A 23 Y/0 GIRL Delayed puberty - PowerPoint Presentation

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A 23 Y/0 GIRLDelayed puberty hair loss & scant pubic hair & lack of axillary hairhigh gonadotropins levelInfantile uterus and ovary46 xx, inv 9 (11p 13q)DiabetesHearing lossHypothyroidismLow learning skills

Problem list

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How can we approach to the patient?Can chromosomal inversion 9 cause morbidity?What is the differential diadnosis ?What can we do for the patient ?Questions

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Delayed pubertyAbsence or incomplete development of secondary sexual characteristics bounded by an age at which 95 percent of children of that sex and culture have initiated sexual maturation.In United States: the upper 95th percentile for initial pubertal development is:12

years for girls

(breast development

: first

sign, Tanner

: B2)

14

years for boys (increase in testicular

size: first

sign, Tanner

:

G2

).

In

girls

(pubic

hair, axillary hair and odor, and acne) are manifestations of adrenal activity (

adrenarche

),

which typically occurs

about

6

months

after the start of

true puberty

(

ie

, ovarian maturation, heralded by breast development

)

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Impairment of any or all functions of the gonads: Testosterone and sperm in men Estradiol, progesterone, and ova in females.

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How can we approach to the patient?Can chromosomal inversion 9 cause morbidity?What is the differential diadnosis ?What can we do for the patient ?

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FSH:40 LH:25 *Hypergonadotropic hypogonadism*

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46 XX inv(9)(11p 13q)

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Other forms of primary ovarian failure:

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How can we approach to the patient?Can chromosomal inversion 9 cause morbidity?What is the differential diadnosis ?What can we do for the patient ?

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Pericentric inversion of human chromosome 9 [inv(9)] is a relatively common cytogenetic fnding.considered a clinically insignifcant variant of the normal human karyotype. However, numerous studies suggested its possible association with certain pathologies, e.g., infertility,habitual

abortions

or

schizophrenia

.

We

analysed

the incidence

of

inv

(9) and the spectrum of clinical indications for karyotyping among

inv

(9) carriers in

three medical

genetics departments in Prague

.

In their cytogenetic databases, among

26,597 total

records

we

identifed

421 (1.6 %) cases of

inv

(9)

without any concurrent cytogenetic pathology.

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The incidence of inv(9) calculated in this way from diagnostic laboratory data does not differ from the incidence of inv(9) in three specifc population based samples of healthy individuals (N = 4,166) karyotyped for preventive (amniocentesis for advanced maternal age, gamete donation) or legal reasons (children awaiting adoption). The most frequent clinical indication in inv(9) carriers was “idiopathic reproductive failure” – 37.1 %. The spectra and percentages of indications in individuals with inv(9) were further statistically evaluated for one of the departments (N = 170) by comparing individuals with inv(9) to a control group of 661 individuals with normal karyotypes without this inversion. The proportion of clinical referrals for “idiopathic reproductive failure” among inv(9) cases remains higher than in controls, but the difference is not statistically

signifcant

for both genders combined. Analysis in separated genders showed that the incidence of “idiopathic reproductive failure” could differ among

inv

(9) female and male carriers

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The syndrome of gonadal dysgenesis (Turner syndrome) and its variantsThe most common form of hypergonadotropic hypogonadism

(female)

99

% of 45,X

:

abort

spontaneously

1

in 15

spontaneous abortions

has a 45,X karyotype.

female phenotype

short

stature

sexual infantilism

various

somatic abnormalities.

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How can we approach to the patient?Can chromosomal inversion 9 cause morbidity?What is the differential diadnosis ?What can we do for the patient ?

