Disorders of Sexual Development

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1 Disorders of Sexual Development 22 nd KSOGA Panel Discussion 8 November

2 Disorders of Sexual Development and Differentiation DSD 8 November

3 CONFUSION Disorders of SEX development 8 November

4 CONFUSION Disorders of SEX Different iation 8 November

5 SEX FEMALE.. FEMALE.? 8 November

6 DISORDERS OF SEX in BRAIN 8 November

7 DISORDERS OF SEX in BRAIN 8 November

8 SEX and GENDER? 8 November

9 DR. ANITA WHAT IS THE MEANING OF GENDER? 8 November

10 Sex and Gender Gender social meaning attached to being male or female gender identity - sense of being male or female gender role - expectations about how a male or female should behave 8 November

11 Defining Sex and Gender Gender identity (Psychological sex) Inner sense of owns maleness / femaleness. Sex of rearing Gender role 8 November

12 GENDER.. 8 November

13 DR. PREMA PRABHUDEV WHAT IS THE MEANING OF SEX? 8 November

14 CONFUSION..SEX..at different times 8 November

15 SEX & GENDER Sexual identity (Organic sex) The biologic sexual differentiation Chromosomal sex Gonadal sex Internal genital sex External genital sex Hormonal sex 8 November

16 Sex and Gender Androgyny - hermaphrodism sex: possessing both male and female reproductive organs gender: possessing both male and female qualities 8 November

17 DR. JYOTHI SHETTY HOW WILL YOU CLASSIFY DSD 8 November

18 CLASSIFIATION OF DSD Sex Chromosome DSD 46, XY DSD 46, XX DSD 45, X Turner syndrome 47, XXY - KFS Disorders of Gonadal (Testicular) Development 45, X/46, XY Mixed Gonadal Complete GD dysgenesis, Ovotesticular DSD Partial GD Gonadal Regression 46, XX / 46 XY (Chimeric, Ovotesticular DSD Ovotesticular DSD) Disorders Of Androgen Synthesis StAR mutation CAIS, PAIS. LH receptor defects Disorders AMH & AMH receptors Disorders of Gonadal (ovarian) Development Ovotesticular DSD (SRY translocation) Testicular DSD (SRY dup SOX9) Gonadal dysgenesis Androgen excess Fetal (CAH) Feto placental Maternal (Luteoma) 8 November

19 DR. RAMESH BABU DO YOU AGREE WITH JYOTHI SHETTY? 8 November

20 CLASSIFICATION OF INTERSEX 1. Virilization of genitically female foetus Female pseudohemaphroditism (xx- MALE) 2. Incomplete musculinization of genitically male foetus Male pseudohermaphroditism (XY-FEMALE) 3. The presence of both ovarian and testicular tissue in the same individual True hermaphroditism 4. Chromosomal abnormality Mixed gonadal dysgenesis ( 45,X0 / 46,XY) 8 November

21 DR. SHRIPAD HEBBAR CAN YOU JUST OUT LINE THE DEVELOPMENT OF MALE AND FEMALE SEX? 8 November

22 Female development Neutral Development Urogenital sinus Mullerian ducts Female external genitalia. Lower part of vagina Absence of androgen exposure Female internal genital Organs. Most of upper vagina. Cervix and uterus. Fallopian tubes 8 November

23 Summary of Normal Sex Differentiation genetic sex is determined at fertilization. testes develop in XY fetus, ovaries develop in XX fetus. XY fetus produces MIS and androgens and XX fetus does not. XY fetus develops Wolffian ducts and XX fetus develops Mullerian ducts. XY fetus masculinizes the female genitalia to make it male and the XX fetus retains female genitalia. 8 November

Normal Prenatal Development: The Brain Sexual differentiation: Male: Testosterone secreted into the blood reaches the brain testosterone converted to estradiol and dihydrotestosterone in the brain

24 Normal Prenatal Development: The Brain Sexual differentiation: Male: Testosterone secreted into the blood reaches the brain testosterone converted to estradiol and dihydrotestosterone in the brain estradiol masculinizes the brain Female: alpha-fetoprotein binds to estradiol prevents estradiol from entering the brain protects female brains from being masculinized by estradiol 8 November

