OB LE#7: PREMATURE RUPTURE OF MEMBRANE, GENETICS

PRELABOR RUPTURE OF MEMBRANES

Decidual activation - mediated by the fetal-decidual paracrine system and

through localized decreases in progesterone concentration.
Intrauterine bleeding or occult intrauterine infection.

The progesterone withdrawal theory stems from studies in sheep. As parturition

nears, the fetal-adrenal axis becomes more sensitive to adrenocorticotropic
hormone, increasing the secretion of cortisol (see Chap. 6, p. 157). Fetal cortisol
stimulates placental 17--hydroxylase activity, which decreases progesterone
secretion and increases estrogen production. The reversal in the
estrogen/progesterone ratio results in increased prostaglandin formation, which
initiates a cascade that culminates in labor. In human beings, serum progesterone
concentrations do not fall as labor approaches. Even so, because progesterone
antagonists such as RU486 initiate preterm labor and progestational agents prevent
preterm labor, decreased local progesterone concentrations may play a role.
Because intravenous oxytocin increases the frequency and intensity of uterine
contractions, oxytocin is assumed to play a part in labor initiation. But serum
concentrations of oxytocin do not rise before labor, and the clearance of oxytocin
remains constant. Accordingly, oxytocin is an unlikely initiator.
An important pathway leading to labor initiation implicates inammatory decidual
activation. At term, such activation seems to be mediated at least in part by the
fetal-decidual paracrine system and perhaps through localized decreases in
progesterone concentration. In many cases of early preterm labor, however, decidual
activation seems to arise in the con- text of intrauterine bleeding or occult
intrauterine infection.

Dr. Maria Anna Luisa L. Festin-Dalawangbayan, MD, FPOGS, FPSUOG

Objectives:

To be able to define Preterm Labor and Premature Rupture of Membranes

To be able to identify the risk factors in PROM

To be able to diagnose PROM

To be able to identify the risks of PROM to the mother and baby

To be able to review the management of patients with PROM

Definition of Terms

PRETERM LABOR
regular contractions before 37 weeks AOG associated with cervical
change

THREATENED PRETERM LABOR

criteria not meant but warrants active intervention

PRETERM BIRTH
birth before 37 week AOG or 259 days from the first day of last normal
LMP
EXTREMELY PRETERM: <28 weeks
VERY PRETERM: 28-32 weeks
MODERATE TO LATE PRETERM: 32-37 weeks
Cervical change of at least 2 cms and or with 80% effacement

PRETERM
neonate that has a function expected of a newborn with age of gestation
<37 weeks

PROM: rupture of membranes before onset of labor

PPROM: PROM before 37 weeks AOG

Prevalence

Prematurity
most common cause of perinatal and infant mortality

Leading cause of neonatal death after pneumonia

Worldwide estimate of 9.1% in Asia and 9.6% in US WHO 2010

Average 11.15% in 15 years - POGS

Reasons for Preterm Delivery

Direct Reasons
Delivery for maternal or fetal indications in which labor is induced or the
infant is delivered by prelabor cesarean delivery
Spontaneous unexplained preterm labor with intact membranes
Idiopathic preterm premature rupture of membranes (PPROM)
Twins and higher-order multifetal births

Medical and Obstetrical Indications

Placental Abruption most common
Pre-eclampsia
Fetal distress
Small for gestational age
Chronic hypertension
Placenta previa
Diabetes
Renal disease
Congenital malformation

PPROM
Intra-amnionic infection
Cigarette smoking
Prior preterm birth
Low socioeconomic status
Low body mass indexless than 19.8
Nutritional deciencies
Without risk factors

Multifetal gestations

Spontaneous
Progesterone withdrawal
the fetal-adrenal axis becomes more sensitive to
adrenocorticotropic hormone secretion of cortisol
stimulates placental 17- -hydroxylase activity - progesterone
secretion and estrogen production increased prostaglandin
formation
Oxytocin initiation: increases only in labor
By: Rem Alfelor

Contributing Factors

Threatened Abortion bleeding between 6-13 weeks with loss before 24 weeks

Lifestyle
Cigarette smoking
Inadequate maternal weight gain
Illicit drug use
Psychological factors: depression, anxiety and chronic stress

Race: Black, African-American, Afro-Caribbean

Work during pregnancy: long hours and hard prolonged

Genetic factors

Birth defects

Interval of pregnancy
Shorter than 18 months and longer than 59 months were associated with
increased risks for both preterm birth and small-for-gestational age
infants.