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Pure gonadal dysgenesiawithout chromosomal abnormalitiesPathogenesisThe cause of the condition is often unclear.1-Abnormalities in the FSH-receptorinactivating mutations of the FSH receptor gene (FSHR; 2p21-p16), mutations in the BMP15 gene (Xp11.2) and mutations in the

NR5A1 gene (9q33

). Inactivating FSHR mutations are inherited in an autosomal recessive manner, BMP15 mutations are inherited in an X-linked manner - NR5A1 mutations are autosomal dominant

2- Germ cells atresia

Familial cases of XX gonadal dysgenesis are on record. In one family mutations in the mitochondrial

histidyl

tRNA

synthetase

have been described as the cause.

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XX and XY gonadal dysgenesisusual phenotype of 46,XX :NL staturesexual infantilismbilateral streak gonadNL female internal and external genitalia1 amenorrhea

The

streak gonad occasionally produces estrogens or

androgens

Incomplete forms

:

hypoplastic

ovaries that produce

enough estrogen

to cause

some breast development

and a

few

menstrual periods

, followed by secondary amenorrhea

.

Associated

with

congenital

malformations.

Perrault

syndrome

In 1951, Perrault reported the association of gonadal dysgenesis and deafness

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DiagnosisFailure to produce sex hormones (both estrogens and androgens): secondary sex characteristics do not develop. The adrenal can make limited amounts of androgens and are not affected by this syndrome: most of these girls will develop pubic hair, though it often remains

sparse.

In Evaluation

of

their delayed

puberty

:

presence

of pubic hair

, but

elevation of

gonadotropins

The

next

steps:

The

karyotype reveals XX chromosomes

and the

imaging demonstrates the presence of a uterus but no ovaries (the streak gonads

)

At

this point it is usually possible for a physician to make a diagnosis of XX gonadal dysgenesis.

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TreatmentHer gonads cannot make estrogen, so her breasts will not develop and her uterus will not grow and menstruate until she is given estrogen. This is often given through the skin now.Her gonads cannot make progesterone, so her menstrual periods will not be predictable until she is given a progestin, still usually as a pill.Her gonads cannot produce eggs so she will not be able to conceive children naturally. A woman with a uterus but no ovaries may be able to become pregnant by implantation of another woman's fertilized egg (embryo transfer). Calcium and vitamin D supplements

Psychological

support

Prognosis

appropriate

management: physiological

and clinical outcome for patients is

good

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Aromatase deficiency (female)Reduced estrogen Increase testosterone Female chromosome pattern: 46XX, NL internal reproductive organAT BIRTH: ambigus genitaliaIN ADOLESCENCE: don’t develop secondary sexual characteristics Hirsutism -Hyerglycemia (the body dosent respond to the insulin correctly)- Tall (excessive growth of long bones )-Delayed bone age: slowed mineralization of bones

-

Osteoporesis

:

thinnig

of the bone

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Autoimmune oophoritisPOF= POI ="premature menopause" = "premature ovarian failureprimary hypogonadism -before the age of 40 years -in women- with a normal karyotype.

EPIDEMIOLOGY

— 4 %of

women who present

with POF

(rare)

May

occur as part of

type I and type II syndromes of

polyglandular

autoimmune

failure

There

is

strong histologic evidence

that primary ovarian insufficiency, when it occurs in association with adrenal

autoimmunity

3

%

of

spontaneous

POI develop adrenal

insufficiency

300-fold

increase compared with the general population.

POF also described with

nonendocrine

autoimmune

: SLE, PA,

and

MG

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PATHOGENESIS :ovarian autoimmunity initiation is unknown .1-"molecular mimicry," exposure to a virus or other substance similar to ovarian tissue ….. lymphocytes or antibodies might react with ovarian tissue.

