EMBRIOLOGIE

Embriologie generala
Gametogeneza
Fecundatia
Maladii genetice

Embriogeneza umana
= descrie procesul de dezvoltare a
embrionului uman de la stadiul de zigot
pana la nastere.
=> nou nascutul: aprox. 3 kg. - 50 cm.

Embr descriptiva = embr formei descrie

structurarea individului in timp si spatiu,
pornind de la celula ou

Embr functionala = embr cauzala si moleculara

permite o mai buna intelegere a determinismului si a
factorilor care controleaza dezvoltarea temporo
spatiala a tesuturilor si organelor.

Embriologie descriptiva - Haeckel drawings

Perioadele de dezvoltare
embrio-fetale
perioada embrionara
aparitia diferitelor foite primordiale
aparitia mugurilor diferitelor segmente ale
corpului

Stadii precoce : de la ou/zigot la stadiul de disc

embrionar - di- (DED) si tri-dermic (DET)
1
2
3
4

I saptamana segmentarea oului

=> morula
aparitia unei cavitati
= blastocist

Embrioblast
Zona pellucida
Trofoblast
Blastocoel

Stadii precoce : de la ou/zigot la stadiul de disc

embrionar - di- (DED) si tri-dermic (DET)

Sapt 2 = DED format din

ectoblast si de endoblast
primar ;
trofoblastul reprezinta
primordiul viitoarei placente
Sapt 3 = DET apare
mezoblastul intra-embrionar
(a3a foita) - primele primordii
ale viitoarelor organe

Stadii ulterioare : plicaturarea si

organogeneza
Sapt 4 inchiderea
structurii discale (2
dimensiuni) cu foermarea
embrionului in 3
dimensiuni plicaturare si
aparitia primordiilor de
organe
Sapt 5-8/10 :
organogeneza formarea
organelor primare

Perioada fetala
de la 3 luni la nastere
= o faza de maturizare si
crestere in volum

Mecanismele specifice
embriologiei
Proliferarea celulara
Migrarea celulara
Diferentierea celulara - pornind de la celulele
suse/stem
Apoptoza moartea celulara programata

EVALUAREA STADIILOR DE DEZVOLTARE

EMBRIO-FETALE
Colectia Carnegie (Washington) - identifica 23 stadii
de dezvoltare
Sistem de referinta care se stabileste prin corelarea
dintre :
varsta prezumata (plecand de la data ultimei ovulatii)
talia (lungimea celui mai mare ax al embrionului in
dezvoltare)
caracterele morfologice specifice si identificabile
pentru fiecare stadiu

Exemple de stadii Carnegie

Stadiul 11 : 2,5
4,5 mm, ~ 29 zile ;
Stadiul 15 : 7 - 9
mm ; ~ 36-38 zile ;
5 vezicule
cerebrale;
cristalin; paleta
mainii.

1
2
3
4
5
6

tub neuronal
neuropor caudal
neuropore rostral care
tocmai se inchide
somite
arc faringian 2
arc faringian 1

1 cordon ombilical
2 proeminenta
cardiaca
3 placoda nazala
4 primordiumul
ocular
5 mugurele
membrului superior
6 mugurele
membrului inferior

GAMETOGENEZA

Divisiunea celulara

Difer. dintre Meioza si Mitoza

Formarea gametilor = Gametogeneza

formarea celulelor reproductive feminine si masculine
ovulul si spermatozoidul
de catre glandele sexuale (= gonade: ovar si testicul)
=> ovogeneza
=> spermatogeneza

Gametogeneza dublu rol:

1.

Reducerea numarului de cromozomi care permit redistribuirea materialului

ereditar prin MIOZA

2.