25 DR. ANITA CAN YOU TELL THE SECRET OF SEX DEVELOPMENT? 8 November

26 Default sex FEMALE Male hormones are needed to promote differentiation into a male 8 November

27 TRANSSEXUALITY 8 November

28 DR. SATISH NAYAK WHAT ARE SEX CHROMOSOME DSDs? 8 November

29 SEX CHROMOSOME DISORDERS Disorders of Gonadal Differentiation and Development 8 November

30 DR. PREMA PRABHUDEV CAN YOU TELL ME SOMETHING ABOUT CLINICAL FEATURES OF TURNER s SYNDROME? 8 November

31 Turner s Syndrome (45 X0) Absence of the second X or Y chromosome means no testicular development Female phenotype Oogonia are unable to complete their development only the stroma of the ovary are present (streak ovaries) No oestrogen production at puberty Absent secondary sexual characters Genes involved in achieving final height are shared by sex chromosomes Absence of 1 sex chromosome Short stature LH, FSH 8 November

Turner s Syndrome (45,XO) No oocytes remain in the ovaries, which become streaks Fertility = 60% pregnancy rate w/art Ovum donation for those with bilateral streaks 1 in 2500 live births 60% are

renal agenesis= 20% malrotation= 15% multiple renal arteries = 90% Four classic features: female phenotype short stature lack of secondary sexual characteristics a variety of somatic abnormalities:

32 Turner s Syndrome (45,XO) No oocytes remain in the ovaries, which become streaks Fertility = 60% pregnancy rate w/art Ovum donation for those with bilateral streaks 1 in 2500 live births 60% are 45,XO and 40% are mosaics Y chromosomal material masculinization & gonadoblastoma (30%) 33% - 60% have structural or positional abnormalities of the kidney horseshoe kidney = 10%, duplication or renal agenesis= 20% malrotation= 15% multiple renal arteries = 90% Four classic features: female phenotype short stature lack of secondary sexual characteristics a variety of somatic abnormalities: Webbed neck Wide spaced nipples Broad chest (shield) Cubitus valgus Short stature peripheral edema at birth, short 4th metacarpal, hypoplastic nails, multiple 8 November 2011 pigmented nevi, coarctation of the aorta, 32 and renal anomalies

33 Turner syndrome work up IVP or renal USG Echocardiography Audiometry TFT (annually) & Ab (at least one) Lipid profile & glucose metabolism (annually) Annual pelvic examination & appropriate screening for gonadal neoplasm as an adnexal mass Expert consultation to pursue further analysis with X- and Y- specific DNA probes 8 November

34 DR. SREELAXMI WHAT ARE THE SALIENT CLINICAL FEATURES OF KLINEFELTER s SYNDROME? 8 November

35 Klinefelter's syndrome 8 November 2011 (Williams Textbook of Endocrinology, 10 th ed, 2003) 35

Seminiferous Tubule Dysgenesis (Klinefelter's syndrome) Syndrome characterized by eunuchoidism, gynecomastia, azoospermia, increased gonadotropin levels, and small, firm testes, 47,XXY karyotype

36 Seminiferous Tubule Dysgenesis (Klinefelter's syndrome) Syndrome characterized by eunuchoidism, gynecomastia, azoospermia, increased gonadotropin levels, and small, firm testes, 47,XXY karyotype nondisjunction during meiosis 1 of 1000 liveborn males associated with 48,XXYY; 49,XXXYY; 48,XXXY; 49,XXXXY; 46,XY/47XXY Gynecomastia can be quite marked at pubertal development 8 X risk for breast carcinoma compared with normal males Seminiferous tubules degenerate and are replaced with hyaline Fertility, with the benefit of ICSI, has been reported in one patient decreased androgens prevents normal secondary sexual development poor muscle development, the fat distribution is more female than male. Normal amounts of pubic and axillary hair, but facial hair is sparse. Patients tend to be taller than average, due to disproportionately long legs Predisposed to malignant neoplasms of extragonadal germ cell origin. Androgen supplementation to improve libido & reduction mammoplasty surveillance for breast carcinoma 8 November

MIXED GONADAL DYSGENESIS Combined features of Turner s syndrome and male pseudohermaphroditism Short stature Streak gonad on one side with a testis on the

