Download GENETICS Lois E Brenneman, MSN, ANP, FNP, C Historical

GENETICS
Lois E Brenneman, MSN, ANP, FNP, C
Historical Perspectives
- 1956 it was discovered that normal chromosom e number was 46 vs 48 as previously believed.
- 1959 discovered trisomy 21 causes Down’s Syndrome
Epidemiology: Chromosom al abnormalities found in 1% of all live births of which
- 0.5-0 .5% ass ociated w ith m ajor m enta l and/o r physical defects
- Remainder are “normal” variants of no known significance
Physiology
Hum ans have 46 chromosom es (each with thousands of genes)
- 44 autosomes (non-sex-determining) arranged in 22 pairs
- 2 sex chromosomes (sex-determining) arranged in 1 pair
- XX for females
- XY for males
Chromosom es are inherited equally from an individual’s parents.
- One chromosom e in a particular pair of chromosom es comes from the m other
- One chromosom e of a particular pair of chromosome com es from the father
Genes are loci on particular chromosomes wherein the DNA governing a particular trait resides
- W ithin a given pair of autosomal chromosom es, each chromosom e contains the same
genes located in the same position on the chromosom e
- Allele are analogous genes on each half of the pair of chromosom es
© 2002 Lois E. Brenneman, MSN, CS, ANP, FNP
all rights reserved - www.npceu.com
TERMINOLOGY
Hom ozygo us: the state where both alleles for a
particular gene are the sam e.
Ex am ple: using the sym bol “B” for the allele
for brown eyes and “b” as the symbol for blue
eyes, the homozygous individual (for that
particular trait ) is one who has inherited the
same allele from each parent i.e. BB or bb.
Heterozygous: The e state wh ere both alleles for a
particular gene are diffe rent.
Exam ple: using the symbol “B” for brown eyes
and “b” for blue eyes, the heterozygous
individual (for that particular trait) is one who
has inherited different alleles from each parent
i.e. bB or Bb
Dom inant trait: physiologic condition whe re one particular allele for a particular trait is expressed and the
other allele for the same trait is repressed in an individual who has inherited one of each for dissimilar
alleles.
Exam ple the individual who has inherited one allele for blue eyes “b” and one allele for brown eyes
(Bb) manifests brown eyes because the “B” allele (brown eyes) is dom inant as compared with the
“b” allele (blue eyes).
Auto somal Dom inan t Trait: Small colored circle represents the
trait (brown eyes) or a mutant gene (Huntington’s Disease). Parent
has a 50% cha nce of pa ssing ge ne to off-s pring rega rdless of s ex.
Unaffe cte d individuals (blu e eyes or p ersons with out Hunting ton ’s
Disease) cannot pass trait or disease to their offspring.
© 2002 Lois E. Brenneman, MSN, CS, ANP, FNP
all rights reserved - www.npceu.com
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Rece ssive trait: physiologic state where one allele fo r a p articu lar trait is suppressed and the other allele
for the same trait is expressed in an individual who has inherited one of each for dissimilar alleles. The
trait which is not expressed is said to be recessive.
Exam ple: The trait for blue eyes (“b” allele) is recessive to the trait from brown eyes (“B” allele)
such that the individual with one of each alleles (bB or Bb) manifests brown eyes.
Auto somal rec ess ive trait : Sm all circle represents the trait (blue eyes) or the mutant gene
(sickle cell anemia). W hen both parents are carriers, there is a 25% chance of having an
affected child, a 50% chance of having a carrier child and a 25% chance of having a nonaffected and non-carrier child, regardless of sex. All children (100% ) of an affected pare nt are
carriers. All children of a blue-eyed parent carrier a gene for blue eyes. If both parents are
affected (both pare nts have blue e yes) then 1 00% of the childre n will have blue eyes.
Incom plete domina nce: the physiologic state where neither of two different alleles is preferentia lly
exp ressed in the ind ividual who h as inh erited both.