Adaptarea celulelor reproducatoare => forma si functie speciale apte pentru

fecundatie

Ovogeneza
Prezinta mai multe cicluri:
Inainte de nastere - de la 15 sapt la 7 luni
embrionul/fatul genetic feminin (46XX) evolutia
celulelor germinale
Dupa 7 luni (fetale) - pana la pubertate
- DIAPAUZA = celulele sunt blocate in profaza I
De la pubertate pana la debutul menopauzei
- grupuri mici de ovocite si de foliculi sunt activate

Ovogeneza
Debut prin evolutia
celulelor germinale
OVOGONIA = mai
multe cicluri de mitoza
(in corticala ovarului)
=> aprox. 7 milioane
(acest stoc de celule
NU se reinnoieste!!! )

Ovogeneza
OVOGONIA prima diviziune a mitoza =>
ovocit I 2N

Aceasta faza a meiozei = PROFAZA I ramane

blocata pana la pubertate !!!

Intre luna a7a de viata

intrauterina - pubertate
celulele germinale si
foliculii intra intr-o
perioada de atrezie
(involutie)
la nastere raman 700 000 1 000 000
ovocite I
la pubertate - DOAR
400 000 ovocite I

De la pubertate la debutul
menopauzei
Mici grupuri de ovocite
si foliculi sunt
activate
= UN OVOCIT/ CICLU
va fi selectionat si va
evolua cu eliberarea
unui ovul

Ciclul ovarian
Evolutia meiozei I => + primul
globul polar
Debutul celei de a2a meioze
(meioza II) inca o data
meioza se blocheaza - in
metafaza
Ovocitul II - expulzat la
suprafata ovarului = ovulatie

Ciclul ovarian
Ovocitul matur (ovocit II) trompa lui
Fallopio:
intalneste spermatozoidul
=> fecundatia
=> meioza se termina
=>o celula ou
+ al doilea globul polar
fara gamet masculin - ovocitul nu termina
meioza
=> evacuat odata cu menstruatia

Ovocit I

Ovocit II

Ovocit II inconjurat de
cumulus oophorus

Anomalii ale ovogenezei

Anovulatia
Ovulatia unui gamet anormal
(diploide sau cu cromozomi
supranumerari; folicului cu 2 ovocite,etc)

Spermatogeneza
Debuteaza la pubertate
este continua pana la
finalul vietii
Se produce la nivelul
tubilor seminiferi
(testicul)
sistemul canalicular

Testiculul
Glanda sexuala masculina
sediul:
spermatogenezei (tubi
seminiferi)
sinteza hormonilor
masculini (testosteron)
cel. Leydig = interstitiale

Doua tipuri de celule la nivelul peretilor tubilor

seminiferi:
Celule mari conice celulele Sertoli epiteliu
celulele germinative

Le spermatozode

1 : Acrosome
2 : Noyau (chromatine condense)
3 : Centriole distale
4 : Centriole proximale
5 : Mitochondries
6 : Axonme
7 : Fibres denses externes

capul - contine nucleul cu:

- patrimoniul genetic patern
- acrozomul = un sac de enzime care sunt eliberate in timpul
fecundatiei si permit penetrarea spermatozoidului in ovul;
piesa intermediara dreapta, cu:
- centriolul care da nastere flagelului/cozii
- mitocondriile - dispuse elicoidal - furnizeaza
energia necesara miscarilor flagelului
flagelul/coada confera mobilitate spermatozoidului

Anomalii ale spermatogenezei

azoospermie secretorie - absenta productiei spermatozoizilor
maturi asociata unei descuamari de celule germinale imature
oligospermie - productia unui numar insuficient de
spermatozoizi (< 20 millioane de spz / ml de sperma)
astenospermie - anomalie a mobilitatii a mai mult de 50%
dintre spermatozoizi
teratospermie: afectarea morfologica a mai mult de 70% dintre
spermatozoizi

necrospermie : productia unui procent ridicat de spermatozoizi

nefunctionali (>25%)

Anomalii - teratospermie

Spermocitograma permite cunoasterea procentului

de forme tipice normale in sperma donata

 Cantitatea (1.5 - 6ml) Mobilitate (> 50%)

pH (7.4 - 7.6)
< 50 % : astenospermie
Numar (60 - 120
Vitalitate (> 50%)
milioane)
> 50% morti : necrospermie
< 20 M : oligospermie
> 200 M : polispermie Forma
> 50% anormali :
0 : azoospermie
teratospermie

varsta, caldura, radiatiile, chimioterapia

produc modificari

Coloration de Schorr

Coloration rapide

Fecundatia
= finalitatea unei cascade de evenimente care
culmineaza cu fuziunea gemetilor
procesul se deruleaza in ampula trompei
uterine (1/3 lat.)

