A closer look at a 15 year old male presenting with gynaecomastia and short phallus to the Endocrine clinic.

1. GYNEACOMASTIA IN AN
ADOLESCENT MALE
DR FREDA DODD-GLOVER, PS2

2. CASE PRESENTATION
 Patient A.A
 15 years old
 First seen at endocrine clinic June 2016
 Presenting complaint : 1. Gynaecomastia- 3/12
2. Short phallus
3. Urine leakage beneath glans on urinating

3. HPC
 Referred from paediatric surgery with above complaints
 Diagnosed with ambiguous genitalia as a child, after evaluation was
assigned male gender.
 Underwent a number of corrective surgeries at Department of Child
Health KBTH.
 Puberty began at age 13 with pubic hair growth
 Axillary hair growth about a year later, but no voice changes
 Enlargement of breasts noticed 3 months prior to presentation, initially
painful to touch but resolved
 No nipple discharge or galactorrhoea

4. ON DIRECT QUESTIONING
 Pregnancy and delivery uneventful
 Delivered at term pregnancy with no neonatal complications
 No history of maternal virilisation or prenatal exposure to androgenic
drugs
 No family history of previously affected relatives or unexplained
infant death.
 No history of parental consanguinity
 No history of exposure to chemotherapy or radiation therapy

5. ON DIRECT QUESTIONING
 No history of mumps , testicular trauma or liver
disease
 No family history of gynecomastia
 Early morning tumuscence + (occassionaly)
 Not on any medications

6. PAST MEDICAL HISTORY
 Presented to paediatric surgeons at 3/7 days old
Referred on account of fusion of penile shaft with scrotum
Undescended testes
 Diagnosed then as “burried penis with bilateral undescended testes”
 Scheduled for orchidopexy at 18/12 if testes undescended
 Seen at 18/12 of age and diagnosis of ambiguous genitalia with
hypospadias made

7. PELVIC USG DONE – (SEPT 2002) :
No retrovesical mass suggestive of uterine tissue noted. Two rounded,
well-defined masses in right inguinal region measuring 11mm and 12mm in
diameter. they show a coarse echopattern devoid of calcification or cystic
changes. The left inguinal area is unremarkable. the masses in the right
inguinal area are highly suggestive of testicular tissue
 Impression: Undescended testes

8. BILATERAL INGUINAL EXPLORATION DONE:
 Right undescended testis and inguinal lymph node found.
 Right herniotomy performed and spermatic cord mobilised.
 Right orchidopexy then performed.
 Exploration of the left groin done but no testes found.
 Mini-laparotomy performed. Left streak ovary found and
biopsied.

9.  HISTOPATHOLOGY REPORT (SEPT 2002) Aged 18/12:
Sections show piece of tissue composed of fibrous stroma (like ovary) with
primordial follicles and oocytes surrounded by a single layer of granulosa cells
 HAD SURGERY (2004) Aged 24/12:
Excision biopsy of left inguinal lump(ovary)
Scrotoplasty
Urethroplasty
Glanuloplasty (urethral opening found on glans penis)
 2007 (6 years) - Presented with fistula formation at site of hypospadias
repair.
 2010 (9 years) - fistula repair done

10. FAMILY HISTORY
 No family history of ambiguous genitalia
 2nd of 3 siblings (1st – 21 years, male; 3rd – 11 years, female . both
developing normally)
SOCIAL HISTORY
 Student. SHS 1 at Labone secondary school. Stays at Labadi with parents.
 No alcohol use or smoking history
 Patient and parents troubled as he was about to start senior high school
and would eventually need to be in a boarding house with other male
students
 Mother particularly troubled about patient’s ability to have sex and
conceive.