Threatened Abortion: bleeding between 6-13 weeks associated with subsequent

pregnancy loss prior to 24 weeks
Lifestyle: Prior preterm birth - first birth 35 weeks

Second birth <34 weeks

5%
<34 weeks
16%
1st and 2nd
<34 weeks
41%

Prior Preterm Birth

Infection
causes 25-40% of preterm birth
release of Interleukins and PGE uterine contractions release of
matrix degrading enzymes PROM

Infection: microorganisms elicit release of ILK and TNF stimulate prod of PGE
uterine contractions stimulate release of matrix degrading enzymes PROM

Bacterial Vaginosis
associated with spontaneous abortion, preterm labor, preterm rupture of
membranes, chorioamnionitis, and amnionic fluid infection
Caused by chronic stress, ethnic differences, and frequent or recent
douching
However, no current evidence supports screening and treating for
bacterial vaginosis
Normal, hydrogen peroxide-producing, lactobacillus-pre- dominant vaginal ora is
replaced with anaerobes that include Gardnerella vaginalis, Mobiluncus species,
and Mycoplasma hominis 25

Diagnosis

Gestational Age: >20 weeks <37 weeks

Uterine activity
regular frequent contractions that may result to cervical dilation and
effacement

Effects of uterine activity

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OB LE#7: PREMATURE RUPTURE OF MEMBRANE, GENETICS

cervical evaluation, biochemical markers (fetal fibronectin)

if (+) and cx is <2 - 26% deliver in 48 hours
if only one or neither test is (+) - risk is <7%

Cervical evaluation digital and by TVS

Biochemical markers- fetal fibronectin

Considered inaccurate predictors and only 10% actually go into labor within 7 days

Cervical evaluation
Digital: subjective
Ultrasound
Superior to clinical assessment and more reliable
Clinically predictive of preterm birth

Ultrasonography
Transabdominal
Transperineal
Transvaginal
reliable and reproducible
cervical length of 2.5 mm

sensitivity 76%

specificity 68%

PPV 20%

NPV 96%

Cervical evaluation digital subjective and differs between examiners and by TVS
Cervical length constant throughout pregnancy
Cervical length shortening is faster for patients with history of preterm birth so a
repeat evaluation may be useful
Biochemical markers- fetal fibronectin

Transabdominal: done full bladder so with associated lengthening of the cervix

Transperineal: not easily reproducible, only advisable if TVS is unacceptable or not
available
Stats: to identify preterm singleton birth at less than 34 weeks AOG
So TVS is preferred route for cervical assessment to identify women at increased
risk of preterm birth

Fetal Fibronectin
an extracellular matrix protein expressed during pregnancy located at
choriodecidual junction, uterus and placenta
50 ng/L detected in cervicovaginal fluid at 24-35 weeks AOG
associated with increased risk of preterm delivery
POGS: no evidence to support or refute its use

PRETERM PREMATURE RUPTURE OF MEMBRANES

Diagnosis of PPROM

History: vaginal leakage of fluid

Physical Examination
Speculum examination: pooling of fluid in posterior vaginal fornix

Ancillary Tests
Ultrasound: AFI, presenting part, Gestational age
pH testing: AF is alkaline (pH 7.1-7.3)
PPROM Risks (mother)

Antepartum
Infection
oligohydramnios
Preterm birth
Abruptio placenta
Psychosocial sequelae