Etapele prealabile fecundatiei

Maturizarea gametilor proces
indispensabil fecundatiei
maturizarea ovocitelor se
produce inperioada ovogenezei
maturizarea spermatozoizilor
incepe la nivelul epididimului si se termina
in caile genitale feminine

Tranzitul spermatozoizilor
prin caile genitale feminine
dupa inseminare naturala
la nivelul vaginului majoritatea spermatozoizilor
mor datorita pH-ului acid
=> ceilalti spermatozoizi
inainteaza prin canalul cervical dupa eliminarea
lichidului seminal.
in perioada periovulatorie:
secretiile glandulare care ocupa canalul cervical
prezinta caracteristici biochimice optime pentru
supravietuirea si tranzitul spermatozoizilor
(mucus fluid, pH alcalin).

Migratia spermatozoizilor prin mucus cervical

1- spermatozoizi, 2 - mucus cervical; 3 cripte glandulare

mucusul cervical = bariera naturala

PENTRU CA
DOAR spermatozoizii cu mobilitate si
morfologie normala pot traversa
Spermatozoizii pot supravietuii la nivelul criptelor
glandulare ale colului - aprox. 3 zile
sunt rapid adusi la nivelul trompei uterine prin
contractia uterina si propria mobilitate
ampula trompei

Capacitatia spermatozoizilor
= modificari membranare
cresc permeabilitatea membranara
pregatesc receptorii spermatici
specifici pentru fixarea la zona pellucida
=> Modificarea mobilitatii spermatozoizilor
care devin hiperactivi

Traversarea cumulus oophorus si

fixarea la zona pellucida

Fixarea la zona pellucida si

reactia acrozomica
Interactiunea spermatozoid/ zona pellucida de tip
ligand receptor
glicoproteinele zonei pellucide (ZP1, ZP2, ZP3)
interactioneaza specific cu proteinele spermatozoizilor

Fixarea spermatozoizilor la zona pellucida

 Fixarea primara a glicoproteinei ZP3 cu

proteinele membranei spermatice eliberarea
enzimelor continute in acrozom
= reactie acrozomica

Etapele reactiei acrozomice

 Consecintele imediate
=> eliberarea continutului acrosomial
- in principal enzime proteolitice si hidrolitice
care favorizeaza penetrarea
spermatozoidului prin zona pellucida
traversarea ZP se realizeaza datorita
miscarilor active de propulsie a spermatozoidului
capacitat

Un singur spermatozoid traverseaza ZP si

intra in spatiul perivitelin!!!

Fuziunea gametilor
Spermatozoizii
recunosc
membrana
plasmatica a
ovocitului
Fuziunea se produce
intre membrana
plasmatica ce
acopera segmentul
ecuatorial al
spermatozoidului
si
membrana
plasmatica a
ovocitului
Cuplarea ligand-receptor intervine in recunoasterea
inetrgametica (1 - zona post acrozomica, 2 - membrana
ovulului, 3 spatiul perivitelin, 4 - zona pellucida)

Activarea ovocitului II
Fuziunea eliberare masiva de Ca++ => activarea
ovocitului:
Emisia de granule corticale in spatiul perivitelin

Enzime ce determina modificari la nivelul ZP

impenetrabila pt alti spermatozoizi

= impiedica polispermia!!!

