A Case of Disorder of Sexual Differentiation

Original Case by

Filippa Pritsini,1,2 Georgios A. Kanakis,1,2 Ioannis Kyrgios,1 Eleni P.Kotanidou,1 Eleni Litou,1 Konstantina Mouzaki,1 AggelikiKleisarchaki,1 Dimitrios G. Goulis,2 and Assimina Galli-Tsinopoulou1

A girl of 11 years and 3 months was referred to our unit due to enlargement of the clitoris associated with obstructive symptoms at micturition. According to her prenatal history, amniocentesis was conducted due to advanced maternal age, revealing a 46, XY karyotype. Pregnancy was otherwise uncomplicated. Cesarean section was performed at the gestational age of 40 weeks and 3 days due to cephalopelvic disproportion and failure to progress. The newborn was a healthy full-term baby, without electrolyte imbalance, presenting with an inadvertent female phenotype. In order to assess the discordance between chromosomal and phenotypical gender, the SRY gene was examined and found to be present, while imaging of the brain, hypothalamus, and pituitary gland was normal. At that time-point, the family decided to take no further action.

Q What are cause of 46 XY with unambiguous female genitalia at birth ?

  • Complete androgen insensitivity syndrome (CAIS)
  • Complete gonadal dysgenesis  (CGD)
  • 17 alpha hydroxylase deficiency

Q How will you distinguish CAIS from Complete gonadal dysgenesis ?

  • CAIS will have absent Mullerian structures while Complete gonadal dysgenesis may have Mullerian structures present.
  • Gonads are not palpable in complete gonadal dysgenesis while they may be present in the inguinal region or labioscrotal region in CAIS
  • On measuring the Serum testosterone- CAIS will have testosterone in normal male range while CGD will have low testosterone.

Anthropometric characteristics at presentation were in the normal range for girls at the patient’s age, while physical examination revealed excessive clitoriomegaly resembling a phallus of 6 cm and a shallow vaginal orifice.

Q Would you plot the patient’s growth with a female growth chart or in the male growth chart ?

  • You will plot it in female growth chart only, however it is an area of debate.
  • However most studies done have plotted it on female growth chart

While physical examination revealed excessive clitoridomegaly resembling a phallus of 6 cm and a shallow vaginal orifice. No testes were palpable.

Q What do you think of the diagnosis now ?

  • It seems odd that the child had normal female genitalia at birth and now has significant clitoromegaly and ambiguous genitalia.
  • It is more likely the ambiguous genitalia was missed at birth which seems strange because they already knew that the child was 46 XY on amniocentesis !
  • However my DD now would be 1) 5 alpha reductase 2 defect b) 17 beta HSD3 c) PAIS d) partial gonadal dysgenesis

Pubertal maturation, pubic hair, breast, and axillary hair were of Tanner stage III, I, and II, respectively

Q The breast they say is Tanner stage I , what will you narrow down your DD do ?

  • With absent breast enlargement ,5 alpha reductase 2 appears to be a more appopriate diagnosis
  • However it is possible that the child has not reached puberty , hence it would be premature to judge

Imaging of the lower abdomen with ultrasound and MRI revealed bilateral testicular tissue at the intraperitoneal space near the inner inguinal ring, hypoplastic penile cavernous bodies within a sizable clitoris, and the presence of a rudimentary prostate along with seminal vesicles.

Q Are wolffian duct derivatives present in CAIS ?

  • No generally not
  • Even if they are present they are rudimentry

Q There are absent Mullerian structures, which differential seems less likely with this ?

  • The presence of testis and absent of Mullerian derivatives make the diagnosis of partial gonadal dysgenesis less likely.

Basal hormones assessment showed elevated T (84.0 ng/dl) in the male reference range for the given pubertal stage, accompanied by mildly elevated LH (2.11 mU/mL) and follicular stimulating hormone (FSH) concentrations (18.56 mU/mL). Estradiol (E2) on the other hand was inappropriately low (14.45 pg/mL).