2- failure

in immune

regulation

(AIRE mutations )

might develop…

loss

of specific tolerance

to

ovarian component

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CLINICAL MANIFESTATION:Unique features of autoimmune oophoritis:1- Enlarged cystic ovaries (early)2- Antiadrenal antibodies 3- Evidence of theca cell destruction (not granulosa)

OTHER S :

Oligo - amenorrhea , arrest of puberty (intermittent

ovarian function

: 50

to 75

%)

Estradiol deficiency ( hot flash & vaginal dryness )

Irregular

menses usually precedes

the

symptomatic

adrenal insufficiency

adrenal

insufficiency can precede POI

:

anorexia

, weight loss, vague abdominal pain, weakness, fatigue, salt

craving,skin

pigmentation

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Laboratory findings21-hydroxylase autoantibodies or adrenal autoantibodies is sufficient to make the diagnosis of autoimmune oophoritis in a woman with proven spontaneous POI. Another autoimmune disorder does not indicate the POI is autoimmune. The presence of thyroid autoantibodies does not prove autoimmune ovarian failure, but identifies women at risk for developing autoimmune thyroid disorders.The predictive value of

serum

anti-ovarian antibody test to identify these women is poor

.

As an example, in a study of 26 women with 46,XX spontaneous POI and 26 normal cycling women, 50 percent (13 of 26) of women with POI and 31 percent (8 of 26) of normal women had ovarian antibodies .Thus, this test has an unacceptably

high false-positive rate

.

ovarian

biopsy to detect autoimmune

oophoritis

was done in the past, we currently do not recommend this approach in view of the availability of validated autoantibody testing for steroidogenic cell autoimmunity .

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In one report of three women with presumptive autoimmune oophoritis and multifollicular development, the following biochemical findings were noted :Serum estradiol - androstenedione : lowInhibin B : highThis observation of normal inhibin B production in the absence of estradiol suggests that theca cells are selectively affected while granulosa cells are spared*Inhibin downregulates FSH*(LH) : In the postmenopausal range(FSH) : The

upper limit of normal for premenopausal

women

This pattern is different from normal menopause and other causes of POI, where serum FSH concentrations generally are higher than LH concentrations.

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IN 2008 In a second study, serum inhibin B were significantly higher in 22 women with autoimmune POI (and steroid cell autoantibodies) compared with 71 women with non-autoimmune "idiopathic" POI (median concentrations 109 versus 18 pg/mL,) The authors concluded that cutoff values of 133

pg

/mL for total inhibin and

60

.5

pg

/mL for inhibin B provided

86 percent sensitivity

and

81 to 85 percent specificity

for autoimmune versus idiopathic POI

.

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Histology lymphocytic infiltration involving secondary and antral follicles but sparing primordial follicleslymphocytic infiltration was most intense in the theca of developing follicles These findings are found almost exclusively in women who have circulating antibodies against adrenal antigens .The fact that the inflammatory reaction is confined to growing follicles that have a theca suggests that the antigens are fully expressed only in these follicles, consistent with the hypothesis that

steroid hormone-producing cells

express the antigens that stimulate the

immune response .

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The diagnosis of autoimmune oophoritis is based upon:1- Clinical evidence of POI, including menstural dysfunction, low estradiol and high gonadotropin2- The presence of steroidogenic cell autoantibodies3- The exclusion of other causes of POI such as X chromosome defects and the FMR1 premutation

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Autoimmune endocrinopathy screeningA recent study comparing neutrophile to lymphocyte ratio NLR between POL and normal population:NLR was significantly lower in POI cases (P < 0.001) NLR ratio 1.5 or less : independent risk factor for POI Although increases in NLR are associated with increases in the severity of inflammatory disorder, prior literature has proposed that lower NLRs are associated with the presence of autoimmunity or chronic inflammation. timely identification of abnormal immunological activity in the setting of suspected POI could help to confirm a diagnosis of autoimmune POI and theoreticall restore ovarian function with early administration of appropriate

immunosuppressive treatment

regimen

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TREATMENTThe management is the same as for any woman with POI. Management focuses on:Emotional health/psychosocial supportConsequences of estrogen deficiency (vasomotor symptoms, vaginal atrophy, osteoporosis, and a possible increased risk of coronary heart disease and stroke if not treated with estrogen)Contraception and fertility, which is dramatically reducedOther autoimmune disorders

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APS1= autoimmune polyendocrinopathy-candidiasisectodermal dystrophy (APECED)AR - females slightly more than males Genetics — APECED due to mutations in autoimmune regulator (AIRE) gene on chromosome 21q22.3 It is most common among Finns, Sardinians, and Iranian Jews; sporadic cases also have been identified elsewhere, including most European countries.