Activarea ovocitului II
Repriza a 2a a diviziunii miotice
Ovulul conserva in totalitate citoplasma ovocitului II
cu pronucleul feminin;
Al 2lea globul polar ce contine mai ales material
genetic este eliminat in spatiul perivitelin

Eliberarea celui de-al 2 lea globul polar si formarea pronucleilor

(A : 1 microtubuli, 2 GP2, 3 ZP, 4 spatiul perivitelin, 5 membrana spermatica, 6 cil ,
7 nucleul spz, 8 centrozomul spz ;
B 1 pronucleu paternal, 2 pronucleu maternal, 3 centrozomi)

Formarea pronucleului masculin

Spz intra in totalitate in citoplasma ovocitului
(piesa intermediara si flagelul incorporate
progresiv si dispar)
Nucleul spz - incorporat in citoplasma ovocitului
sufera urmatoarele modificari:
Decondensarea cromatinei
Formarea unei noi membrane nucleare
Stadiul de pronuclei dureaza 24 ore
si corespund fazelor G1, S si G2 ale ciclului
celular.

Fuziunea pronucleilor si formarea

zigotului
A : 1 pronucleu patern
2 pronucleu matern
3 centrozom patern
4 corpusculi interni
5 microtubuli
B: 1 pronucleu patern
2 pronucleu matern
3 centrozom
4 corpusculi interni

Zygote

Embryon 2 cellules

Blastocyste (4me jour)

Blastocyste clos

Morula (3me jour)

Eclosion du blastocyste (5me jour)

Migratia embrionului
In timpul dezvoltarii embrionul se
deplaseaza prin trompe
DATORITA
cililor de pe peretii trompei

uter - ziua a 4a

Nidatia
Blastocistul se va fixa la nivelul endometrului
= nidatia
embrionul se va conecta la vasele uterine
(placenta) - pentru obtinerea de substante
nutritive necesare dezvoltarii
=> faza proliferativa faza secretorie

Morula, 8 cell stage

1 - morula, 2 - blastula

1 - blastula, 2 - gastrula
with blastopore; orange ectoderm, red endoderm.

5 saptamani

6 saptamani

Common Genetic
Syndromes and their
Medical Consequences

Incidence of Common
Syndromes

Down Syndrome 1/700

Noonan Syndrome 1/1000-3000
Turner Syndrome 1/5000
Neurofibromatosis I 1/3000
22q11 Deletion 1/4000
Achondroplasia 1/ 15,000-40,000
Fragile X 1/3600 males, 1/6000 females

Down Syndrome
1/650-700 births most common aneuploidy;
most common cause of genetic MR
Langdon Down in 1866; 1959 the
chromosome cause became clear
Etiology: maternal nondisjunction (90%)
rarely paternal nondisjunction; chromosome
translocation (5%), mosaic (<5%)
Increase risk with increase maternal age or
parent is a translocation carrier
Risk of reoccurrence typically depends on
mothers age for full trisomy

Trisomy 21

47, XX,+21

Robertsonian translocation
46, XY, rob (14;21), +21

Down Syndrome phenotype

Down Syndrome

Down Syndrome infant-child

85% survive to 1 year and 50% live >age 50
30-50% CHD with endocardial cushion
defects most common (Atrioventicular canal)
Gastroesopageal reflux, otitis media, mixed
hearing loss
Ophthalmologic abnormalities: strabismus,
cataracts glaucoma
Increased risk of leukemia (10-50 times)
Hypothyroidism (30%)
Hirschsprung disease
Increased risk for epilepsy

Down syndrome Intestinal

Atresias
Duodenal atresia,
esophageal
atresia
Usually present
with bilious
vomiting in the
newborn period,
double bubble
sign

C1-C2 instability/dislocation
C1

laxity of the transverse ligament (13-14%

instability)

Development
Developmental delay
obvious after first year
IQ 20-85; Significant
variability among
children
Early infant toddler
connection
Most children require
special education,
some can be
mainstreamed