Intrapartum
Increased cesarean delivery
Increased morbidity
By: Rem Alfelor

Postpartum
Endometritis
Retained Placenta
Postpartum hemorrhage
Psychological and Lactation problems

PPROM Risks (Neonate)

Prematurity

Infection

Cord compression

Fetal distress

Necrotizing enterocolitis

Intraventricular hemorrhage

Cerebral palsy and developmental delay

Management

Confirmation of PPROM

Avoid digital vaginal examination

Ultrasonography

Antibiotics
IV for 48 hours
Ampicillin 2 g q6 hours and
Erythromycin 250 mg q 6 hours
Oral (after IV)
Amoxicillin 250 mg 8 hours
Erythromycin 333 mg q 8 hours
Oral to complete 7 days in patients with PPROM being managed
expectantly

Corticosteroids given 24-34 weeks

Betamethasone 12 mg IM q24 hours x 2 days
Dexamethasone 6 mg IM q12 hours x 4 doses
Associated with a decrease in rated of RDS, NEC and IVH

Tocolytics
Not used routinely
only when clear benefits exist : transport to a tertiary hospital with a NICU;
to complete corticosteroid
Nifedipine And Atosiban: comparable effectiveness
Nifedipine

calcium channel blocker and preferred agent (POGS)

because of its efficacy and more acceptable side effects

suggested dose: initial dose of 20 mg then 10-20 mg 3-4x a

day
Atosiban: only tocolytic that is superior as maintenance therapy
Beta-adrenergic agonist
Magnesium Sulfate: neuroprotection
Associated with a decrease in rated of RDS, NEC and IVH

Fetal monitoring
Daily until delivery
Fetal well-being and growth

Monitoring of Maternal Infection

Primary indicator for the need to deliver
Clinical signs: fever, tachycardia, uterine tenderness, foul-smelling vaginal
discharge
Diagnostic tests: culture, serial increase in WBC and CRP

TERM
Delivery usually by induction
Group B streptococcal prophylaxis recommended
Pen G
5 mU IVLD then 2.6 mU q4 until delivery
Ampicillin
2 g IV initial dose, then 1 g q 4 until delivery

NEAR TERM (34-36 weeks): Same as for term

PRETERM (32-33 weeks)

Expectant management, unless fetal pulmonary maturity is documented
Group B streptococcus prophylaxis recommended
Corticosteroid
Antibiotics to prolong latency if there are no contraindications

PRETERM (24-31 weeks)

Expectant management
Group B streptococcus prophylaxis recommended
Single course corticosteroid
Tocolytics: no consensus
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OB LE#7: PREMATURE RUPTURE OF MEMBRANE, GENETICS

Antibiotics to prolong latency if there are no contraindications

LESS THAN 24 WEEKS
Patient counselling
Expectant management or induction
Group B streptococcus prophylaxis is not recommended
Corticosteroid not recommended
Antibiotics-incomplete data on use in prolonging latency

Prevention

Genetics
Natividad F. Generalao-Ko, M.D. FPOGS, FPSUOG

GENETICS: Study of genes, heredity, and the variation of inherited characteristics.

By definition genetics is the study of genes, heredity, and the variation of inherited
characteristics

Basic Concepts in Genetics:

Knowledge of the basic principles of genetics and an understanding of their

application are essential in current medical practice such as the etiology and
pathogenesis of human diseases which are genetic in origin, along with their
prediction and prevention.

These principles form the basis for screening, diagnosis, and management of
genetic disorders.
GENOMICS: study of how genes function and interact
GENES

The basic units of heredity

Are segments of deoxyribonucleic acid (DNA)

Reside on chromosomes in cell nuclei.

