Microdeletion Syndromes by sammyc2007

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									Microdeletion syndromes
Microdeletion syndrome:
 a syndrome caused by a chromosomal
 deletion spanning several (contiguous)
 genes that is too small to be detected under
 the microscope using conventional
 cytogenetic methods. Depending on the size
 of the deletion, other techniques, such as
 FISH or other methods of DNA analysis can
 sometimes be employed to identify the
• part of a chromosome has been lost or is
  missing (deleted)

• can occur on any chromosome, at any band,
  and can be any size (large or small)

• consequences or severity of deletion
  depends upon size of missing piece and
  genes in missing piece

• “partial monosomy” or haploinsufficiency
Common themes of aneuploidy (imbalance of
chromosomal material) syndromes include:
•Growth retardation
   •small for gestational age / failure to thrive

•Neurologic impairment
   •mental retardation / learning disabilities / seizures /
   microcephaly / hypotonia / psycho-emotional dysfunction

•Dysmorphic features
•Cardiovascular malformations
•Other congenital anomalies

With microdeletion syndromes sharing
many common features between them,
shed light on unique characteristics so
that you can learn what is interesting,
memorable and important about each one.
Prior to the 1960’s, only whole
chromosomal aneuploidy was recognized
as an etiology for genetic syndromes.
Improvements and cytogenetic techniques
and clinical observations led to the discovery
of “large segment” chromosomal changes
that were visible by standard karyotyping.
In the early 1980’s, further improvements
in cytogenetic techniques - mainly FISH -
coupled with clinical observations, led to
the discovery of many more forms of
Chromosomal microdeletions are now
recognized as a common etiology for
multiple syndromes.
The mechanism underlying the deletion is
thought to be unequal meiotic
recombination, probably mediated by the
highly homologous DNA sequences that
flank the commonly deleted region.
These homologous regions are known as
low copy repeats or LCRs.
Syndromes to be covered
1p36.3          Monosomy 1p36 syndrome

7q11.2          Williams syndrome

11p13           WAGR syndrome

(mat) 15q11.2   Angelman syndrome (70%)

(pat) 15q11.2   Prader-Willi syndrome (70%)
17p13.3   Miller-Dieker syndrome

17p11.2   Smith-Magenis syndrome

17q11.2   Neurofibromatosis type 1 (5%)

20p12     Alagille syndrome (5-10%)

22q11.2   Velocardiofacial syndrome
    Deletion 1p36.3

Monosomy 1p36 syndrome
• 1 in 5,000 to 1 in 10,000 live births

• Microcephaly, seizures, hypotonia, feeding problems,
  mental retardation, behavior problems, self-injurious

• Sensorineural and conductive hearing loss, visual

• Dilated cardiomyopathy from non-compaction, patent
  ductus arteriosus (PDA)

• Small, flat midface, deep-set eyes, straight eyebrow

• DDx: Angelman, Prader-Willi, deletion 22q11.2
Monosomy 1p36.3 syndrome
 Deletion 7q11.2

Williams syndrome
• 1 in 20,000 live births

• Growth and mental retardation, hypercalcemia,
  distinctive “elfin” facies that coarsen over time,
  distinctive “cocktail party” personality, very colicky
  babies, hyperacousis, hoarse voice, lax skin

• Supravalvar aortic stenosis, and other elastin

• Elastin (ELN) and LIM Kinase (LIMK1) are genes in the
  region that are associated with the arteriopathy and
  visuospatial impairment respectively
deletion 7q11.2; Williams syndrome
             Deletion 11p13

           WAGR syndrome

Wilms / Aniridia / Genitourinary / Retardation
• Incidence unknown

• Wilms’, Anirdia, Genitourinary and Retardation

• WT1 and PAX6 are associated with the Wilms’/GU
  anomalies and Aniridia respectively

• Mental retardation is variable, hemihypertrophy is
  sometimes seen

• Screening for Wilms’ tumor regularly in early childhood
  is a key management issue
deletion 11p13; WAGR syndrome
 (mat) Deletion 15q11.2

Angelman syndrome (70%)
• 1 in 10,000 to 1 in 20,000 live births

• Imprinted, the maternal component is absent,
  approximately 70% of cases have a deletion of the
  critical region, but methylation studies are somewhat
  more sensitive for confirming the diagnosis

