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

GENETICS
Lois E Brenneman, M SN, ANP, FNP, C
Historical Perspectives
- 1956 it was discovered that norm al chrom osom e num ber was 46 vs 48 as previously believed.
- 1959 discovered trisom y 21 causes Down’s Syndrom e
Epidem iology: Chrom osom al abnorm alities found in 1% of all live births of which
- 0.5-0.5% associated with m ajor m ental and/or physical defects
- Rem ainder are “norm al” variants of no known significance
Physiology
Hum ans have 46 chrom osom es (each with thousands of genes)
- 44 autosomes (non-sex-determ ining) arranged in 22 pairs
- 2 sex chromosomes (sex-determ ining) arranged in 1 pair
- XX for fem ales
- XY for m ales
Chrom osom es are inherited equally from an individual’s parents.
- One chrom osom e in a particular pair of chrom osom es com es from the m other
- One chrom osom e of a particular pair of chrom osom e com es from the father
Genes are loci on particular chrom osom es wherein the DNA governing a particular trait resides
- W ithin a given pair of autosom al chrom osom es, each chrom osom e contains the sam e
genes located in the sam e position on the chrom osom e
- Allele are analogous genes on each half of the pair of chrom osom es
© 2004 Lois E. Brenneman, MSN, CS, ANP, FNP
all rights reserved - www.npceu.com
TERMINOLOGY
Homozygous: the state where both alleles for a
particular gene are the sam e.
Exam ple: using the sym bol “B” for the allele
for brown eyes and “b” as the sym bol for blue
eyes, the hom ozygous individual (for that
particular trait ) is one who has inherited the
sam e allele from each parent i.e. BB or bb.
Heterozygous: The e state where both alleles for a
particular gene are different.
Exam ple: using the sym bol “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
Dominant trait: physiologic condition where one particular allele for a particular trait is expressed and the
other allele for the sam e trait is repressed in an individual who has inherited one of each for dissim ilar
alleles.
Exam ple the individual who has inherited one allele for blue eyes “b” and one allele for brown eyes
(Bb) m anifests brown eyes because the “B” allele (brown eyes) is dominant as com pared with the
“b” allele (blue eyes).
Achondroplastic
dwarf
Autosomal Dominant Trait: Sm all colored circle represents the
trait (brown eyes) or a m utant gene (Huntington’s Disease). Parent
has a 50% chance of passing gene to off-spring regardless of sex.
Unaffected individuals (blue eyes or persons without Huntington’s
Disease) cannot pass trait or disease to their offspring.
© 2004 Lois E. Brenneman, MSN, CS, ANP, FNP
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Recessive trait: physiologic state where one allele for a particular trait is suppressed and the other allele
for the sam e trait is expressed in an individual who has inherited one of each for dissim ilar 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) m anifests brown eyes.
Autosomal recessive trait : Sm all circle represents the trait (blue eyes) or the mutant gene
(sickle cell anem ia). 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 parent are
carriers. All children of a blue-eyed parent carrier a gene for blue eyes. If both parents are
affected (both parents have blue eyes) then 100% of the children will have blue eyes.
Incomplete dominance: the physiologic state where neither of two different alleles is preferentially
expressed in the individual who has inherited both.
Exam ple the person who has inherited the allele for type A blood from one parent and type B
blood from the other results in said person having type AB blood because neither allele is
dom inant over the other. Both A and B alleles, however, are dom inant as com pared with type O
allele. Accordingly, the person who inherits two A alleles (AA) m anifests type A blood while the
person who inherits both A and O alleles (AO) also m anifests type A blood.
Autosome: a chrom osom e which is not a sex-chrom osom e - 22 prs in hum ans
Sex-linked chrom osom e: a non-autosom e i.e. an X or Y chrom osom e
M ales: 22 pairs of autosom es plus XY sex-linked chrom osom e
Fem ales: 22 pairs of autosom es plus an XX sex-linked chrom osom e
Sex-linked recessive trait or disease - carried on the X-chrom osom e
therefore wom en inherit the trait from either father or m other and are
“carriers” passing it along to m ale offspring. They can only be affected if
they inherit trait from both parents (rare). Males inherit trait from carrier
m om and are affected. They can pass trait to daughter but not son who
gets their Y chrom osom e.