Exam ple the person who has inherited the allele for type A blood from one parent and type B
blood from the other res ults in said person having type AB blood because neithe r alle le is
dominant over the other. Both A and B alleles, however, are dominant as compared with type O
allele. Accordingly, the person who inherits two A alleles (AA) manifests type A blood while the
person w ho inherits both A and O alleles (AO ) also m anifests type A blood.
Au to so me: a chromosom e which is not a sex-chromosom e - 22 prs in humans
S ex-lin ked c hro m os om e: a non-autosome i.e. an X or Y chromosom e
Males: 22 pairs of autosomes plus XY sex-linked chromosom e
Females: 22 pairs of autosomes plus an XX sex-linked chromosom e
Sex-linked recessive trait or disease - carried on the X-chromosom e therefore women inherit the
trait from either father or mother and are “carriers” passing it along to male offspring. They can
only be affected if they inherit trait from both parents (rare). Males inherit trait from carrier mom
and are a ffec ted. T hey can p ass trait to daugh ter bu t not son who gets their Y chromosom e.
© 2002 Lois E. Brenneman, MSN, CS, ANP, FNP
all rights reserved - www.npceu.com
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Allele: alternative form of a gene occupying the same locus on a particular chromosome
Exam ple: brown vs blue eye color is controlled by 2 alleles - brown (B) and blue (b). Each person
inherits two alleles BB, bB, Bb or bb. For ABO blood type there are three alleles - A, B and O how ever eac h individual ca n inhe rit only two - A A AO, B B, BO, A B, O O
Genotype: refers to the particular chromosomes (and genes) an individual has inherited
Exam ple: a person may inherit one gene for blue eyes (b) from one parent and one gene for
brow n eyes from the other parent (B). This person’s genotyp e would be Bb and the person would
be said to be heterozygous for the particular trait in ques tion. A different person m ay inherent a
gene for brown eyes from each parent. In this case the genotype would be BB and the person
would be said to be homozygous
Phen otype: refers to the actual physical expression of the genes.
Exam ple: where the person inherits one gene for blue eyes (b) from one parent and one gene for
brown eyes from the other parent (B), the phenotype would be said to be that for brown eyes
since that is the color which would be expressed. The phenotype of brown eyes results from
either the homozygous state (BB) or the heterozygous state Bb
Penetrance: the degree to which a gene - even a dominant gene - is expressed
A given gene (either a single allele of a dominant gene or two alleles of a recessive gene) may be
inherited by tw o different individuals. One m ay be slightly effecte d and the other severely
affected . As an ex am ple, neurofibrom ato sis can be expressed as minimally as a simple “café au
lait” spot or as extensively as gross deformities in the fashion of the ‘elephant man.’ W hen a gene
is not fully expressed we spea k of ‘incomplete penetrance’ or ‘variable expression’ Other
genes as w ell as othe r facto rs m ay effe ct th e degree of pe netrance W here a parent is slightly
effected and a child is severely affected, an illusion of ‘generation skipping’ is crea ted.
Certain genes suppress the expression of other genes. For e xam ple, there is a gen e in ca ts
causes the coat to be white regardless of what color coat that cat had inherited. An orange cat or
a black cat who inherits this “white coat” gene will express a white coat but produce kittens
according to whatever color coat that cat would otherwise have been.
Spontaneous mutation: a situation where a particular gene variant appears “de-novo”
The particular gene mutation suddenly due to factors other than inheritance. There can be
spontan eous biochem ical changes in the DN A , c hrom osom e dam age, etc. with the end re sult
that a particular trait is expressed “out of the blue.” W here this trait is favorable, it may offer the
individual a se lective a dvantag e or the op pos ite situation wh ere th e trait is a h and icap.
Achondroplastic dwarfism can occur as an inherited gene or it can occur spontaneously as a gene
m utation and frequen tly does so.
Pop ulation oc currenc e: degree to which a particular gene occurs within a given population
A pa rticular g ene m ay be d om inant but ha ve a very rare oc currenc e he nce one will not see it with
much frequency within a given population (example: amyotrophic lateral sclerosis or
neurofibromatosis type I ). Similarly, a gene may be recessive but highly pervasive within a
population an accordingly occur very comm only (example: type O blood is recessive to all other
types but is the most comm only occurring blood type)
.