The ratio of T to -androstenedione (Δ4A) was >0.8, excluding 17β-hydroxysteroid dehydrogenase-3 (17β-HSD-3) deficiency, while the ratio of T to dihydrotestosterone (DHT) was <20, excluding 5α-reductase deficiency. The high elevation of T concentration (ΔΤ) after the hCG stimulation (>100 ng/dl) indicated the presence of testicular tissue, excluded gonadal dysgenesis, and supported the diagnosis of AIS (Table 2). Imaging control revealed the presence of bilateral testicular tissue. The combination of almost female phenotype with minimal virilization and proper male gonadal function was supportive for the diagnosis of severe PAIS

Q Give a typical protocol for HCG stimulation test ?

  • There are various protocol for HCG stimulation test. We will discuss one protocol which we follow
  • Baseline Testosterone, DHT and Androstenedione are sent
  • HCG is given as a single dose of 5000 IU for an older child IM
  • The sample are repeated after 72 hours

Q What ratios suggest 5 alpha reductase 2 and 17 beta HSD 3 ?

  • Stimulated T:DHT ratio > 27:1  – suggest 5 alpha reductase 2 defect
  • T: A ratio <0.8 suggests 17 beta HSD 3 deficiency

Q What small care you must take while calculating the ratios of T:A in this case?

The values of androstenedione are in ng/ml. Hence when we calculate the ratio, we need to convert it to ng/dl

Q What would you do for further management of this case ?

  • This is a case of PAIS raised as a female.
  • Since the child is already raised as female it would be wise to continue the same gender assignment.
  • I would consider going a gonadectomy and replacing the child with estrogen replacement.
  • I would also consider doing appropriate genital reconstruction.

Q What is the risk of gonadoblastoma in this case ?

  • PAIS with non scortal gonad have high risk of gonadoblastoma.

Reasonably, the assignment of female gender was recommended, since the patient had already been raised as a girl and the relevant interventions would be minimal. In addition, the testes that were found during imaging studies had to be removed, as they were atrophic and of increased risk for malignant change. Interestingly, the parents suggested that the child itself should be fully informed and participate in the final decision, and therefore, from the very first beginning, the patient was involved in all discussions made with the attending physicians. It is noteworthy that, being aware of the condition, she stated: “It does not matter if I am female or male, most of all I am a human being and thus gender assignment will not play any significant role in my future life.” Eventually, female gender was preferred by both the patient and the parents, and gonadectomy as well as cosmetic surgery of the external genitalia were successfully performed.

Learning points

  1. Be careful while calculating the T:A and T:DHT ratios. The units of the numerator and denominator should be the same.
  2. PAIS with non scrotal gonad have a high risk of gonadoblastoma and  gonadectomy must be done , generally before puberty.
  3. Female sex assignment is not inappropriate for PAIS, especially if the child is raised as a female.



Editorial note: In this case we have questioned the diagnosis the authors have made. The idea of this is not to criticize the efforts of the authors, but to point out an obvious flaw or error made in the diagnosis in this case. If you disagree with our explanation please feel free to send me an email on endocrinecases@gmail.com

A 11 years old girl of a consanguineous parents belonging to a low socioeconomic status, hailing from Nazirabazar, Dhaka, was admitted at Dhaka Medical College Hospital on 07/03/07 with inward bending of both legs for last 4 years, not gaining height in comparison to other children of same age and dental caries for 2-3 years.


She had no history of polyuria, dysuria, jaundice, recurrent chest infections or recurrent attacks of diarrhoea and not on long term anticonvulsant drugs.


Q  What is the importance of Polyuria in case of Rickets ?


  • Polyuria with rickets is suggestive of Renal tubular acidosis, Barrter’s syndrome and certain cases of CKD.


Birth history was uneventful and was partially immunized as per EPI schedule. After birth she was predominantly breast fed for only 5 successive months and currently she is on family diet, i.e., rice, vegetable, fruits but low quantity of fish, meat, milk and egg as they are unable to afford those.


Q  Are any of these good sources of vitamin D ?


