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A 23 Y/0 GIRL Delayed puberty hair loss & scant pubic hair & lack of axillary hair high gonadotropins level Infantile uterus and ovary 46 xx, inv 9 (11p 13q) Diabetes Hearing loss Hypothyroidism Low learning skills. Problem list. How can we approach to the patient?

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  1. 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

  2. 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

  3. Delayed puberty Absence 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)

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

  5. 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 ?

  6. FSH:40 LH:25*Hypergonadotropic hypogonadism*

  7. 46 XX inv(9)(11p 13q)

  8. Other forms of primary ovarian failure:

  9. 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 ?

  10. 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,habitualabortions or schizophrenia. • We analysedthe 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 identifed421 (1.6 %) cases of inv(9) without any concurrent cytogenetic pathology.

  11. 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

  12. The syndrome of gonadal dysgenesis(Turner syndrome) and its variants • The most commonform 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.

  13. 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 ?

  14. Pure gonadal dysgenesia • without chromosomal abnormalities • Pathogenesis The cause of the condition is often unclear. • 1-Abnormalities in the FSH-receptor • inactivating 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 histidyltRNAsynthetase have been described as the cause.

  15. XX and XY gonadal dysgenesis usual phenotype of 46,XX : NL stature sexual infantilism bilateral streak gonad NL female internal and external genitalia 1 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

  16. Diagnosis • Failure to produce sex hormones (both estrogens and androgens): secondary sex characteristics do not develop. The adrenalcan 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.

  17. Treatment • Her 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

  18. Aromatase deficiency (female) • Reduced estrogen • Increase testosterone • Female chromosome pattern: 46XX, NL internal reproductive organ • AT BIRTH: ambigus genitalia • IN 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

  19. Autoimmune oophoritis POF= POI ="premature menopause" = "premature ovarian failure primary 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

  20. 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

  21. CLINICAL MANIFESTATION: Unique features of autoimmune oophoritis: • 1- Enlarged cystic ovaries (early) • 2- Antiadrenalantibodies • 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,skinpigmentation

  22. Laboratory findings • 21-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 .

  23. In one report of three women with presumptive autoimmune oophoritis and multifollicular development, the following biochemical findings were noted : • Serum estradiol - androstenedione : low • Inhibin B : high This 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.

  24. 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 133pg/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.

  25. Histology • lymphocytic infiltration involving secondary and antral folliclesbut sparing primordial follicles • lymphocytic 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 .

  26. The diagnosis of autoimmune oophoritis is based upon: • 1- Clinical evidence of POI, including menstural dysfunction, low estradiol and high gonadotropin • 2- The presence of steroidogenic cell autoantibodies • 3- The exclusion of other causes of POI such as X chromosome defects and the FMR1 premutation

  27. Autoimmune endocrinopathy screening A 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

  28. TREATMENT The management is the same as for any woman with POI. Management focuses on: • Emotional health/psychosocial support • Consequences 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 reduced • Other autoimmune disorders

  29. APS1 = autoimmune polyendocrinopathy-candidiasisectodermaldystrophy (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 .

  30. Clinical manifestations • Hypoparathyroidism 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

  31. APS 2 more prevalent than type I Women 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 disease • type 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.

  32. galactosemia mutation in the galactose-1-phosphate uridylyltransferasegene (GALT) primary ovarian failure failure to develop puberty 1 or 2 amenorrhea premature menopause FTT ,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 Detected by newborn screening programs.

  33. FSH Receptor Resistance AR disorder A mutation in the extracellular ligand-binding domain of the FSH receptor Delayed (40%) or normal puberty but primary amenorrhea Hypergonadotropic ovarian dysgenesis with arrest of ovarian follicular development at the primary follicle stage and continued atresia Responsible for most cases of the resistant ovary syndrome.

  34. LH/hCG Resistance. females: • does not affect pubertal maturation • amenorrhea • high serum LH levels • normal FSH and estradiol concentrations.

  35. 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.

  36. FRAGILE X SX • the 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

  37. FRAGILE X SX MORE VARIABLE IN GIRL INTELLECTUAL DISABILITY ( 50% NL IN GIRL) AUTISM LONG –NARROW FACE PROMINENT FOREHEAD – CHIN MIDFACE HYPOPLASIA STRABISMUS SEIZURE

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