Disorders of sexual development Flashcards
Mechanism of Turner syndrome inheritance
Usually sporadic due to non dysjunction during meiosis
Increased risk if parent carries balanced rearrangement or maternal mosaic
Turner Indications prenatal
Abnormally high levels of human chorionic gonadotropin
Cystic hygroma ( excess fluid on nape of neck on scan)
Lymphadema - usually resolves if survives to term
IUGR
Turner Indications newborn
Small
Lymphadema ( hands and feet)
Nail hypoplasia
Excess skin at nape of neck
Turner Indications childhood
Short stature
High arched palate
Short neck/ low hairline
Hypoplastic widely spaced nipples
Broad chest
Nail hypoplasia
Lymphadema
Prominent ears
Excess nevi
Turner Indications adolescence/adulthood
Short stature
Primary or secondary amenorrhea
Delayed puberty with no secondary sexual characteristics
Recurrent pregnancy loss in adulthood
What is the risk for Turners due to presence of Y chromosome material?
Those mosaic for a cell population with Y material have risk of gonadoblastoma in streak gonads (7-30%)
Cytogenetic X of Turner syndrome
~50% 45,X
~20% 46,X, abnormal X ( i(Xq) most common)
Remainder mosaic for 45,X and other cell lines (numerical or structural)
Characteristics of classical Turner syndrome
Congenital heart malformations (17-45%, no clear genotype- phenotype correlation), most commonly coarctation of aorta and bicuspid aortic valve
Structural kidney abnormalities 40% (single horseshoe)
Adult mean height 147cm
Streak ovaries
Infertile
No secondary sexual characteristics if untreated
Treatment of Turner syndrome
Growth hormone
Secondary sexual characteristics can be developed by treatment with oestrogen and progesterone at appropriate age
Fertility: egg donation
Removal of streak ovaries if Y chromosome material present
Features of numerical mosaics in Turner
Milder phenotype Maybe taller May enter puberty spontaneously More likely to have secondary amenorrhea or premature menopause Maybe fertile or subfertile
Features of structural mosaics in Turner syndrome
45,X and isochromosome, ring, or deletion of p or q arms
Milder phenotype
May only show short stature and gonadal dysgenesis
Presence of mitotically unstable structural abnormality of X results in post-zygotic generation of 45,X cell line
Turner Mosaics with markers
FISH to determine if marker is derivative of X or Y
Maybe elevated risk of gonadoblastoma if Y (critical region GBY, candidate gene TSPY)
Those X derived usually classic Turner phenotype
May have more severe phenotype if XIC absent (functional disomy) dependent on genes present
Incidence of Turner syndrome
1 in 2500-3000 live born girls
> 95% conceptuses fail to reach term
Incidence of Klinefelter syndrome
1 in 500 to 1000 newborn males
Clinical features of Klinefelter syndrome
Taller than average with disproportionately long limbs
30-50% gynaecomastia (usually mild)
Infertile (azoospermia)
IQ lower than sibs
Most not detected until present with infertility
May have: Small testes Delayed or incomplete puberty Reduced facial or body hair Cryptorchism Hypospadias
Klinefelter mosaics
Commonly found with normal cell line and less severely affected
Inheritance of Klinefelter
Not inherited
Arises from non disjunction during meiosis in one parent
Mosaic forms occur due to abnormality in mitosis in early embryonic development
Variants of Kleinfelter
Extra copies of the X 48,XXXY or 49,XXXXY
ID Distinctive facial features (flat nose,epicanthic folds, prognathia) Skeletal abnormalities Poor coordination Speech problems
48,XXXX features
- ID
- Normal to tall height
- Speech delay
- Down syndrome like features including upward slanting paperback fissures, Microcephly, epicanthic folds, midface hypoplasia
- menstrual disorders and reduced fertility
- Additional X usually maternally derived
SHOX micro deletion
SHOX= short stature homeobox gene
PAR1
Loss in Turner syndrome due to deletion causes short stature
Mutations cause Leri-Weill dyschondrosteosis
Leri-Weill dyschondrosteosis
Autosomal dominant
Short stature
Abnormal wrist and forearm bones (curving) Madelung deformity
Muscle hypertrophy
High arched palate
More severe in females ( possible hormonal)
Kallmann syndrome features
Anosmia due to a Genesis of the olfactory lobes
Hypogonadism secondary to deficiency in GnRH
Males may have micropensis and chryptorchism and fail to develop secondary sexual characteristics
Females fail to menstruate, little or no breast development
Mild ID
Colour blindness
Forms of Kallmann syndrome
Autosomal dominant (loss of function of FGFR1)
Sex linked (mutation or deletion of KAL1 (ANOS1)) x linked recessive
X linked icthyosis
1 in 2000-6000 males births
Scaling of skin, placental steroid sulphatase deficiency
Complete or partial deletion of STS gene Xp22.3
Disorders of sexual development
Rare disorders in which there is a discordance between chromosomal, gonadal, and phenotypic sex.
A minority of patients receive a molecular diagnosis
isodicentric Y
SRY present- male phenotype
No AZF: lack of spermatogenesis
Y chromosome microdeletions
AZFa Complete absence of germ cells (sertoli cell only syndrome)
AZfb Arrest of maturation at spermatocyte
AZfc Variable- SCOS to oligozoospermia. Yq11.23 contains DAZ multigene family
Myotonic dystrophy
Myotonia-cannot relax mucles
CUG repeat expansion
Male:
- gonadal atrophy
- reduced fertility
Female:
- POF
- higher miscarriage rate
- obstetric problems (prematurity, faliure to progress)
cause of infertility not well understood
Primary ciliary dyskinesia
Abnormal sperm motility
Around 50% males infertile
Females can be infertile due to impaired ciliary function in oviduct
AD polycystic kidney disease (ADPKD)
Affects motility of spermatozoa