© 2002 Lois E. Brenneman, MSN, CS, ANP, FNP
all rights reserved - www.npceu.com
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Ploidy: the number of chromosom es found in a “set” of chromosom es
- Dip loid: the number of chromosom es found in normal somatic cells i.e. 2 sets
- Ha plo id: the nu m ber o f chrom oso m es fo und in germ (gam ete) c ells i.e. 1 set
- Aneup loid: a chrom osom e num ber not an exa ct m ultiple of the norm al haploid num ber
Ex am ple: an individual with 47 vs the norm al 46 chrom osom es - se e “S om y”
Note: a variety of aberrant conditions exist wherein individuals have abnormal numbers of
entire chro m oso m e se ts due to faulty cell replication e .g. triplo id, tetraploid, etc. Most
cases wherein individuals have abnormal ploidy are lethal and the individual does not
survive. By contrast, aberrations of individual chromosom es e.g. three copies of
Ch rom oso m e 21 (Do wn’s syndrom e) m ay well be viable.
Som y: the num ber of copies of an individual chrom osom e per cell.
The norm al num ber of copies of a c hrom osom e is two - bisom y. Aberrations exist
wherein individuals can inherit three copies of a given ch rom osom e - trisomy (ex am ple
trisomy 21 = Down’s syndrome or XXY = Klinefelter’s syndrome) or one copy of a given
chrom osom e - m o no so my (example XO = Turner’s syndrome). Somic abnormalities
can be less lethal than abnorm alities of ploidy but affected individuals can have seve re
abnormalities.
Translocation: transfer of piece of one chromosom e onto a non-homologous chromosom e
Deletion: loss of a part of a chromosom e
REPRODUCTION PROCESS: MITOSIS VERSUS MEIOSIS
M itosis: reproduction proce sses for non -gam ete cells
- Process where cell splits into two daughter cells each with identical chromosom es
- Exam ple: reproduction of blood cells in the bone marrow
MITOSIS: Cell divides forming 2 daughter cells
Prophase: Chromatin condenses into pairs chromosomes
joined at centromere; nuclear membrane
disappears, spindles form between centrioles at
opposite poles of cell
Metaphase: Chromosomes align along spindle (equatorial
plane) then pull apart along spindles
Anaphase: Newly divided chromosomes move to opposite
poles; centromeres divide; pull through
cytoplasm by spindles
Telophase: nuclear envelope forms; chromosomes unravel
and return to chromatin; cytoplasm divides, cell
splits
© 2002 Lois E. Brenneman, MSN, CS, ANP, FNP
all rights reserved - www.npceu.com
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Crossing over
Meiosis: rep roductive process for germ (ga m ete ) cells
Process where each cell splits into two cells, each of which contain ½ the chromosomes
(gen etic m aterial) of the origina l cell. - sperm and ova formation
Mechanism of Meiosis: Sta ges of m eiosis lead to red uction of the chrom osom e num ber by h alf
and to the production of functional gametes. During the first meiotic division, pairs of
chromosom es are separated from each other. In the male, the second m eiotic division res ults in
form ation of four functional sperms (23 c hrom oso m es e ach ) from a sing le precursor germ cell.
In the fem ale, a haploid polar body (23 chromosomes) is extruded at each of the two divisions
resulting in a single functional ovum with 23 chromosom es and 3 polar bodies.
