is still the better choice over this method

Question 11

How is the dx of MAP established

Answer 11

biallelic PVs in MUTYH, many individuals are dx w a gene panel

Question 12

What is indicated if a KRAS PV is identified

Answer 12

KRAS PV c.34G>T in codon 12 is present in less than 5-10% of sporadic CRC but found in 40-100% of adenomas and 60-90% of CRCs in ppl w MAP
10-25% of ppl w CRC with this KRAS variant have biallelic germline MUTYH PVs
often routine to order this testing in advanced CRCs to identify individuals who are eligible for MUTYH germline molecular testing

Question 13

What are the cancer risks associated w MAP

Answer 13

Lifetime risk of 80-90% of CRC in the absence of timely surveillance; have between 10-a few hundred colonic polyps w a mean presentation of 50yo; right sided in 29-69%
duodenal-4%
ovarian- 6-14%; avg age of dx @51yo
bladder- 6-8% in females; 6-25% in males
breast- 12-25%
endometrial- 3%
gastric- 1%

Question 14

What are the tx recommendations for MAP

Answer 14

Colonoscopy and polypectomy q1-2yrs until polypectomy cannot manage the large size and density of the polyps, at which point colectomy may be necessary
endoscopic or sx removal of duodenal and/or ampullary adenomas is recommended if polyps exhibit villous changes or severe dysplasia, exceed 1cm in diameter, or cause symptoms
abnormal thyroid findings should be evaled by a specialist

Question 15

What are the surveillance recommendations for pts w MAP

Answer 15

colonoscopy and polypectomy q1-2yrs beginning @25-30
upper endoscopy w side viewing duodenoscopy q3mo-4yrs @30-35
consider thyroid u/s annually
consider skin exam annually

Question 16

What is the heterozygous MUTYH risk for cancer

Answer 16

2-3 fold increased risk for late onset CRC

Question 17

How can ataxia telangiectasia be identified on NBS

Answer 17

Newborns with the classic version may have low TRECs comparable to those with SCID and thus may have a positive NBS
Since variant AT is not associated w immunodeficiencies, NBS for SCID does not detect variant AT
Newborns w abnormal NBS for SCID require immediate subspeciality immunology evaluation

Question 18

What are the laboratory findings consistent with classic ataxia telangiectasia

Answer 18

serum AFP high (only reach normal levels around 2yo, so may not be a reliable dx marker in children)
serum IgA, IgG, and IgG subclasses are decreased; 10% have hyper IgM phenotype w the previous antibodies elevated
B and T cells (CD4+ and CD8) may be decreased
lymphocyte functional tests: restricted responses to antigens and abnormal B cell class switching may be found

Question 19

What laboratory findings are consistent with variant ataxia telangiectasia

Answer 19

AFP not as high as those with classic AT and can eventually become normal
no immunologic findings

Question 20

How is the dx of ataxia telangiectasia made

Answer 20

biallelic PVs in ATM
sequence then del/dup

although most PVs are in exons, there are several that have been identified in introns

Question 21

What are the clinical features associated with classic ataxia telangiectasia

Answer 21

cerebellar ataxia, postural instability, wobbly gait progresses into rapid broad based gait, dystonia, choreoathetosis, myoclonic jerks, and tremor; Parkinsonism in the 2nd-3rd decade of life
by 8yo, sensorimotor neuropathy, decreased/loss of deep tendon reflexes, muscle weakness and atrophy, use a wheelchair
speech problems, dysarthria, dysphagia which makes eating frustrating/exhausting, oculomotor apraxia
ID is not common but cognitive deficits can occur in the later half of the first decade of life
immunodeficiency remains stable over time (due to severe immune deficiency, those with hyper IgM phenotype have a shorter life span); thymic hypoplasia; severe infections are uncommon
pulmonary dz is common and can be exacerbated by recurrent upper respiratory infections at all ages
endocrine abnormalities: poor linear growth due to nutritional problems, recurrent infections, low serum growth hormone levels (more common in females); gonadal failure and abnormal spermatogenesis in males and ovarian failure in females; insulin resistance
telangiectasias (vascular abnormalities on sun exposed parts of skin) evident by 6yo but not at dz onset; can occur in internal organs as well
premature ageing (grey hair, cafe au laits, adolescent onset of DM and liver dz)
increased sensitivity to radiation
cutaneous granulomas
elevated serum liver enzymes and hepatic steatosis in adults

since this is a DNA repair defect, risk of malignancy is ~25% w median age of onset around 12-13yo; children prone to leukemia and lymphomas; adults prone to developing solid tumors including breast cancer, ovarian ca, gastric ca, liver ca, esophageal carcinomas, melanomas, leiomyomas, and sarcomas

Question 22

What is the life expectancy for someone with classic ataxia telangiectasia

Answer 22

most do not live longer than 30yo
individuals w the hyper IgM phenotype have a poorer prognosis and most die before 15yo due to respiratory failure

