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Reproductive and Genetic Diseases

Dysfunctional Uterine Bleeding

Presentation Pathology
347191562.doc347191562.doc Proliferative pseudostratified glands w/
Dysfunctional uterine bleeding is abnormal uterine andsecondary
bleeding stromal breakdown (disordered
to ovulatory
and appear crowded due to stromal necrosis
dysfunction. Thus, specific pathologic processes such as polyps, carcinoma, exogenous
and collapse)
hormones, complications of pregnancy and postmenopausal bleeding are excluded.
Anovulation is the most common cause of dysfunctional bleeding.
- Anovulatory Cycles:
o Follicles develop but ovulation does not occur; follicles continue to produce
estrogen (since no ovulation, no LH surge or progesterone)
Estrogen withdrawal (endometrium outgrows structural support)
Estrogen breakthrough (estrogen levels fall)
- Luteal Phase abnormalities (inadequate progesterone so you have an abnormally short
menstrual cycle)
o Luteal phase defect
o Persistent corpus luteum (irregular shedding)
Diagnosis made w/ pelvic US and endometrial biopsy. This is a diagnosis of exlusion, thus
normal anatomy and normal endometrial biopsy.
Treat using IV conjugated estrogens, oral contraceptive pills, or MPA (medroxyprogesterone


Presentation Pathology
Pelvic pain Acute PMNs
Bleeding Chronic plasma cells

Endometritis (inflamed endometrium) is a histological diagnosis based on the finding of an

abnormal inflammatory cell infiltrate in the endometrium)

3 types:
1. Acute endometritis seen in the context of spontaneous abortion, delivery or medical
instrumentation ; post-partum.
2. Chronic endometritis due to PID , intrauterine contraceptive devices/actinomyces,
retained products of conception, TB (see chronic inflammatory cells + granulomatous
3. Pyometra secondary to cervical stenosis (puss filling endometrium cavity), from tumor
or scarring from surgical treatment of the cervix.
Reproductive and Genetic Diseases


Presentation Pathology
Pelvic pain, menorrhagia, dysmenorrhea Multiple chocolate cysts are present Can also
Infertility have unilocular cysts or inconspicuous
Endometrial glands and stroma in places they
should not be w/ hemosidderin laden

Endometriosis is endometrial glands and stroma in ectopic locations

Sites of involvement are: ovaries (most frequent), uterine ligament,s rectovaginal septum,
pelvic peritoneum, lapartomy scars, umbilicus, vagina, vulva, appendix
It affects women of reproductive ages and regresses following natural or artificial
Its incidence is unknown.
Theories of pathogenesis are the following: Tubal regurgitation (retrograde menstruation),
metaplasia of coelomic epithelium, lymphatic or hematogenous dissemination, direct
implantation during surgical procedures.
- infertility (30-40%)
- pelvic pain
- dysmenorrhea, menorrhagia
- pelvic adhesions
- malignancy: endometroid adenocarcinoma and clear cell adenocarcinoma may develop
in longstanding endometriosis

Endometrioma a cystic lesion in the ovary caused by endometriosis in the ovary

- endometrial epithelium lines the cyst
- there are numerous hemosiderin-laden macrophages present

Presentation Pathology
Abnormal bleeding and pain Gross markedly thickened (but not
nodular wall) w/ multiple tiny
hemorrhagic cysts
Histo -- glands and stroma extend deeply
into the myometirum
Adenomyosis is downgrowth of endometrial basalis into the myometrium
Occurs in 15-20% of uteri
Regresses after menopause
Reproductive and Genetic Diseases

Endometrial Polyp
Presentation Pathology
Abnormal bleeding (due to surface Most arise in the fundus; most are
ulceration or hemorrhagic infarction) solitary,
Histo core of polyp is composed of 1)
endometrial glands, usually cystically
dilated and hyperplasic 2) fibrous
stroma 3) thick-walled, coiled, dilated
bld vessels

Endometrial polyps are benign focal hyperplasia of the basalis. They occur in the
perimenopasual period and are virtually unknown prior to menarche. They are thought
to arsie from endometrial foci that are hypersensitive to estrogen stimulation or
unresponsive to progesterone.
They are not preneoplastic

Endometrial Hyperplasia
Presentation Pathology
Simple few dilated glands w/ non-
complex budding and no evidence of
Complex pseudostratified proliferative
appearance; more glands than stroma
Atypia cytologic atypia: epithelial cells
have round nuclei w/ nucleoli.

Endometrial hyperplasia refers to a spectrum that ranges from simple glandular crowding
to conspicuous proliferation of atypical glands, which are difficult to distinguish from
early carcinoma.
Usually are due to unopposed estrogen. May result from anovulatory cycles, polycystic
ovary syndrome, an estrogen producing tumor or obesity
- simple hyperplasia w/out atypia: proportionate increase in glands and stroma
- complex hyperplasia w/out atypia: increase in glands greater than stroma
- atypical hyperplasia: simple or complex w/ cytologic atypia
Risk of progression to carcinoma:
- simple hyperplasia 1% over 10-15 years
- complex hyperplasia - 3% over 10-15 years
- atypical hyperplasia 25-35% over 4-5 years
Reproductive and Genetic Diseases

Endometrial Adenocarcinoma
Presentation Pathology
In peri or postmenopausal women Gross ragged and thickened
Abnormal bleeding, (90%) endometrial lining.
Endometroid crowded, back to back
glands w/ cytological atypia. epithelium
have a proliferative appearance
Serous papillary w/ high grade
cytologic features. Nuclear
Endometrial adenocarcinoma is the most common invasive cancer of the female genital
tract. 4th most common cancer in women. It accounts for 6% of all cancers in women.
Most paitents present at an early stage b/c of the warning sign of bleeding.
Histologic types:
- endometroid (most common, 80%)
- serous
o serous intraepithelial carcinoma is the in situ phase of serous carcinoma
which is rarely found prior to the development of invasive disease
o lymph invasion w/ serous carcinoma
- clear cell
Type 1 Type 2
Unopposed estrogen Present absent
Patient Younger and heavier Older and thinner
Menopausal status Pre and peri Post
Hyperplasia Present Absent (atrophy)
grade low high
Myometrial invasion Minimal (less Deep (more aggressive)
subtypes endometroid Serous and clear cell
Behavior Stable progresisve
genes MSI, ras, PTEN P53
Risk Factors:
- increasing age
- exogenous estrogen (unopposed estrogen increases risk 10 fold)
- menstrual factors (late menopause and early menarche)
- nulliparity (2x the risk; infertility, anovulation, high serum levels of androstenedione,
lack of monthly menses)
- polycystic ovary disease
- estrogen producing tumors
- endometrial hyperplasia
- tamoxifen
- obesity (results from adipose cells aromatase-mediated conversion of androstenedione
to estrone)
- diabetes
- genetic (DNA mismatch repair genes HNPCC)
Protective factors: OCPs smoking, multiparity, ovulation and progestin therapy
Reproductive and Genetic Diseases

Prognositc Factors
- stage (extent of disease) depth of myometrial invasion, +/- peritoneal washings,
nodal status, distant metastasis
- grade differentiaion
- histologic subtype endometroid (favorable), serous and clear cell (unfavorable)
- steroid receptors: tumor + for estrogen and progesterone receptors has a better

Recurrence of endometrial cancer usually happens in the first 3 years. Most will be
symptomatic w/ abnormal bleeding. It is very rare to cure distant recurrences. 50% vaginal
recurrences cured .

The 5 year survival is good b/c most present at an early stage. However, if present at a late
stage then prognosis is not good.

Treatment Other
- Surgery Diagnosis is made via
o Total abdominal - endometrial biopsy
hysterectomy - D&C
o Bilateral salpingo- - Transvaginal US
o Cytology (peritoneal Who needs a biopsy?
washings) - postmenopausal bleeding
o Lymph node dissection - postmenopausal pyometria (purulent
- radiation therapy (for stage I and II discharge from cervix b/c PID is
has no impact on distant mets!!) unlikely)
- chemotherapy - postmenopausal women w/
- hormonal therapy endometrial cells on pap
Likes to spread to pelvic and then peri- - perimenopasual intermenstrual
aortic lymph nodes bleeding
Surgical staging: - premenopausal abnormal bleeding
- stage I: uterus w/ history of anovulation
- stage II: cervix - thickened endometrial stripe
- stage III: abdomen (tubes, ovaries,
nodes) or vagina

Other Endometrial malignancies:

- endometrial stromal sarcoma malignant tumor of the endometrial stromal cells; rare
- carcinosarcoma tumor w/ mixed carcinoma and sarcoma elements; poor
prognosis; tumor of elderly women (postmenopausal)
Reproductive and Genetic Diseases

Leiomyoma or fibroid
Presentation Pathology
Most occur in women older than 30, rare Gross well circumscribed white tan firm
before 20, and most regress after menopause mass w/ whorled appearance w/out capsule
Bleeding, pain (esp if undergo torsion) Histo bland smooth muscle
Can cause infertility
Leiomyoma is a benign tumor of smooth muscle in the uterus. It is the most common
neoplasm of the uterus affecting 25% of women of reproductive age.
it is hormonally responsive/dependent (estrogen promotes their growth) . Often multiple
Malignant transformation is rare or absent
They can be intramural (embedded in the myometrium), submucosal (close to the
endometrium), subserosal (beneath the serosa covering) or pedunculated.
Treatment they may require surgicical removal for bleeding or infertility

Leiomyosarcoma malignant, solitary lesion a rare myometrial malignancy. These do not

always arise from a leiomyomas. Suspect this if the leiomyomas is soft, shows areas of
necrosis on gross examination, has irregular borders (invasion into neighboring myometrium),
or does not bulge above the surface when cut. Histologically, it shows mitotic activity,
cellular atypia, and geographical necrosis.
These are highly malignant and 5 year survival is about 40%. They metastasize widely and
tend to recur after removal.

Abnormal Uterine Bleeding: Nature of the Lesion

- Dysfunctional
o Anovulatory cycles
o Luteal phase (luteal phase defect or persistent corpus luteum)
- Atrophy
- Complications of pregnancy
o Abortion
o Ectopic pregnancy
o Gestational trophoblastic disease
- Inflammation
o Acute: retained POC
o Chronic: PID, IUD, retained POC, TB
o Pyometra : cervical carcinoma, post irradiation, congential, post cervical cone
- Organic lesions
o Benign tumors and growths
Polyps: endometrial or endocervical
o Endometiral hyperplasia
- Malignant tumors
o Endometrial carcinoma
o Cervical carcinoma
Reproductive and Genetic Diseases

o Sarcoma
- Other
o Exogenous hormones
o Clotting disroders

Abnormal Uterine Bleeding: Age Group

- newborn maternal estrogens
- childhood
o iatrogenic (trauma, FB, infection)
o Precocious puberty
o Vaginal neoplasms
- Adolescence
o Complications of pregnancy
- Reproductive years
o Complications of pregnancy
o Organic lesions: endometritis, leiomyomas, polyps, hyperplasia, cracinoma
- Perimenopause
o Organic lesions : polyps, hyperplasia, carcinoma
- Postmenopause
o Atrophy
o Organic lesions : polyps, hyperplasia, carcinoma
Reproductive and Genetic Diseases

Pelvic Inflammatory Disease

Presentation Pathology
Pelvic pain, dysmenorrheal, fever Acute salpingitis -- Numerous neutrophils
Menstrual abnormalities w/in tube lumen
Acute abodomen Chronic salpingitis
Gross: markedly dilated, club-like
fallopian tubes
histo: plicae fused forming separate
channels in the lumen
Actinomyces can see organisms
surrounded by neutrophils; seen in both
salpingitis and endometritis

Pelvic Inflammatory Disease (PID) is an ascending infection beginning in the vulva, vagina or
cervix that spreads upward to involve all structures of the female genital tract and potentially
other pelvic organs to varying degrees
Causes of PID:
- polymicorbial: most infections
- N gonorrhea: most common single agent, upward migration from mucinous glands to
eventually involve the tubo-ovarian region
- Other bacteria: E. coli, Staph, Strep, Clostridium: spread via lympahtics or vascular
channels following surgical procedures
- Chlamydia
- Mycoplasma
- Actinomyces (associated w/ IUDs)

- infertility from tubal scarring
- ectopic pregnancy
- tubo-ovarian abscess
- peritonitis
- intestinal obstruction from adhesions
- bacteremia

Tubo-ovarian complex

Salpingiits inflammation of the tube, usually occurs as a consequence of PID

Acute: neutrophils, edema and congestion of mucosal folds (plicae)
Chronic: lymphocytes and plasma cells (common cause of ectopic pregnancy)
Diagnosis quickly and give antibiotic therapy
Reproductive and Genetic Diseases

Ectopic Pregnancy
Presentation Pathology
Pelvic pain w/ or w/out menstrual Resembles placenta increta or placenta
irregularity percreta of the uterus

Ectopic Pregnancy refers to implanation outside the endometrium. Over 95% occur in the
fallopian tube.
Pre-disposing factors: anything that alters the normal structure and function of the fallopian
tube: PID, prior pelvic surgery, endometriosis
Complications are rupture and hemorrhage

Diagnoses is via hCG levels and an ultrasound

Surgery or chemotherapeutic intervention
Use of methotrexate terminates ectopic pregnancy and is used when the conceptus is
smaller than 4 cm.