  • Since this case is from Bangladesh, food fortification status of general foods is not known.
  • However, fatty fishes are good source of vitamin D , so the child may be receiving some vitamin D


Though her milestones of development were normal, her linear growth and also weight were not satisfactory as compared to that of other children of her age. Exposure to sunlight was adequate as she used to play along with other children in open air. Her father did not have the same disease and died of kidney disease two years back. Her mother and sibs are healthy


On examination, her pulse was 40/min, BP-100/60 mm Hg and temperature was normal.

Anthropometric measurement revealed height – 108 cm (74.2% of

NCHS median), weight – 18 kg (55.3% of NCHS median) and weight for height – 98.5% of NCHS median.

Both wrist and knee joints were widened , knocked knee was obvious on standing.

The chest examination demonstrated pegion chest deformity, mild rachitic rosary but there was no Harrison’s sulcus or other deformities of the limbs or joints.

However, dental caries were present in both upper and lower molar teeth


Radiologically, cupping, fraying and widening of growing lower ends of femur as well as radius and ulna, thinning of cortex and generalized osteopenia were revealed.


Q  What are X-ray features of Hypophosphatemic rickets ?


  • Hypophosphatemic rickets will show metaphyseal changes like widening and splaying, but calcipenic changes like fraying and osteopenia will not be seen.
  • Sclerosis may be seen.


Laboratory investigations showed TC of WBC 8000/cmm, DC: polymorph 60%, lymphocyte 37%, monocyte 2%, basophil 1%, eosinophil 2%. Total platelet count was within normal range. Anisocytosis and poikilocytosis of RBC and mature WBC were showed in peripheral blood film.


Biochemical investigations showed near serum calcium (Ca++) level of 8.4 mg/dL (N: 8.8-10.8 mg/dL), serum phosphate 2.5 mg/dL (N: 4-7 mg/dL), while alkaline phosphatase was 630 IU/L which was much higher than normal range (N: 115-431 IU/L). Serum creatinine was 0.8 mg/dL and SGPT 40 IU/dL. The parathyroid hormone level was within normal limit 11 pg/mL (N: 7-53 pg/mL). Urine examination showed phosphaturia and its level was 24.5 mg/dL. Urinary creatinine was 22.5 mg/dL (N: 15-20mg/dL). As there is no definite range of the urinary phosphate level of 11 years old girl, tubular reabsorption of phosphorus (TRP) was calculated

The TRP was 68% (N: 78-98%) which confirmed loss of excess phosphate through urine. However, serum 1-α-hydroxylase level could not be done. All parameters of electrolytes were normal. Benedict’s test showed no glucosuria.


Both the clinical features and laboratory parameters were consistent with familial hypophosphatemic rickets.


Q  Do you agree with the diagnosis ?


  • No
  • Infact in my opinion the diagnosis in this case is most likely nutritional rickets due to vitamin D deficiency

Q  What is the most important investigation that has been missed out in this analysis ?


  • A 25-hydroxy- vitamin D level is not done.


Q  What are the points in favour of this being a nutritional rickets ?


  • Osteopenia in X-ray is a features of nutritional rickets and it is NOT seen in XLRH
  • 25(OH) vitamin D is not obtained
  • Serum calcium levels are low. XLRH patients generally have normal serum calcium levels.

Q  if it is nutritional rickets, what explains the phosphate wasting ?


  • Vitamin D deficiency typically produces secondary hyperparathyroidism.
  • Increase PTH typically causes phosphate loss.
  • The increase TRP can be very well explained by the secondary hyperparathyroidism.


Q  You say it is secondary hyperparathyroidism , but the PTH levels is normal !


  • PTH assay depends much on the transport.
  • Improper transport of sample in cold chain can lead to reduction in PTH values and hence false low PTH.
  • This is a well known fact and activation of thrombin is responsible for lowering of PTH values in the sample.
  • Hence I believe that the PTH levels were false low.


Both the clinical features and laboratory parameters were consistent with familial hypophosphatemic rickets. So, she was treated with Joulie solution, an oral phosphate suspension made up of sodium phosphate (136 gm/L) and phosphoric acid (58.8 gm/L)5 1.5 tsf every 4 hourly. Active form of vitamine D (1-25 dihydroxy cholecalciferol) was also given in the form of Dicatrol capsule (0.25mcg) 6 hourly.