PHASES OF MEIOSIS
Meiosis 1: number of cells is doubled; chromosom e number unchanged
- Results in ½ num ber of chrom osom es per cell
- Prophase 1, metaphase 1, anaphase 1, telophase1
M eiosis 2: division is similar to mitosis
- The number of chromosom es does not get reduced
- Prophase 2, metaphase 2, anaphase 2, telophase 2
Synapse of homologous chromosom es produce tetrads (bivalents)
Crossing over - betw een hom ologous chro m oso m es o ccu rs at s everal different p oints
Results in mixtures of the original two chromosom es
Chias ma ta: areas where crossing over has occurred (remain attached until anaphase)
Crossing over and independent assortment promotes variation in gametes
Re sults in gam etes with so m e ge nes from eac h of the two pare nts
Accounts for why various children from sam e parents are unique
© 2002 Lois E. Brenneman, MSN, CS, ANP, FNP
all rights reserved - www.npceu.com
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GAMETOGENESIS
OOGENESIS
Primary oocyte (2N) -> First meiotic division -> secondary oocyte (1N) + 1st polar body (1N) *
Secondary oocyte (1N) - 2nd meiotic division -> mature ovum (1N) + 2nd polar body (1N)
* Meiosis arrested at this stage if no fertilization; if fertilized a second meiotic division occurs; 2nd polar body may
divide mitotically resulting in a total of 3 polar bodies and one ovum per primary oocyte
SPERMATOGENESIS
Spermatogonia (stem cells 46 chromosomes) divide mitotically
- 1 Spermatogonia progenitor cell - 2N
- 1 Stem cell spermatogonia - 2N
Spermatogonia progenitor cell divides mitotically forming 2 primary spermatocytes (2N)
Primary spermatocyte (2N) - > first meiotic division -> 2 secondary spermatocytes (1N)
Secondary spermatocytes (1N) -> second meiotic division -> 4 spermatoids (1N) each
- 22 autosomes and 1 X or Y chromosome
- Second meiotic division is actually a simple mitosis of the secondary spermatocyte
Spermatids transform into spermatozoa (1N)
- head - nucleus and acrosome *
- middle piece - mitochondria
- tail - whip-like for locomotion
* acrosome contains proteolytic enzymes which dissolve ovum outer layer
© 2002 Lois E. Brenneman, MSN, CS, ANP, FNP
all rights reserved - www.npceu.com
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NOMENCLATURE FOR CHROMOSOMES
Rules of nom enclature
- Classed according ot overall length and placement of centromere (primary constriction)
- Long arm is termed “q” and short are is term “p”
Karyotype:
- Arrangement of the 22 chromosomes in pairs on basis of morphologic landmarks
- 22 num bered pairs( num bered 1 thru 22); 1 sex-link ed pair
- Photographs of karyotypes (comm only used in books and slides)
Created via photog raphing naturally occurring haph azard arrangem ents of
chrom osom es in a cell, identifying the various chrom osom e pairs by num ber,
cutting them out, pa sting th em in orde r and then reph otog raph ing the prod uct.
Autosomes versus sex-linked chromosom es
- Autoso me s: one of the 23 pairs of non-sex-linked chromosom es
- numbered pairs 1 through 23 for identification purposes
- Sex-linked -chrom osom es: the X chromosome and the Y chromosome
Fem ales XX (plus 23 autosome pairs)
Males XY (plus 23 autosome pairs)
RULES OF INHERITANCE
Offspring contain ½ genetic material from each parent
- One c hrom osom e of each p air from the m other;
- One chromosom e of each pair from the father
Father determines sex of offspring depending on which chromosom e is passed
- Offspring is fem ale if receives X chrom osom e from father
- Offspring is m ale if receives Y chrom osom e from father
Once cytochromic sex has been determined various interactions result in anatomic or
phenotyp ic sex. In th e presence of a Y chrom osom e, th e m edulla of the prim ordial
genital ridge proliferates to form a testes and gives rise to a male. In the absence of a Y
chromosom e, the cortex proliferates to rise to ovaries and a female .