© 2004 Lois E. Brenneman, MSN, CS, ANP, FNP
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Allele: alternative form of a gene occupying the sam e locus on a particular chrom osom e
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 - however each individual can inherit only two - AA AO, BB, BO, AB, OO
Genotype: refers to the particular chrom osom es (and genes) an individual has inherited
Exam ple: a person m ay inherit one gene for blue eyes (b) from one parent and one gene for
brown eyes from the other parent (B). This person’s genotype would be Bb and the person would
be said to be heterozygous for the particular trait in question. 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
Phenotype: 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 hom ozygous state (BB) or the heterozygous state Bb
Penetrance: the degree to which a gene - even a dom inant gene - is
expressed
A given gene (either a single allele of a dom inant gene or two
alleles of a recessive gene) m ay be inherited by two different
individuals. One m ay be slightly effected and the other severely
affected. As an exam ple, neurofibrom atosis can be expressed
as m inim ally as a sim ple “café au lait” spot or as extensively as
gross deform ities in the fashion of the ‘elephant m an.’ W hen a
gene is not fully expressed we speak of ‘incomplete
penetrance’ or ‘variable expression’ Other genes as well as other factors m ay effect the
degree of penetrance W here a parent is slightly effected and a child is severely affected, an
illusion of ‘generation skipping’ is created.
Certain genes suppress the expression of other genes. For exam ple, there is a gene in cats
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.
© 2004 Lois E. Brenneman, MSN, CS, ANP, FNP
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Spontaneous mutation: a situation where a particular gene variant appears
“de-novo”
The particular gene m utation suddenly due to factors other than
inheritance. There can be spontaneous biochem ical changes in the
DNA , chrom osom e dam age, etc. with the end result that a particular
trait is expressed “out of the blue.” W here this trait is favorable, it
m ay offer the individual a selective advantage or the opposite
situation where the trait is a handicap. Achondroplastic dwarfism can
occur as an inherited gene or it can occur spontaneously as a gene
m utation and frequently does so.
Population occurrence: degree to which a particular gene occurs within a
given population
A particular gene m ay be dom inant but have a very rare occurrence hence one will not see it with
m uch frequency within a given population (exam ple: am yotrophic lateral sclerosis or
neurofibrom atosis type I ). Sim ilarly, a gene m ay be recessive but highly pervasive within a
population an accordingly occur very com m only (exam ple: type O blood is recessive to all other
types but is the m ost com m only occurring blood type)
.
Ploidy: the num ber of chrom osom es found in a “set” of chrom osom es
- Diploid: the num ber of chrom osom es found in norm al som atic
cells i.e. 2 sets
- Haploid: the num ber of chrom osom es found in germ (gam ete)
cells i.e. 1 set
- Aneuploid: a chrom osom e num ber not an exact m ultiple of the
norm al haploid num ber
Exam ple: an individual with 47 vs the norm al 46
chrom osom es - see “Som y”
Note: a variety of aberrant conditions exist wherein individuals have
abnorm al num bers of entire chrom osom e sets due to faulty cell
replication e.g. triploid, tetraploid, etc. Most cases wherein
individuals have abnorm al ploidy are lethal and the individual does
not survive. By contrast, aberrations of individual chrom osom es
e.g. three copies of Chrom osom e 21 (Down’s syndrom e) m ay
well be viable.
Somy: the num ber of copies of an individual chrom osom e per cell.
The norm al num ber of copies of a chrom osom e is two - bisom y.
Aberrations exist wherein individuals can inherit three copies of a
given chrom osom e - trisom y (exam ple trisom y 21 = Down’s
syndrom e or XXY = Klinefelter’s syndrom e) or one copy of a
given chrom osom e - m onosom y (exam ple XO = Turner’s
syndrom e). Som ic abnorm alities can be less lethal than
abnorm alities of ploidy but affected individuals can have severe
abnorm alities.
© 2004 Lois E. Brenneman, MSN, CS, ANP, FNP
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Translocation: transfer of piece of one chrom osom e onto a non-hom ologous chrom osom e
Deletion: loss of a part of a chrom osom e
REPRODUCTION PROCESS: MITOSIS VERSUS MEIOSIS
M itosis: reproduction processes for non-gamete cells
- Process where cell splits into two daughter cells each with identical chrom osom es
- Exam ple: reproduction of blood cells in the bone m arrow
V
© 2004 Lois E. Brenneman, MSN, CS, ANP, FNP
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M eiosis: reproductive process for germ (gam ete) cells
Process where each cell splits into two cells, each of which contain ½ the chrom osom es
(genetic m aterial) of the original cell. - sperm and ova formation
Mechanism of Meiosis: Stages of m eiosis lead to reduction of the chrom osom e num ber by half
and to the production of functional gam etes. During the first m eiotic division, pairs of
chrom osom es are separated from each other. In the male, the second m eiotic division results in
form ation of four functional sperms (23 chrom osom es each) from a single precursor germ cell.