36 %

of women with APECED exhibited ovarian failure before age 20

Autoimmune

oophoritis

occurs in

20%

of patients with autoimmune adrenal

insuffciency

.

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Clinical manifestationsHypoparathyroidism or chronic mucocutaneous candidiasis is usually the first manifestation, The hypoparathyroidism may occur in association with antiparathyroid gland antibodies (against the calcium-sensing receptor) Oral mucous SCC has been rarely reported in association with the candidiasis of APECED Adrenal insufficiency usually develops later, at age 10 to 15 years

. The antigen targets are adrenal enzymes including P450scc (side-chain cleavage enzyme), P450c17 (17-alpha-hydroxylase), and P450c21 (21-hydroxylase)

Adrenal ab

has a high (92 percent)

positive predictive value

for development of adrenal insufficiency

Malabsorption

and other gastrointestinal disorders occur in about 25

percent

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APS 2more prevalent than type IWomen 3 times more than men .onset : childhood to late adulthood primary adrenal insufficiency is its principal manifestation .Antibodies to steroidogenic enzymes also are present Autoimmune thyroid diseasetype 1 diabetes mellitus are also common formerly referred to as "Schmidt's syndrome."

Approximately

one-half of cases are familial and several modes of inheritance (autosomal recessive, autosomal dominant, and polygenic) have been reported.

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galactosemiamutation in the galactose-1-phosphate uridylyltransferase gene (GALT) primary ovarian failurefailure to develop puberty1 or 2 amenorrhea premature menopauseFTT ,Jaundice, hepatomegaly, cataract ,hemolytic anemia

Dietary

restriction

have not

prevented the ovarian

failure

Dx

: absence of GALT activity RBCs (Gold )

pathogenesis of ovarian toxicity:

unclear

D

etected

by newborn

screening programs

.

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FSH Receptor ResistanceAR disorder A mutation in the extracellular ligand-binding domain of the FSH receptorDelayed (40%) or normal puberty but primary amenorrheaHypergonadotropic ovarian dysgenesis with arrest of ovarian follicular development at the primary follicle stage and continued atresiaResponsible for most cases of the resistant ovary syndrome.

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LH/hCG Resistance.females: does not affect pubertal maturation amenorrhea

high serum LH levels

normal

FSH and estradiol concentrations.

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Noonan Syndrome. AD (pseudo-Turner syndrome, Ullrich syndrome) :webbed neck, ptosis, down-slanting palpebral fssures, low-set ears, short stature, cubitus valgus, and lymphedema, which explains why this phenotype has been called pseudo-Turner syndrome. Features that differentiate from those with Turner syndrome include :triangular

facies

, pectus

excavatum

, right-sided heart disease

compared

with the left-sided heart disease in

Turner syndrome

, hypertrophic cardiomyopathy, varied

blood clotting

defects, and an increased incidence of

mental retardation

.

Stature is decreased

after normal birth length and weight:

Females

with Noonan syndrome have normal ovarian function.

Puberty

is often delayed as 44% of girls enter puberty after age 13 years.