DNA is a double-stranded helical molecule. Each strand is a polymer of

nucleotides made up of three components:
Base
Purine: adenine [A] or guanine [G]
Pyrimidine: cytosine [C] or thymine [T]
5-carbon sugar
phosphodiesterase bond

DNA is a double-stranded helical molecule. Each strand is a polymer of nucleotides

made up of three components:
1)
a base, which is either a purine (adenine [A] or guanine [G]) or a pyrimidine
(cytosine [C] or thymine [T])
2)
a 5-carbon sugar
3)
a phosphodiester bond
Strands of the DNA helix run in an antiparallel fashion, adenine binding to thymine
and cytosine binding to guanine. These base pairs, in their nearly limitless
combinations, constitute the genetic code.

Genetic Disorder

Passed from parent to child.

Many conditions are unique to the mother while others are passed on from the
father.

Certain disorders are also more prevalent among different sexes and races.
1989 Human genome mapping project was started.
3-5% of all newborns have a recognizable birth defect and the causes are myriad and
frequently not identifiable.
Anomalies are increased in:

Spontaneous abortion
By: Rem Alfelor

Preterm
Stillborn infants
20-25% of congenital malformations are the result of:
chromosomal abnormalities
single-gene defects
65-75% of birth defects are from
unidentifiable causes
multifactorial inheritance
complex interaction between genetic predisposition and fetal
environmental factors
Note that in many cases early detection of many of these Genetic Disorders can
be lifesaving.

Etiology of human malformation during the first year of life:

1)
Genetic 10-25%
Chromosomal and single-gene defects.
2)
Fetal infections 3-5%
Cytomegalovirus, Syphilis, Rubella, Toxoplasmosis , others
3)
Maternal disease 4%
Diabetes Mellitus, Alcohol abuse, Seizure disorders, others
4)
Drugs and medications
5)
Unknown or multifactorial
46: normal or diploid number of human chromosome.
44: paired from 1-22.

Called the autosomes which are involved in the development and physiology
that do not involve sex determination.
2: sex chromosomes X & Y

X chromosomes contains many genes crucial to other aspect of development.

Y chromosomes carry only genes involved in the production of maleness.

Genetic
10-25%

Chromosomal and single-gene defect

50% of Spontaneous abortions are caused by:

1.
Turner Syndrome (45X)
Most common
One of the X chromosome is missing.
2.
Trisomy 16.
TURNER SYNDROME

1:2,500 female birth

Chromosomal condition related to x chromosome

Identified SHOX GENE that is missing which is important for bone development
and growth resulting in short stature and skeletal abnormalities.

Normal height in their 1st year of life then will have slow growth rate

Do not have usual grow spurt in their puberty

Non-functioning ovaries thus do not produce sex hormones (estrogen &

progesterone)

Wide neck (webbed neck)

Low or indistinct hairline

Broad chest and widely space nipples

Arms that turn out slightly at the elbow

Heart murmur associated with narrowing of the aorta high blood pressure.

Minor eye problems that can be corrected with glasses

Scoliosis

Endocrine problems like hypothyroidism, diabetes mellitus, osteoporosis,

infertility.
TRISOMY 16

Not compatible with life

Aberration or 3 copies at chromosome 16 rather than 2.

X-chromosomal monosomy
Source of cells for procedures & diagnosis:
1.
Peripheral blood
2.
Amniotic fluid
3.
Chorionic villi
4.
Bone marrow
5.
Skin
6.
Internal organs
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OB LE#7: PREMATURE RUPTURE OF MEMBRANE, GENETICS

Cell is cultured until adequate number of dividing cells is available for analysis Cells
are induced to divide Captured in the process of chromosome division Fixed,
Stained Analysis under light microscope Chromosomes from individual nuclei
are photograph Cut and arranged on a karyotype chart

Each chromosomes is identified by its specific pattern of banding following staining,

structural alteration

Staining Technique:
1)
Giemsa or G-banding: most common.
2)
C-banding: is useful for staining material near the centromeres
3)
NOR: banding use for staining satellites and stalks of acrocentric chromosomes

Each chromosome has its individual pattern corresponding to the dark and light
bands produced by staining.