37 MIXED GONADAL DYSGENESIS Combined features of Turner s syndrome and male pseudohermaphroditism Short stature Streak gonad on one side with a testis on the other Unicornuate uterus & fallopian tube- side of streak gonad Karyotype 46XY / 45X0 Considrable variation in the sexual phenotype 11/8/2011 JOSHI SUYAJNA D. 37

38 True Hermaphroditism Individuals who have both testicular tissue with well-developed seminiferous tubules and ovarian tissue with primordial follicles, which may take the form of one ovary and one testis or, more commonly, one or two ovotestes. External genitalia and internal duct structures of true hermaphrodites display gradations between male and female (Williams Textbook of Endocrinology, 10th ed, 2003) 11/8/2011 JOSHI SUYAJNA D. 38

39 True Hermaphroditism In most patients, the external genitalia are ambiguous but masculinized to variable degrees, and 75% are raised as male Internal ductal development are influenced by ipsilateral gonad Fallopian tubes are consistently present on the side of the ovary a vas deferens is always present adjacent to a testis Fallopian tube is present with 66% of ovotestes, vas or both in 33% Most have urogenital sinus and and uterus 80% of those raised as male have hypospadias and chordee Ovaries usually on left in normal position, testis usually on right and located anywhere along path of descent 60% of gonads palpable in canal or labia are ovotestes 11/8/2011 JOSHI SUYAJNA D. 39

40 True Hermaphroditism Ovarian portion of the ovotestis is frequently normal, whereas the testicular portion is typically dysgenetic 66% of patients are 46 XX Gonadal tumors is approximately 10% in 46,XY true hermaphroditism and 4% in 46,XX true hermaphroditism Most important aspect of management in true hermaphroditism is gender assignment Sex assignment should be based on the functional potential of external genitalia, internal ducts, and gonads, according to the findings at laparoscopy or laparotomy. Unlike patients with most other forms of gonadal dysgenesis, true hermaphrodites have the potential for fertility if raised as female with the appropriate ductal structures Males, remove ovaries and/or ovotestis and mullerian duct structures consider gonadectomy Females remove all testicular and wolffian structures 11/8/2011 JOSHI SUYAJNA D. 40

41 TRUE HERMAPHRODITISM Gonads : - ovary one side and testis on the other or - bilateral ovotestis Karyotype : 46,XX most common(57%); XY(13%) and XX/XY(30%) Internal genitalia : Both mullerian and wolffian derivates Phenotype is variable Gonadal biopsy is required for confirming diagnosis 11/8/2011 JOSHI SUYAJNA D. 41

42 DYSEMBRYOGENESIS genital ambiguity with associated anomalies Can occur in both genitic males and genitic females Most common genital malformation : - Penoscrotal transposition - Agenesis of phallus in a genitic male Coexistence of other caudal or urologic abnormalities should strongly suggest dysembryogenisis 11/8/2011 JOSHI SUYAJNA D. 42

43 Drugs with Androgenic side effects ingested during pregnancy - Testosterone - Synthetic progestins - Danocrine - Diazoxide - Minoxidil - Phenetoin sodium - Streptomycin - Penicillamine 11/8/2011 JOSHI SUYAJNA D. 43

44 How many children are born with DSD conditions? A conservative estimate is that 1 in 2000 children born will be affected by an intersex condition. 98 % of affected babies are due to congenital adrenal hyperplasia 8 November

45 DR. SHRIPAD HEBBAR WHAT IS MEANING OF FEMALE PSEUDOHERMAPHODITISM? 8 November

46 FEMALE PSEUDOHERMAPHRODITISM EXCESS FETAL ANDROGENS Congenital adrenal hyperplasia 21 -hydroxylase deficiency 11-hydroxylase deficiency 3ß-hydroxysteroid dehydrogenase deficiency EXCESS MATERNAL ANDROGENS Maternal androgen secreting tumours (ovary, adrenal) Maternal ingestion of androgenic drugs 8 November

47 DR. SREELAXMI CAN YOU TO TELL THE IMPORTANT FEATURES OF CAH? 8 November

Female Pseudohermaphroditism 46,XX individuals with

ambiguous genitalia CAH is most common cause Uncommon

tumors in the mother Marked virilization with

48 Female Pseudohermaphroditism 46,XX individuals with ovaries have a partially masculinized phenotype and ambiguous genitalia CAH is most common cause Uncommon etiologies: Maternal ingestion of androgens Virilizing tumors in the mother Marked virilization with hypospadiac-appearing phallus clitoromegaly labioscrotal fusion 8 November