Chromosom es contain gen es; gen es c ontro l the inhe ritance of tra its
- Each chromosome of a given pair contains the same genes
- Gene s are inherited in pairs - one from the father; one from the m other
Genes exist in variations called alleles
- Alleles are different forms of a gene which express a particular trait in different ways
- Alleles may be dominant or recessive (or ne ither) fo r particular tra its
Certain characteristics are said to have sex-linked inheritance
- Certain normal male characteristics appear only on Y chromosom e (hair on ear pinna)
- Certain pathological conditions are inherited only on X chromosom e
- hemophilia, color-blindness, muscular dystrophy
- Certain non-pathological traits are inherited as X-linked (orange coloring in cats)
© 2002 Lois E. Brenneman, MSN, CS, ANP, FNP
all rights reserved - www.npceu.com
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Chara cteristics of sex-linked recessive disorders (or traits)
- Carried via genes as recessive alleles on X chromoso me
- Females need two affected X chromosom es to express the trait (rare)
- Males need one affected X chromosom es to express the trait (more com mon)
- Females with one affected X chromosome becom e carriers
- Carriers have inherited one affected X chromosom e (from father) and one
norma l X chrom osom e (from m other)
- Carriers do not express the trait but pass it to male offspring
- Fem ales are carriers vs non-ca rriers depending on w hich X chro m osom e they have
inherited from their father
- Males who express the trait (have the condition) have inherited affected X chromosom e
from their mother
- Males can not inherit trait from their fath ers (versus females who can)
- Father does not contribute X chromosom e to male offspring
- Father c ontributes Y chrom oso m e to the m ale offspring.
- Father contributes X chromosom e to female offspring
- Males who do not express the trait (do not have the condition) inherit the normal X
chromosom e from their mother
- Males who do not express trait cannot pass the trait to offspring
- Individuals can no t pass traits which they do not have
- W ould have express ed trait if they had inherited it
- Fem ales need two a ffected X ch rom osom es to expres s the trait hence express ion is rare
(but no t impos sible) in fem ales.
Affected females inherit one affected chromosom e from their fathers who express
the trait and one affected chromosom e from their mothers who are carriers or
affected.
- Sex linked dominance inheritance is known but very rare (vitamin D resistant rickets)
Abnormal or pathologic traits may be the result of inheriting aberrant genes or aberrant
chromosomes
- Exam ple: aberrant genes: Sickle cell gene (one a m ino acid is substituted)
- Example: aberrant chromosom es: Down’s Syndrome: trisomy of chromosom e 21
Mu ltifac torial or po lygenic inheritance: not simple Mendelian genetics; multiple genes and
environmental factors determine express of a condition (e.g. asthma, diabetes)
© 2002 Lois E. Brenneman, MSN, CS, ANP, FNP
all rights reserved - www.npceu.com
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TERMINOLOGY AND PATTERNS OF INHERITANCE
Autoso ma l dom inant inheritance
- Trait is carried on an autosomal chromosom e where affected allele is dom inant.
- No carrier state is possible
- Exam ples: achond roplastic dw arfism in hum ans , polydactyl in cats
Autosomal recessive inheritance
- Trait is carried on auto som al chrom osom e where affected allele is recessive
- Carrier state is possible
- Example: sickle cell disease; blue eyes
Sex-linked recessive inheritance
- Trait is carried on x chromosome where affected allele is recessive
- Exam ples: color-blindedness, hemophilia
Sex-linked dom inant inheritance - very rare
- Trait is carried on X chromosom e where affected allele is dominant
- Vitam in D re sistant rick ets
Letha l traits
- Homozygous off-spring die in utero or m ale offspring die in utero
- Inheritance patterns will be different from that which is expected (suspe ct letha l trait)
- 1/3 normal and 2/3 carrier vs the typical 1/4 normal, ½ carrier, 1/4 affected
GENETIC PATHOPHYSIOLOGY
PATHOPHYSIOLOGY OF CHROMOSOME ABNORMALITIES
Num erical Abnorm alities: 2 types - num erical or structure
Ploidy (aneuploidy): abnormalities which involve whole sets of chromosom es
- Alm ost alw ays lethal -> aborted fetuses or s m all fe tus es surviving for few days
- Term inology
- Haploid 23(N)
- Diploid 46 (2N)
- Triploid 69 (3N)
- Tetraploid 92 (4N)
So mic: involve one chromosom e
Monosom ic - 45 chromosom es
Bisomic: - 46 chromosom es (normal state)
Trisomic - 47 chromosom es
Tetrasomom ic - 48 chromosom es
Pentasomic - 49 chromosom es
Note : extrem ely ra re for autos om es - m onosom ic chrom osom e - b ut occ urs (e.g . Turner’s
Syndrome) for x chromosome in approximately 1 per 5000 births
© 2002 Lois E. Brenneman, MSN, CS, ANP, FNP
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Aneuploidy - Mechanism for aneuploidy (abnormal number of chromosom es)
Nondisjunction
Separation of chromatids occurs but w/o normal segregation of chromatids into the two
daughter cells. Therefore, both chromatids are retained wi a single cell, yielding 47
chromosom es (trisomy), and the second daughter cell has only 45 chromosom es
(m onoso m y)
Mo nosom ic condition m ost like ly lethal if a uto som e (n on-sex cell chrom osom e) is
involve d; Tris om ic cell may be viable in som e cases (Down ’s syndrom e).