The level of banding achieved is a measure of how well the chromosomes are
spread out and what regions can be identified.

400-500 moderate level of banding

Greater levels of banding allow for a greater detection rate of chromosomal

abnormalities

1)

2)

Each chromosome has its individual pattern corresponding to the dark and light bands
produced by staining.

Specific parts of a chromosome are identified by a combination of the following:

Chromosome number

Arm

Region (numbered from the centromere)

Band

Sub band

Deletions (del)
Refers to a portion of a chromosome that is missing and is caused by a
chromosome break either in the short or p arm long arm or q arm.
Occur spontaneously or may be the results of meiotic distribution of an
inheritance distribution, thus, chromosomal studies should always be
performed on parents of an infant found to have a chromosomal deletion.
recently, genetic conditions have been identified secondary to
microdeletion - deletions that was previously too small for detection using
FISH DNA probe like in Di George syndrome
Translocations
Rearrangement of material between chromosomes.
Clinically most significant type
They result when portion of 2 or more chromosomes have broken and
rejoined to form a new chromosomes.
This type may interfere with normal segregation of chromosome during
meiosis which may in turn have significant clinical implications.
2 Types of Translocation:
1.
Robertsonian

Always involves the acrocentric chromosomes, and, thought

to be caused by centric fusion after loss of the satellite region
of the short arms of the original acrocentric chromosomes.

It involves the entire long arms of the chromosomes.

E.g. clinical phenotype of Down syndrome.

3 Types of Chromosomes as To Their Position of the Centromere

Metacentric centromere near the middle

Acrocentric centromere at the tip

Sub-metacentric centromere between the tip and middle.

FISH: Fluorescence in Situ Hybridization

New technique that allows for the rapid identification of additional (trisomies) or
missing (deletions) chromosomal material.

Involves the use of a

fluorochrome-labeled
DNA probe that
hybridizes to a specific
chromosome region in
question.

E.g. Trisomy 18 the

chromosome 18 probe
would be expected to
show fluorescence
(hybridization) in three
separate
chromosomes.
3 Basic Categories Chromosomal abnormalities
1)
Numerical: number of chromosomes is either greater or less than 46.
2)
Structural: chromosomes is lost, gained, or rearranged. It could be single or
multiple.
3)
Mosaicism: 2 or more cytogenetically distinct cell lines are present in the same
individual.
Numerical number of chromosomes is either greater or less than 46.
a)
Aneuploidy
Chromosomes: < 46.
Cells do not contain abnormal multiple of 23 chromosomes
b)
Polyploidy
Chromosomes: > 46
Cells contain abnormal multiple of 23 chromosomes.
c)
Non-disjunction
Common cause
Uneven distribution of chromosomes at cell division
Occur during mitosis or meiosis
E.g. Trisomies 21, 18, 13
Structural Autosomal Abnormalities
By: Rem Alfelor

2.

Reciprocal Translocation

Can involve 2 or more non-homologous chromosome

Occur when there is breakage and reunion of portions of the

involved chromosomes to yield new products.

Carriers of balanced reciprocal translocations have 46

chromosomes, with both rearranged derivative unbalanced
meiotic product.

Trisomy 21

Trisomy 21 (47, +21): 94 %

Frequency of trisomy increases with increasing maternal age.

Robertsonian Translocation involving chromosome 21

Approx. 3-4 %, not related to maternal age.