Down Syndrome (older

childhood-teenager )
Increased risk of sleep apnea (mid face
hypoplasia, adenoid hypertrophy)
Celiac disease
Large adenoids sleep apnea, airway
obstruction
Hypothyroidism
Early adulthood: obesity, insulin
resistance, premature cardiovascular
disease

Aging and Down Syndrome

Increased

risk of
testicular cancer

Premature senility
associated with
characteristics of
Alzheimer disease (AD)
Up to 10-25% show
signs of AD before age
50 and up to 50% before
the 6th decade
Cortical atrophy,
ventricular dilation,
neurofibrillar tangles
AD affects Down
Syndrome patients at
an earlier age than
general population

Noonan syndrome
The RASopathies are developmental syndromes caused by
germline mutations in genes that alter the Ras subfamily and
Mitogen-activated protein kinases that control signal
transduction
One of the most common genetic disorders with
congenital heart defect (1/3000)
Wide range of clinical variability and phenotype
expression
Autosomal dominant with normal chromosomes
NOT the male Turners syndrome
Affect male and females equally

Noonan syndrome: features

Broad, short or webbed neck
Unusual chest shape with superior pectus
carinatum, inferior pectus excavatum
Apparently wide low-set nipples
Cryptorchidism in males
Down slanting palpebral fissures, ptosis, low
set ears
Congenital heart defect , hypertrophic
cardiomyopathy
Developmental delay of variable degree,
hypotonia
Increased incidence of malignancy

Noonan syndrome

Noonan Syndrome
Pulmonic stenosis
often diagnosed in
infancy (20-50%)
Cardiomyopathy
(20-30%) may
present at birth or
develop in
childhood
Lymphatic dysplasia
and cystic hygroma
can be present
Coagulation
abnormalities

Noonan syndrome
Diagnosis can be
missed if features are
subtle
Failure to thrive with GE
reflux present in
infancy;
Short stature late
childhood adolescence
sometimes with growth
hormone deficiency;
mean female ht 150
females, 160 males

Noonan: Inheritance
Autosomal
dominant 30-75%
will have an affected
parent
PTPN11 (50%)
SOS1 (16-20%),
RAF1 (3-17%)
KRAS <5%
SHOC2, NRAS <5%
Clinical diagnosis

Autosomal Dominant
Inheritance
Affects males and females equally
Vertical transmission (one generation
to the next)
High spontaneous mutation rate
50% reoccurrence risk for affected
child when parent affected

Pedigree of Autosomal
Dominant Inheritance

Noonan syndrome: education

Hypotonia contributes to gross motor delays
in childhood
Most are mainstreamed (25% have learning
disabilities), verbal performance lower than
nonverbal
Hearing loss common
Mild mental retardation 30%
Self esteem is usually comparable to age
related peers
Sometimes depression, anxiety

Noonan syndrome malignancy

Genes responsible for this condition
part of the RAS/MAPK pathway
Juvenile myelomonocytic leukemia
(JMML); individuals with PTPN11 have
predisposition to this unusual
childhood leukemia

Turner Syndrome
Incidence 1/2000-5000
Karyotype 45,X (50%) high rate of
spontaneous miscarriage
Other 50% associated with mosaicism (can
be with Y) or an abnormal X chromosome
70-80% result from sperm lacking sex
chromosome
Usually sporadic
Xq chromosome necessary for ovarian
maintenance and female fertility, Xp
responsible for short stature

Turner Syndrome

Turner Syndrome (Common

presentations)
Newborn infant with lymphedema of
hands and feet, low posterior hairline
16 y/o female presents with
amenorrhea and short stature, absent
of secondary sexual characteristics,
ovarian dysgenesis

Turner Syndrome
Features: Cystic hygroma, lymphedema,
webbed neck, low posterior hairline
Cardiac 50% biscuspid aortic valve,
coarctation of the aorta
Other: Renal abnormalities (60%), short
stature, broad chest, ovarian dysgenesis
Most are of normal intelligence, some may
have learning disabilities particularly spatial
perception
Treat GH therapy (gain 6-10 cm height)
followed by female hormone replacement

Turner Syndrome
May have impaired social adjustment,
hyperactivity, anxiety, depression
Some may have chronic health issues
including diabetes mellitus type 1 and 2,
thyroiditis, osteoporosis
Increased risk of intestinal disorders: IBD,
celiac, intestinal telangiectasia (malformation
of the blood vessels)
Increased risk of hypertension,
atherosclerosis and ischemic heart disease
(estrogen effect?)