Anaphase lag
Migration of chrom osom es to the poles of the division plane is affected by the nuclear
m em bran e, wh ich re-form s be fore all of the c hrom oso m es h ave m igrated. Leads to
monosom ic conditions.
M o sa ic is m : coexistence of two or more stem lines of cells within the same individual
- Can result from either non-disjunction or anaphase lag
- Abnormal cell division occurs after meiosis (on subsequent mitotic divisions)
Results in mosaic morula where some cells are normal (from the union of two
normal gametes) while a subset of cells are abnormal (from abnorm al m itotic
division somewhere down the line)
- May be important indication of temporal etiology of chromosomal defect
Evidence for post fertilization, nondisjunctional event
- W here abn orm ality occu rs w m eiosis (prior to fertilization) -> no n-m osa ic zygote
- Mosaic individuals are often less severely affected
Exam ple: mosaic Down’s Syndrome m ay be mildly affected
Trisom y: Com mon Trisomy Abnormalities
- Trisomy 21 - Down’s Syndrome (1:650 births) - comm on with advanced maternal age
- Trisomy 22 Syndrome
- Trisomy 13 Syndrome - Edward’s syndrome (1:3000 births)
- Trisomy 18 Syndrome - Patau’s syndrome (1:5000 births)
Translocation Abnormalities (Structu ral abnorm ality)
- Caused by chromosom e breakage
- Comm on is a reciprocal translocation or mutual exchange
- Translocations have involved every group of chromosom e and have far-reaching
consequences
Dow n’s syndrome can result from inheritance of translocation chromosom es as well as
from the classic trisomy 21
- Clinically indistinguishable from those with trisomy 21
- Represents translocation between the missing number 14 chromosom e and the
extra number 21 chromosom e
- Results from one of the parents being a balanced carrier (see below)
© 2002 Lois E. Brenneman, MSN, CS, ANP, FNP
all rights reserved - www.npceu.com
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Several variations of translocations can yield Down’s Syndrome
Translocatio n betw een tw o G -group* ch rom osom es. If such a translocatio n is
inherited (i.e. one of the parents is a carrier) and the two chromosom es involved
are both m em bers of pair 21, all off-spring born w ill have Down ’s Syndrom e. If,
however, number 21 and 22 chromosom es are involved in the translocation, then
norm al, carrier an d affe cte d offs pring will re sult
Other trisomy states can result from inheritance of translocated chromosom es
Exam ple: trisomy 13 syndrome from a balanced carrier parent
Trisomy states can result from translocation of chromosom e within the affected individual
Direct result of translocation and not secondary to balanced carrier parent
Balanced carrier
Portion of chromosome is translocated on another chromosome
On ly 45 chrom oso m es a re prese nt, with one e ach m issing in grou ps D and G.* In
additional the “C-group-like”* submetacentric element is present. (Offspring of these
person’s have Down’s Syndrome)
Phenotypically, these persons appear normal
They have the correct numbers of genetic material but it has been
translocated in non-normal pattern.