Trisomy 21 Mosaicism (2 to 3 % case)

Incidence in 1 in 1000 pregnancy

Clinical Features
Head and neck
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OB LE#7: PREMATURE RUPTURE OF MEMBRANE, GENETICS

Brachycephaly
Up-slanting
palpebral fissures
Epicanthal folds
Brushfield spots
Flat nasal bridge
Folded or dysplastic
ears
Open mouth
Protruding tongue
Short neck
Excessive skin at
the nape of neck
Most common disorders are
Refractory error 35 to 76 percent
Strabismus 25 to 57 percent
Nystagmus 18 to 22 percent
Cataract occurs in 5 % of newborns.
Frequency increases with age

TRISOMY 21

Incidence 1:600-800

Incidence increases with maternal age

Characteristic facial features:

Upward-slanting palpebral fissures
Epicanthal folds
Flat nasal bridge
Brushfield spots

Major malformations
1% general population
Functional significance

TURNER: XO

Incidence 1:10000 females

Most conceptions result in miscarriage

Low fertility rate and high chance of chromosomal abnormalities in offspring

Estrogen replacement therapy

Webbed neck with low hairline

Shield chest with widespread nipples, abnormal ears, and micrognathia

Prominent lymphedema of hands and feet

Webbed neck, edema of hands/feet

Coarctation of the aorta

Triangular facies, short stature

Short stature, shield chest, wide-spaced nipples

Streak ovaries, absence of secondary sex characteristics

Chromosomal Disorders ANEUPLOIDY

Chromosomes: <46

Cells do not contain abnormal multiple of 23 chromosomes

Midline defect

Clenched hand with overlapping fingers

Postaxial polydactyly

Equinovarus deformity

Punched-out scalp lesions of Aplasia Cutis Congenita

TRISOMY 13 (PATAU)

Microphthalmia, coloboma, loose skin, rocker bottom feet, missing rib

Syndactyly or polydactyly

Cardiac dextroposition, ASD, PDA, VSD

Incidence 1:12000

5% survive first 6 months

Death usually by heart failure or infection

Prominent occiput and low-set, posteriorly rotated malformed auricles

Clenched hand showing typical pattern of overlapping fingers

Rocker-bottom feet
TRISOMY 18 (EDWARD)

Incidence 1:4000 live births

Males : females 1:3

5-10% survive first year

Death usually due to heart failure or pneumonia

Meckels diverticulum, horseshoe kidneys

Hypertonicity clenched fists and crossed legs, prominent occiput, 5th fingernail
hypoplasia, dorsiflexed short hallux

Short sternum, mental retardation

Bridged palmar crease: two transverse palmar creases are connected by a

diagonal line

Wide space between first and second toes

Short fifth finger

Small ears

Flat occiput

By: Rem Alfelor

Associated defects

Congenital heart defects

Mental retardation

Leukemia

Hearing loss, otitis media

Hirschsprung disease, duodenal atresia

Cataracts

Thyroid disease

Hip dislocation

Atlantoaxial instability/dislocation

KLINEFELTER: XXY

Incidence 1:1000

Prepubertal boys have normal phenotype

Diagnosis often made after puberty

Treatment: testosterone replacement

Relatively narrow shoulders

Increased carrying angle of arms

Female distribution of pubic hair and normal penis but with small scrotum due to
small testicular size

Small testes and penis

Gynecomastia

Microorchidism

Sterility/azoospermia

Gynecomastia

Normal-borderline IQ

Diminished facial hair

Lack of libido

Tall, eunuchoid body

Chromosomal Disorders: Deletions, Etc
CAT-EYE SYNDROME

extra chromosome from Chr. 22

Iris coloboma

Downslanting palpebral fissures, malformed pinna

Anal atresia

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OB LE#7: PREMATURE RUPTURE OF MEMBRANE, GENETICS

WOLF HIRSCHHORN (Del 4p)

Microcephaly, growth deficiency

Hypotonia, seizures, developmental delay

micrognathia, cleft palate/lip

hypospadias

ASD

Detectable by FISH

Greek warrior helmet appearance of nose and eyes

CRI DU CHAT (Del 5p)

Slow growth

Cat-like cry

Hypotonia, low IQ

Microcephaly

Single palmar crease

Hypertelorism

Deletion is of paternal origin in 80% of de novo cases

Multigene Sequence Disorders
DIGEORGE (Del 22q11)