Neurofibromatosis I
One of the most common Autosomal
dominant inherited conditions
Also known as Von Recklinghausen Disease
Incidence 1/3000 with 50% de novo
mutations (50% with first degree relative
affected)
NF1 on chromosome 17
Diagnosis is based on clinical features
Wide range of clinical severity among
patients

Neurofibromatosis I (NF1)
Consensus diagnostic criteria
Need at least 2:
6 or more caf au lait macules (at least 5 mm
before puberty and 15 mm after)
Axillary or groin freckling
2 or more neurofibromas
Lisch nodules (iris hamartomas)
Optic glioma
Osseous lesions (sphenoid or tibial
dysplasia)
Positive family history

Children and NF1

Only 50% affected children with no
family history meet criteria by age 1
Almost 100% will by age 8
Caf au lait macules usually present at
birth and increase in number
Other features, axillary freckling, Lisch
nodules, appear later in childhood

Diagnosis in young children

Diagnostic criteria are usually
unequivocal in all but the youngest
children
If child have family history only one
diagnostic criteria are needed
Gene sequencing can be used in those
that do not yet meet diagnostic criteria
yet in the absence of family history

NF1 clinical findings

Medical Problems NF1

Complications can involve multiple body
systems
Central Nervous System: symptomatic optic
gliomas usually present before age 6
(proptosis or loss of visual acuity) usually
slowly progressive, some spontaneous
regress; treatment surgical or chemotherapy
Other brain tumors: brain stem and
cerebellar astrocytomas
Headache, seizures, vasculopathy
Learning disabilities in 50%; attention
deficits

Optic Glioma

Eye (2004) 18, N. R Miller

Medical Problems NF1

Musculoskeletal: dystrophic scoliosis
requires surgical management
Cardiovascular: Vasculopathy,
hypertension, pulmonic stenosis
Neoplasia: Malignant peripheral nerve
sheath tumors (neurofibrosarcomas);
rapidly growing often painful
neurofibroma can occur in adolescence
and adults (10%)
Rarely leukemia (CML)

Neurofibromas
Discrete cutaneous or subcutaneous
lesions can be removed surgically;
peripheral nerve sheath tumors
Surgery can be complicated by
bleeding and return of growth after
procedure
CO2 laser (scarring)
Can be severely disfiguring affecting
quality of life; most distressing aspect
of the disease for most individuals

Neurofibroma:Dermal vs.
Plexiform

Plexiform Neurofibroma
Surgical treatment of of plexiform
neurofibromas often unsatisfactory
(develop in 50%)
Radiotherapy contraindicated risk of
inducing malignant peripheral nerve
sheath tumor
Pirfenidone in phase II clinical trials
(antifibrotic agent)

Neuroimaging NF1
Controversy exists regarding the use of
routine MRI scanning of the brain in
asymptomatic individuals
Most proponents usefulness in finding
complications before they become clinically
evident
Those against; nonspecific findings and
clinical management based on symptoms,
regularly repeated MRIs add to cost and
patient family anxiety

Microdeletion disorders
22q11 deletion syndrome
Also known as velocardiofacial syndrome
(VCFS), DiGeorge syndrome (DGS)
Incidence 1/4000
Old acronym CATCH 22 : cardiac, abnormal
facies, thymic hypoplasia, clefts,
hypoparathyroidism (low Ca)
From haploinsufficiency of genes (deletion)
at 22q11.2 detected by array CGH or FISH
Increased risk of psychiatric disorders in
adolescents and adults