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FRAGILE X SXthe most common inherited cause of mental retardation and autism abnormal expansion of an unstable trinucleotide (CGG) repeat sequence in the FMR1 (Fragile X Mental Retardation) gene, located on the long arm of the X chromosome (Xq27.3). The gene normally contains about 30 CGG repeats but in those with Fragile X syndrome, the number exceeds 200. The prevalence of premutations : 14% in women with familial

POF

Women

with POF therefore should be offered testing

for FMR1

premutations

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FRAGILE X SXMORE VARIABLE IN GIRLINTELLECTUAL DISABILITY ( 50% NL IN GIRL)AUTISMLONG –NARROW FACEPROMINENT FOREHEAD – CHINMIDFACE HYPOPLASIA

STRABISMUS

SEIZURE

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17 hydroxylase deficiency17-Hydroxylase deficiency syndrome is a rare genetic disorder of steroid biosynthesis : decreased GCs and sex steroids increased synthesis of mineralocorticoid precursors. It is a rare form of congenital adrenal hyperplasia resulting from loss-of-function mutations involving the CYP17 gene.This syndrome is characterized by both of the following:Decreased production of glucocorticoids and sex steroids, resulting in sexual infantilism in 46,XX

females and ambiguous genitalia in 46,XY males

Increased synthesis of mineralocorticoid precursors, resulting in varying degrees of

hypertension and hypokalemia

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WHAT S THE DIAGNOSIS?

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WHAT CAN I DO?FMR1 Gene for fraxile x sx ?Anti 21 hydroxylase ab for autoimmune POL ?Inhibin for GD ?

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How can we approach to the patient?Can chromosomal inversion 9 cause morbidity?What is the differential diadnosis ?What can we do for the patient ?

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Hormonal Substitution Therapy in HypogonadismGoal: to approximate normal adolescent developmentInitial therapy: ethinyl estradiol 5 mg by mouth or conjugated estrogen 0.3 mg (or less) by mouth daily for 4-6 mo or preferably

estradiol

transdermally

After 6

mo

of therapy (or sooner if breakthrough bleeding occurs

), begin

cyclic therapy:

Estrogen:

frst

21 days of month

Progestagen

: (e.g.,

medroxyprogesterone acetate 5 mg PO) 12

th

to 21st

day of

month

Gradually increase dose of estrogen over next

2-3

yr

to

conjugated estrogen

0.6-1.25

mg or

ethinyl

estradiol 10-20 mg daily

for

frst

21 days of month or estradiol

patch

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HRT : Women with POI seeking fertility may benefit from pSSRPssr = psychological sex steroid replacement (Transdermal estradiol & vaginal progesterone)Preserving neurocognitive function :Neurocognitive

decline has been reported in

the setting

of estrogen

deficiency

HRT did not counteract the

negativecognitive

effects when taken during

premature menopause

; however, it may potentially

benefit visual memory

Androgen :

Testosterone improving

general and

sexual well-being

has been

investigated

IS

controvertial

– Safety?

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Compounded bioidentical hormones:DHEA:significantly increased antral follicle count after 16 weeks of treatment, but did not significantly affect anti-mullerian hormone or FSH level?Fertility preservation:The most optimal autografting locations along with detecting residual follicle count in POI patients, cryopreservation of one ovary through

this method

may serve as a means of early fertility preservation in young

patients

Alternative management strategies:

Exercise , ca

, D , acupuncture

significant reduction of FSH & LH &Self rate

anexiety

score ( but

controvertial

)

,…

Psychopharmacological

management: bupropion

is

osteoprotective

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Autoimmune endocrinopathy screeningNLR was significantly lower in POI cases (P < 0.001) that an NLR ratio 1.5 or less was an independent risk factor for POI Although increases in NLR are associated with increases in the severity of inflammatory disorder, prior literature has proposed that lower NLRs are associated with the presence of autoimmunity or chronic inflammation. A more accurate determination of the cause of POI will help to establish more specialize treatment regimens thereby potentially

producing More effective outcomes.

timely

identification of abnormal immunological activity in

the setting

of suspected POI could help to confirm

a diagnosis

of autoimmune POI and

theoreticall

restore

ovarian function with early

administration of

appropriate

immunosuppressive treatment

regimen