Cardiac

Abnormal facies

Thymic Hypoplasia

Cleft palate

Hypocalcemia

Mild microcephaly

Cleft palate

Speech delay

Long tapering fingers

Emotional liability

T cell malfunction leads to fungal and viral infections

WILLIAMS (7q11.23)

Contiguous gene disorder involving elastin and other genes

FISH testing available

Ca restriction may be necessary

Short stature

Supravalvular Aortic Stenosis (SVAS)

Elfin-facies

Hypercalcemia

Developmental delay

Friendly personality (Cocktail Personality)

MILLER-DIEKER (17p13)
Lissencephaly (smooth brain)
Severe cognitive, developmental delay and seizures

Due to multiple mutations in multigenic sequence of 17p13.

Single Gene Disorders

Incidence 1:20,000

Abnormality in cholesterol biosynthesis due to single gene mutation: sterol delta7 reductase gene

Autosomal recessive

Cholesterol supplementation may be helpful

SMITH-LEMLI -OPITZ (11q12)

Anteverted nostrils

Low-set ears

Small chin

Clenched hand

Ambiguous genitalia (pts may also have hypospadias or cryptorchidism)

Failure to thrive

Low IQ

Microcephaly, ptosis, anteverted nostrils, micrognathia

Simian crease, syndactyly

Genital abnormalities (hypospadias, micropenis, bifid scrotum)

Renal anomalies, UPJ obstruction

MARFAN (15q21)

Mutations in fibrillin gene

By: Rem Alfelor

Disproportionate growth
Joint hyperextensibility
Lens dislocation
Dilation of the aortic root
Genetic testing is difficult
Arachnodactyly (both fingers and toes)
Clubbing due to associated cardiopulmonary problems
Flattening of the arch of his foot
Severe pectus carinatum
Significant kyphosis and joint contractures
Long arms
Marked hyperextensibility of the skin
Widened atrophic scars have thin papery texture
Hyperextensibility of the joints of the elbow and fingers

EHLERS DANLOS (2q31)

Defect in Type 3 Collagen

Autosomal dominant

Hyperelasticity

Hyperflexible, hypermobile joints

NEUROFIBROMATOSIS I (17q11)

Six or more caf au lait spots >5mm in diameter

2 or more Neurofibromas

Axillary or inguinal freckling

D2 or more LISCH NODULES (A)

benign iris hamartoma

Optic pathway tumor (B)

Bowing of bone structure

First degree relative with NF1

Mutation in Neurofibromin Gene

Abnormal peripheral nerve growth

Incidence of 1:4000

Autosomal dominant
TUBEROUS SCLEROSIS

Autosomal dominant

TSC1 gene (Chr. 9) or TSC2 gene (Chr. 16) are tumor suppressors

Seizures/MR/Adenoma Sebaceum

Seizures in early infancy correlate with later MR

Renal lesions (cysts, Angiomyolipomas)

CV: Rhabdomyomas

Retinal Hamartomas
ACHONDROPLASIA (4p16.3)

Mutation in the fibroblast growth Factor Receptor-3 Gene (FGFR3)

Autosomal dominant

Short-limb dwarfism

Frontal bossing, midface hypoplasia

Cranio-cervical junction problems

sometimes leading to Cord Compression or Hydrocephalus

Lumbar lordosis

Normal intelligence
RUBENSTEIN-TAYBI (16p13)

Deletion in the transcriptional regulator CREB binding protein

Developmental delay, feeding problems

Growth failure

Microcephaly, broad thumbs

Prominent nose, small chin2

25% detectable by FISH

Autosomal dominant with variable penetrance

Often with mental retardation

HOLT ORAM (12q2)

Autosomal dominant

Mutation in TBX1 gene

Marked variability in expression

Upper limb and shoulder defects:

Absent thumb, triphalangeal, or bifid
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OB LE#7: PREMATURE RUPTURE OF MEMBRANE, GENETICS

Syndactyly
Phocomelia
ASD alone, or VSD

Probably caused by mutations in the TBX gene unknown function

Long, wide, and protruding ears

Elongated face
Flattened nasal bridge
Macro-orchidism

FRAGILE X SYNDROME

Mutation of FMR1 gene on chromosome X (trinucleotide repeat expansion)

1:4000 males

Most present with MR

Trinucleotide expansion is unstable, making in the inheritance unpredictable.