Fallopian Tube Tumors:

- Primary tumors are rare
- Adenomatoid tumor: benign tumor of mesothelial origin
- Malignant tumors are Adenocarcinomas similar to those seen in the ovary
- Metastases or implants from ovarian or endometrial tumors are far more common
than primary tumors
Reproductive and Genetic Diseases

Cystic Lesions of the Ovary (benign serous cystadenoma)

Presentation Pathology
Asymptomatic Fluid filled cysts; unilocular, can be single or
Occur at any age up to menopause multiple, unilateral or bilateral

Cystic lesions of the ovary are the most common cause of enlarged ovaries. Most airse from
ovarian follicles.
Follicle cysts are thin-walled, fluid filled structures that are lined internally by granulose cells
and externally by a layer of theca interna cells. lined by cuboidal epithelium w/out atypia
If the cyst persists, the hormonal output can cause precocious puberty in a child and menstrual
irregularities in an adult
Rupture of the cyst can lead to intraperitoneal bleeding

Surface epithelial inclusion cysts: small cysts formed from involution of surface epithelium
Functional cysts: follicular and corpus luteal cysts
Reproductive and Genetic Diseases

Polycystic Ovary Syndrome (stein-leventhal syndrome)

Presentation Pathology
3rd decade w/ a history of premenarcheal Gross - Multiple, small subcortical cysts
obesity, secondary amenorrhea or surface is smooth (absence of ovulation),
oligomenorreha, infertility and hirsutism cortex is thickened. Ovaries are enlarged
Unopposed estrogen may result in Histo numerous follicles in early stages of
menometorrhagia, endometrial hyperplasia development, follicular atresia, increased
or carcinoma stroma. The cysts are lined w/ granulosa
theca cells
Oligomenorrhea perimenarchial onset
Hirsutism later onset, gradual progression
Obesity (50-75)
Insulin resistance (compensatory Stein-leventhal syndrome secondary
hypersinulinemia, diabetes, impaired glucose amenorrhea, obesity, hirutism, infertility,
tolerance, fasting glucose/insulin ratio) bilaterally enlarged, polycystic ovaries

Polycystic Ovary disease describes: 1) clinical manifestations related to the secretion of

excess androgenic hormones (inappropriate gonadoptropin secretion and hyperandrogenemia)
2) persistent anovulation (increased peripheral conversion of androgens to estrogens) and 3)
ovaries containing many small subcapsular cysts. This occurs in YOUNG women
This affects 3.5-7% of the female population
- young women
- persistent anovulation
- increased LH secretion
- infertility
- oligomenorrhea
- hirsutism
- obesity
- endometrial hyperplasia/carcinoma (Due to unopposed estrogen)
Increased ovarian production of androgens act locally to cause premature follciular atresia,
multiple follicular cysts, persistent anovulatory state, and decreased progesterone. Excess
androgens are also converted to estrogens in peripheral adipose tissue. The long-term effects
of unopposed estrogen are endometrial hyperplasia/carcinoma

Diagnostic criteria:
- chronic anovulation, hyperandrogenism (acne, hirsutism, hyperandrogenemia),
Ultrasound (string of pearls) , and must exclude other related disorders such as non-
classical congenital adrenal hyperplasia.
- testosterone (to exclude androgen producing neoplasm): if it is 200 ng/dl (androgen
producing neoplasm), then do a transvaginal US or adrenal CT/MRI
- 17 hydroxyprogesterone (to exclude nonclassical CAH): if it is 2 ng/ml then do an
ACTH stimulation test
- 24 hour urinary free cortisol (to exclude Cushings) : if signs and symptoms raise
significant suspicion.
Reproductive and Genetic Diseases

Treatment: wedge resection (remove the cysts and the theca cells) will restore normal menses
Ovary Neoplasms: 3 categories:
and fertility
Presentation Pathology
Most are asymptomatic in early stages
Urinary frequency or constipation as tumor
compresses pelvic structures, vaginal bleeding
Distention, bloating, pressure, pain, early satiety
as tumor/fluid fills abdomen
b/c ovarian cancer symptoms are common to so
many benign disease processes, by the time
ovarian cancer is diagnosed it it is usually at
an advanced stage!!!

Ovarian Cancer is 6% of all cancer mortalities in women leading cause of death from GYN
malignancy. It is a silent killer tends to present at high stage, thus is cause of of deaths
related to tumor of the female genital tract. 80% of ovarian tumors are benign
Risk Factors:
- Old age
- Nulliparity
- Family hx of ovarian or breast cancer
- Infertility
- Family history
- ovulation/ovulatory drugs and talc do not cause ovarian cancer
Protective Factors:
- Breast feeding
- Oral contraceptives (50% reduction in ovarian cancer in women to take the pill for 6+
- Pregnancy
- Tubal ligation
Prognostic factors:
- Stage-extent of disease at presentation (most important)
o Carcinomas have tendency to implant in the peritoneal cavity and omentum
and spread by lymphatic dissemination to lymph nodes
- Histologic type of tumor
o Serous and clear cell are poor pronogis types
- Grade of tumordegree of differentiation
- Amount of residual tumor following surgical debulking
Molecular Origins of ovarian carcinoma
- Sporadic
o Activation of oncogenes: c-myc, K-ras, HER2/neu
o Inactivation of tumor suppressor genes: p53, p16
o Aneuploidy
- Hereditary
o 5-10% of ovarian cancers develop in women w/ a familial susceptibility to
ovarian and/or breast cancer
o Germline mutations in DNA repair genes
o BRCA 1 (chromosome 17) and BRCA (chromosome 13)
Reproductive and Genetic Diseases

There are 3 main types:

1. surface epithelial neoplasms (60% of tumors) these tumors of the ovary increase in
incidence w/ the number of ovulations, thus OCP and pregnancy reduce risk)
a. serous serous cystadenocarcinom--- w/ psammoma bodies (lamellated purple
calcifications) usually bilateral
b. mucinous (most mucinous tumrs are benign) mucin appears gray w/in cell
cytoplasm w/ solid gross appearance composed of noncilated columnar
mucus secreting cells, unilateral
c. endometroid (most are malignant)
d. clear cell (most are malignant) can be solid or cystic
e. Brenner/transitional rare, most are benign
f. Undifferentiated
2. sex-cord stromal neoplasms may be functioning neoplasm producing hormones such
as estrogen or androgens
a. fibroma/thecoma uniformly solid white mass composed of bland spindle
i. Meig syndrome triad of ovarian fibroma, hydrothorax, and ascites
b. granulosa cell tumor solid, lobulated gross appearance w/ multiple Call-
Exner bodies formed by cell degeneration and nuclear grooves
i. call-exner bodies, usually estrogen secreting so associated w/
endometrial hyperplasia and carcinoma and breast cancer.
c. sertoli-leydig cell tumor produce masculination, anovulation, and sterility
d. steroid (lipid-cell) tumor
3. germ cell neoplasms composed to a number of histologically different tumors
derived from the primitive germ cells of the embryonic gonad. In kids and
adolescents, more than 60% of ovarian neoplasms are of germ cell origin, and 1/3 are
malignant. In adults, the great majority (95%) of germ cell tumors are benign mature
cystic teratomas (Dermoid cysts)
a. teratoma : mature (benign) vs immature (malignant)
i. immature teratoma has grossly solid appearance w/ necrosis and
hemorrhage and hiso has primitive neuroepithelial rosettes
1. fast growing and invasive the more immature the cells and
the more neuroepithelium, the higher the grade and the worse
the prognosis
ii. mature teratomas (dermoid cysts) benign and are filled w/ keratin
and hair. Tx is w/ surgery
1. gross: unilateral, small, unilocular cyst
2. hito: structures derived from 3 germ layers endoderm,
ectoderm, mesoderm
b. dysgerminoma analgous to testicular seminoma. Composed of sheets of
large cells w/ clear cytoplasm. These are very radiosensitive
c. yolk sac tumor (endodermal sinus) - solid mass w/ hemorrhage and
necrosis w/ Schiller-Duval Bodies. Hyaline droplets contain AFP
i. Produce alpha fetoprotein
ii. Rapid growing and aggressive surgery and chemo
d. choriocarcinoma produce hCG and are widely metastatic
4. Unclassified
5. Metastatic: from colon, gastric (called Krukenberg tumor has signet ring cells;
bilateral mucin-producing adenocarcinoma ), pancreas, appendix, breast (lobular
carcinoma). Mets tumor may mimic primary ovarian neoplasms, both clinically and
Reproductive and Genetic Diseases

Serous/endometrois --------Ca125
Mucinous --------------------CEA
Yolk sac tumor --------------AFP
Choriocarcinoma -------------hCG
Tumor markers ::
- CA125 is an antigenic determinant on a glycoprotein shed into the bloodstream by
malignant cells derived from coelomic epithelium. Serum levels of CA125 are
increased in about 80% of patients with epithelial ovarian cancers, more frequently in
patients with non-mucinous histologic types. Levels of CA125 are also increased in
patients with endometrial and pancreatic cancer.
- CA125 may be increased in patients with benign conditions, including endometriosis
and uterine leiomyoma; in patients with pelvic inflammatory disease (PID), in early
pregnancy, and with benign ovarian cysts; and in patients with cirrhosis and
CA125 is most useful in monitoring response to therapy and detecting recurrent disease

Treatment Other
First line treatment: Debulking
surgery/staging chemo (platinum + taxol) Diagnosis:
every 3 wks for 6 cycles) second look - Pelvic exam
- Pelvic US
- CA-125 but there is really no good
Debulking surgery goal: optimal debulking
screening tests
of patient at primary surgery
o You can get False positive
- Optimal debulking: no residual tumor
remaining 2 cm following surgery
- Sub-optimal debulkin: residual tumor
remaining 2 cm following surgery
Surgery options:
- Total abdominal hysterectomy Hepatitis
- Bilateral salpingo-oophorectomy CHF
- Peritoneal samping and washings Cirrhosis
- Omentectomy and nodal dissection
- Removal of all visible tumor
Second line treatment: ovarian cancer
recurrence other chemo? Hormonal tx?
Internal debulking surgery? Radiation?
- Stage I: ovaries
- Stage II: pelvic extension
- Stage III: abdominal implants or
lymph node spread
- Stage IV: distant mets
Reproductive and Genetic Diseases

Surface Epithelial Tumors:

- Cystadenoma: benign, cystic w/ smooth cyst wall; can be multilocular or unilocular
o Lining is non-stratified serous epithelium
- Tumors of low malignant potential: LMP, borderline, atypically proliferating: cystic w/
internal nodules/excrescences. Almost all behave in benign fashion can be serous or
- Cystadenocarinoma: malignant, cystic and solid or solid

Ovarian Neoplasm Review

Tumor Clincal Features Pathology
Tumors of Surface Eptihelium
- serous cysadenoma
- borderline serous tumor - usually benign - unilateral
- serous adenocarcinoma - adenexal mass, - 25% bilateral
moderately aggressive
Mucinous - most common - Bilateral
- mucinous cystadenoma malignant ovarian
- borderline mucinous tumor
- mucinous - benign - Unilateral
- Moderately aggressive - Multiloculated cysts
Endometroid carcinoma
Clear cell adenocarcinoma - Malignant - Hemorrhagic/necrotic
Brenner tumor
- Malignant
- rare, malignant - Glandular structures
- rare, benign - Solid or cystic
- unilateral
Germ Cell Tumor
- mature (dermoid cyst) - benign - unilateral, mix of
- immature - rare, invasive - immature tissues
Dysgerminoma - rare, radiosensitive - unilateral
Endodermal sinus tumor - rare, produces AFP - hemorrhagic, necrotic
(yolk sac)
Choriocarcinoma - Elevated hCG - oftem metastatic
Sex Cord Stromal Tumor
Granulosa theca cell - produces estrogens or - unilateral
Fibroma - meig sydrome - unilarteral
Sertoli-leydig - Masculinizing in some - unilateral
Gonadoblastoma - rare - immature
Reproductive and Genetic Diseases

sertoli/granulosa cells


The indications for evaluation of amenorrhea are:

- no period by 14 in absence of growth or development of secondary sex characteristics
- no period by 16, regardless of growth, development or presence of secondary sex
- absence of period for 6 months
The requirements for a normal menses in women is an intact, functional HPO axis, a
functional uterus, and a patent outflow tract. Disruptions in any of these can result in
amenorrhea. (input from the envt CNS GnRH release from hypothalamus FSH and
LH release from pituitary E and P release from ovary which causes the uterus to have
menses and does negative feedback to the hypothalamus and pituitary

Amenorrhea due to abnormal genital anatomy:

- absent vagina/cervix
o imperforate hymen
no obvious vaginal orifice
thin bulging, blue perineal membrane
fluctuant pelvic mass
o mullerian agenesis
absent vagina, absent/rudimentary uterus
46 XX w/ normal ovaries so normal secondary sexual development
o transverse vaginal septum/cervical atresia
blind vaginal pouch
46 XX w/ normal ovaries and normal secondary sexual development
Cryptomenorrhea (outflow obstruction)
o androgen insensitivity syndrome
blind vaginal pouch
46 XY but with a female phenotype
Sparse/absent pubic hair b/c are not sensitive to androgens
Inguinal/abdominal testes b/c genotypically male
Normal male T levels , high FSH and LH
o Asherman syndrome (endometrium is denuded and the endometrial cavity is
filled w/ adhesions
Strong suspicion based on history
Uterine curettage: retained products of conception or
IUD related infection or severe PID
Genital TB, schistosomiasis
Reproductive and Genetic Diseases

