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Chromosomal Disorders - Karyotype Indications

I-Constitutional chromosomal disorders

I-1. Incidence
I-2. Etiology I-2. 1. 1. Chromosomal factors
I-2. 1. 2. Genetic factors
I-2. 2. Parental age
I-2. 3. Environmental factors

II- Karyotype indications II-1. Synopsis II-1.1 Karyotype
II-1.2 Fluorescent in situ hybrization (FISH)
II-2. Indications II-2.1. Perinatal period II-2.1.1. Stillbirth
II-2.1.2. Neonatal period II-2.1.2.1. triad :dysmorphism, malformation, neurological deficit
II-2.1.2.2. ambiguous genitalia
II-2.2. During infancy and adolescence
II-2.3. In adulthood
II-2.4. In the foetus
II-2.5. Acquired diseases - cancerology

 

I-Constitutional chromosomal disorders

I-1 Incidence
6 for 1000 births

I-2. Etiology

I-2.1 Genetic factors
I-2.1.1. Chromosomal factors
the incidence of balanced chromosomal defects is 2/1000; their sibs will have:

  • have a normal karyotype,
  • a normal phenotype with a balanced chromosomal complement,
  • an abnormal phenotype with an unbalanced chromosomal complement
  • I-2.1.2. genetic factors
    unknown but suspected due to the recurrence of trisomy 21 (1 to 2%).

    I-2.2. Parental age
    Maternal age:

  • Increased risk of trisomy 21, Klinefelter syndrome ( XXY), trisomy 13, trisomy 18, triple X
  • However some chromosomal disorders are not linked to maternal age ( Turner syndrome, trisomy 16)
  • Causes of meiotic non disjunction related to maternal age are not well defined:
  • I-2.3 Environmental factors
  • ovulation induction, ionizing radiations, antimitotic agents

  •  

    II-Karyotype indications

    II-1. Synopsis

    II-1.1. Karyotype

  • The karyotype is the study of the individual chromosomal complement through which one can detect chromosomal rearrangements constitutional or acquired on at least one band equivalent to 103 to 104 K bases; since the scale is not at the gene level the karyotpe is useless in monogenic diseases (except in research).
  • 10 % of children with a congenital defect would have a chromosomal anomaly

  • karyotype can be done on peripheral lymphocytes, tumour cells ( bone marrow) fibroblasts, gametes, amniocytes or trophoblasts upon indications.
  • a mitogen stimulates cell growth ( lymphocytes), mitoses are blocked in metaphase by a spindle poison, a hypotonic solution will disperse the chromosomes and the banding techniques will reveal a number of successive bands on each chromosome.
  • II-1.2. Fluorescent in situ hybridization (FISH)

  • Extemporaneous tissues, cells in culture, fixed tissues, cells embedded in parafin
  • Indications : II-2. Indications

    II-2.1. During the perinatal period
    II-2.1.1 In a stillbirth
    Karyotype on fibroblasts(umbilical cord, lung, muscle) if the etiology in unknown or when one suspects a chromosomal disease ( for instance in dysmorphic syndromes and / or visceral anomalies); a complete anatomo-pathological examination is indicated ( foeto-pathology).

    II-2.1.2 During the neo-natal period.
    II-2.1.2.1. in any dysmorphic syndrome and/or malformation (s) and / or neurological deficit, unless a known etiology is likely involved (teratogenic embryopathy or monogenic disease).
    II-2.1.2.2. in ambiguous genitalia

  • Pseudohermaphrodism
  • gonadal dysgenesis: ( variable karyotype: XY, XY/X0), XX/XY, XX /XXX /X0 etc
  • true hermaphrodyte (variable karyotype: XX, XY, XY/X0, XX/XY, etc)
  • histology of gonadal tissues will be useful in the differential diagnosis of those syndromes
  • karyotype is only one of several elements on which is based the gender choice.
  • II-2.2. during childhood and adolescence if

  • Psycho motor retardation ( fra X, Klinefelter)
  • Dysmorphism with visceral anomalies undetected during infancy
  • Unexplained short stature (Turner)
  • Hypogonadism (Klinefelter, Turner).
  • II-2.3. during adulthood

  • Parents of a child with a chromosomal disorder
  • Sterility workup once gynaecological or endocrine causes have been ruled out (Klinefelter, Turner,

  • Testicular feminization).
  • If more than two spontaneous miscarriages cytogenetic studies are indicated on the parents to rule out a translocation carrier; a foetal karyotype is recommended if at all possible.
  • II-2.4. during pregnancy
    Tissues: amniotic fluid cells obtained by amniocentesis, chorionic villi, lymphocytes obtained by cordocentesis.
    Indications:

  • Advanced maternal age
  • Balanced chromosomal rearrangement ( translocation, inversion,...) or not ( marker, mosaicism, sexual aneuploidy) in one of the parents
  • Abnormal maternal serological screening test
  • Abnormal foetal ultrasound
  • Risk of an unstable chromosomal syndrome
  • II-2.5. Acquired diseases ? cancerology
    De novo chromosomal anomalies ( on tumour cells) while the constitutional karyotype remains normal ( note: although neoplasic diseases are considered as acquired, some have a hereditary component; see: Cancers héréditaires those anomalies are characteristic, often pathognomonic in leukemias and sarcomas: t(9;22) in chronic myelogeneous leukemia, t(3;13)(q35;q14) in the alveolar rhabdosarcoma].
    Those anomalies may confirm the diagnosis and help defining the prognosis. However several are identified and most give little insight on solid tumours.
    Role of oncogens (ABL in 9q34, MLL in 11q23, ETV6 in 12p13, AML 1 in 21q22 ), and or tumour suppressor genes (Rb in 13q14, P53 in 17p13) ? in diagnosis.
    Tissues: peripheral lymphocytes, bone marrow, lymph nodes, solid tumours, pleural effusion, ascites,..
    Indications:

  • diagnostic
  • follow up of the disease: disappearance of the clone under treatment and/or remission, relapse, acute phase.



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    indexed on : Fri Nov 25 11:45:36 CET 2016

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