Language and motor delays, hypotonia

Prominent ears, long face
Hyperextensible joints
Flat feet
High arched palate
Macroorchidism
Hyperactivity, autistic features

Uniparental Disomy
ANGELMAN

Seizures

Jerky, ataxic movements

Abnormal facies

Chromosome 15 deletion with maternal imprinting

Maxillary hypoplasia

Large mouth

Prognathism
PRADER-WILLI

Low tone

Large appetiteobesity

Hypogonadism

Developmental delay/MR

Chromosome 15 deletion, paternal imprinting

Marked obesity

Excess fat over the trunk, buttocks, and proximal extremities

Small hands (and feet)

Hypoplastic penis and scrotum

Genetics still poorly defined
NOONAN (12q24)

Autosomal dominant

Short stature

Congenital heart disease

Webbed neck

Downslanting palpebral fissures

Low set ears

Mild developmental delay

One form of Noonan syndrome, that which maps to 12q24.1, is due to mutations in PTPN11
(176876), a gene encoding the nonreceptor protein tyrosine phosphatase SHP2, which
contains 2 Src homology-2 (SH2) domains

CORNELIA DE LANGE (5p13)

Sporadically occurring

Severe growth retardation, limb anomalies

Congenital heart disease

Synophrys

Thin, downturned lips

Usually sporadic, autosomal dominant

Homologous gene in Fruitflies is known: Nipped B facilitates enhancer-promoter
communication upstream of the notch developmental pathway

Finely arched heavy eyebrows

Long eyelashes
Small upturned nose
Long smooth philtrum
Cupid's-bow mouth
Small hands

By: Rem Alfelor

Hypoplastic proximally placed thumb

Short fifth finger with mild clinodactyly

GOLDENHAR (14q32)

Vertebroauriculofacial Syndrome

Hemifacial microsomia

Ear anomalies, deafness

Epibulbar dermoid (fatty tumor of eye)

Vertebral anomalies (Chiari I)

MR or Normal intelligence

Most cases are sporadic, unclear whether this is autosomal dominant with variable
penetrance or autosomal recessive

KABUKI

Hypertelorism, long palpebral fissures, large pinnae

Developmental delay

Hearing loss

Possibly due to 8p deletion

Face: large ears, profused, with low implantation, hypertelorism, long eyelid cleft,
retrognatia, strabism

PIERRE ROBIN SEQUENCE

Glossoptosis, micrognathia, cleft palate

1:8500 live births

Airway and feeding problems

Unknown cause

Surgical treatment

Glossoptosis: a tongue which tens to ball up at the back of the mouth and fall back
towards the throat

Short palpebral fissures and ptosis

Low-set, dysplastic ears
Small chin
Choanal atresia necessitated tracheotomy
Prominent forehead
Hypertelorism
Narrow palpebral fissures
Hypoplasia of the right naris
Cupid's-bow mouth

CHARGE

Incidence 1:10,000

Coloboma

Heart

choanal Atresia

Retardation

Genital hypoplasia

Ear abnormalities, deafness

Facial features are not dysmorphic

Preaxial polydactyly of the thumb (which was associated with radial dysplasia)
VACTERL

Vertebral defects

imperforate Anus

Cardiac malformations (VSD)

TracheoEsophageal fistula

Renal anomalies

Limb (radial ray) anomalies

Short palpebral fissure length

Mild ptosis

Long simple philtrum

FETAL ALCOHOL SYNDROME

Short palpebral fissure length

Mild ptosis

Long simple philtrum

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