In the female, a haploid polar body (23 chrom osom es) is extruded at each of the two divisions
resulting in a single functional ovum with 23 chrom osom es and 3 polar bodies.
© 2004 Lois E. Brenneman, MSN, CS, ANP, FNP
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NOMENCLATURE FOR CHROMOSOMES
Rules of nom enclature
- Classed according ot overall length and placem ent of centrom ere (prim ary constriction)
- Long arm is term ed “q” and short are is term “p”
Karyotype:
- Arrangem ent of the 22 chrom osom es in pairs on basis of m orphologic landm arks
- 22 num bered pairs( num bered 1 thru 22); 1 sex-linked pair
- Photographs of karyotypes (com m only used in books and slides)
Created via photographing naturally occurring haphazard arrangem ents of
chrom osom es in a cell, identifying the various chrom osom e pairs by num ber,
cutting them out, pasting them in order and then rephotographing the product.
Autosom es versus sex-linked chrom osom es
- Autosomes: one of the 23 pairs of non-sex-linked chrom osom es
- num bered pairs 1 through 23 for identification purposes
- Sex-linked-chromosomes: the X chrom osom e and the Y chrom osom e
Fem ales XX (plus 23 autosom e pairs)
Males XY (plus 23 autosom e pairs)
RULES OF INHERITANCE
Offspring contain ½ genetic m aterial from each parent
- One chrom osom e of each pair from the m other;
- One chrom osom e of each pair from the father
Father determ ines sex of offspring depending on which
chrom osom 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 cytochrom ic sex has been determ ined various interactions result in anatom ic or
phenotypic sex. In the presence of a Y chrom osom e, the m edulla of the prim ordial
genital ridge proliferates to form a testes and gives rise to a m ale. In the absence of a Y
chrom osom e, the cortex proliferates to rise to ovaries and a fem ale .
Chrom osom es contain genes; genes control the inheritance of traits
- Each chrom osom e of a given pair contains the sam e genes
- Genes are inherited in pairs - one from the father; one from the m other
Genes exist in variations called alleles
- Alleles are different form s of a gene which express a particular trait in different ways
- Alleles m ay be dominant or recessive (or neither) for particular traits
Certain characteristics are said to have sex-linked inheritance
- Certain normal male characteristics appear only on Y chrom osom e (hair on ear pinna)
- Certain pathological conditions are inherited only on X chrom osom e
- hem ophilia, color-blindness, m uscular dystrophy
- Certain non-pathological traits are inherited as X-linked (orange coloring in cats)
© 2004 Lois E. Brenneman, MSN, CS, ANP, FNP
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Characteristics of sex-linked recessive disorders (or traits)
- Carried via genes as recessive alleles on X chrom osome
- Females need two affected X chrom osomes to express the trait (rare)
- M ales need one affected X chrom osomes to express the trait (m ore com m on)
- Fem ales with one affected X chrom osom e becom e carriers
- Carriers have inherited one affected X chrom osom e (from father) and one
norm al 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-carriers depending on which X chrom osom e they have
inherited from their father
- Males who express the trait (have the condition) have inherited affected X chrom osom e
from their mother
- M ales cannot inherit trait from their fathers (versus fem ales who can)
- Father does not contribute X chrom osom e to m ale offspring
- Father contributes Y chrom osom e to the m ale offspring.
- Father contributes X chrom osom e to fem ale offspring
- Males who do not express the trait (do not have the condition) inherit the normal X
chrom osom e from their m other
- Males who do not express trait cannot pass the trait to offspring
- Individuals can not pass traits which they do not have
- W ould have expressed trait if they had inherited it
- Fem ales need two affected X chrom osom es to express the trait hence expression is rare
(but not im possible) in fem ales.
Affected fem ales inherit one affected chrom osom e from their fathers who express
the trait and one affected chrom osom e from their m others who are carriers or
affected.