11. PHYSICAL EXAMINATION
 A young boy, stout-looking
 Weight – 55kg (5Oth centile)
 Height – 1.53m (3rd centile)
 BMI - 23.5 kg/m2
 Arm span - 1.62m (Longer than height)
Not pale or jaundiced. Hydration fair. No peripheral lymphadenopathy. No
stigmata of thyroid, chronic liver disease nor renal disease.
CVS: P- 92bpm BP: 84/63 mmHg. Apex 4LICS MCL
RESP: chest clinically clear
ABD: full. Umbilicus inverted. No organomegaly. No masses palpable

12. TANNER-STAGING:
 Breast = equivalent
to tanner stage 2 in female
 Phallus length from base
2.5cm = tanner 1
 Pubic hair = tanner 3
 Testes volume (R) = 1cm3
( 0.7cm length)
(L) = Absent
CNS:
 Grossly normal

14. SUMMARY
 15 year old male
 History of ambiguous genitalia at birth . Had excision biopsy of left
streak gonad - ovary on histopathology. No Uterus on USG
 Presenting with 3/12 history of gynaecomastia, short phallus for age
and urethrocutaneous fistula from breakdown hypospadias repair.
DIFFERENTIAL DIAGNOSES
 ? Disorder of Sexual Differentiation
 Male with undervirilization
 Female with virilisation (absent uterus on USG)
 Ovotesticular disorder

15. INVESTIGATIONS
 LH/FSH, S-Testosterone, S-oestradiol, S-DHEA, S-SHBG, S-PSA, S-hCG
 BUE & CR, 17-hydroxyprogesterone, Pelvic USG
 Karyotype,
Patient presented with lab results done 2/12 earlier.

16.  LABS DONEDATE TEST RESULT REFERENCE RANGE
25/04/2016
(Health Quest)
FSH 3.8 mIU/ml Male
2.0 – 14.0 mIU/ml
LH 2.2 mIU/ml Pre-Adolescent
<3.0 mIU/ml
Testosterone 0.94 ng/ml
(3.3 nmol/L)
Boys 13- 17 years
0.28 – 11.11 ng/ml
FBC NORMAL
BUE & Cr NORMAL
TFT NORMAL
29/08/2016
(MDS Lancet)
Testosterone 0.6 nmol/L Male Tanner 3:
0.52-9.72
S-17b-oestradiol(E2) 38 pmol/L low Male : 94.8 – 223
Female follicular
45-854
Sex hor. Binding Glob. 66.10 nmol/L 11.2-78.1
S-DHEA 2.56 1.2 – 10.4
S-ANDROSTENEDIONE < 0.30 ng/ml low 0.6 -3.1
KARYOTYPE 46 XX

17. FINAL DIAGNOSIS
 46 XX, Ovotesticular DSD being brought up as male
(possible translocation of SRY region of paternal Y chromosome unto
paternal X chromosome)

18. FOLLOW UP REVIEW WITH PEAD. SURGEON
 BREAST: Tanner 2
 EXT. GENITALIA : Pubic Hair - Tanner 3
Phallus - Buried penis within over-riding scrotum.
Atrophic Rt testis
Penile length from mons - approx. 2.5cm.
Actual penile length (palpating beneath over-
riding scrotum) - approx. 5.5cm

19. PLAN :
 Counselled on surgical options available :
1. Mastectomy
2. Scrotoplasty
3. Urethrocutaneous fistula repair
 Concerns about sexual relations and infertility addressed
 Patient and parents saw psychologist and were counselled on likelihood of
infertility
 Surgery scheduled for December 2016
 Patient will be followed-up post surgery at the endocrine clinic to assess
need for possible start of hormonal therapy with testosterone if needed.

20. LITERATURE REVIEW
DISORDERS OF SEXUAL DIFFERENTIATION
(DSD)

21. OUTLINE
 DEFINITION
 EPIDEMIOLOGY
 EMBRYOLOGY
 TYPES OF DSDs
 INVESTIGATIONS
 MANAGEMENT

22. COMMON CAUSES OF GYNAECOMASTIA
 Idiopathic
 Physiologic
 Drug-induced
 Renal failure
 Hyperthyroidism
 Malnutrition
 Malignancies secreting hCG
 Hypogonadism (primary and secondary)

23. INVESTIGATIONS FOR GYNAECOMASTIA
 NONE - Physiologic
 LFTs, BUE & Cr
 Testosterone ,
 LH),
 Estradiol,
 DHEAS
 TSH
 F-T4
 Imaging – mammogram, USG, CT scan
 Biopsy