49 21-hydrxylase deficiency congenital adrenal hyperplasia Cholesterol Pregnenolone Progesterone 17-OH progesterone Pituitary ACTH Adrenal cortex 21-hydroxylase Cortisol Androgens Cortisol Androgens 8 November

50 CAH Looking for an urogenital opening 8 November

51 CAH Urogenital opening NOT seen 8 November

52 CAH Urogenital opening seen 8 November

Congenital adrenal hyperplasia The commonest cause of genital ambiguity at birth 21-Ohas deficiency is most common form Autosomal reccessive Salt wasting form may be

53 Congenital adrenal hyperplasia The commonest cause of genital ambiguity at birth 21-Ohas deficiency is most common form Autosomal reccessive Salt wasting form may be lethal in neonates SERUM 17OH-progesterone (21OHase) SERUM deoxycorticosterone, 11-deoxycotisol (11- OHase) Treatment : cortisol replacement and? Surgery 8 November

54 DR. SHRIPAD HEBBAR WHAT IS MALE PSEUDOHERMAPHRODITISM CAN OU DIGNOSE IT AT BIRTH 8 November

Enzymatic testicular failur Failure to utelize testosterone 5-alpha-reductase deficiency Androgen

55 Male pseudohermaphroditism (XY- FEMALE) Failure to produce testosterone Pure XY gonadal dysgenesis (swyer s syndrome) Anatomical testicular failure (testicular regression syndrome) Leydig-cell agenesis Enzymatic testicular failur Failure to utelize testosterone 5-alpha-reductase deficiency Androgen receptor deficiency * Complete androgen Insensitivity (TFS) * Incomplete androgen Insensitivity 8 November

56 Swyer s syndrome 46, XY No SRY OR its receptors STREAK GONADS - NO MIF (Uterus +) - NO SEX STEROIDS Female external Genitalia Female Internal Genitalia 8 November

57 Testicular regression syndrome (congenital anorchia) 46-XY/SRY Testis MIF (self destruction) ± testosterone ± DHT Female or ambiguous External genitalia ± Male Internal genitalia 8 November

58 46-XY/SRY Leydig-cell agenesis TESTIS MIF ( partial/ complete absence Of leydig-cells) No or testosterone No or DHT Female or ambiguous external Genitalia ± Male Internal Genitalia 8 November

46-XY/SRY Testicular enzymatic failure Testis MIF (defects in testosterone Synthesis) testosterone precursors DHT Ambiguous External Genitalia Male Internal Genitalia

59 46-XY/SRY Testicular enzymatic failure Testis MIF (defects in testosterone Synthesis) testosterone precursors DHT Ambiguous External Genitalia Male Internal Genitalia Autosomal recessive enzyme deficiency : desmolase -3-ß-ol-dehydrogenase hydroxylase -17,20-desmolase -17-ß hydroxysteroid oxyreductase 8 November

60 46-XY/SRY Testis MIF 5-alpha-reductase deficiency Testosterone 5- -rductase DHT Female or Ambiguous external Genitalia Male Internal Genitalia 8 November

61 DR. JYOTHI SHETTY WHAT ARE THE FEATURES OF TESTICULAR FEMINISATION SYNDROME? 8 November

62 46-XY/SRY TESTIS MIF Testosterone Testicular feminization syndrome 5- -reductase DHT Absent androgen receptors Female External Genitalia Male Internal Genitalia 8 November Incomplete form Ambigious genitalia

63 Diagnosis of XY Female Testosterone concentration Low Concentration of Testosterone precurcers Normal Male level DHT High Low Low Normal Testicular enzyme Failure Absent testes or Absent leydig-cell Surgical exploration 5 -reductase Deficiency Testicular Feminization Syndrome 8 November

64 ACTUAL PROBLEM.. 8 November

65 DR. ANITA WHAT ARE THE CLINICAL PRESENTATIONS OF DSD 8 November

66 How do DSD present in clinical practice? Atypical genitalia at birth is the common presentation Atypical genitalia presenting late in childhood and adolescence Primary amenorrhea, delayed puberty or atypical secondary sexual features Infertility Premature menopause 8 November