W hen these individuals create offs pring, the y pass the aberrant chromosom al
material to the gametes and create abnormal offspring
Exam ple: Down’s Syndrome
* Represents arbitrary grouping of chromosomes according to a system of standard
nomenclature where group A (1-3); group B (4-5), group C (6-12 + X); group D (13-15);
group E (16-18); group F (19-20); group G (21-22 + Y)
Deletion Type Chromosom e Abnormalities
Chromosom al breaks which result in loss of blocks of genes in terminal (one break) or
interstitial (2 breaks) segment deleted
C ri-d u-c ha t s yn dro m e
- Partial deletion of s hort arm of n um ber 5 c hrom osom e (d egree of de letion is
variable
- Syndrome occurs sporadically or inherited via translocation
- Distinctive high-pitched mewing cry resembles a kitten
- Cry occurs imm ediately after birth and disappears after weeks
- Other abnormalities
Low birth wt, moo n facies, m icrocephaly, antim ongoloid facies, downw ard
sloping palpebral fissures, with or without epicanthal folds. Micrognathia,
short neck, heart defects and hypotonia. Mental and physical
development are markedly retarded.
- Considerable degree of variation in clinical manifestations
4 p- s yn dro m e
- Deletion of short are of chromosom e 4
- Profound re tarda tion an d birth d efects
© 2002 Lois E. Brenneman, MSN, CS, ANP, FNP
all rights reserved - www.npceu.com
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1 8q - s yn dro m e
- Deletion of long arm of number 18 chromosom e
- Profound birth defect with classic facies
1 8p - s yn dro m e
- Short arm of one of the number 18 chromosom es
- Profound birth defects and mental retardation
P hila de lp hia ch ro m os ome
- Chronic m yelocytic leuke m ia
- Only chromosom al abnormality associated with specific form of neoplasia
- ½ to 2/3 of the long arm of chromosom e 22 is missing
Christchurch chromosom e
- Not always associated with pathology
- Associated with myelocytic leukem ia and other conditions
- Deletion of short arm of either 21 or 22 chromosom e
Antimongoloidism
- Deleted chromosom e 21
- Some clinical features suggest opposite of Down’s syndrome
- Menta l retardation, hypertonia an d pro found b irth defects
T he ca t-e ye sy nd ro m e: extensive birth de fects
T he 13 q- s yn dro m e: profound mental/physical retardation
The long arm numb er 15: retinoblastom a
Ring Chromo somes
- Results from two breaks and rejoining of broken ends of chromosom es to each other
- Structural aberrations lead to deletion of chromosom al material from both ends
- Unstab le fo rm s w hich encourage difficulty in m itos is
Results in breakage and fusion to form rings during cell division
- Rings of various size w concomitant variable deletions
- Can affect any chromosom e
- Phenotype and stigmata varies considerable pending on what chromosom e and how
much is affected
Inversions
- Structural aberrations resulting from two breaks in a chromosom e and a 180 degree
rotation of the seg m ent betwe en the bre ak points
- direction of the reading of the DNA codes wi reversed within the broken segment
- may or may not result in clinical difficulty as function of genes involved
DERMOGRAPHICS
- Study of patterns on fingertips (loops, arches, whorls) , palms, soles
- Correlated with certain of the chromosom al syndromes
- Us eful adjun ct to diagnosis of so m e ch rom oso m al abn orm alities an d birth d efects
© 2002 Lois E. Brenneman, MSN, CS, ANP, FNP
all rights reserved - www.npceu.com
13
ABNORMALITIES OF SEX CHROMOSOME
FEMALE PHENOTYPE
XO - T u rn er’s Syn dro m e
- 50% or more have lym phedem a (transient phenomenon)
- Hands and feet
- Fingers
- Toes and posterior aspect of the neck
- May extend to knees or elbows
- Gradually resolves within a period of up to 2 years; rare to persist
- P os te rio r n uc ha l ly m phedem a -> webb ed neck
- Extrem e case: m assive sac res em bles m eningocele
- More comm on is redundant folds -> resolve -> develop into webb ed neck
- Other stigm ata are difficult to identify in newb orn