Along with treatment we consulted with orthopaedic department. She was advised to continue the treatment and for regular follow up. After 2 weeks of treatment with oral phosphate and dicatrol, significant radiological improvement was documented. Genetic counseling was also done. As the disease is X-linked, the defective gene may come either from father or from mother. Unfortunately, the genetic study is not possible in Bangladesh. As the father died two years back, there is no chance to have any more children.


Q  So if the diagnosis was probably incorrect, why did the child respond to treatment ?


  • The child was given active vitamin D supplementation.
  • If the child truly has vitamin D deficiency as we are thinking, she would have responded to active vitamin D supplementation as well.

Learning objective

  • When dealing with a case of rickets, it is always important to rule out common things first. Vitamin d deficiency (nutritional rickets) is far more common compared to other forms of rickets and must always be ruled out before further investigations are considered.
  • Vitamin D deficiency with secondary hyperparathyroidism ALSO causes loss of urine phosphate and hence TRP will be reduced in such cases.

A Case of Gonadotropin-independent precocious puberty (GIPP) in a young boy

Original Case by Bahar Özcabı,1 Feride Tahmiscioğlu Bucak,1 Serdar Ceylaner,2 Rahşan Özcan,3 Cenk Büyükünal,3 Oya Ercan,1 Beyhan Tüysüz,4 and Olcay Evliyaoğlu1,*


  1. PP- Precocious puberty
  2. CPP- Central perocious puberty
  3. GIPP – Gonadotropin independent preocious puberty
  4. GDPP- Gonadotropin dependent preocious puberty. 
  5. FMPP- Familial Male limited precocious puberty

A 1.4-year-old boy was admitted with complaints of pubic hair development, penile enlargement, linear growth acceleration, acne and increased aggressive behavior. His mother had become aware of enlargement of the genitals by 6 months of age

Q What is definition of precocious puberty ?

  • Age of onset of puberty 2 -2.5  SD earlier than normal
  • Ie Onset of puberty before 8 years on girls and before 9 year in boys

Q Classify the various causes of precocious puberty (PP)in boys based on age of onset ?

Onset in infancy

  • Hypothalamic hamartoma
  • Adrenal tumor

Onset in early childhood

  • Hypothalamic hamartoma
  • Familial male limited precocious puberty (FMPP)

Onset in late childhood

  • CNS tumors
  • CAH
  • Idiopathic

He had healthy parents non-consanguineously married and there was no family history of precocious puberty.

At physical examination, his height was 96 cm (+5.38 standart deviation score (SDS)) and weight was 17 kg (+2.0 SDS). He had an extremely muscular body build, a deepened voice and acne. Penile stretch length was 13 cm (>2 SDS); the left testicular volume was 3 mL and the right was 4 mL. Pubic hair was appropriate for Tanner stage 3 (Figure 1a). He did not have any café au lait spots.

Q Can you deduce from this clinical presentation whether the patient has GDPP or GIPP (gonadotropin dependent or independent precocious puberty)

  • From this history  and examination it seems the child most likely has GIPP.
  • Boys with GIPP typically have isosexual precocity with disproportionate penile enlargement compared to testicular enlargement.
  • Testicular enlargement in these cases may often be prepubertal.
  • In this case one of his testis is already pubertal, however if you compare this to the penile growth, the child most likely has GIPP.

Q What are the causes of GIPP in boys ?

  1. CAH (21 hydroxylase deficiency)
  2. Exposure to exogenous testosterone
  3. FMPP
  4. McCune Albright syndrome
  5. Primary hypothyroidism
  6. Androgen producing adrenal tumor
  7. HCG producing germ cell tumor
  8. Leydig cell tumor of testis.

Q Which testicular tumor leads to precocious puberty in boys ?

  • Leydig cell tumor lead to PP

Q why doesn’t HCG producing tumors produce GIPP in girls ?

  • In girls both FSH and LH are required for pubertal activation and just activation of LH receptors as in HCG secreating tumors will not lead to PP in girls

Q  What happens to testicular size in GIPP in boys ?