If you have normal genitalia- then do a basic endocrine evaluation w/ TSH, FSH, and
- TSH evaluation:
o High TSH with low Free T4 = hypothyroid, or normal free T4 = subclinical
hypothyroidism ---- both have thyroid auto-antibodies
o Low TSH and with high free T4 or normal T4 with high free T3 = hyperthyroid.
o If have low TSH and low free T4 get an MRI
o Normal TSH levels are euthyroid
- Prolactin evaluation
o High prolactin do hypothalamic-pit imaging. If it is normal then you have a
hypothalamic dysfunction. If it is abnormal then you either have
hypothalamic/pit tumor or empty sella syndrome
o Hyperprolactinemia
There is a strong association of high prolactin levels w/ menstrual
disorders b/c the high prolactin levels disrupt the pulsatile hypothalamic
GnRH release. Oligo/amenorrhea is the most common (common cause
of secondary amenorrhea or short luteal phase polymenorrhea)
Galactorrhea is only found in 1/3 w/ hyperprolactinemia b/c breast milk
production has numerous requirements, like estrogen.
Prolactin secreting pituitary adenomas
Other pituitary/hypothalamic tumors
Drugs phenothiazines, reserpine, benzos, butyrophenones,
amphetamines, opiates, TCAs, metaclopramide
Hypothyroidism (high FSH levels stimulate prolactin secretion)
Exogenous estrogens (OCP)
Lung/renal tumors, renal failure
- FSH evaluation:
o High FSH ovarian failure
Premature ovarian failure most common
Due to early follicular depletion, genetic predisposition (sex
chromosome abnl or point mutation in FSH receptor gene),
radiation/chemo, autoimmune dz
Do a karyotype on 30 yrs or younger. If the karyotype is normal
then they have premature menopause and do an autoimmune
screen. If the karyotype is abnormal gonadal dysgenesis
o Karyotype excludes Y chromosome- risk for germ cell
tumors (30% w/ Y chrom will not virilize
o Exceptions to doing a karyotype is if you are over 30
(b/c tumors are virtually unknown so consider it
premature menopause) and if you have a hx of pelvic
radiation or chemo
Do autoimmune screen if karyotype is nl: Ca, P, TSH, free T4,
ANA, CBC, fasting glucose, 24 hr urinary free cortisol
Gonadal dysgenesis 1o amenorrhea
Single gonadotropin deficiency rare
Resistant ovary syndrome rare
Galactosemia rare
Reproductive and Genetic Diseases

o Low or normal FSH hypothalamic/pit dysfunction

Polycystic ovary syndrome (see other chart)
Hypoathalamic amenorrhea
Secondary amenorrhea
o Emotional stress
o Weight loss (dieting)
o Poor nutrition (eating disorders, chronic illness)
o Regular strenuous exercise (endurance training)
Low or nl body weight
Poorly estrogenized
Evaluation of estrogen status
o Clinical sign/symptom: cervical mucus (helpful but
unreliable), hot flashes (not generally present)
o Estradiol (easy, insexpensive, unreliable due to erractic
o Progestin challenge test MPA or P in oil, only fair
correlation w/ estrogen status
Diagnosis of exlusion - normal MRI
It is a psychobiologic response to life events where reproduction
is suspended to support essential metabolic functions. Decreased
hypothalamic GnRH secretion is final common pathway
Pituitary tumors
- prolactin producing
- non-functioning
- ACTH-producing (ACTH and 24 h urinary cortisol)
- GH producing (Acromegaly) GH during OGTT, IGF-1
Empty Sella Syndrome:
- congenital defect in sellar diaphragm
- extension of subarachnoid space into sella
- results from surgery, radiation, tumor infarction
- benign condition, not progressive
Reproductive and Genetic Diseases

Abnormal Uterine Bleeding

Presentation Pathology
Oligomenorrhea: 35 days interval 6 mo Uterine abnl gross: enlarged (myomas),
Polymenorrhea: regular intervals 21 days irregular (myomas), soft (pregnancy or
Menorrhagia: regular intervals 7 days or adneomysosi) or tenderness (endometritisis)
Metrorraghia: irregular intervals 7 days or
80 ml in volume

The differential for abnormal uterine bleeding is the following:

- ovulatory dysfunction
o anovulation; endometrial growth excessive due to constant stimulation,
increased density of abnormal vessels with fragile support structure (prone to
rupture, lacking stromal support). Endometrial shedding is focal, asynchronous.
Thythmic vasoconstriction is absent (tissue loss and repair is focal and
superficial). Normal mechanisms of coagulation and hemostasis do not operate
- complications of pregnancy
o threatened/incomplete abortion
o ectopic pregnancy
o gestational trophoblastic disease
o retained products of conception
- benign uterine neoplasia
o endometrial polyp
o submucous myoma
- reproductive tract malignancy
- bleeding disorders Von Willebrands or thrombocytopenia
- Inflammatory dz : acute or chronic endometritis
- Lower genital tract lesions
o Vagina; atrophy or ulcers
o Cervix: polyps, ulcers, or masses

Indications for evaluation:

- irregular, unpredictable menses
- 25 days intermenstrual intervals 35 days
- Menstrual flow 7 days duration
- Excessvily heavy flow ( 80ml) or interference w/ daily activities or associated w/
anxiety or concern
Exclude pregnancy via history or pregnancy test
Identify anemia, thrombocytopenia via CBC
Assess ovulatory function menstrual history , timed serum progesterone, endometrial biopsy
Indications for an endometrial biopsy;
- age 40 yrs
- history of chronic anovulation
- confusing/suspicious history
Reproductive and Genetic Diseases

- use cyclic progestin for anovulation, when no contraception is needed and when there
is no suspicion for anatomical abnormality
- use OCP for oligo-ovulation when contraception is needed
- for acute episodes of dysfunctional uterine bleeding do OCP taper
- for hypoestrogenism causing anovulation where there is a thin, inactive endoemtirum
do not give progestin. Make sure you give estrogen.
- If the biopsy yields minimal tissue or an attenuated endometrium (stripe 4 mm) then
give estrogen first and then progestin
- For breakthrough bleeding give OCP or supplemental estrogen. Or progestin

Differential diagnosis:
- uterine myomas
- endometrial polyps
- bleeding disorders
- medical: evaluation reveals no cavitary lesion
o NSAIDS (reduces flow by 20%)
o OCP reduces volume/duration by inducing a decifualized, inactive
o Depot MPA 80% amenorrehiec by 1 year
o LNG-IUS (merina) reduces volume/duration in 75-90%
- surgical: cavitary lesions (submucous myoma, polyp) or failed medical
- Uterine imaging via US or hysteroscopy
- Endometrial biopsy if older than 40
- Coagulopathy screen for adolescents, suspicious personal/family hx, or unexplained
Reproductive and Genetic Diseases

Benign Breast Diseases

Benign Breast diseases are a heterogenous group of lesions that may represent a palpable
mass, nonpalpable abnormality on imaging, or an incidental microscopic finding
two goals in the pathologic evaluation of a benign breast biopsy:
1. distinguish benign from insitu and invasive tumors
2. assess the risk of subsequent breast cancer associated with the lesion identified.
Components in the workup of a breast problem are the
- Hx of chief complaint onset, duration, changes over time, associated symptoms
such as pain, skin change, nipple inversion, discharge, fevers, trauma
- reproductive factors menarche, LMP, pregnancies/age of first live birth, OCP vs
HRT use
- associated factors family hx (1st degree relatives mom, sister, daughter), radiation
exposure (such as for tx of Hodgkins dz), prior breast biopsy, weight change, diet
(caffeine and high saturated fat, salty foods), past medical history for diabetes,
immunocompromised (lupus, fibromyalgia, HIV).
- imaging studies
- clinical breast exam.
Classification of benign dz is necessary to stratify for risk of future cancer:
1. Nonproliferative lesions no increased risk (unless family hx)
a. Cysts
b. Papillary apocrine change
c. Epithelial calcifications seen on radiograph
d. Mild hyperplasia usual type
2. Proliferative lesions w/out atypia risk is 1.5-2x
a. Moderate/florid hyperplasias
b. Intraductal papillomas (nipple discharge)
c. Sclerosing adenosis
d. Radial scar (radiographic finding)
e. Fibroadenomas
3. atypical hyperplasias risk is 3.3-5x. if have both then 6.8x defined as proliferative
lesions that possess some, but not all features of carcinoma insitu
a. Atypical ductal hyperplasia
b. Atypical lobular hyperplasia
Factors modifying breast cancer risk w/ women w/ benign dz:
- family history (first degree relatives)
- time since biopsy (if biopsy is benign and has been over 15 years than normal risk,
but if biopsy revealed ADH or ALH then its increased for many years)
- menopausal status
- laterality of risk
- consistency of histolofic classification (pathologists classify things differently by
looking at them)
Reproductive and Genetic Diseases

Cystic Masses Fibrocystic disease (cystic hyperplasi)

Presentation Pathology
Perimenopausal women Fibrosis unilateral, not premalignant, dense rubbery mass,
(younger) increase in stromal tissue
Cysts wax/wane - Cystic Disease predispose to malignancy, multifocal and
Tender and lumpy breasts bilateral; cysts are nodular and firm and filled w/ serous fluid
Hormonal changes and maybe hemorrhagic. Cysts are lined w/
cuboidal/columar or flated epithelium and have papillary
Sclerosing adenosis not premalignant, unilateral and focal
and causes ill-defined firm area. Glandular patterns and nests
of cells in a fibrous stroma
This develops during reproductive life and represents a distortion of the normal breast changes
associated with the menstrual cycle. It is thought to be due to high estrogen levels.
Cystic masses result from lobular involution and the acini degenerate into microcysts that then exp
Imaging depends on age: Aspiration or core biopsy, Surgical biopsy, and into larger masses.

Medications bromocriptine, danzal, alleve
Supplements Vit E and B6

Solid Masses
False negative rate for mammography is 10-20% (mammography cannot catch everything)
Dominant noncystic masses under 40 is common. The incidence of breast cancer under 30 is
2.5% so it can happen if you feel something clinically and the mammogram and US are clear
DONT STOP- continue to monitor the patient b/c they can still have caner.
Imaging Studies for solid masses:
- Mammography
- Ultrasound used as an adjunct
- MRI of breast used in evaluating abnormal breast. Not helpful in benign cystic
Diagnostic Studies:
- core biopsy to determine histology not perfect b/c there is sampling error. Make sure
your results from the mammogram correlate w/ the results from the biopsy. If it does not
then do a surgical biopsy.
- followup management based on pathology

Differential for solid masses:

- fibroadenoma (most common) - lipoma
- adenoma - PASH (pseudoangiomatous stromal hyperplasia_
- radial scar - Leiomyoma
- granular cell tumor - hamartoma
- fibromatosis - hematoma
- vascular lesions (hemangiomas): rule out angiosarcomas
Reproductive and Genetic Diseases

Presentation: Pathology:
Mobile (not adherent to skin) , round, Gross: small, freely movable, round and
nonpainful encapsulated w/ grey-white cut surface
Shows menstrual variation Histo: glandular epithelial-lined spaces w/ a
Increased growth during pregnancy fibroblastic stroma. Network of ducts w/in a
proliferated, edematous stroma

Fibroadenomas are the most common benign solid masses. are pseudo-encapsulated
demarked, ovoid. They are mobile and multilobulated. They are present in women of
reproductive age, usually before 30 and may be related to increased estrogen sensitivity.
There are different kinds, such as:
- complex
- juvenile
- giant/phyllodes rapid growth can be malignant
If you leave fibroadenomas alone, they can infarct and become calcified
Imagining is based on age. You can do a core biopsy

Surgical excision
Only remove if they are growing or over


Nipple adenomas can present w/ bloody

Adenomas are well-circumsciribed tumors of benign epithelium elements w/ sparse

stroma. These are benign solid mass tumors.
There are three types: tubular, lactating, nipple (papillomas)
Nipple adenomas can present w/ bloody discharge

Differential for Benign Reactive Inflammatory lesions of the breast:

- mammary duct ectasia/periductal mastitis
- granulomatous mastitis
- Fat necrosis (simulates breast cancer clinically; hemorrhage indurated fat
cavitation necrosis subsequent inflammatory reaction)
- Mondors disease: phlebitis of the breast: thoracodorsal vein is traumatized
Reproductive and Genetic Diseases

- Diabetic Mastopathy: autoimmune, painful mass development w/ fibrotic

nodularity Looks like cancer clinically and diagnosed clinically do not do a core
Mammary Duct Ectasia / Periductal mastitis plasma cell mastitis
Presentation Pathology:
Perimenopasual Dilated, thick walls, fibrotic stroma,
Pain, nipple inversion, greenish rupture, leakage of pasty secretion into
discharge, redness, swelling around the surrounding tissue inflammation and
areola fat necrosis . usually unilateral

Mammary duct ectasia-periductal mastitis is a benign reactive inflammatory lesion of

the breast. It is characterized by dilated ducts and starts as a nipple disorder.
Do not send off the nipple discharge to cytology b/c will not help w/ differential. You
do not care that the discharge is green, but you worry if there is blood b/c it could be
Skin fixation, nipple retraction and axillary lymphadenopathy distinguish from
Medications (pain +/- antibiotics)
Surgical duct excision

Acute masitits

Fissures in nipples during early pregnancy or from skin disorders may predispose to bacterial
infection of the breast usually by Staph aureus or Strep. It is usually unilateral, with pus in the
ducts. Necrosis may also occur. Antibiotics and surgical drainage may be adequate therapy, but
necrosis and subsequent fibrosis of a localized area of breast tissue may occur.

Granulomatous Mastitis
Presentation: Pathology:
Firm, tender nodules Capsule formation, varying fibrosis and
inflammatory changes

Granulomatous Mastitis is another benign reactive inflammatory lesion of the breast.