- Sex linked dominance inheritance is known but very rare (vitam in D resistant rickets)
Abnorm al or pathologic traits m ay be the result of inheriting aberrant genes or aberrant
chromosomes
- Exam ple: aberrant genes: Sickle cell gene (one am ino acid is substituted)
- Exam ple: aberrant chrom osom es: Down’s Syndrom e: trisom y of chrom osom e 21
Multifactorial or polygenic inheritance: not sim ple Mendelian genetics; m ultiple genes and
environm ental factors determ ine express of a condition (e.g. asthm a, diabetes)
© 2004 Lois E. Brenneman, MSN, CS, ANP, FNP
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TERMINOLOGY AND PATTERNS OF INHERITANCE
Autosomal dominant inheritance
- Trait is carried on an autosom al chrom osom e where affected allele is dominant.
- No carrier state is possible
- Exam ples: achondroplastic dwarfism in hum ans, polydactyl in cats
Autosom al recessive inheritance
- Trait is carried on autosom al chrom osom e where affected
allele is recessive
- Carrier state is possible
- Exam ple: sickle cell disease; blue eyes
Sex-linked recessive inheritance
- Trait is carried on x chrom osom e where affected allele is
recessive
- Exam ples: color-blindedness, hem ophilia
Sex-linked dominant inheritance - very rare
- Trait is carried on X chrom osom e where affected allele is
dominant
- Vitam in D resistant rickets
Lethal traits
- Hom ozygous off-spring die in utero or m ale offspring die in utero
- Inheritance patterns will be different from that which is expected (suspect lethal trait)
- 1/3 norm al and 2/3 carrier vs the typical 1/4 norm al, ½ carrier, 1/4 affected
GENETIC PATHOPHYSIOLOGY
PATHOPHYSIOLOGY OF CHROMOSOME ABNORMALITIES
Num erical Abnorm alities: 2 types - num erical or structure
Ploidy (aneuploidy): abnorm alities which involve whole sets of chrom osom es
- Alm ost always lethal -> aborted fetuses or sm all fetuses surviving for few days
- Term inology
- Haploid 23(N)
- Diploid 46 (2N)
- Triploid 69 (3N)
- Tetraploid 92 (4N)
Somic: involve one chrom osom e
Monosom ic - 45 chrom osom es
Bisom ic: - 46 chrom osom es (norm al state)
Trisom ic - 47 chrom osom es
Tetrasom om ic - 48 chrom osom es
Pentasom ic - 49 chrom osom es
Note : extrem ely rare for autosom es - m onosom ic chrom osom e - but occurs (e.g. Turner’s
Syndrom e) for x chrom osom e in approxim ately 1 per 5000 births
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Aneuploidy - Mechanism for aneuploidy (abnorm al num ber of chrom osom es)
Nondisjunction
Separation of chrom atids occurs but w/o norm al segregation of chrom atids into the two
daughter cells. Therefore, both chrom atids are retained wi a single cell, yielding 47
chrom osom es (trisom y), and the second daughter cell has only 45 chrom osom es
(m onosom y)
M onosomic condition m ost likely lethal if autosom e (non-sex cell chrom osom e) is
involved; Trisomic cell m ay 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 brane, which re-form s before all of the chrom osom es have m igrated. Leads to
m onosom ic conditions.
M osaicism : coexistence of two or m ore stem lines of cells within the
sam e individual
- Can result from either non-disjunction or anaphase lag
- Abnorm al cell division occurs after m eiosis (on subsequent
m itotic divisions)
Results in m osaic m orula where som e cells are norm al
(from the union of two normal gam etes) while a subset
of cells are abnormal (from abnorm al m itotic division
som ewhere down the line)
- May be im portant indication of tem poral etiology of
chrom osom al defect
Evidence for post fertilization, nondisjunctional event
- W here abnorm ality occurs w m eiosis (prior to fertilization) -> non-m osaic zygote
- Mosaic individuals are often less severely affected
Exam ple: m osaic Down’s Syndrom e m ay be m ildly affected
Trisomy: Com m on Trisomy Abnorm alities
- Trisom y 21 - Dow n’s Syndrom e (1:650 births) - com m on with advanced m aternal age
- Trisom y 22 Syndrom e
- Trisom y 13 Syndrom e - Edward’s syndrom e (1:3000 births)
- Trisom y 18 Syndrom e - Patau’s syndrom e (1:5000 births)
Translocation Abnormalities (Structural abnorm ality)
- Caused by chrom osom e breakage
- Com m on is a reciprocal translocation or mutual
exchange
- Translocations have involved every group of chrom osom e
and have far-reaching
consequences
Dow n’s syndrom e can result from inheritance of
translocation chrom osom es as well as
from the classic trisom y 21
- Clinically indistinguishable from those with trisom y 21