67 CLINICAL PRESENTATION OF DSD AT BIRTH Ambiguous genitalia DURING CHILDHOOD Heterosexual features AT ADOLESSCENCE Delayed or Heterosexual Puberty 8 November

68 DR. SREELAXMI HOW DOES A NORMAL TERM FEMALE EXTERNAL GENITALIA LOOK LIKE? 8 November

69 What s normal in a term newborn? Female: Vaginal opening fully visible: 3-4 mm slit or stellate orifice with heaped-up mucosa Clitoris width 2-6 mm Absence of gonads in labia majora or inguinal region 8 November

70 DR. SREELAXMI HOW DOES A NORMAL MALE LOOK LIKE IN A TERM MALE CHILD? 8 November

71 What s normal in a term newborn? Male: Urethra at tip of glans (may be inferred by a fully developed foreskin) Penis of normal stretched length (2.5-5 cm) and diameter ( cm) Bilateral testes of normal size (8-14 mm) in the scrotal sacs 8 November

72 DR. PREMA PRABHUDEV WHAT IS AMBIGUOUS GENITALIA? 8 November

73 Ambiguous genitalia: what is it? Evaluation of DSD problem required for: 1. Male-appearing genitalia with micropenis, mod/severe hypospadias, bilateral cryptorchidism, or two mild defects (e.g. mild hypospadias and unilateral cryptorchidism) 2. Female-appearing genitalia with posterior labial fusion, clitorimegaly, or a labial or inguinal mass 8 November

74 How would you evaluate a newborn baby with genitalia as shown below? 8 November

75 AMBIGUOUS GENITALIA AT BIRTH The external genital organs look unusual, making it impossible to identify the sex of the newborn from its outward appearance. Any one of the following : A small, hypospadiac phallus and unilaterally undescended gonad. An enlarged phallus with bilaterally impalpable gonads. An enlarged phallus and a vagina in the same infant. 8 November

76 DR. JYOTHI SHETY WHAT ARE THE PRINCIPALS OF MANAGEMENT OF AMBIGUOUS GENITALIA AT BIRTH? 8 November

77 MANAGEMENT OF NEWBORN WITH AMBIGUOUS GENITALIA GENERAL GIUDELINES Medical and social emergency Avoid immediate declaration of sex Proper counselling of the parents Team management; obstetrician, neonatologist, pediatric endocrinolgist, genetist and paediatric surgeon. 8 November

78 MANAGEMENT OF NEWBORN WITH AMBIGUOUS GENITALIA DIAGNOSIS History : pregnancy; family Detailed examination : abdomen; pelvis; external genitalia; urethral and anal openings. Federman s rule: a palpable gonad below the inguinal ligament is testes until proven otherwise 8 November

79 MANAGEMENT OF NEWBORN WITH AMBIGUOUS GENITALIA Investigations Rule out cong. Adrenal hyperplasia: Serum electrolytes; 17-OHP level and urinary levels of 17-ketosteroids Karyotype ( buccal smear; blood) Pelvic US and sometimes MRI or Genitogram Skin biopsy; fibroblast culture to measure 5alpha-reductase activity or dihydrotestosterone binding Laparoscopy Gonadal biopsy (laparotomy) 8 November

80 DR. HEBBAR WHAT IS THE MANAGEMENT PROTOCOL? 8 November

81 A PROTOCOL FOR INVESTIGATION OF A NEWBORN WITH AMBIGUOUS GENITALIA Karyotype all Palpable gonad NO YES CAH Sreen. Biochemical profile Positive Negative. US / MRI /? genitogram - US / MRI -? Genitogram.? Gonadal biopsy 8 November

82 OPEN QUESTION HOW TO ASSIGN SEX? 8 November

83 Sex assignment General guidelines Sex assignment should be decided after detailed assessment, investigations and accurate diagnosis Complete gender assignment by age 18 months 8 November

84 Sex assignment Male gender assignment : - stretched phallus > 2 cm - erectile tissue - lack of severe hypospadias Female gender assignment : - inadequate phallus - cervix and uterus present In difficult cases; sex assignment should be to the sex which can be surgically made to be adequate for coitus 8 November

85 SURGICAL CONSIDERATIONS Phallic / clitoral reduction if the assigned sex is female, before 3 years of age Removal of intra-abdominal gonads / streaks in newborns carrying Y chromosome Vaginal construction / repair is better performed around puberty 8 November