It is thought to be an immune response

Surgical excision
Reproductive and Genetic Diseases

Nipple Disorders
- Nipple inversion/retraction congenital vs acquired (duct ectasia, mastitis, CA, TB)
- Pagets disease vs spongiotic dermatitis: both present with scaly irritated nipple areolar.
Thus start off with a steroid cream and if no response after 1 week it is pagets dz and
do a skin punch biopsy
Nipple discharge:
- 95% benign etiology: hormonal papilloma
- Worrisome if unilateral, single duct, spontaneous or bloody
- Age of patient is an important distinguishing variable a predictor for malignancy. As
your age increases, higher likelihood it is malignant
- Management: do a QUIAC (to check for blood) NOT a cytology. Also, surgical duct
excision or meds/supplements

- cellulitis w/ or w/out abscess formation
o at risk: overweight, large breasted, previous surgery, radiation, sebaceous cysts
o staph aureus is the most common
- Hyradenitis
o Involves distribution of sweat glands in axillae, inrammaotry folds, groins
o At risk: more common in smokers and AA women
o Symptoms: extensive, painful boils
o Management: chronic antibiotics, surgical excision, aggressive local hygiene

Nonlactional Infections:
- periareolar: younger women, smokers: 50% recurrence rate
- mammary duct fistula: most common after I&D, can be spontaneous
- peripheral nonlactional abscess: less common, associated w/ diabetes, RA, steroid RX,
- tuberculosis: rare in western cultures, presents as acute abscess w/ sinus tract from axilla.

Lactational infections:
- most common during first 6 months during breastfeeing
- symptoms: pain, swelling, tenderness, cracked nipple/abrasion, fever, chills
- manage w/ antiobiotics (dicloxillin, flucloaxillin, augmentin, erythromycin, clindamycine).
o Tetracycline, cipro, and chloremphenicol should NOT be used
- Continue breast feeding unless Post I&D w/ general anesthesia

Breast pain/ Mastalgia:

- most common symptoms associated w/ FBD
- cyclic vs noncylci assessment
- etiology: hormonal dysfcn, xanthines, saturated fate diets, stress
Reproductive and Genetic Diseases

- treatment: lifestyle modifications, dietary and vit supplements, NSAIDs, hormonal

therapies, prescription meds

Breast Cancer
Most present w/ local, early stage dz that is curable.
6% present w/ metastatic dz (and is more common in AA women than Caucasian) and
symptoms bone , lung, and chest wall/skin. HER2 + in brain

Breast carcinoma is the most common malignancy of women in the US. It is the second most
common cause of cancer mortality in women (after lung cancer). 1 in 8 will get breast cancer
and 1/3 of women w/ breast cancer will die. Regular risk is 8-10% (not if have history)
Risk factors for the development of breast cancer:
- Genetic
o Family hx of breast cancer esp in 1st degree relatives (mom, daughter, sister).
Risk is greatest if the relative has bilateral dz or is affected at a young age.
o BRCA1 gene on 17q21 (breast/ovarian)
85% lifetime risk of breast cancer
By age 50, breast cancer has developed in and may be responsible for
up to of inherited breast cancers (10% of all cancers)
Increased risk of ovarian and colon cancers
o BRCA2 gene on 13q (breast women and men)
Responsible for up to 70% of inherited breast cancer not due to BRCA1
30-40% lifetime risk
o High penetration: BRCA1 and 2, p53, ATM, PTEN, NBS1, LKB1
o Low penetration: polymorphism
- Hormonal proliferation and/or differentiation of cycling breast epithelium
o Early menarche and late menopause (more time for estrogen)
o Nulliparity
o Late age at 1st term pregnancy
o OCP use and HRT
o High Mammographic breast density
o Lack of breast feeding
o Longer interval b/w births, longer interval b/w menarche and first birth
- Environmental
o Industrialized countries (USA and western countries) - (alcohol, high fat diet,
xenoestrogens, phytoestrogens, physical inactivity, decreased parity, parity at
later age, obesity post menopause, folate deficiency, night work, flavenoids,
deodarnt use, fertility drugs, smoking, pesticide exposure, PBBs, dairy
- Radiation
o Environmental radiation exposure or radiation exposure for Hodgkins dz in
young women ionizing radiation exposure in childhood
o Increased risk when exposure is at a young young but little increase in risk when
age is 40 indicates that the risk is greatest to the developing and hormonally
cycling breast
- proliferative fibrocystic change
o non-proliferative fibrocystic change NO increased risk
o proliferative fibrocystic change 1.5-2X increased risk
o proliferative fibrocystic change w/ atypia (ADH or ALH) 4-6X increased risk
o carcinoma in situ (ductal or lobular) 8-10X increased risk
- history of previous breast cancer
Reproductive and Genetic Diseases

Protective factors:
- oophorectomy age 35
- early age at first pregnancy, more children, breast feeding for extended time
- pre-menopausal obesity (obesity pre-menopause is protective but post-menopause is

- The most commonly occurring cancer among women and the second as a cause of cancer
death in women
- over the last 2 decades, the annual incidence has been increasing in the US and
- mortality rates have fallen world-wide, faster in developed countries (w/ greatest
decrease in women under 50)
- incidence rates are higher in developed countries and are higher in urban areas and higher
in NE
- for women over 40 it is higher in whites, but in women under 40 it is higher in blacks
- risk increases as you get older
- migrant studies have shown that first and second generation US Chinese women have
higher rates of incidence than Chinese women in china
Why these trends?
- Incidence trends - inherent genetic differences, differences in data completeness, lifestyle
factors, access to healthcare, screening and diagnosic services, access to better tx
- Mortality trends age distribution differences in populations, stage at diagnosis and
Prevention via exercise, diet, reproductive choices

Screening for Breast Cancer mammography has reduced breast cancer mortality as well as
allowed earlier more successful treatment
Does screening fit criteria for population screening?
- breast cancer is prevalent in the populaton
- it has an early detection phase
- it is acceptable (though not inexpensive)
- treatment is available for early detected cancers
- screening reduces mortality a 30% reduction in mortality for women 50-69 regularly
screened and a 10-20% reduction for women 40-49.
Start screening annually for women starting at age 40 yearly mammography + yearly
clinical breast exam. It does not detect all breast cancers but does reduce mortality. Lesions
detected early are more likely to be cured! It is more difficult in patients w/ denser breasts and
younger patients
MRI is used in high risk patients
Ultrasound is not a standard screening tool, but is useful to evaluate lumps and abnl on
- performance of mammorgraphy is equal in black and white women but the cancer
characteristics are different
o black women had higher grade, larger, more advanced tumors
o black women have a higher proportion of tumors that are ER and PR -
Reproductive and Genetic Diseases

Breast Cancer Staging:

- stating stratifies patients for therapy, it is useful for assessing patients, nad makes
comparison of outcome and trends possible.
- TNM classification:
o tumor size (T) size is the one of most significant prognostic variable
increasing tumor size decreased survival and increased # of axillary
lymph nodes involved by mets
o regional axillary lymph nodes MOST impt prognostic factor
higher # of + nodes worse prognosis
60% will have axillary LN
We can stage the axilla w/ less than a full dissection (clinical exam is
inaccurate) and we can identify the first draining lymph node (sentinel
Sentinel node is not always the closest node and is not always in
the lower axilla (level 1)
o metastases
common sites: non-regional lymph nodes, bone, lung, pleura, liver, skin,
lobular carcinoma may mets to unusual sites gynecologic or GI tract
- Multifocal and multicentric disease
o Multifocal: 1 tumor focus in same quadrant
o Multicentric: tumor foci in different quadrants
Major Prognostic Markers of Breast Carcinoma
- Clinical Stage: TNM
- Histologic grade (well, mod, poorly differentiated)
- Histologic subtupe (ductal and lobular are worse prognosis and tubular and colloid/mucinous are
better prognosis)
- Steroid hormone receptor status: ER/PR + is good prognosis longer dz-free survival, better
overall survivial and longer survival after recurrence.
o Predicts response to Tamoxifen (anti-estrogen)
o Test w/ immunohistochemisty or FISH (gold std)
- Oncogene expression: HER2 gene + is worse prognosis (shorter dz free interval following tx,
decreased survival)
o HER2/neu shartes sequence homology w/ EGFR.
o It is amplified in 15-25% of cancers.
o Predicts response to Herceptin
- Tumor gene expression profiling (in early stages)

Breast Cancer is more than one disease

- luminal: ER+ or PR+
- HER2+: ER- HER2-
- Basal: ER- , HER2+
Atypical ductal hyperplasia (ADH)
- benign overgrowth of the cells that line either the ducts or the lobules
- 4-5X higher risk of breast cancer than general population
- 8-20% risk of cancer w/in 5 yrs, depending on family Hx
Lobular Carcinoma in situ (LCIS)
- abnormal growth in milk-making glands, does not invade wall of lobules
- is not a precursor but a marker for 6-7x higher risk of cancer
Ductal Carcinoma in situ (DCIS)
- most common type of noninvasive breast cancer
- confined to ducts, not invading into the fatty tissue
- often associated w/ invasive cancer, and is a precursor lesion
Infiltrating (invasive) carcinoma (IDC and ILC)
- invades through the ducts, into the fatty tissue of the breast
- 80% are ductal, 10% lobular, 10% are various subtypes (tubular, mucinous)
Reproductive and Genetic Diseases

- determine the sentinel lymph node via radioactive technetium-labeled sulfur colloid and
isosulfan blue then submit it to path and immunohistocehmistry for cytokeratin. If the
SLN is negative, no further surgery required. If the SLN is positive then completion of
the axillary node dissection is performed: (complete removal of the axillary LN is not
longer the tx)
- Axillary lymph node dissection - causes arm edema, increased risk of infection, nerve
injury, winged scapula, rare is the development of angiosarcoma in the setting of long-
term lymphedema (high grade sarcoma w/ rapid spread and dismal prognosis)
- Metastatic work-up = CT scan of chest, ab, and pelvis + bone scan (not necessary if small
tumor and few/no + LN
- Brain CT or MRI only in symptomatic patients
- Most patients you do a conservative therapy of lumpetctomy + radiation =
o Contraindications for breast conserving therapy: large tumor, multiple widely
separated tumors, skin involvement
o Radiation daily therapy of external beam x 5-r wks
SE- fatigue, skin changes/burns, potential damage to heart, lungs, bone
- Systemic therapy for early breast cancer
o Estimate risk of recurrence based on known prognostic factors: LN status***,
tumor size, lympathic vascular invasion, histologic grade hormone receptor
status, HER-2/neu status, patient age.
o Oncotype Dx evalutes the expression level of 17 genes in the tumor and
generates a recurrence score that predicts prognosis better than above and it can
help estimate the risk and decision for future therapy
Adjuvant treatment treatment to prevent relapse
- Hormonal ( 75% of breast cancers are hormone receptor +) only effective for cancers
that are either ER + or PR + or both; strongly + ER and PR benefit the most
o Tamoxifen (if ER+) reduces by 50%
Pre-menopausal women
Selective estrogen receptor modulator that blocks the effects of estrogen
at tumor estrogen receptors.
Acts like estrogen in bones (builds bones) and in uterus endometrium
(increase risk of uterine cancer), and lipids.
SE: hot flashes, nausea, fatigue, vaginal discharge, cataractsserious are
thromboembolism, stroke, uterine cancer
- Chemo
o Polycehmoterhapy reduces the risk of recurrence in early breast cancer by 30-
o Combined tamoxifen + chemo is better than either alone!
o Benefit in ER/PR+ may be due to the indirect endocrine effect b/c chemo causes
ovarian suppression and induction of menopause
o In hormone receptor negative patients, chemo is the only means to reduce the
risk of recurrence!
Reproductive and Genetic Diseases

o CMF = cyclophosphamide, methotrexate, 5-Flourouracil and AC = adriamycin

and cyclophosphamide are 1st-2nd generation
Adriamycin a topiosomerase II inhibitor and DNA intercalating agent
that causes strand breask in DNA
SE: myelosuppresion, N/V, mucositis, alopecia,
Rare risk of leukemia and dose dependent risk of cardiac toxicity
Cyclophosphamide an alkylating agent binds to DNA and forms cross-
links that prevent cell replication and cause cell death
SE: myelosuppresoin, N/V
Rare toxicities of hemorrhagic cystitis and SIADH
o Do it every 3 weeks X 4 cycles or dose dense therapy w/ AC + taxol
- Ovarian Suppression
o Bilateral oopherectomy or radiotherapy or ablation or medically by Gn-RH
agonists (goserelin or leuprolide)
Pre-menopausal women, ER+
- Aromatase inhibitors (post-menopausal, ER+)
o Anastrozole, letrozole, exemestane
o post-menopausal women, where estrogen is produced from the conversion of
androgens in peripheral tissues by enzyme aromatase
o AIs do not block estrogen from the ovary and thus are inappropriate for pre-
menopasual women.
o SE worry about osteoporosis b/c not making any estrogen
- Herceptin (trastuzumab)
o Recombinant humanized monoclonal anti-HER2 antibody
o Inhibits growth of breast cancer cells that overexpress c-erbB-2.
o Enchances tumoricidal effects of chemotherapy
o Good SE profile, rare risk of CHF
o Role model drug for targeted therapy of malignancies
- Neoadjuvant therapy pre-operative chemo
o Allows immediate tx of microscopic distant dz in advanced cases
o Allows assessment of response to therapy
o Provides additional prognostic info
o Allows increase % of patients w/ large tumors to have option of breast
conserving lumpectomy
o NO difference b/w pre-operative chemo and post-op chemo in terms of dz free of
overall survival .
Long-term SE of adjuvant therapy
- persistent complications from chemo: fatigue, ovarian failure w/ menopausal symptoms,
neuropathy, cognitive dysfunction, weight gain, psychological distress, sexual dysfxn
- late complications of chemo: increased risk of leukemia, osteoporosis from premature
ovarian failure, increase risk of cardiac dysfxn due to antrhacyclines
- persisent complications of hormonal therapy: hot flashes/menopausal symptoms, sexual
dysfxn, muscle aches, psychological distress
- tamoxifen: increased risk of thromboembolic events, stroke, uterine cancer
- AIs: increase risk of osteoprosis and fracture
Recommendations for Surveillance post cancer:
- annual mammography and periodic Hx and physical
- annual clinical breast exam and annual pelvic exam
- monthly breast self-exam
- breast MRI in high risk patients
NOT recommended tumor markers, CT , CXR, bone scan, liver US, routine CBC
Reproductive and Genetic Diseases