Background
VCFS originally described in 1978 by Dr.
Robert Shprintzen emphasis on facial
dysmorphology
DGS identified earlier in 1965 with
predominant T cell deficiency and heart
defects
Inherited as AD disorder from interstitial
deletions of chromosome 22q11/ 93%
sporadic

Major clinical
characteristics/phenotypes
cardiac malformation (74%) especially
conotruncal defects,TOF, IAA, VSD
Palate abnormalities (83%) cleft to VPI,
immune deficiency(mostly T-cell),
parathyroid deficiency with hypocalcemia
Typical facies: hypoplastic nasal alae
bulbous tip and prominent root,long face,
narrow paprebral fissures, small cupped
ears, long slender fingers
Other features tortuous vessels,growth
retardation,urinary anomalies, autoimmune
disorders

22q11 Deletion Syndrome

22q11 deletion

FISH diagnosis of 22q11

22q11 DS
hypotonia with developmental delays
common in infants and children
Learning disabilities common school
age children with predominance of
nonverbal LD
Schizophrenia (~15-20%), bipolar,
anxiety in adolescents and adults
Brain malformation can be present in
some including polymicrogyria

Polymicrogyria
Polymicrogyria (PMG) is
a developmental
malformation of the human
brain characterized by an
excessive number of small
convolutions (gyri) on the
surface of the brain.
Either the whole surface
(generalized) or parts of
the surface (focal) can be
affected.;
Bilateral generalized
polymicrogyria (BGP)Cognitive and motor delay
of variable severity,
seizures ; location can
affect what seen clinically

Skeletal Dysplasia
Achondroplasia
Autosomal Dominant FGFR3 mutation
Most common cause of dwarfism,
1/15,0000
Most cases (90%) are a cause of a de
novo mutation
Increased risk with advanced paternal
age (>35)
Frontal bossing, macrocephaly, trident
hands, lumbar lordosis, bowing of legs,
rhizomelic shortening of limbs

Achondroplasia

Achondroplasia
At risk for hydrocephalus (narrowing of
jugular foramina), brain stem
compression at the craniocervical
junction 10% (from narrowing of
foramen magnum) during infancy;
treatment decompression
Most are of normal intelligence,
although will have delayed motor
development (hypotonia,
hyperextensible joints)

MRI achondroplasia

Achondroplasia chronic issues

Mid face hypoplasia, dental crowding,
adenoidal hypertrophy contribute to
sleep apnea
Obesity, lumbar spinal stenosis from
exaggerated lumbar lordosis
Genu varum
Issues with social adjustment

Spinal stenosis

Fragile X Syndrome (MartinBell)

Most common cause of inherited mental
retardation in males
Affects 1/3600 males, females male
incidence~ 1/6000
Due trinucleotide expansion disorder
(sequence of 3 base pairs) in FMR1 gene
(Xq27.3) CGG
FMR1 gene expressed abundantly in neurons
Normal is 5 to 40 repeats
>58 repeats to 200 premutation carrier
>200 fragile X mutation, turns off gene,
decrease FMR protein (hypermethylation)

Fragile X location: Xq27.3

Fragile X
Premutation females: premature
ovarian failure
Premutation males: Fragile X tremor
ataxia (late onset cerebellar ataxia,
intension tremor, memory loss,
dementia); females occasionally
affected
Premutation may expand to full
mutation only in female meiotic
divisions (increased risk based on
length of repeat)

Fragile X

X-linked dominant

Fragile X
Moderate mental retardation in males; most
have normal lifespan
High rate of behavioral abnormalities: autism,
hyperactivity, hypersensitivity, poor eye contact
Females mild mental retardation to LD (depends
on X-activation pattern)
seizures
Connective tissue abnormalities:
hyperextensibility, flat feet, mitral valve prolapse
Potential for multiple affected in family tree