Question 23

What are the clinical features associated with variant ataxia telangiectasia

Answer 23

can occur in childhood to adulthood with most having their first manifestation by 10yo
dystonia, dystonic tremor, central motor manifestations, axonal sensorimotor polyneuropathy
occasional feeding problems due to neurologic decline
increased risk of developing malignancies; premenopausal women at increased risk to develop breast cancer and hematologic malignancies
telangiectasias in half
increased sensitivity to ionizing radiation

Question 24

What leads to the different phenotypes seen in ataxia telangiectasia

Answer 24

nonsense and/or frameshift variants lead to the classic form
missense and splice site variants lead to the variant form (typically)

Question 25

What are the recommended txs for pts with ataxia telangiectasia

Answer 25

Ataxia: nicotinamide riboside, a form of vitamin B3 significantly reduces ataxia
Dystonia: focal- botulinum toxin A; generalized- GABA mimetics and anticholinergics
PT to provide exercises to maintain muscle strength, overall condition, and activity to prevent contractures
dysarthria: SLP to provide practical advice to improve speech intelligibility and support familites
manage dysphagia (thicken liquid, for example; underlying molecular defect itself makes affected individuals more prone to linear growth)
oculomotor problems: visual aids
respiratory: need to be referred to a multidisciplinary respiratory management team
endo: shortened life expectancy of those w classic AT can result in decision NOT to tx high cholesterol; in females w gonadal failure, estrogen supplement to prevent osteoporosis; growth hormone therapy for those w severe growth failure

prophylactic antibiotic tx; immunoglobulin replacement therapy for those w severe IgG deficiency and in those w hyper IgM phenotype; inactivated vaccines are safe BUT do not give rubella vaccine (increased risk for granulomas)

Question 26

What specialists should someone see if they have ataxia telangiectasia

Answer 26

peds neurology, pulmonology, immunology, IM, rehab medicine, PT/OT/speech, nutrition specialist, oncology, endocrinology, orthopedics, derm, mental health, social work

Question 27

What is contraindicated for pts with ataxia telangiectasia

Answer 27

Radiation therapy
allogenic stem cell transplant when there is NOT an adjusted conditioning regime

Question 28

What is the recommended surveillance for someone with ataxia telangiectasia

Answer 28

neuro eval annually
screen for educational needs before school age
immunodeficiency/infection screening annually
pulmonary dz screening by lung function testing annually
for increased susceptibility to malignancy, annual clinical assessment for leukemia/lymphoma; blood counts, immunoglobulin levels, LDH, IgM, u/s of abdomen in adulthood; breast MRI in females annually starting @25
endocrine screening for DM, growth deficiency, and pubertal development annually
feeding/nutrition eval annually

Question 29

What is the molecular pathogenesis for ataxia telangiectasia? Lab considerations?

Answer 29

individuals w classic version have no ATM kinase activity whereas those w variant form have residual activity (and therefore more mild dz)

multiple deep intronic ATM PVs have been identified that would not be detected by standard exome

IF A VUS IS IDENTIFIED, ADDITIONAL TESTING SUCH AS IMMUNOBLOTTING FOR ATM AND/OR FUNCTIONAL ANALYSIS OF ATM KINASE ACTIVITY IS RECOMMENDED

Question 30

How is the dx of Bloom syndrome established

Answer 30

biallelic PVs in BLM
Increased frequency of sister chromatid exchanges (SCEs) on cyto studies may be helpful in circumstances where BLM variant analysis is inconclusive

Question 31

What molecular testing is available for Bloom syndrome

Answer 31

sequence and del/dup of BLM

individuals have a mean of 40-100 SCEs per metaphase (normally less than 10); increased frequency of SCEs demonstrated in BSyn cultures but the presence of SCEs alone is not sufficient to confirm the dx (bc also seen in AR RMI1, RMI2, and TOP3A disorders)

Question 32

What clinical features are consistent w Bloom syndrome

Answer 32

growth deficiency: affects height, weight, head circumference (head shape is described as long and narrow); smaller than normal for GA
Subcutaneous adipose tissue sparse in childhood but adults may have central obesity
feeding problems: many infants w gastrostomy tubes; eat slowly, decreased appetite, limited variety of foods eaten
skin lesions: red, sun sensitive rash on the nose and cheeks, sometimes on the hands and forearms; cheilitis, blistering and fissuring of the lips, eyebrow and eyelash hair loss, alopecia, cafe au laits, hypopigmented skin
immunodeficiency: usually plasma IgM and IgA are abnormally low; more childhood infections but no opportunistic infections (ex: bacterial sepsis)
fertility: most men are infertile w azoospermia or severe oligospermia; women are fertile, but may enter menopause prematurely
NORMAL INTELLECT
medical complications: cancer, DM (resembles type 2 diabetes at a younger age AND low BMI), pulmonary dz, hypothyroidism

Question 33

What are the cancers associated w Bloom syndrome

Answer 33

cancer is the most frequent medical complication in these pts and is the most common cause of death
leukemia (AML, ALL)
lymphoma
oropharyngeal (tongue, pharynx, tonsil)
upper GI (esophageal, gastric)
CRC
genitourinary (testicular, cervical)
breast
skin (BCC, SCC)
Wilms tumor
Lung