Metastatic Dz
- presents w/ symptoms and is incurable w/ a median survival of 2 years
- poor prognostic factors: age 50, ER - , HER2 +, presence of visceral dz, short dz free
interval from initial diagnosis and tx
- skeletal dz as 1st site of mets is more likely in ER+ and has better prognosis than
presentation w/ visceral dz.
- Tx:
o Goals are to improve survival and maintain QOL b/c incurable; use local therpay
only for pallation
o HR + - treat w/ hormone therapy first. Following progression ,then treat w/ other
hormonal therpay or chemo.
o HR and organ failure due to visceral dz treat w/ chemo first.
o HER2 + - treat w/ herceptin containing regimen
o Combo therapy yields higher response rates but no difference in survival.
o Use one drug at a time unless impending organ failure
o Bevacizumab (avastin) humanized monoclonal antibody against vascular
endothelial growth factor (VEGF)
o Bisphosphonates inhibit osteoclast acitivty leading to improved bone mass
and mineralization b/c many get bone mets that cause pain and fractures.
- CNS mets tx is palliative
o surgery or radiosurgery for few brain mets and whole brain radiation for multiple
brain mets. Efficacy is limited.
o Corticosteroids give short term palliation by decreasing vasogenic edema
o Leptomeningeal dz presents as HA, CN defects, - can respond to intrathecal

Breast Cancer during Pregnancy:

- rare: 1 in 3,000
- there is an increased risk of BC during pregnancy but a long-term protective effect
- prognosis maybe worse and cancer may be more aggressive.
- Chemo can be given safely after 1st trimester but hormonally and XRT should be delayed
until delivery .
- Herceptin may be safe.
- No evidence that pregnancy after breast cancer hurts OS, may help
Reproductive and Genetic Diseases

Ductal Carcinoma In Situ (DCIS)

Presentation Pathology
Does NOT present as a palpable Carcinoma cells present but confined to the ducts and
mass. lobules. No involvement/invasion of breast stroma
If it presents as a mass- its high- Gross comedo type: necrosis (white chalky areas)
grade and a large lesion
Mammogram: suspicious linear Comedo (high-grade) grade 3 (of 3) nuclei w/ central
and branching calcifications necorsis w/ associated microcalcifications

Non-comedo can be solid (carcinoma fills and distends

the duct), cribiform (rigid cartwheel glandular pattern),
micropapillary (micropapillary tufts that emanate from a
single epithelail cell layer) or papillary (intraductal
proliferation w/ fibrocasvular support0

Ductal carcinoma in situ means that it is confined to the ductal tree (not invasive).
Thus, it does not show invasion through the myoepithelial layer and basement
membrane lining the ducts and lobules.
DCIS is the precursor lesion to invasive carcinoma! DICS usually originates in the
terminal duct lobular unit .
The likelihood of developing recurrent DCIS or an invasive carcinoma varies with the
- histologic subtype/grade of DCIS
- extent of disease (size)
- distance of tumor to the margins of excision
The most common method of detection is by suspicious calcifications on
mammography that are biopsied by stereotactic core biopsy or needle-localized
excisional biopsy.
There are two types of DCIS comedo (higher grade and more aggressive) and non-
comedo (many different patterns)

Treatment: prognosis is favorable Other

Surgically excise (utilizes anatomic distribution
of the involved segment to best obtain negative
margins) radiology + anatomy = good excision
w/ clear margins. If not clear margins, go back
and excise some more!!!!
If ER+ then give anti-estrogen after surgery
Mastectomy or lumpectomy + radiation
Reproductive and Genetic Diseases

Lobular Carcinoma In Situ (LCIS)

Presentation Pathology:
Monotonous cell population w/ low nuclear
Lobular acini fill and distend w/ uniform cell
Lobular carcinoma in situ is a proliferation of neoplastic cells w/in breast lobules which
usually fill and variable distend the lobules, and may extend into adjacent ducts.
LCIS is considered a risk factor for invasive cancer in both breasts.
LCIS is NOT a precursor lesion to cancer and thus LCIS is not re-excised when present at a
surgical margin.

Infiltrating Ductal Carcinoma (NOS) (invasive carcinoma of the breast)

Presentation Pathology
Firm, palpable mass Gross: firm, pale gray/white, gritty, often stellate
Skin dimpling (from traction on Coopers Histo: infiltrating ducts w/in breast stroma.
ligament) or nipple retraction Variable degrees of differentiation (1-3) based on
Mammogram: stellate lesion +/- degree of tubule formation, nuclear grade, and
calcifications mitotic rate
Desmoplastic stromal response (reactive fibrosis)
Infiltrating ductal carcinoma (NOS) is the most common form of breast cancer. The
precursor lesion to it is DCIS. It is characterized by invasive malignant glands infiltrating
the breast stroma.
A mammogram shows a stellate (speculated) density w/ or w/out calcifications
Reproductive and Genetic Diseases

Infiltrating Lobular Carcinoma (invasive breast carcinoma)

Presentation Pathology:
May or may not have mass Gross: solid mass but maybe completely
No desmoplastic response so hard to see undetectable
and feel clinically and mammogram Histo: linear, single cells or targetoid
occult pattern of malignant cells, low nuclear
grade, minimum mitotic activity
NO desmoplastic response

Infiltrating Lobular Carcinoma is the second most common form of invasive breast
cancer. Because it does not create a reactive desmoplastic response in the tissue, it may
be clinically and mammographically occult. It also tends to be larger than clinically
estimated preoperatively.
It has an increased propensity to be multicenteric (involve more than one part of the
breast) and to be bilateral (affect both breasts). It also has the propensity to metastasize
to unusual sites, such as the gynecologic and GI tract.
It has the same prognosis (comparable survival) as infiltrating ductal carcinoma, when
matched, stage for stage!
It is usually ER+/PR+ , CerbB-2/HER2
It usually has single cells invading the stroma, thus it is hard to see on low power. You
can do a positive cytokertain stain to confirm the epithelial nature of the lobular

Subtypes of Invasive Carcinoma of the breast

1. Mucinous (Colloid) carcinoma:
a. Older women
b. Malignant cells floating in pools of mucin
c. Good prognosis (better than invasive ductal or lobular carcinoma). It
grows slowly and is ER+ so responds well to treatment
2. Tubular Carcinoma
a. Younger women
b. Well-differentiated (low grade), charactierzied by haphazardly arranged
c. Excellent prognosis

Carcinoma of the Male Breast

Carcinoma of the male breast is 1% of all breast cancers. The most common is infiltrating
ductal carcinoma . It tends to present at a more advanced stage because there is less fat and
breast tissue so it involves the chest wall earlier. It has a similar prognosis when matched,
stage for stage, with female breast cancer. It is associated with the inherited BRCA2
Reproductive and Genetic Diseases

Inflammatory Carcinoma
Presentation Pathology:
Erythema and induration of the skin Inflammatory changes = Peau dorange: dimpling
of involved skin due to retraction caused by
lymphatic movt and obstruction
Histo dermal lymphatic spaces have tumor cells
Inflammatory Carcinoma is an invasive carcinoma involving superficial dermal lymphatic
spaces and is associated with characteristic skin changes. It has a very poor prognosis!
If you are unsure if you are dealing with inflammatory carcinoma or cellulites, then do a
punch biopsy and if you see tumor cells invading the lympathic spaces then you have
inflammatory carcinoma
Aggressive tx is necessary
No breast conservation

Pagets Disease
Presentation Pathology
Skin erythema, scaling, ulceration Malignant cells in small nests or singly w/
abundant pale cytoplasm and atypical
nuclei infiltrating the skin epidermis

Pagets disease is epidermal involvement of the nipple or areola by malignant cells, singly
or in small nests. It is almost always (95%) associated with an underlying in situ or
invasive carcinoma.

Reproductive and Genetic Diseases

Phyllodes Tumor (Cystosarcoma Phyllodes)

Presentation Pathology
Discrete, solitary, circumscribed, firm mass Gross: 4-5 cm, circumscribed, firm gray-
Large size ( 4cm) and/or hx of rapid white tissue w/ visible clefts. Funcating or
growth favors phyllodes over a ulcerated irregular mass
fibroadenoma Histo: biphasic glandular (benign) and
45 years (15 yrs older than fibroadenoma stromal (malignant) proliferation
Leaf-like processes
Low grade vs high grade based on
cytologic atypia, mitotic activity,m stromal
overgrowth, and infiltrative border

Phyllodes tumor is a biphasic (epithelial and stroma) tumor with risk for local
recurrence or metastasis.
The classification of grade (low vs high) reflects the probability of local recurrence and
- low grade: low ( 5%) risk of metastasis, but likely ( 25%) to locally recur if
not adequately excised
- high grade: high (25%) risk of metastasis, and high (25%) incidence of local
recurrence (behaves like a sarcoma)
Local recurrence is not required prior to metastaisis.
It mestatasis to the lungs, bone, heart (via vascular invasion-hematogenous spread)

Complete exisicion to prevent local

Intraductal Papilloma
Intraductal papilloma is a solitary lesion w/in a duct or cyust and is most common in
women 20-50 years of age. It may present w/ nipple discharge (serous or bloody), nipple
retraction, or a small subareolar mass.
Gross small lesion usually close to the nipple in major ducts. Sessile or peduncualted
Histo multiple papillae
A single intraductal papilloma are benign but multiple papillomas are associated w/ an
increased risk of cancer.
Reproductive and Genetic Diseases

Cervical Intraepithelial Neoplasia (CIN)

Cervical Intraepithelial neoplasia (CIN) is a pre-invasive phase of cervical carcinoma. It
represents a spectrum of disease and they are not always continuous.
CIN is identified by morphologic changes to squamous cells including: increased N/C ratio,
nuclear hyperchomasia and membrane irregularities, apoptosis and mitotic figures above the
basal layer, and loss of maturation of epithelium. CIN may be detected by pap smear and a
cervical biopsy allows treatment (cone biopsy) of lesions before malignant features occur.
Mostly, CIN I (low grade SIL) is observed and CIN II and CIN III (high grade SIL) are are
CIN 1 takes 5 yrs to progress to CIS
- Natural history has a high rate of spontaneous regression so observe
- 9-16% progression to CIN II/III and only 0.3% progression to CA
- Tx
o After a satisfactory colpscopy:
Tx is excisional
Test for HPV at 12 months OR do 2 repeat paps at 6 and 12 months (if
you repeat and get ASC or more OR high risk HPV then go back and do a
o After an unsatisfactory colpscopy
Diagnostic exisional procedure (not ablative)
If pregnant, adolescent, immunosuppressed women may be followed as
CIN II takes 3 years and CIN III takes 1 year
- poorly reproducible histologic diagnosis
- more likely to persist than regress:
o CIN II 35% persist and 22% progress
o CIN III 56% persist and 14% progress
- excisional therapy
o Cold knife
o Laser
o Cryotherapy
- Tx:
o After satisfactory colposcopy perform excisional or ablative therapy that removes
the ENTIRE transformation zone
o After unsatisfactory colposcopy then do a diagnostic exicisional conization up
to 7% will have occult invasive cervical carcinoma
o Margins are risk factors for recurrence/persistent
- Followup: 65% recur in 12 months, 90% recur in 24 months so follow up with a pap
every 4-6 months for 2 years!
Reproductive and Genetic Diseases

Cervical Cancer
Presentation Pathology
Firm and bulky Gross: punctuation and mosaicism - vascular changes
Postcoital Histo: squamous (85-90%), adenocarcinoma, adenoaquamous (glassy
bleeding, cell)
intermitten Normal maturation: cell size increases and the cytoplasm volume and
spotting, watery density increases, the nucleus decreases and the chromatin goes from
vaginal discharge finely granular dark and pyknotic. The N/C ratio decreases
Intermitten Abnl: Koilocytes (Condyloma) HPV, clear cytplasic, well defined
painless vaginal vacuole w/ enlarged irregular and dark nucleus, binucleation is common
bleeding Squamous cell carcinoma in situ pap: 3D aggregates w/ high N/C
Invasive pap: keratinizing or non-keratinizing (irregular chromatin
clumping, prominent nucleoli, background is necrotic
Normal anatomy is that the ectocervix is lined with squamous epithelium and the endocervix
is lined with columar epithelium. Squamous metaplaisia occurs at adolescence and
pregancny. The transformation zone is the squamnocolumnar junction and is the site of
cervical dysplasia and carcinoma!! Thus, impt to sample this region while doing a pap and
visualize this zone during colposcopy.
Cervical cancer is caused by Human Papilloma Virus.
There are many types of HPV: (HPV is a small circular DNA virus 200 types identified bu
30 infect the anogential tract.
- low risk types: 6, 11, 42,43,44 ---- condylomatas
- high risk types: 16.18, 31, 33, 35, 39, 45, 51, 52, 56, 58 ---- HSIL, cancer.
o 16 = squamous cell 18 = endocervical glandular neoplasia adenocarcinoma
o HPV is best studied at molecular level b/c most infections are not microscopically
HPV testing
- DIGENE HCII assay uses 2 RNA probes to differentiate b/w low and high risk HPV.
Can test this on the liquid based pap smear
HPV may produce a 1) transient/self limited infection or a 2) persistently expressed infection.
The vast majority of HPV infections spontaneously regress (intact immune system. Less than
of HPV infections persist for 24 months or more. A major factor in progression to cancer is
persistence of the HPV infection.
Most carcinomas are of squamous cell carcinoma (75-90%) and then adenocarcinoma (10-
20% and increasing) . precursor lesion to adenocarcinoma is adenocarcinoma in situ
Risk Factors for Cervical Cancer:
- prior affected partner gives new partner 2-3 X risk
- early initiation of intercourse
- multiple partners
- smoking (3-5X)
- high parity
- infection w/ high risk HPB subtypes (HPV 16, 18, 45, 31, 33)
- immunocompromised HIV, organ transplants, Hodgkins (b/c cannot clear the virus)
Reproductive and Genetic Diseases

Pap Smear Screening: - most effective prevention of cervical squamous carcinoma and detects
precursor lesions of SCC
- reasonably sensitivity and specificity, disease (CIN) has long latent periods, it is a
common disease, low morbidity of test, treatment and cure available, inexpensive, and
easy to perform .
- different guidelines: some say iniate at sexual activity or 18 years of age OR 3 years after
onset of vaginal intercourse but no later than 21 yrs
- you must sample entire transformation zone: use a spatula for the ectocervix and a brush
for the endocervix. In pregnant pts, use a broom.
- Includes palpation of the cervix.
- 90% effective in detecting precursor lesions
o Sampling and diagnostic errors failure to sample abnl cells, too few abnl cells
not diagnosed, failure to properly catecorgize cells,
False negative diagnostic errors too few abnl cells, smears w/ obscuring
o inflammation/blood limiting evaluation
o 3% real error rate in missing cervical SCC (60-90% due to inadequate screening
of population at risk the patient is not getting regular pap screening)
o If a lesions is suspicious clinically, it must be evaluated further irrespective of
negative pap smear results .