- Short stature or amenorrhea or both in later childhood/adolescence
-
Carrying angle is increased (cubitus valgus)
Chest is broad (shield chest) w widely spaced nipples
Minimal breast development
Axillary and pubic hair scant or absent
Face abnormalities
Micrognathia, flattened nasal bridge, low-set ears which are large/deformed
Epicanthal folds, ptosis and hypertelorism are com mon
Ha nds : show sh ort 4 th metacarpal crenating the 4 th finger (dim ple w fist )
Short 4 th metatarsal
Low hairline
Comm on: multiple pigmented nevi (46)
Many develop keloids: impacts decision to cosmetically repair webbed neck
Retarded bone are and osteoporosis seen
- Other comm on malformations of Turner’s Syndrome
Congenita l heart defects (coarctation of aorta); malformations of the kidney
(especially horseshoe kidney and duplication of urinary tract); malformations of the
thyroid gland and significantly increased incidence of thyroiditis and H ashim oto ’s
disease , intestinal telangiectasia (may lead to massive GI hemorrhage)
- Severe m enta l retardation ra re, mild mental defects common; occasional high intellect
- Verbal higher than nonverbal
- Low score on perceptual organization
- Particular difficulties with spacial relationships
- Uterus remains infantile; ovaries replaced by fibrous tissue streak
- Not premalignant lesion
- Y karyotype anywhere (m osaic or 46,XY ) is pre m alignant, w arrants surgery
46 XX or 46 XY: F ra gile X s yn drom e (1:2000)
- Phenotype is female tall with eunuchoid body habitus
- Infantile genitalia and reproductive organs
- Fetal castration; lack of sex hormones
© 2002 Lois E. Brenneman, MSN, CS, ANP, FNP
all rights reserved - www.npceu.com
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Noonan’s syndrome: gonadal dysgenesis in males and females with normal karyotypes
- Rare but occurs in families
- Typical symptom s of gonadal dysgenesis with some differences/exceptions
- Mental retardation; pectus excavatum: both comm on
- Congenital heart disease esp pulmonic stenosis comm on
- Can have underdeveloped but functional genitalia; some bear affected children
- Father son transmission reported thus r/o x-linked inheritance
Poly-X Syndromes
47 XXX
- Variable clinical features
- No suggestion of increased occurrence of mental retardation
- Severa l kno wn to be norm al/fertile -> no chrom oso m al abn orm al infan ts
48 XXXX
- Physically normal; post-pubertal normal m enstruation
- Severely mentally retarded; no physical findings
XXXX
- Severe mental and growth retardation
- M ild upw ard slant of palpebral fis sures; s m all hands w clinodactyly
- Fail to thrive; frequent vomiting and respiratory infections
PHENOTYPE MALES
X XY - K lin efe lte r’s Syn dro m e
-
Eunuchoid with truncal obesity, gynecomastia, decreased muscle mass
Incomplete virilization: small phallus, testes w fibrosis and hyalinization
Dull m entality a nd severe m ental reta rdatio n are invariable
Psychopathology as behavior problems/disturbed body image
Diagnosis rarely m ade until pubescence but dete ctio n in childhood would be preferable
- Screening for edu cationally subnorm al (IQ 50 or greater)
- Screening based on behavioral or psychiatric problems
- Age-appropriate physiologic testosterone ensures more normal growth/development
- May prevent gynecomastia and hypogonadism
- Relatively long legs even before adolescence
48 XXXY and 49 XXXXY syndromes - variations of Klinefelter’s syndrome
- Profound mental retardation
- Genitalia markedly underdeveloped; sexual hair scant
- Multiple congenital malformations of many organ systems
Y CHROMOSOME ABNORMALITIES
- Most va riable m orph ologically - extrem ely variab le in length
- Length is inherited - constant from father to son
XYY karyotype
- Increased numbers of these men in prisons esp maximum security institutions
- Ta ll statue; m ild m enta l deficits
- Increased incidence of sociopathic behavior
© 2002 Lois E. Brenneman, MSN, CS, ANP, FNP
all rights reserved - www.npceu.com
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