Question 34

What are the tx recommendations for pts with Bloom syndrome

Answer 34

growth deficiency: used cautiously since there is an increased risk of developing tumors; if prescribed need to closely monitor
standard tx for feeding issues, dietary tx for dyslipidemia
derm: sunscreen, UV-protective clothing and sunglasses
immune: recurrent infections and defects in humeral immunity-> tx with immunoglobulins
cancer: due to hypersensitivity to DNA damaging chemicals and ionizing radiation, ppl tolerate less than 50% of standard chemo dosing; HSCT not a very successful tx regimen
endocrine: standard tx of DM, thyroid replacement hormone as recommended for hypothyroidism
may need cough assist devices, vibration vests, and daily nasal lavage for bronchiectasis

Question 35

What is the recommended surveillance for someone with Bloom syndrome

Answer 35

lipid profile (for dyslipidemia) annually @10yo
skin exam when recognition of suspicious lesions and annually after
immunology assessment at each visit
abdominal u/s, screen for painless abdominal mass and hematuria indicating Wilms tumor q3mo from time of dx to 8yo
leukemia/lymphoma screening at every health visit; whole body MRI q1-2yrs @12-13yo
colonoscopy annually @10-12yo; fecal immunohistochemical testing q6mo @10-12yo
breast MRI in females annually @18yo
screening for DM w fasting A1c and blood glucose annually @10yo
screen for hypothyroidism annually @10yo
assess for recurrent/chronic pulmonary dz at each visit

Question 36

What is the molecular pathogenesis of Bloom syndrome

Answer 36

is the prototype of the class of human diseases known as the chromosome breakage syndromes; major loss of BLM function for a somatic cell is an abnormally high rate of recombination and mutation
LOF

Question 37

What supportive laboratory findings are consistent w the dx of Nijmegen breakage syndrome

Answer 37

immunodeficiency of the humoral:
deficit of IgG (subclasses are deficient, serum concentration may still be normal) and/or IgA
and cellular systems:
most commonly include reduced absolute #s of total B cells, CD3+ cells, and CD4+ cells

Question 38

What signs of chromosome instability can be seen in pts w Nijmegen breakage syndrome

Answer 38

invs and t’s involving chrom 7 and 14 in 10-50% of metaphases
breakpoints most commonly involved are 7p13, 7q35, 14q11, 14q32 which are the loci for immunoglobulin and T cell receptor genes

Question 39

How is the dx of Nijmegen breakage syndrome established? what testing can be done to confirm dx?

Answer 39

biallelic PVs in NBN and/or absent nibrin protein on immunoblotting assay

single gene: targeted analysis for common founder variant (c.657_661del5) accounts for 100% of PVs in Slavic ancestry and 70% in the US if the common PV is not found in a homozygous form, can do SEQUENCING ONLY analysis of NBN
Immunoblotting to determine if nibrin protein is present/absent although this is usually done in a research setting

Question 40

What are the clinical features associated w Nijmegen breakage syndrome

Answer 40

weight below normal, microcephaly that progresses w age causing disproportionate head dimensions compared to the rest of the body
slopping forehead, upward-slanted palpebral fissures, prominent nose, relatively large ears, retrognathia
linear growth starts slow but tends to normalize; respiratory infections that can lead to pulmonary failure and early death
40% w malignancy before 20yo, mostly lymphomas; can also develop medulloblastomas, gliomas, rhabdomyosarcomas, and bilateral ovarian germ cell tumors
intellectual abilities are normal at first but decline w mild-moderate ID during childhood; have a cheerful, shy personality
females are infertile w hypergonadotropic hypogonadism
irregular skin pigmentation

Question 41

What are heterozygotes at risk for with a NBN PV

Answer 41

observed in several different cancer including breast, prostate, medulloblastoma, and melanoma
there are no consensus guidelines for screening heterozygotes

Question 42

What are the tx recommendations for someone w Nijmegen breakage syndrome

Answer 42

immunodeficiency: antibiotics as needed for infections; consider Ig replacement in those w severe hypogammaglobulinemia and frequent infections; acellular vaccines recommended but live vaccines (MMR, TB, varicella) should NOT be given
standard tx for pulmonary infections
malignancy: requires careful following by an oncologist, low chemo doses not associated with lesser side effects but an increased risk of disease recurrence and poorer overall survival; radiotherapy and radiomimetic chemos are avoided; HSCT recommended after 1st remission from malignancy of hematologic origin
consider HRT for hypergonadotropic hypogonadism

Question 43

What is the recommended surveillance for someone with Nijmegen breakage syndrome

Answer 43

immunology: concentrations of total serum immunoglobulins, absolute #s of Bcells, Tcells, and T cell subsets q3-6mo
malignancy: assessment via u/s, MRI, bx in those w symptoms or w/out symptoms annually; breast self exam monthly for females
endocrine: assess for POI in females, ensure appropriate pubertal development in both sexes
neuro: assess cognitive development and intellectual abilities

Question 44

What is the molecular pathogenesis for Nijmegen breakage syndrome

Answer 44

most known PVs in NBN are predicted to result in truncation of the nibrin protein
LOF