Bethesda System standardized method for reporting of pap smears

- specimen type and adequacy
o specimen can be either conventional pap smear or liquid based thin prep
o adequacy:
conventional smears: 10% of slide covered by cells
thin prep: 5000 cells
epithelial or glandular abnl present even if there are less than
adequate numbers of cells is satisfactory
specify reasons
o specimen rejected b/c improper patient identifiers or
slides were broken
o too few squamous cells
o poor preservation
o totally obscured by blood
- general categorization
o w/in normal limits
o negative for intraepithelial lesion or malignancy (no precursor lesion)
benign cellular changes
other: endometrial cells in women 40 yrs b/c it can indicate
endometrial hyperplasia or carcinoma
o epithelial cell abnl: squamous (ASCUS, LGSIL, HGSIL, squamous carcinoma
Reproductive and Genetic Diseases

o epithelial cell abnormality (precursor lesions and carcinoma)

atypical squamous cells
Squamous cell carcinoma
Atypical (NOS) endocervical or endometrial cells
Atypical (favor neoplastic) endocervical or endometrial
o Endocervical adenocarcinoma in situ
o Adenocarcinoma endocervical, endometrial, extrauterine , NOS
o Other malignant neoplasms sarcoma, lymphoma, melanoma, etc
- descriptive diagnosis
o benign cellular changes:
infection: trichomonas, candida, coccobacilli, actinomyces, herpes
reactive changes (multinucleation, atypical repair, foreign body giant
cells) : inflammation, atrophy, radiation/cehmo, IUD
benign endometrial cells: normally found in first 11 days of menstrual
cycle. Abnormal if present in patient 40 years (could be hyperplasia or
o epithelial cell abnl: squamous (ASCUS, LGSIL, HGSIL, squamous carcinoma)

Pap Smear results:

- normal
- LFSIL low grade squamous intraepithelial lesion === CIN I
- HGSIL high grade squamous intraepithelial lesion === CIN II or CIN III
- ASCUS atypical cells of undetermined significance
- ASCUS H atypical cells of undetermined significance, but cannot rule out high grade
- AGCUS atypical glandular cells of undetermined significance
- 10-15% of mild/moderate dysplasia progress to invasive cancer if not treated

Cervical dysplasia in pregnancy:

- follow up w/ pap/colposcopy each trimester
- biopsy if suspect cancer
- plan tx 6 wks postpartum
Cervical Cancer staging: the ONLY gynecologic cancer that is clinically, not surgically
staged! You stage it based on physical exam, cystoscopy, barium enema, and intravenous
pyelogram. Survival
- stage I cervix 85%
- stage II beyond uterus, not to sidewall 60%
- stage III lower vagina/pelvic sidewall 30%
- stage IV beyond true pelvis 10%
Reproductive and Genetic Diseases

Treatment Other
Stage I simple hysterectomy Colposcopy:
Stage II radical hysterectomy - binocular microsopce of low mag (10X to
stage III/IV radiation/chemo 40X) w/ focal length 12-15cm
- clean cervix w/ 4% acetic acid
- Microinvasive stage Ia1 cervical - native squamous epithelium is gray
conization, simple hysterectomy - columnar epithelium is red, grapelike
- Advanced cancer: stage IIb-IV external - nl bld vessels branch like a tree
raidaiont and internal radiation and - acetowhtie changes are hallmark of
chemosensitization dysplasia
- early cancer: stage Ia2-IIa radial - must view all of transformation zone
hysterectomy, lymph node dissection
Surgical options: HPV vaccine:
- radical hysterectomy (hysterectomy - HPV 16 and 18 (66% of cervical cancers)
w/ radiacal resection of parametria - HPV 6 and 11 (90% of genital warts)
and upper vagina)
- lymph node dissection Tumor spreads from cervix to involve
- ovarian conservation possible in parametrial tissues and adj bladder/rectum.
young patient Mets to regional lymph nodes (illaic LN).
distantly to the aortic and mediastinal LN, lung
and bone

Cervicitis is inflammation of the cervix. It can be from a non-infectious cause, such as a
chemical or mechanical in origin. Or, it can be from an infectious cause, such as a sexually
transmitted disease, or it may represent an endogenous flora. Endogenous flora of the cervix
are Staph and Group B strep. Other pathogens, such as Neisseria gonorrhea, Chlamydia
trachomatis, and Herpes are also agents.
Infectious cervicitis is the initial site of infection in PID and may be associated w/ ascending
infections that complicate pregnancy (acute chroioamnitis)

Herpes path multinucleated epithelial cell w/ marginated chromatin (ground glass


Benign Lesions of the Cervix

Cervical Polyps these are benign hyperplasitc polyps arising in the endocervix. Polyps
may be associated w/ discharge or bleeding, and sometimes pain
Nabothian cysts these are benign mucinous cyst-like distensions of endocervical glands
secondary to obstruction from squamous metaplasia, These prevent mucin from being
Microglandular hyperplasia these are benign proliferation of endocervical glands, likely
to be hormone driven (progestational stimulation) it has nothing to do with endometrial
hyperplasia. This is seen in pregnant women or women on OCP (b/c hormonally driven)
Endometriosis endometrial glands and/or stroma involving the cervix
Reproductive and Genetic Diseases

- lined by stratified squamous epithelium
- vaginitis is very common
o infectious: fungi (candida), bacteria (vaginosis-gardnerella), trichomonas
o atrophic: postmenopausal women, loss of estrogen
- DES exposure during pregnancy (used to prevent spontaneous abortions) has been
associated w/ a variety of non-neoplastic and neoplasic changes in the female genital tract
o Congenital anomalies of the cervix and/or vagina
o Vaginal adenosis
o Cervical ectropion
o Clear cell adenocarcinoma of the vagina and/or cervix rare
- Tumors primary tumors of the vagina are rare. Most tumors involving the vagina are the
result of either metastasis or direct extension from nearby malignaneis (cervix and
o Primary tumors:
Squamous cell carcinoma (95%) arise from dysplasia, termined
vaginal intraepithelial neoplasia (VAIN) and is graded VAIN 1-3, using
similar criteria as for the cervix
DES assocated clear cell adenocarcinoma
Sarcomas evaluating vaginal masses in kids (rhabdomyosarcoma)

- covered by skin (keratinizing squamous epithelium). Thus any dermatologic condition may
involve the vulva
- vulvar dystrophies:
o lichen sclerosus painful, pale white plaques, cause unknown
o squamous hyperplasia pruritic and related to a wide variety of irritants
- Neoplasia
o Vulvar intraepithelial neoplasai (VIN 1-3) similar to cervix
o HPV infections of the vuvla are usually subtypes 6 and 11 resulting in
condyloma acuminatum (genital warts) papillomatosis, hyperkeratosis,
parakeratosis, and koilocytes
o Majority of invasive tumors of the vulva (85%) are squamous cell carcinoma
arising from VIN
- Pagets disease rare malignant tumors
o Glandular tumors cells w/in the epidermis and skin appendages. The tumor
cells stain for mucin indicative of their glandular origin. Most cases are NOT
associated w/ an underlying adenocarcinoma (thus not like the breast)
- Melanoma pathology similar to melanomas in other sites invasive or in situ
Reproductive and Genetic Diseases

Down Syndrome
Typical facies round face, upslanting palpebral fissures, epicanthal folds, flat nasal bridges,
open mouth w/ protruding tongue secondary to hypotonia, short neck w/ excess nuchal skin,
small dysmorphic low set ears, microcephaly, brachycelphaly
Brushfield spots around iris margin
Short and broad hands w/ transverse crease and 5th finger clinodactylyl, wide gap b/w 1st and
2nd toes with furrow extending along length
Short stature, short fingers, hypotonia, single palmar crease
Heart defects (VSD, ASD, endocardial cushion defect) , GI atresia

Down Syndrome is the most common single, known cause of mental retardation (1/700
Other characterisitics:
- mild-moderate MR (IQ: 30-60) need early intervention programs. IQ is about 50%
that of siblings
- hypotonia
- heart defects: AVSD, and VSD need newborn echo and cardiology eval
- GI: duodenal atresia, hirschprung, pyloric stenosis, TE fistula, omphalocele, annular
pancreas, imperforate anus
- Hearing loss
- Vision problems need ophthalmologist at 1 year
- Hip dislocation
- Endocrine: hypothyroidism need newborn thyroid screen (rpt @ 6mo, then
- Hematologic: leukemia (15X increase, but overall risk is 1%)
- Alzheimers disease in middle age
Inherritance pattern: chromosomal
- 95% are due to nondisjunction trisomy 21 (most by maternal meiotic NDJ)
- 1-2% are due to mosaics w/ a normal cell line (mos46XX/47XX+21) a milder
phenotype but cannot predict on an individual basis. The mocaisim can be a result of
either 1) a normal conception followed post-zygotic non-disjunction or 2) trisomic
conception rescured by a nondisjunction or anaphase lag (more common).
- 3-4% are due to an unbalanced robertsonian translocation their phenotype is
indistinguishable from that associated w/ NDJ form of DS. (46XY, der (14:21)
(q10;q10), +21 ) -- most common
- Less common translocations: der(13:21); (15;21); and (21;22)
(21;21) risk for unbalanced offspring is 100% (50% eggs w/
der(21;21) DS and 50% eggs w/ nullisomic lethal monsomy 21)
- 40% of translocations are inherited from a carrier parent that is balanced.
Testing and Management

Lab tests karyotyping. Peripheral blood karyotype detects almost all cases, prenatal
diagnosis avl using cells from CVS or amniocentesis
Management echo and peds cardiology eval for newbornd, newborn thyroid screen (repeat
at 6 months and annually), monitor hearing, check vision (opthamlogist @ 1 yr), track growth,
obesity may be a problem in late childhood. C-spine Xrays b/w 3-5 to assess for atlantoaxial
instability or subluxation.
Reproductive and Genetic Diseases

Genetic Counseling:
The recurrence risk of having a second child w/ DS secondary to nondisjunction is related to
maternal age but remains low:
- 30 yrs old = 8X in age related risk (1%)
- 30 yrs old = 2X in age related
The increased recurrence risk seen in young women w/ a previous child w/ trisomy 21 may be
explained by gonadal (germline) mosaicism (results in the same trisomy) or an increased
predisposition to meiotic error (results in the same or a different trisomy). The increased
recurrence in older women is a function of her age!
You should offer prenatal diagnosis for all future pregnancies.
Parental karyotyping is NOT needed the abnormal meiotic events that produce numerical
abnormalities are sporadic events.
An individual w/ DS (secondary to nondisjunctioN) is at a 50% risk of having a child w/ DS.
There is no significant risks for other relatives!