24. DISORDER OF SEXUAL DIFFERENTIATION(DSD)
 Also known as disorder of sexual development.
 Congenital condition with atypical development of chromosomal,
gonadal & anatomical sex.
 In 2006, changes to the previously used nomenclature and definitions
of DSD published. **
 These changes were to reflect advances in our understanding of the
pathophysiology of DSDs while being sensitive to the needs and
concerns of patients affected by them.
** The Lawson Wilkins Paediatric Society(LWPES) and the European Society For Paediatric
Endocrinology (ESPE)

25. PREVIOUS REVISED
Female pseudohermaphrodite 46,XX DSD
Male pseudohermaphrodite 46,XY DSD
True hermaphrodite Ovotesticular DSD
XX male 46,XX testicular DSD
XY sex reversal
46,XY complete gonadal
dysgenesis
2006 LWPSE-ESPE REVISED CLASSIFICATION

26. EPIDEMIOLOGY
 Testicular or mixed gonadal dysgenesis is estimated at 1:10,000
live births .
 The worldwide incidence of 46 XX DSD, consisting primarily of CAH
- mostly 21-hydroxylase deficiency, has been estimated to be 1 in
14,000-15,000 live births, but it varies by regions because of ethnic
differences in gene mutation frequency.
 CAH and Mixed Gonadal Dysgenesis constitute about half of all DSD
patients presenting with genital ambiguity .
 The incidence rate of 46XY DSD has been estimated to be 1:20,000
births.
 Ovotesticular DSDs occur in 1 of 100,000 live births.

27. EPIDMIOLOGY
Of the Ovotesticular disorders, Krob et al, reviewed 283 cases
worldwide and found the following :
1. 46 XX – 70.6% - common in South and West Africa
2. 46 XX/46XY - 20.2% - common in Europe and North America
3. 46 XY - 7% - common in Japan, Sri Lanka and Brazil

28. EMBRYOLOGY
 Gender is determined by 3 main factors:
1. Chromosomal sex
2. Gonadal sex
3. Phenotypic sex.
 The chromosomal sex at conception determines the type of
gonads formed.
 Hormones formed by gonads determine the
differentiation/regression of the internal ducts (ie, müllerian
and wolffian ducts) and ultimately determine the phenotypic
sex.

29. GONADAL DIFFERENTIATION
 During the second month of fetal life, the indifferent gonad is
guided to develop into a testis by genetic information present on
the short arm of the y chromosome.
 Testis-determining factor (TDF) is a 35–kilobase pair (kbp)
sequence on the 11.3 subband of the y chromosome, an area
termed the sex-determining region of the y chromosome (SRY).
 When this region is absent or altered, the indifferent gonad
develops into an ovary.

30. GONADAL DIFFERENTIATION
 The existence of patients with 46,xx testicular DSD, who have
testicular tissue in the absence of an obvious Y chromosome or SRY
genetic material, clearly requires other genetic explanations.
Other genes important to testicular development include
 DAX1 on the x chromosome,
 SF1 on band 9q33,
 WT1 on band 11p13,
 SOX9 on bands 17q24-q25,
 AMH on band 19q13.3.
 Fetal ovaries develop when the TDF gene (or genes) is absent.

31. DIFFERENTIATION OF INTERNAL DUCTS
 Development of the internal ducts results from a paracrine effect from
the ipsilateral gonad.
 When testicular tissue is absent, the fetus morphologically begins and
completes the internal sex duct development and external phenotypic
development of a female.

32. DEVELOPMENT OF INTERNAL DUCTS
 When testicular tissue is present, two
produced Substances, testosterone and
Müllerian-inhibiting Substance (MIS) or
Anti-Mullerian Hormone (AMH) are critical
for development of male internal sex ducts
and an external male phenotype.

33. DIFFERENTIATION OF EXTERNAL GENITALIA
 The external genitalia of both sexes are identical during the first 7 weeks
of gestation. Without the hormonal action of the androgens testosterone
and dihydrotestosterone (DHT), external genitalia appear phenotypically
female.
 In the gonadal male, differentiation toward the male phenotype actively
occurs over the next 8 weeks.

34. DIFFERENTIATION OF EXTERNAL GENITALIA
 Moderated by testosterone. Converted to 5-DHT by the action of an
enzyme, 5-alpha reductase, present within the cytoplasm of cells of
the external genitalia and the urogenital sinus.
 DHT is bound to cytosol androgen receptors within the cytoplasm and
is subsequently transported to the nucleus, where it leads to
translation and transcription of genetic material.