• Severe cognitive impairment, microcephaly, seizures,
  speech impairment, poor handling of oral secretions,
  wide-spaced teeth and prognathism

• Inappropriate laughter and uplifted arms & ataxia are
  mindful of a “happy puppet”

• Ubiquitin (UBE3A) is the key gene from the region
(mat) deletion 15q11.2; Angelman syndrome
(pat) deletion 15q11.2

Prader-Willi syndrome
• 1 in 10,000 to 1 in 20,000 live births

• Imprinted, the paternal component is absent, about 70% of
  cases have a deletion of the critical region, 99% will have
  methylation anomalies, SNRPN is a key gene

• Congenital hypotonia and severe feeding problems lead to
  failure to thrive in infancy. Ironically, pronounced
  hyperphagia occurs between 2-3 years of age leading to
  morbid obesity

• Cognitive impairment, hypogonadism, and short stature
  are commonly seen

• Interventions are key: behavioral modification and growth
  hormone supplementation are methods that significantly
  reduce the obesity
(pat) deletion 15q11.2; Prader-Willi syndrome
   Deletion 17p13.3

Miller-Diecker syndrome
• Incidence not available

• Microcephaly, lissencephaly and other CNS
  malformations, seizures, severe cognitive impairment,
  classic facial appearance: hypertelorism, flat nasal
  bridge, anteverted nares, micrognathia, post-axial

• The key gene from the deleted region is LIS1
17p13.3; Miller-Diecker syndrome
   Deletion 17p11.2

Smith-Magenis syndrome
• 1 in 25,000 live births

• Severe sleep disturbance, self-injurious behaviors, in
  toddler years, ADD, temper tantrums, aggression,
  polyemoilokomania (inserting foreign bodies in all
  orifices), and other stereotypical behaviors: self-hug,
  hand licking, body rocking

• Facial features sometimes compared to Down
  syndrome. Feeding difficulties, hypotonia, failure to
  thrive in infancy, melatonin cycle disturbance, hearing
  loss, short stature, velo-pharyngeal insufficiency

• Retinoic acid induced 1 (RAI1) is the critical gene
  associated with the deleted region
deletion 17p11.2; Smith-Magenis syndrome
      Deletion 17q11.2

Neurofibromatosis type 1 (5%)
• 1 in 3,500 live births

• but < than 5% of NF-1 is from a microdeletion of the
  critical region

• Café au lait spots, axillary / inguinal freckling,
  fibromas / neurofibroma, optic pathway glioma,
  skeletal dysplasia, Lisch nodules

• Microdeletion is associated with a more severe
  phenotype, higher risk of mental retardation,
  congenital anomalies, distictive facial appearance
  and more importantly a 3x higher incidence of nerve
  sheath malignancy.
deletion 17q11.2; Neurofibromatosis type 1 (5%)
   Deletion 20p12

Alagille syndrome (5%)
• 1 in 50,000 to 1 in 75,000 live births

• Only 5% from microdeletion of the clinical region

• Classic features of the condition of biliary atresia,
  cardiovascular anomalies, “butterfly” vertebra,
  posterior embryotoxon and distinctive facial
  features: broad forehead, deep-set eyes, long nose
  and prognathism. Intelligence is usually normal

• Jagged 1 (JAG1) is the critical gene associated with
  the deleted region
deletion 20p12; Alagille syndrome (5%)
          Deletion 22q11.2

 Velocardiofacial syndrome / DiGeorge
Shprintzen / Svedlakova / Cayler / Kouseff
  CATCH 22 / Takao / CTAF / Opitz-BBB
• 1 in 3,000 live births

• The highly variable presentation has led to multiple
  eponyms: VCF / DiGeorge / Shprintzen / Svedlakova /
  Cayler / Takao / Opitz-BBB

• Classically described as the triad of cardiovascular
  malformations, thymic aplasia and hypocalcemia, all
  stemming from branchial arch malformations

• Also seen are: borderline cognitive impairment, speech
  impairment, hypotonia, poor feeding, socialization
  problems and growth retardation

• Transcription Box 1 (TBX1) is probably a crucial gene
  associated with the deleted region
deletion 22q11.2; Velocardiofacial syndrome

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