For DS due to mosaicism counseling should proceed as if the child has standard NDH form
of DS (this will result in an overestimation of risk for parents in which NDJ occurred during
Those DS resulting from an unbalanced robertsonian translocation have a substantial
recurrence risk. 40-50% of the time robertsonian translocations are inherited from a balanced
carrier parent. It is necessary to karyotype the parents
- For a de novo robertsonian, a reuccorence risk of 1% is given and a prenatal dx is
- For a carrier parent the recurrence risk will be higher
- 80% of DS conceptions die in utero only 20% survive to birth. The theoretical
recurrence risk for live born DS is 33% and the empiric recurrence risk is 3-5% for
male and 10-15% for female carriers.
For genetics counseling for robertsonian translocations discuss carriers risk for miscarriages,
infertility and live born child w/ unbalanced (+13 or +21) karyotypes. Offer prenatal testing,
and recommend parental karyotypes to assess risk of relatives and other children of
Reproductive and Genetic Diseases

Trisomy 13- Patau Syndrome

Growth retardation, microcephaly, sloping forehead, scalp defects, cleft lip/palate,
micropthalmia, anopthalmia, post axial polydactylyl of hands and feet
Congetial heart defects esp VSD and PDA
Renal anomalies
CNS malformations arhinencephalaly and holprocencephaly

Trisomy 13, or Patau Syndrome occurs in 1/12, 000 births. It is a cause of severe mental
retardation. The mean life expectany is only 130 days (86% die during year 1)
Inheritance is chromosomal
- 75% is due to trisomy 13 due to nondisjucntion.
o Recurrence risk is low (1%) for live birth
- 5% due to mosaic (47X_+14/46X_)
- 20% due to translocations
o All are robertosonians and are mostly 13;14
Most common translocation in man - 1/1,100 individuals
50% of 13;14 are inherited from parent
Balanced 13;14 rob carrier has 1% risk of unbalanced offspring
Mental retardation, failure to thrive, severe heart malformations, hypotonia, clenched fists
(2nd and 518
th Edwards Syndrome
digits overlap 3rd and 4th), rocker bottom feet, prominent heel bone,
Prominent occiput, receding jaw, low-set and malformed ears

Trisomy 18 ,or Georges syndrome, occurs in 1/7,500 births. It also cuases mental retardation.
Less than 10% survive beyond 1st year. The median survival is only 5 days!!!
Inheritance: chromosomal
Caused by
- 80% are due to trisomy 18 (NDJ) the recurrence risk is low ( 1%)
- Some mosaics
- 20% w/ translocations most w/ partial trisomy 18
Reproductive and Genetic Diseases

Turners Syndrome
Prenatally increased nuchal thickness, lymphadema, cystic hygroma, hydrops fetalis and
high risk of fetal demis w/ a 45 X karytoype
Newbon lymphadema, webbed neck, cardiac abnl 50% have coartaction of the aorta ,
usually normal linear growth until 2-3 years.
Childhood low posterior hairline, cubitus valgus, short 4th metacarpals, short stature
(progressive decline in growth velocity), disproportanitly short legs, broad chest, prominent
ears, pigmented nevi, scoliosis, micrognathia
Adolescence short stature and delayed puberty, delayed epiphyseal fusion. nipples are
widely spaced, increased carrying angle
Adults infertility/anovulation
Increased risk of LD involving spatial perception NO mental retardation.
Infertile w/ streak ovaries. Most will not develop secondary sex characteristics w/out hormone
replacement. Renal abl are common. Phenotypic and karyotypic variability
Turner Syndrome is in 1/ 4-5000 female births. 1-2% of all conceptions, 6-7% o all SABs.
Other features:
- cardiac abnormalities (bicuspid aortic valve, aortic dissection, coarctation of the aorta)
need a cardiac evaluation and ECHO
- renal abnormalities (horseshoe kidneys, unilateral renal agenesis) need a renal US
- short stature avg height is 4;7 need endocrine and growth hormone tx
- delayed puberty - secondary sex characteristics need hormone replacement
- hearing impairment
- learning disabilities spatial perception need intervention programs
Caused by:
- 50% are due to 45X paternal sex chromosome preferentially lost
- The remainder contain other sex chrom abnormalities
o Structurally abnl sex chromosome (X or Y) isochromosomes, deletions, rings,
duplications, etc
o Mosaicism for a normal or abnormal cell line - most common are 46XX, 46XY,
and/or 47XXX cell lines.
- There is a risk of gonadoblastoma if Y bearing cell line is present thus do a
prophylactic gonad removal
Testing and Management
Lab tests karyotying. Peripheral blood karyotype, extended analysis may be needed to
detect mosaicisms
Management issues ped cardiology evalulation, ECHO and renal US. Increased risk for
chronic otitis (and hearing loss), hip dysplasia, strabismus, HTN, sciolosis, and
hypothyroidism. Use TS growth charts at age 2, evaluated speech and development. Referral
to ped endocrinologist for growth and sex hormone replacement therapy!
Genetic Counseling
- there is no need for parental karyotyping b/c the sex chromosome is loss due to a
sporadic error during cell division.
- The recurrence risk is 1%
- The risk for a female w/ TS to have a clinically abnl child most TS patients are
infertile/ 1% have unassisted pregnancies (mosaics w/ nl cell line) thus assisted
reproduction techniques are possible. You need to offer prenatal diagnosis (increased
incidence congenital and chromosomal abnl)
o 5-10% may begin puberty, 1% may have periods
Reproductive and Genetic Diseases

Other Sex Chromosome Aneuploidies

Disorder Phenotype Sexual Intelligence Behavioral
Development problem
Klinefelters Tall male, thin Infertile Learning diff Poor
47 XXY Hypogonadism psychosocial
2nd sex char adjustment
XYY Tall male nl Learning Common
syndrome difficulties ADHD,
(50%) impuslive
Trisomy X Tall female normal Learning common
47 XXX difficulties
- each has an incidence of 1/1000 male or female births
- recommend prenatal testing for fertile individuals
- risk is low for having a chrom abnl child

DiGeorge Syndrome

DiGeorge syndrome is the most common microdeletion syndrome w/ an incidence if 1/2-4,000.

There are greater than 180 features associated w/ DiGeorge, but no one feature is seen in all
patients .
Facial features (majority) prominent nose, squared nasal root, narrow alar base, eye and ear
abnl, malar flatness
Abnormal palate (69%) velopharyngeal incompetence, overt/submucous
Congenital heart defect (74%) conotruncal, double outlet right ventricles
Learning (70-90%)
Hypocalcemia (40-50%)
Immune deficiency infections, death at 6 months
Psych disorders
A cytogenetically visible deletion is seen in only 25% of patients w/ DiGeorge syndrome
Detected via FISH does not hybridize to the deleted chrom 22.

Genetic Counseling
Parental karyotyping is recommended
- 94% of deletions are de novo
o Small recurrence risk (less than 1%)
o Risk for germline mosaicism is unknown
- 6% of deletions are inherited
o Recurrence risk is 50%
o Prenatal FISH is avl
o Consider gentics evaluation and/or FISH to relevant family members
Complementatary duplications and deletions can occur secondary to unequal crossing over
(nonallelic homologous recombination)
Crytpic duplication involving the DiGeroge cirtical region detected prenatally
Reproductive and Genetic Diseases

Cystic Fibrosis:
Presentaiton: (lung dz, liver dz, meconium ileus, sweat cl, pancreatic dz, male infertility)
Chronic congestive lung dz + high levels of salt in sweat. 85% have pancreatic insufficiency
(bulky foul smelling stools), 10-20% have meconium ileus at birth
Poor weight gain, recurrent lung infections, diabetes in 10-15%, severe lung dz in 5%. 95%
of males are infertile (CBAVD). Males can also have isolated congenital bilateral absence of
vas deferens (w/out other symptoms of CF) and have 2 mutations in the CF gene.

Cystic Fibrosis is a genetic condition that affects 1 in 2500 to 1 in 3200 N european and
ashkenzai jews, and 1 in 1500 AA. Carrier frequency is 1/25 to 1/150. The mean survivial of
a person w/ CF is 31. Death is usually secondary to pulmonary complications. Diagnosis is
made by age 3 (although some have milder symptoms)
Classic CF severe lung dz, pancreatic insufficiency, sweat Cl, liver dz, CBAVD
Moderate CD moderate lung dz, pancreatic insuff, sweat Cl, CBAVD
Mild CF mild lung dz, pancreatic insuff, normal/borderline sweat CL, CBAVD
Non-classic CF isolated CBAVD, idiopathic pancreatitis, atypical sinopulmonary
dz/sinusisits/nasal polyps
The inheritance pattern is autosomal recessive w/ variable expression
Mutations: allelic heterogeneity more than 1400 different mutations on the CFTR gene
(cystic fibrosis conductance regulator) on chromosome 7q31.2. Most common mutation is
the deltaF508, a 3 base pair deletion accounting for 70% of mutations.
There is some genotype/phenotype correlation. Six mutations account for 98% of those in
Ashkenazi Jews.

Lab Testing and Management

Labs: standard panel of 23 mutations. DNA testing should be used in conjunction w/ clinical
suspicion and sweat chloride testing for diagnosis. Detection rate of carriers based on DNA
testing is 90%. Prenatal testing is avbl. Newborn screening w/ immunoreactive tyrpsinogen
assasys performed on blood spots (not in NC)
Magagment: postural drainage, exercise, antibiotics, aerosols, enzyme and vitamin
replacement for pancreatic insufficiency. Some candidates for lung transplantation. Gene
therapy potential in the future.

Genetic Counseling
Recurrence risk is 25% when both parents are carriers and it is 2% if someone has CF has a
partner from the general population.
Offer carrier testing to siblings and other relatives.
For CF carrier screening in the general population, false negative rate of carrier testing should
be explained. Do not test asymptomatic children.
Reproductive and Genetic Diseases

Fragile X Syndrome
Presentation variable but becomes more pronounced w/ age
Physical prominent forehead, long, thin face w/ prominent jaw, large protuberant ears,
post-pubertal macroorchidism (enlarged testes)
Cognitive mild to severe developmental delay. (males worse than females, 50% of females
w/ full mutation have normal intellect)
Behavior hyperactivity, lack of eye contact, repetitive behaviors, preservative speech,
autistic like behaviors, social shyness, low self-esteem
Fragile X syndrome is a common hereditary cause of mental retardation. The incidence is
1/4000 males and 1/8000 females. (down syndrome is most common cause)
People w/ fragile X are at an increased risk for strabismus, cleft-palate, joint laxity, dislocated
hips, seizures, mitral valve prolapse .
The inheritance pattern is X-linked w/ anticipation due to trinucleotide repeat expansion.
The expansion of CGG trinucleotide repeat is in the first exon of FMR1 gene on Xq27.
Repeat sizes: normal is 5-44, intermediate is 45-58, permutation is 59-200 and full mutation is
over 200 and highly methylated.
Premutations expand into full mutations ONLY when inherited from a permutation carrier
female. Permutation carriers are not clinically affected. The daughters of males w/ a
permutation are obligate carriers but are intellectually normal.
Due to the increasing size of permutations through generations, the risk of an affected child is
greater in later generations = anticipation (the progressively earlier onset and increased
severity of certain diseases in successive generations of a family) However, no correlation b/c
age of onset and severity with repeat numbers instead the more repeats you have the more
likely you are to be affected and once you have the mutation you have it
CpG island a region of genome containing an unusually high concentration of 5-CG-3
and the Cs are susceptible to methylation. A high level of methylation in a promoter can lead
to transcriptional inactivation of a gene. When the CGs of Fragile X is over 200 it gets
mehtylated and the gene turns off and get a loss of function mutation so that the gene product
is not made.
Lab testing and management
Lab testing: Southern Blot detects presence of full and permutations, approximation of
repeat number, and methylation status.
PCR yields accurate estimates of normal and small permutation alleles.
Diagnositc and carrier testing is very accurate; prenatal testing is avl
Management ophthalmologic (strabismus, myopia, nystagmus), audiology (recurrent
serous otitis), orthopedic (flat feet, scoliosis), and neurologic (seizures). Developmental
evaluation, review school placement, assess needs for PT, OT, and speech and hyperactivity

Genetic Counseling
Young asymptomatic kids may not benefit from carrier testing.
Permutation carrier females have 20% risk of premature ovarian failure w/ premature
Premutation males have a high risk of late-onset ataxia/tremor syndrome : intention tremor,
ataxia, cognitive decline, eventual brain atrophy.
Reproductive and Genetic Diseases

Side note: CAG repeat disorders are different CAG repeat disorders result from much smaller
expansion and methylation is not involved in expression of the genes, and expansion can occur in
both sexes but they tend to be larger when the expanded allele is inherited from the father!
Huntingtons Disease
67% present w/ neurologic features incoordination, jerks, 33% have pyschatiric changes
(depression, irritability)
Mean age of onset is 35-44.
25% have onset after 50
10% have juvenile onset before 20 - seizures and rapid decline
Progressive chorea (not repetitive), dysarhria/dysphagia, outbursts of aggressive behavior,
social disinhibition, paranoid delusions.
72% have signiifiacnt personality changes.
Late stages: weight loss ,total dependence, no speech
Huntingtons Disease is a progressive disorder of cognition, motor and psychiatric disturbance.
It includes voluntary and involuntary movements, cognitive decline and/or personality
changes. Involuntary, spasmodic movements (chorea) w/ progressive dementia. The median
survival after time of onset is 15-18 hears. The average age of death is 55 years and suicide is
12%. It is a degenerative brain disease resulting from loss of cells in the basal ganglia.
The incidence is 3-7/100000 in Western Europe descent and less in Asia and Africa
The inheritance pattern is dominant. Most will have an affected parent. New mutations rae
very rare. HD shows decreased penetrance and anticipation
The mutation in HD is a CAG triplet repeat expansion w/in the HD gene on chromosome 4p.
There is an inverse correltion b/w number of repeats and age of onset.
Repeat sizes: normal is less than 26, intermediate that confers no increased risk for individual
but can expand to offspring who can become affected is 27-35, reduced penetrance alleles
which causes symptmoms in some but not all is 36-39. adult onset is 40-59 repeats and
juvenile onset is above 60 repeats.
Expansions are more likely to occur during paternal gametogenesis, w/ juvenile onset HD
almost exlusively inherted through affected fathers. For adult onset, repeat size is not
correlated w/ appearance of clinical features or w/ rate of progression

Lab testing and management

Lab testing PCR detects repeat #
Management symptomatic treatment (neuroleptics, anti-parkinsonian psychotropic drugs).
Dietary, special equipment, and help in qualifying for disability benefits. Children living w/ an
affected parent may have special needs.