86 Before surgery After surgery 8 November

87 Concluding remarks on Management of newborn with genital ambiguity The causes of ambiguous genitalia are many and complex, so it is important to approach the treatment of children with this disorder in a systematic fashion. Evaluation should be done expeditiously, and parents should be kept informed during the evaluation to help them understand the embryologic anomaly that led to their child's genital ambiguity. Endocrine supplementation should be instituted when necessary, and a pediatric surgeon should be actively involved in assigning the child's sex of rearing as well as performing any necessary reconstructive surgery. 8 November

88 DSD PRESENTING AT ADOLESCENCE Primary amenorrhea - Complete androgen insesitivity (TFS) - Congenital anorchia ( early testicular regression syndrome) - Complete leydig-cell agenesis - Some forms of enzymatic testicular failure Ambiguous genitalia - Neglected congenital adrenal hyperplasia - Mixed gonadal dysgenesis - Partial androgen resistance - Congenital anorchia ( Late ) - Testicular enzymatic failure - Leydig cell agenesis ( incomplete) - True hermaphrotidism 8 November

89 MANAGEMENT OF DSD PRESENTING AT ADOLESCENCE Cortisol replacement therapy and? Corrective surgery in CAH Corrective surgery in drug induced cliteromegally In almost all other instances (XY- FEMALE), whatever the diagnosis is to Maintain the gender role as female In some cases of enzymatic testicular defects or 5 -reductase deficiency : Some May seek to change the gender role 8 November

90 DSD PRESENTING AT ADOLESCENCE Surgical aspects of management Clitoral reduction Removal of gonads in the presence of Y chromosome Vaginal repair and construction 8 November

91 Before surgery After surgery 8 November

92 GONADECTOMY 8 November

93 VAGINAL CREATION 8 November

94 Vaginal dilatation 8 November

95 McIndoe Vaginoplasty 8 November

96 William s vulvo-vaginoplasty 8 November

97 Colo-vaginoplasty 8 November

98 LABIAL RELEASE 11/8/2011 JOSHI SUYAJNA D. 98

99 Surgical treatment of CAH 11/8/2011 JOSHI SUYAJNA D. 99

100 VAGINOPLASTY - BEFORE 11/8/2011 JOSHI SUYAJNA D. 100

101 VAGINOPLASTY - AFTER 11/8/2011 JOSHI SUYAJNA D. 101

102 VAGINOPLASTY FINAL APPPEARANCE 11/8/2011 JOSHI SUYAJNA D. 102

103 INGUINAL GONADS 11/8/2011 JOSHI SUYAJNA D. 103

104 11/8/2011 JOSHI SUYAJNA D. 104

105 11/8/2011 JOSHI SUYAJNA D. 105

106 11/8/2011 JOSHI SUYAJNA D. 106

107 Agenesis of Scrotum 11/8/2011 JOSHI SUYAJNA D. 107

108 Mixed gonadal dysgenesis 11/8/2011 JOSHI SUYAJNA D. 108

109 Other congenital anomalies Lower 1/3 rd of vaginal agenesis 11/8/2011 JOSHI SUYAJNA D. 109

110 Concluding remarks Management of adolescent with DSD By following an approach that is based on a few embryological; physiological and anatomical principles-and with a minimum of tests- the clinician can arrive at a prompt and accurate diagnosis in patients with DSD If such a patient is managed correctly, she or he may live a happy, well adjusted life and may even be fertile If the patient is managed incorrectly, she or he may be doomed to live as a sexual freak in loneliness and frustration Gynecologists, endocrinologists, plastic surgeons, urologists and psychiatrists should be actively involved in the management of these patients 8 November

111 THANK YOU 8 November

IN SUMMARY HST 071 NORMAL & ABNORMAL SEXUAL DIFFERENTIATION Fetal Sex Differentiation Postnatal Diagnosis and Management of Intersex Abnormalities

IN SUMMARY HST 071 NORMAL & ABNORMAL SEXUAL DIFFERENTIATION Fetal Sex Differentiation Postnatal Diagnosis and Management of Intersex Abnormalities Harvard-MIT Division of Health Sciences and Technology HST.071: Human Reproductive Biology Course Director: Professor Henry Klapholz IN SUMMARY HST 071 Title: Fetal Sex Differentiation Postnatal Diagnosis