35. DIFFERENTIATION OF EXTERNAL GENITALIA
 In turn, these actions lead to normal male external genital
development from primordial parts, forming
1. The scrotum from the genital swellings,
2. The shaft of the penis from the folds, and
3. The glans penis from the tubercle.
4. The prostate develops from the urogenital sinus.
 Incomplete masculinization occurs when testosterone fails to convert to
DHT or when DHT fails to act within the cytoplasm or nucleus of the
cells of the external genitalia and urogenital sinus.

37. ADRENAL CORTEX HORMONE SYNTHESIS

38. CONGENITAL ADRENAL HYPERPLASIA

40. Journal of Paediatric
Surgical Specialties; Vol
8/No 3/2014
Late-presenting
ovotesticular disorder in an
11 year old female
Diagnostic laparoscopy
demonstrated the presence of an
intra-abdominal left testis and of a
rudimentary right ovary, instead of
the two ovaries identified in the
MRI. A rudimentary uterus and a
right fallopian tube were also
identified. Biopsies were done.

41. In the absence of uterus in 46 XX, Ovotesticular DSD, consider:
 Translocation of SRY of paternal Y chromosome onto paternal X
chromosome during meiosis or other genes:
1. DAX1 on x chromosome
2. SF1
3. AT1
4. SOX9
5. AMH

42. MORBIDITY/MORTALITY
 Infants born with ambiguous genitalia represent a true medical
and social emergency.
 Salt-wasting nephropathy occurs in 75% of infants born with CAH,
the most common cause of ambiguous genitalia.
 If unrecognized, the resulting hypotension can cause vascular
collapse and death. Male infants with this syndrome may be
phenotypically normal, and the diagnosis may be missed.
 Malignant transformation may occur in dysgenetic gonads
especially in XY cases.

43. INVESTIGATIONS
A logical workup in infants with ambiguous genitalia includes the following:
 Chromosomal analysis/Karyotyping
 Endocrine screening (FSH, LH, TESTOSTERONE, ESTRADIOL, SHBG,
ANDROSTENEDIONE, DHEA)
 Serum chemistries/electrolyte tests
 Androgen-receptor levels
 5-Alpha-reductase type II levels
IMAGING
 Abdomino-pelvic USG
 Genitography
 CT scan/MRI
 Gonadal biopsies

44. MANAGEMENT:
Multidisciplinary approach
 Paediatrician/paediatric surgeons in childhood
 Physician/endocrinologists
 Psychologist
 Cytogeneticist
 Social workers
MEDICAL MANAGEMENT
 Depends on the underlying cause.
 Indicated for the conditions associated with ambiguous genitalia,
including congenital adrenal hyperplasia (CAH).
 Supplemental hormone therapy may be implemented if gonadal function
is compromised.

45. SURGICAL MANAGEMENT
 Virilized females: Feminizing genitoplasty
 Undervirilised males: Correction of hypospadias
Orchidopexy in crytorchidism
 Sexual reassignment: Timing debatable
Consider genotypic, phenotypic sex,
funtional ability of gonads/internal
ducts
Socio-cultural environment
MEDICATIONS:
 Depend on the underlying cause

46. The following consultations may be obtained:
 Geneticist/genetic counsellor
 Endocrinologist
 Surgeon
 Obstetrician/urologist
 Psychologist

47. TAKE HOME MESSAGE:
 Karyotype alone does not determine sex
 Ambiguous genitalia must be investigated early
(*hypotension, malignancy)
 Multidisciplinary approach
 Long-term management
 On-going psychological support for patient, parents and other
family members is critical

48. REFERENCES:
 Medscape
 Endocrine practice journal, volume 21, 2015
 Endotext
 Paed. Dev. PATH, 2015, Nistal M et al
 Journal of Paediatric Surgical Specialties, Vol 8, no 3, 2014
 Epidemiology and initial management of ambiguous genitalia,
Thyen U et al

49. ACKNOWLEDEMENT
 Patient A.A and family
 Dr Apeadu-Mensah (paediatric surgeon)
 Dr Araba Sefa Dedeh (psychologist)
 Ps 2 consultants, residents, H/0
 Dr Isabella Asamoah
 Dr Louise Sarr