Genetic Counseling
Genetic testing of asymptomatic individuals is predictive (increases or decreases prior risk)
but is NOT diagnostic. Age-related penetrance figures are avl.
Does the individual at risk really want to know what s/he will die of and when? How will the
individual cope w/ results? Confidentiality, possible genetic discrimination.
Reproductive and Genetic Diseases

- all autosomal dominant repeat expansion disorders show anticiatpion and most show
parental bias in transmission of larger expansions to offspring. CAG repeats are
moderately unstable, whereas other repeats are prone to very large expansions. CAG
repeats in coding regions leads to toxic proteins.
- Expanded Repeats in DM1 and DM2 result in toxic mRNA.
- Other expansions can lead to loss of function

Duchenne Muscular Dystrophy

Boys have a normal phenotype at brith and for first 1-2 years. Diagnosis is made at 3-5 years
b/c of difficult climbing stairs, and rising from sitting position to floor, calf hypertrophy, toe
walking, and waddling gait.
Developmental delay in 1/3 and cardiomyopathy
DMD is a progressive muscle-wasting disease of children and adolescents resulting in
confinement to wheelchair by the age of 13, with death usually in the 20s of respiratory or
cardiac failure.
Beckers MD is a similar but more slowly progressive disease with a longer lifespan.
DMD is the most common childhood muscular dystrophy 1 in 3500 male births and female
carriers are estimated to be 1 in 1500.
The inheritance pattern is X-linked recessive with the gene located on Xp21. 2/3 of mothers
are carriers and 1/3 of cases are a result of a de novo new mutation. DMD is a genetic lethal
b/c affected males rarely, if ever, reproduce.
DMD shows allelic heterogeneity. the gene is large and codes for the protein dystrophin.
70% of boys with DMD and 85% of boys w/ BMD have a deletion or duplication detecteable
by PCR or southern blot.
30% of boys w/ DMD will have a small insertion, deletion, point mutation, or splice site
mutation detectable by mutation scanning and/or sequencing

Lab testing and Management

Lab test DNA analysis via PCR or Southern Blotting looks for deletions and
duplications. If negative, then mutation scanning/sequencing for other types of mutations.
Linkage studies are avl using intragenic markers for those w/out an identifiably mutation or
for testing for carrier status when family mutation is not known and affected individual is not
Creatine kinase levels are usually elevated
Dystrophin testing on muscle biopsy can confirm the diagnosis when mutation is not detected
(used more often w/ BMD).
Prenatal and carrier testing is avl
Management no effectively proven treatment! Symptomatic tx weight control, physical
therapy to promote mobility, monitoring for scoliosis and cardiomyopathy.
Prednisone used in pts who are still ambulatory to improve strength and function.
Genetic Counseling
If the proband is an isolated case, they could have a new mutation or mother could be a carrier
b/c of germline mosacism. Thus, ALL mothers of affected boys should be offered prenatal
diagnosis in subsequent pregnancies.
Identify other females in the family at risk and offer carrier testing.
Most carriers exhibit no symptoms but they are at an increased risk for left ventricular
dilatation and cardiomyopathy.
Reproductive and Genetic Diseases

Phenylketonuria (PKU)

Untreated children severe mental retardation, seizures, increased irritability, musty odor and
eczema. They are NOT dysmorphic
Elevated levels of phe in older kids and adults w/ PKU put them at risk for behavioral and
learning problems, regardless of good early treatment
(kids have progressive developmental delay/MR, autistic like behavior, hyperactivity)

PKU is an inborn error of metabolism caused by significant decreased activity of the liver
enzyme phenylalanine hydroxylase, resulting in increased blood levels of the amino acid
1-2% of individuals w/ hyperphenylalanemia will have impaired synthesis or recycling of
tetrahydrobiopterin (BH4), a necessary cofactor for phenylalanine hydroxylase.
The incidence is 1/15000 to 1/20000 newborns in the general US population. More common
in those of N European ancestry. In that population, carrier frequency is 1/50.
The inheritance pattern is autosomal recessive w/ variable expression due to varying levels of
enzyme activity and other epigenic effects which may modulate the phenylalanine such as
absorption during the digestive process or its transport across the BBB.
PKU displays allelic heterogeneity, w/ over 400 mutations in the phenylalanine hydroxylase
gene on chromosome 12q. most affected individuals are compound heterozygotes (2 different
mutations w/in the gene)
Lab Testing and Management
Lab testing screening lab measures blood Phe levels from samples taken in the newborn
nursery and spotted on filter paper (every state). This is accurate when performed on blood of
infants older than 24 hours.
Carrier testing is accurately detected by molecular analysis when the mutations have already
been identified in the proband.
Prenatal diagnosis is possible if mutations in the family are known.
Screening for BH4 deficiency should be completed in all neonates w/ persistent
Management MR can be prevented if tx is initiated before 4 wks of age w/ a special
individualized diet low in Phe. A life-long diet consisting of a metabolic formula w/out Phe,
and includes measured amts of fruits, veggies, limited grains, and specially processed low-
protein foods.
Blood levels of Phe are obtained weekly: want it to be b/w 120-180 micromoles/L.
Adjustments on phe intake are needed based on individuals growh, intercurrent illness, and
phe tolerance.
Indiviuals who are hyperphenylalanemia due to BH4 deficiency require biopterin replacement
therapy and NT replacement terappy. They are typically not on a low Phe diet.
Reproductive and Genetic Diseases

Genetic Counseling
Children born to women w/ PKU are at increased risk of birth defects and MR b/c of the
teratogenic effects of Phe. Thus, keep maternal Phe levels at 120-360 micromoles/L prior to
conception and throughout pregnancy.
If maternal blood levels are 1200 micromoles/L during prenangy high risk of IUGR,
microcephaly and MR and a moderate risk for specific dysmoprhic features (bypertelorism,
epicanthal folds, upturned nose, long philtrum, high arched palate) and congenital heart
defects and spontaneous abortions.

Presents w/in the first 2 weeks of life w/ jaundice (due to conjugated hyperbilirubinemia),
lethargy, cataracts, hepatomegaly, and FTT, an rapidly processed to death if untreated

Galactosemia is due to the deficiency of the enzyme galactose-1-phosphate uridyltransferase

Any infant suspected of having galactosemia should be on a galactose-free diet (soy formula)
Life-long restriction of galactose and lactose-containing products is essential.
**short stature, ovarian failure, and visual-preceptual speech and learning disabilities are
common in patients treated from birth (different from PKU where you can prevent symptoms)


This could be a from a urea cycle defect.

The key is to manipulate dietary nitrogen intake in order to minimize the requirement for
waste nitrogen sytnehsis (so restrict protein intake and subsitite only essential amino acids)
Also, decrease endogenous protein breakdown.
Increase waste nitrogen excretion by: arginine or citruline, sodium benzoate, sodium
phenylacetate, or sodium phenylbutryate
Removal of plasma ammonia by: exhange transfusions, peritoneal dialysis, hemodialysis

Glycogen Storage Diseases

The chronic episodeic hypoglycemia results in Hepatomegaly, poor growth, lactic acdisosi,
hyperlipidemia, easy bruising, and if severe and untreated, life threatening hypoglycemic
Reproductive and Genetic Diseases

GSD type 1 = Glucose 6 phosphatase defieeincy (cant move glucose out of the liver) is
characterized by hypoglycemia occurring 2-3 hours after eating.
The hypoglycemia is secondary to an inability to release glucose from the liver

Frequent feedings w/ glucose or glucse polymers
Raw cornstarch, a slowly digested glucose polymer, can act as a time-release source of
glucose and can be very helpful in mainitng glucose levels when taken orally every 4-6 hours.

Biotinidase Deficiency
Seizures, ataxia, hypotonia, developmental delay, skin rash, alopecia

Biotinidase cleaves the biotin from biocytin and biotinyl peptides released during proteolytic
degradation. Thus do not have biotin.

5 and 20 mg oral biotin (in the free, unbound form) per day
Reproductive and Genetic Diseases

Prader Willi Syndrome

Newborn: severe central hypotonia and feeding difficulties
12 months 6 yrs: excessive eating and development of morbid obesity (esp b/w 2-4yrs).
Food seeking behaviors such as hoarding or foraging for food, eating of inedibles, and stealing
of food
Short stature, facial features such as bitemporal narrowing, almond-shaped paleprebal
fissures, down-turned mouth, small hands and feet, hypogonadism, thick saliva, strabismus,
scoliosis, reduced growth hormone secretion,
developmental delay and cognitive impairment (mild range of mental retardation)
behavioral concerns temper tantrums, obsessive-compulsive behavrior, stubbornness,
rigidity, stealing, lying, manipulative behavior, skin picking

Prader-Willi Syndrome is caused by a microdeletion. It can either be from uniparental disomy

or from an imprinting center defect. The incidence is 1/10,000 to 1,15000.
It is from an absence of expression of the paternally contributed Prader-Willi/Angelman
Lab testing and Management
syndrome region on chromosome 15q11.2-q3.
Lab test methylation detects 99%. If diagnosis is established by mehtylation test, it is
70% of cases have a cytogenetic deletion involving the promximal chromosome 15 inherited
necessary to do further testing to establish the molecular class of the mutation either FISH or
from the father!
25% do not have deletions but have two chromosome 15s inherited from the mother =
Deletion of paternal PWS region is detected by FISH in 70%.
maternal uniparental disomy
Maternal uniparental disomy identified by analysis of microsatellite markers detected in 25%.
The last 5% of patients assumed to have imprinting defect it both DISH and UPD studes are
normal, mutation analysis can detect some imprinting center mutations, but not all.
Management Issues -->
Infancy: special feeding techniques, early intervention services, esp for PT, and screening for
Childhood: Counseling:
consideration of growth hormone therapy, monitoring of growth parameters,
Recurrence risks: these
dietary management, are less than eval
developmental 1% ifw/a implementation
deletion or UPDofistherapies
identifiedifand may be
needed, up to
50% for imprinting center defects.
management programs, screening for scoliosis, sleep study if disturbed sleep patterns reported
(and beforechanging phenotype
GH therapy from infancy to early childhood.
is instituted)
Adult: managmnet of psych problems if present, behavior and weight management,
Reproductive and Genetic Diseases

Marfan Syndrome
Presentation affects cardiovascular, ocular, and skeletal systems!
Cardiovascular aortic root dilation, dissecting aortic aneurysm, mitral valve
prolapse/regurg, dilation of pulmonary artery or descending aorta
Ocular dislocated lenses (ectopia lentis), detached retina, myopia
Skeletal tall stature, relatively long arms and legs compared to trunk, arachnodacytly (long
thin spider-like digits), dolichostenomelia (long thin extremetieis), limitation of elbow
extension, joint laxity, scoilisosi, pectus excavatum or carinatum, flat feet (pes planus),
protrusion acetrabulae)
Other dural ectasia, recurrent or incisional hernias, stretch marks (striae), spontaneous
pneumothorax, apical blebs, high-arched palate, dental crowding, typical facies
(dolichocephaly, malar hypoplasia, enopthalamos, retrognathia, downslanting palpebral
Marfan Syndrome the incidence is 1/10,000
25% of cases are due to new mutations
It is autosomal dominant with variable expression. It also shows allelic heterogeneity with
various mutations within the FBN1 gene on chromosome 15q21 protein is fibrillin

Lab Testing and Management

Lab test Diagnosis is made from clinical features and a family history!
Genetic testing by mutation scanning and sequence analysis detects b/w 70-90% of genetic
mutations in those individuals fulfilling diagnostic criteria. Thus, only sequence if fit criteria.
Genotype-phenotype correlations have not been elucidated, so genetic testing cannot predict
specific complications for any one individual. Thus, genetic testing is usually not performed!!
Management Issues
Cardiac features can be life-threatening and require life-long follow up. Obtain ECHO and
long term follow-up w/ cardiologist to assess need for medical and/or surgical intervention.
Monitor skeletal abnormalities.
Opthalomologic exams slit-lamp evaluation, follow up for myopia, lens subluxation, and
Genetic Counseling
Determine which relatives need counseling and evaluation.
Discuss genetic risks and lifestyle education no contact sports or extremely strenuous
Pregnant women w/ Marfan need high-risk OB and cardiac management b/c of the risk of
aortic dissection/rupture
Reproductive and Genetic Diseases

Neurofibromatosis Type I

At least 2 of the following:
- 6 or more caf au lait spots (CLS) 15 mm postpubertal or 5mm prepubertal
- 2 or more neurofibromas of any type or 1 plexiform neurofibroma
- Axillary or groin freckling (small CLS macules 5mm)
- Optic glioma
- 2 or more Lisch nodules (benign, raised iris hamartomas seen by slit lamp exam)
- A distinctive bony lesion (Dysplasia of sphenoid bone, thinning of long bone cortex)
- A 1st degree relative w/ NFI by independent diagnostic criteria
NF type I progresses w/ age, and some features are age-dependent. Children may only have
CLS. Lisch nodules and cutaneous fibromas usually develop in late childhood to adulthood.
Plexiform neurofibromas often appear to be congenital. There are increased risk for learning
problems (40-60%), seizures, HTN (due to rental artery stenosis or rarely pheocromocytoma)
and malignant neoplasms
NF type I has an incidence of 1/3000.
50% are due to new mutations!!!!
It is autosomal dominant with variable expression and nearly complete penetrance.
It also shows allelic heterogeneity o the NF1 gene chromosome 17q, protein is neurofibromin.

Lab testing and Management

Lab Test diagnosis depends on clinical features and family history. NF1 mutation anlaysis
is being offered on a clinical basis, although it is expensive and not helpful clinically.
A multi-step detection protocol including protein truncation testing, sequencing, FISH, and
Southern Blotting detects up to 95% of gene mutations in those individuals who meet criteria.
Gene sequencing along detects up to 89% of gene mutations.
Genotype-phenotype correlations have not yet been elucidated.
Management Issues Complications increase w/ age.
Some may only have CLS and cutaneous/subcutaneous nodules throughout life. Usual
progression is CLS at birth increasing in number, freckling and Lisch nodules before
adulthood, and neurofibromas later in adolescence/ early adulthood.
Some rarer complications are age-dependent: if severe mental retardation present it is evident
early, optic gliomas, and progressive scoliosis in childhood, plexiform neurofibromas before
Patients need developmental assessment and recommendations for school placement and help.
Opthmaology f/u (screen for optic glioma), monitor for HTN, HA, and chronic pain
elsewhere, rapid growth of neurofibromas, other neurological symptoms.
Surgical removal of neurofibromas are generally not recommended unless compromising
essential organ

Genetic Counseling
50% have mild manifestations and 30% have severe complications.
Intrafamilial variability is common.
First degree relatives need examination
Prenatal genetic diagnosis is feasible but cannot predict severity!
Puberty and pregnancy associated w/ increase in size and number of neurofibromas in some
Reproductive and Genetic Diseases