1-33 Numerical and Structural Abnormalities Flashcards
What are the sex chromosome aneuploidies?
- Klinefelter syndrome: 47,XXY
- XYY male
- XXX female
- Turner syndrome: 45,X
What are the clinical features of the 47,XXX female?
- Often undetected throughout life
- Usu. due to maternal meiosis I error
- Average to tall stature
- Learning deficit possible
- Some fertility problems possible
What are the clinical features of the 47,XYY male?
- Often undetected throughout life; clinically indistinguishable from 46,XY
- EXCLUSIVELY due to failure of paternal meiosis
- Tall stature
- Normal intelligence
- Normal fertility
What are the clinical features of the 47,XXY male?
47,XXY males have Klinefelter syndrome. Clinical features include:
- 50% due to meiosis I error in father
- Tall stature, long legs
- Infertility
- Some female characteristics may develop
- Learning deficit possible
The most common reason for referral is post-pubertal hypogonadism; female-like breast development; and infertility due to small testicles, hyalinized testicular tubules, and azoospermia.
What are the clinical features of the 45,X female?
45,X females have Turner syndrome. Clinical features are highly variable but include:
- Short stature (< 4’ 11”)
- Webbed neck (in utero cystic hygroma)
- At birth, edema of the hands and feet; after birth, short hands and fingers
- Heart and renal anomalies
- Increased carrying angle of the elbow (cubitus valgus)
- Shield chest
- Low posterior hairline
- Usu. normal intelligence, though may have learning difficulties
- Gonadal dysgenesis, primary amenorrhea
- Usu. infertile (but not always)
What are the typical and atypical genotypes for individuals with Turner syndrome?
The critical region for female differentiation has been narrowed to a region of the short arm of the X just proximal to the centromere. If that region is missing or inactive, an individual with Turner syndrome will result. About half of all Turner syndrome patients have the classic 45,X chromosome complement, which represents the only viable live born monosomy.
Another, more complicated possibility is the 45,X/46,XY mosaicism, which may result in a male OR female phenotype. Those with the male phenotype are usually OK, but those with the female phenotype have an increased risk of gonadoblastoma (a lethal tumor). These patients are recommended to remove their gonads.
What are the recommendations for realized and/or potential cases of Turner syndrome?
- Monitor for heart malfunctions
- Treatment option: growth hormones; to be effective, it must be started in the first few years of life
- Karyotype to be sure no Y chromosome is present; if gonadoblastoma is an issue, surgical removal should be planned
- Counseling for individuals of reproductive age; possibility of pregnancy with donor egg
What are the clinical features of an XY female?
- Androgen insensitivity
- Phenotypically normal female with testes
- Infertility
In XY females, though the Y chromosome is intact, and the TDF is present and functional, a mutation of the androgen receptor gene (located on the long arm of the X chromosome) results in blocked production of androgen receptor protein.
What are the clinical features of an XX male?
- X-Y recombination near pseudoautosomal region
- Usu. normal, possible Klinefelter phenotype
The reciprocal (OPPOSITE) translocation (TDF/SRY is replaced by Xp material, which is transmitted to a child) results in a Turner female phenotype with an apparent 46,XY karyotype.
With regard to structural chromosomal abnormalities, what are the four kinds, and what are the two types of recombination rearrangements?
- Deletion
- Duplication
- Translocation
- Inversion
- Balanced: all of the chromosomal material is present and functional but simply arranged in a different conformation. Usu. benign, but may increase the risk of meiotic error (and chromosomal imbalances in fetuses/live born children).
- Unbalanced: there is loss and/or duplication of some chromosomal material. Associated with an abnormal clinical phenotype that often includes developmental delay and mental retardation.
What is the result of a deletion, and what are the two kinds?
A deletion results in the loss of part of a chromosome and partial monosomy. There are two kinds:
- Terminal deletion: the distal end of one arm of a chromosome is lost. Requires only 1 break
- Interstitial deletion: an internal region of the chromosome is lost. Requires 2 breaks
Some deletion syndromes include:
- Williams-Beuren syndrome
- Prader-Willi/Angelman syndrome
- Miller Dieker lissencephaly
- Velocardiofacial syndrome
What is the result of a duplication, and what are the two kinds?
A duplication results in an dditional copy of a chromosome segment and partial trisomy. Usually, the duplication is of adjacent DNA regions. There are two kinds:
- Terminal duplication: addition to the end of a chromosome
- Interstitial duplication: addition within a chromosome
Williams-Bueren region duplication syndrome is an example of a duplication syndrome.
What is a translocation, and what are the two kinds?
A translocation is a rearrangement involving two or more nonhomologous chromosomes. Each chromosome breaks once, and the pieces exchange places, producing two (or more) derivative chromosomes. As long as the breaks do not occur within an important coding gene, the rearrangement should be clinically benign. Translocation types include:
- Reciprocal translocations
- Robertsonian translocation: a reciprocal translocation that occurs ONLY between two acrocentric chromosomes (can be homologous or non-). It appears as a fusion of the long arms at the centromere. The translocation results in the loss of both short arms (repeat copies of the rRNA genes), but because this material is present on the remaining 8 acrocentric chromosomes, the loss as a result of the translocation is not deleterious.
What are some concerns for balanced translocations?
- Relatively common: pop. freq. of 1 in 500
- Carriers are usually phenotypically normal
- Translocations can be inherited (other members of the family may have the rearrangement) or de novo
- If detected prenatally, may not be able to tell if it is balanced or not
For carriers of translocations:
- Increased risk that another pregnancy will have an unbalanced chromosome complement
- Increased risk of infertility or spontaneous fetal loss
- Increased risk of an abnormal live born (@10% for each pregnancy)
What is an inversion, and what are the two kinds?
An inversion is a reversal of a chromosomal segment with respect to the normal gene arrangement. There are 2 kinds:
- Pericentric: breaks occur on opp. sides of centromere; segment reverses order, generating a new chromosome with the same genes in a different order. Chromosome morphology may change (e.g., go from submetacentric to metacentric).
- Paracentric: breaks occur on same side of the centromere (same arm); centromere not involved in rearrangement.