- Represents translocation between the m issing num ber 14 chrom osom e and the
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extra num ber 21 chrom osom e
- Results from one of the parents being a balanced carrier (see below)
Several variations of translocations can yield Down’s Syndrom e
Translocation between two G-group* chrom osom es. If such a translocation is
inherited (i.e. one of the parents is a carrier) and the two chrom osom es involved
are both m em bers of pair 21, all off-spring born will have Down’s Syndrom e. If,
however, num ber 21 and 22 chrom osom es are involved in the translocation, then
norm al, carrier and affected offspring will result
Other trisom y states can result from inheritance of
translocated chrom osom es
Exam ple: trisom y 13 syndrom e from a balanced
carrier parent
Trisom y states can result from translocation of
chrom osom e within the affected individual
Direct result of translocation and not secondary
to balanced carrier parent
Balanced carrier
Portion of chrom osom e is translocated on another chrom osom e
Only 45 chrom osom es are present, with one each m issing in groups D and G.* In
additional the “C-group-like”* subm etacentric elem ent is present. (Offspring of these
person’s have Down’s Syndrom e)
Phenotypically, these persons appear normal
They have the correct num bers of genetic m aterial but it has been
translocated in non-norm al pattern.
W hen these individuals create offspring, they pass the aberrant chrom osom al
m aterial to the gam etes and create abnorm al offspring
Exam ple: Down’s Syndrom e
* 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 Chrom osom e Abnorm alities
Chrom osom al breaks which result in loss of blocks of genes in
term inal (one break) or interstitial (2 breaks) segm ent deleted
Cri-du-chat syndrom e
- Partial deletion of short arm of num ber 5 chrom osom e
(degree of deletion is
variable
- Syndrom e occurs sporadically or inherited via
translocation
- Distinctive high-pitched m ewing cry resem bles a kitten
- Cry occurs im m ediately after birth and disappears after weeks
- Other abnorm alities
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Low birth wt, m oon facies, m icrocephaly, antim ongoloid facies, downward
sloping palpebral fissures, with or without epicanthal folds. Micrognathia,
short neck, heart defects and hypotonia. Mental and physical
developm ent are m arkedly retarded.
- Considerable degree of variation in clinical m anifestations
4p- syndrom e
- Deletion of short are of chrom osom e 4
- Profound retardation and birth defects
18q- syndrom e
- Deletion of long arm of num ber 18 chrom osom e
- Profound birth defect with classic facies
18p- syndrom e
- Short arm of one of the num ber 18 chrom osom es
- Profound birth defects and m ental retardation
Philadelphia chrom osome
- Chronic m yelocytic leukem ia
- Only chrom osom al abnorm ality associated with specific form of neoplasia
- ½ to 2/3 of the long arm of chrom osom e 22 is m issing
Christchurch chrom osome
- Not always associated with pathology
- Associated with m yelocytic leukem ia and other conditions
- Deletion of short arm of either 21 or 22 chrom osom e
Antimongoloidism
- Deleted chrom osom e 21
- Som e clinical features suggest opposite of Down’s syndrom e
- Mental retardation, hypertonia and profound birth defects
The cat-eye syndrom e: extensive birth defects
The 13q- syndrom e: profound m ental/physical retardation
The long arm number 15: retinoblastom a
Ring Chrom osomes
- Results from two breaks and rejoining of broken ends of chrom osom es to each other
- Structural aberrations lead to deletion of chrom osom al m aterial from both ends
- Unstable form s which encourage difficulty in m itosis
Results in breakage and fusion to form rings during cell division
- Rings of various size w concom itant variable deletions
- Can affect any chrom osom e
- Phenotype and stigm ata varies considerable pending on what chrom osom e and how
m uch is affected
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Inversions
- Structural aberrations resulting from two breaks in a chrom osom e and a 180 degree
rotation of the segm ent between the break points
- direction of the reading of the DNA codes wi reversed within the broken segm ent
- m ay or m ay not result in clinical difficulty as function of genes involved
DERMOGRAPHICS
- Study of patterns on fingertips (loops, arches, whorls) , palm s, soles
- Correlated with certain of the chrom osom al syndrom es
- Useful adjunct to diagnosis of som e chrom osom al abnorm alities and birth defects
