Chromosome Breakage Disorders

Question 1

Ataxia-Telengectasia

Answer 1

Inheritance: Autosomal recessive
Gene: ATM
Disrupted repair: Double-stranded break repair
Major features:
●Ataxia
●Telangiectasias in the whites of the eyes
oMay appear in other areas especially sun-exposed areas
●Oculomotor apraxia
●Involuntary movements
●Recurrent ear/sinus/upper respiratory infections
●Delayed onset of puberty
●Premature menopause
●Growth delay
●Drooling
●Dysarthria (slurred speech)
●Premature aging
●Type 2 diabetes at a young age
●Increased risk for cancer, especially lymphomas and leukemias
●Neurologic symptoms are typically stable in the first 4-5 years of life and slowly progressive afterward
●Shortened lifespan (anywhere from 25-50 years)
Heterozygous carriers of ATM mutations are at an increased risk for breast cancer

Question 2

Bloom syndrome

Answer 2

Inheritance: Autosomal recessive
Gene: BLM
Disrupted repair: Increased sister chromatid exchanges/double-stranded break repair
Major features:
●IUGR
Short stature
●Extreme growth deficiency
●“Butterfly shape” skin lesions/rashes after sun exposure
●Characteristic high-pitched voice
●Feeding difficulties
●Immune deficiency
●Premature menopause
●Azoospermia/oligospermia
●May have learning problems though many are intellectually normal
●Significantly increased risk for cancer
    oColon
    oBreast
    oLiver
    oRespiratory tract
    oLymphatic
    oSarcoma
    oGerm-cell
    oCNS
    oRetinoblastoma

Question 3

Cockayne Syndrome

Answer 3

Inheritance: Autosomal recessive
Genes:
Disrupted repair: Nucleotide excision repair
Major features:
●Postnatal growth failure
●Progressive microcephaly
●Leukodystrophy
●Neurologic dysnfunction
●Developmental delay
●Behavioral problems
●Intellectual deterioration

Question 4

Cockayne Syndrome: Minor features

Answer 4

Minor features
●Photosensitivity
●Demyelinating peripheral neuropathy
●Pigmentary retinopathy
●Cataracts
●Sensorineural hearing loss
●Dental anomalies
●Characteristic physical appearance (“cachectic dwarfism”)
●Premature aging
●Not predisposed to cancer or infection
Type I onsets by the 2nd year of life with death in the first or second decade of life
Type II is congenital with death typically by age 7
Type III is milder and individuals may survive to adulthood

Question 5

Fanconi Anemia

Answer 5

Inheritance: Autosomal recessive, X-linked recessive (FANCB)
Genes: FANCA-FANCP, BRCA2 (FANCD1), BRIP1 (FANCJ), PALB2 (FANCN), RAD51C (FANCO), SLX4 (FANCP)
Disrupted repair: Cross-link repair, homologous recombination repair
Major features:
●Short stature
●Skeletal anomalies
      oAbnormal limbs and digits, dysplastic, hyoplastic, or absent
●Microcephaly
●Skin lesions
        oHyper- and hypopigmentation
        oCafé au lait macules
●Dysmorphic facial features
●Genitourinary abnormalities
●Azoospermia
●Developmental delay
●Intellectual disability
●Conductive hearing loss due to middle ear skeletal anomalies
●Congenital heart defects
●GI issues (atresia, malrotation)
●Kidney problems
●Pituitary/CNS hypoplasia
●Pancytopenia/bone marrow failure
●Significantly increased risk for cancer
      oLymphatic/leukemia
      oHead and neck tumors
Treatment with androgens and hematopoietic growth factors may help/stem cell transplant

Question 6

Nijmegen Breakage Syndrome (NBS)

Answer 6

Inheritance: Autosomal recessive
Gene: NBN (NBS1)
Disrupted repair: Homologous recombination repair
Major features:
●Microcephaly
●Growth delay
●Recurrent sinopulmonary infections
●Progressive decline in intellectual ability leading to borderline-to-moderate ID
●Dysmorphic features
●T and B-cell lymphomas are common

Question 7

Weaver syndrome

Answer 7

Inheritance: Autosomal recessive
Gene: WRN
Disrupted repair: Double-stranded break repair
Major features:
●Short stature
●Premature aging
●Skin atrophy with sclerodermic lesions
      oCan lead to gangrene/amputation
●Lipodystrophy
●Change in voice
      oWeak and high-pitched
●Gonadal atrophy with associated infertility
●Telangiectasias
●Early onset of diseases normally associated with aging
      oOsteoporosis
      oDiabetes Mellitus
      oAtherosclerosis
      oCalcinosis
●Increased risk for cancer
      oMelanoma
      oSarcoma
      oThyroid
      oLiver
      oMyelodysplastic syndrome
      oMalignant fibrous histiocytoma

Question 8

Xeroderma Pigmentosum (XP)

Answer 8

Inheritance: Autosomal recessive
Gene: XPA, ERCC1, ERCC3 (XP-B), XPC, ERCC2 (XP-D), DDB2 (XP-E), ERCC4 (XP-F), and ERCC5 (XP-G)
Disrupted repair: Nucleotide excision repair
Major features:
●Extreme sun sensitivity
●Development of multiple freckles at an early age
●Solar keratoses
●Extreme ocular sun sensitivity
●Skin blistering with sun exposure
●Spider veins
●Dry skin
●Corneal ulcerations
●Sensorineural hearing loss
●Neuropathy
Cancer risks:
●Non-melanoma skin cancer (BCC and SCC)
●Cutaneous melanoma
●Gliomas
●Increased risk for any internal neoplasm due to NER defects