MISC GENETIC DISORDERS
Arachnodactyy
Testicular fem inization syndrom e
Marfan’s syndrom e
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14
ABNORMALITIES OF SEX CHROMOSOME
FEMALE PHENOTYPE
XO - Turner’s Syndrom e
- 50% or m ore have lym phedem a (transient phenom enon)
- 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
- Posterior nuchal lym phedem a -> w ebbed neck
- Extrem e case: m assive sac resem bles m eningocele
- More com m on is redundant folds -> resolve ->
develop into w ebbed neck
- Other stigm ata are difficult to identify in newborn
- 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
Minim al breast developm ent
Axillary and pubic hair scant or absent
Face abnorm alities
Micrognathia, flattened nasal bridge, low-set ears which
are large/deform ed
Epicanthal folds, ptosis and hypertelorism are com m on
Hands: show short 4 th m etacarpal crenating the 4 th finger (dim ple w fist )
Short 4 th m etatarsal
Low hairline
Com m on: m ultiple pigm ented nevi (46)
Many develop keloids: im pacts decision to cosm etically repair webbed neck
Retarded bone are and osteoporosis seen
- Other com m on m alform ations of Turner’s Syndrom e
Congenital heart defects (coarctation of aorta); m alform ations of the kidney
(especially horseshoe kidney and duplication of urinary tract); m alform ations of the
thyroid gland and significantly increased incidence of thyroiditis and Hashim oto’s
disease, intestinal telangiectasia (m ay lead to m assive GI hemorrhage)
- Severe m ental retardation rare, 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 prem alignant lesion
- Y karyotype anywhere (m osaic or 46,XY) is prem alignant, warrants surgery
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15
46 XX or
-
46 XY: Fragile X syndrom e (1:2000)
Phenotype is fem ale tall with eunuchoid body habitus
Infantile genitalia and reproductive organs
Fetal castration; lack of sex horm ones
Noonan’s syndrom e: gonadal dysgenesis in m ales and fem ales with
norm al karyotypes
- Rare but occurs in fam ilies
- Typical sym ptom s of gonadal dysgenesis with som e
differences/exceptions
- Mental retardation; pectus excavatum : both com m on
- Congenital heart disease esp pulm onic stenosis com m on
- Can have underdeveloped but functional genitalia; som e bear affected children
- Father son transm ission reported thus r/o x-linked inheritance
Poly-X Syndrom es
47 XXX
- Variable clinical features
- No suggestion of increased occurrence of m ental retardation
- Several known to be norm al/fertile -> no chrom osom al abnorm al infants
48 XXXX
- Physically norm al; post-pubertal norm al m enstruation
- Severely m entally retarded; no physical findings
XXXX
- Severe m ental and growth retardation
- Mild upward slant of palpebral fissures; sm all hands w clinodactyly
- Fail to thrive; frequent vom iting and respiratory infections
PHENOTYPE MALES
XXY - Klinefelter’s Syndrom e
- Eunuchoid with truncal obesity, gynecom astia, decreased
m uscle m ass
- Incom plete virilization: sm all phallus, testes w fibrosis and
hyalinization
- Dull m entality and severe m ental retardation are invariable
- Psychopathology as behavior problem s/disturbed body im age
- Diagnosis rarely m ade until pubescence but detection in
childhood would be preferable
- Screening for educationally subnorm al (IQ 50 or greater)
- Screening based on behavioral or psychiatric problem s
- Age-appropriate physiologic testosterone ensures m ore norm al
growth/developm ent
- May prevent gynecom astia and hypogonadism
- Relatively long legs even before adolescence
48 XXXY and 49 XXXXY syndrom es - variations of Klinefelter’s syndrom e
- Profound m ental retardation
- Genitalia m arkedly underdeveloped; sexual hair scant
- Multiple congenital m alform ations of m any organ system s
© 2004 Lois E. Brenneman, MSN, CS, ANP, FNP
all rights reserved - www.npceu.com
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Y CHROMOSOME ABNORMALITIES
- Most variable m orphologically - extrem ely variable in length
- Length is inherited - constant from father to son
XYY karyotype
- Increased num bers of these m en in prisons esp m axim um security institutions
- Tall statue; m ild m ental deficits
- Increased incidence of sociopathic behavior
Siam ese cats: partial albinism (tem p sensitive)
CC: cloned kitten in beaker
Vitalogo- patches of albinism
© 2004 Lois E. Brenneman, MSN, CS, ANP, FNP
all rights reserved - www.npceu.com
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