  • Testis is not enlarged in GIPP
  • This is because testis mass is due to semineferous tubules which in turn is dependent on FSH for enlargement

Q Which are the sites for germ cell tumors ?

  • Brain- mainly pineal region
  • Gonads
  • Anterior mediastinum
  • Liver
  • Peritoneum

Q Which test must be done in males with anterior mediastinal germ cell tumors ?

  • Karyotype must be done to diagnose Klenilfeter’s in all males with anterior mediastinal germ cell tumors

Q What is the etiology of testitoxicosis ?

  • Activating mutation in LH receptor
  • It is autosomal dominant transmitted

Q What are the causes of testicular enlargement associated with GIPP ?

  1. Primary hypothyroidism
  2. Familial male limited precocious puberty
  3. McCune Albright syndrome
  4. HCG secreating tumors
  5. CAH with TART
  6. Testicular tumors (unilateral testicular enlargement) with precocious puberty.

Q Why do patient with Familial male related precocious puberty have testicular enlargement ?

  • FMPP is a form of peripheral precocity with activating mutation in LH receptor.
  • LH receptor activation causes production of testosterone and not the growth of seminiferous tubules.
  • Hence enlargement of testis should not be seen in these patients.
  • However , in practice it is often seen that these patients have mild testicular enlargement.
  • This is because of following possible reasons:
  1. Intratesticular testosterone causing growth of the seminiferous tubule by paracrine effect
  2. Leydig cell hyperplasia which is typically seen in LH receptor activation states which can cause mild testicular enlargement
  3. Secondary activation of the central HPG axis (peripheral precocity causing secondary central precocity)
  • Similar picture may also be seen in boys with MAS and HCG secreting tumors who present with precocity.
  • However the testicular enlargement is mild as it is seen in this case.

Bone age was 4 years by the Greulich-Pyle method. Mid-parental height (MPH) SDS was 0.83. Clinical, auxological and endocrinological findings at admission are summarized in Table 1.

Q What do you derive from the table for patient 1 ?

  1. Patient surely has precocious puberty as evidenced by
  • Growth acceleration
  • Penile enlargement
  • Advanced bone age
  • Testosterone in late pubertal range.
  1. It is most likely GIPP
  • This can be derived form
  • Disproptionate growth of Penis compared to the testis
  • Basal LH in prepubertal range (<0.3)
  • Peak LH post GnRH also in prepubertal range (<3.3)

Q What tests would you perform for further evaluation of GIPP ?

  1. Adrenal androgens –17 OHP and DHEAS to r/o of adrenal causes of GIPP which include CAH and Adrenal tumors.
  2. Clinical examination to look for Café-au luit spot for diagnosis of McCune Albright syndrome
  3. Clinical examination and scrotal ultrasound to look for testicular mass.
  4. HCG level to look for HCG secreting tumor
  5. Thyroid function test (though unlikely diagnosis since the child has obvious growth acceleration)

The patient’s serum testosterone level was very high and gonadotropin-releasing hormone (GnRH) stimulation test revealed a prepubertal response.

Thyroid function tests (free triiodothyronine (T3): 4.4 pg/dL; free thyroxine (T4): 1.1 ng/dL; thyroid-stimulating hormone (TSH): 2.5 mIU/L) and adrenal cortex hormone levels (dehydroepiandrosterone sulfate (DHEA-SO4): 37.2 µg/dL; 17-α-hydroxyprogesterone (17-OHP): 0.9 ng/dL; androstenedione: 0.5 ng/mL; cortisol: 10.7 µg/dL) were within normal ranges.

Peripheral precocious puberty findings with a testicular volume of 4 mL suggested a tumor secreting beta-human chorionic gonadotropin (hCG) or a testicular tumor secreting testosterone; an activating mutation in the LH receptor and McCune Albright syndrome were also considered.

Abdominal magnetic resonance imaging (MRI) revealed normal findings.

A low serum beta-hCG (presence of a beta-hCG-secreting tumor.

He did not have any abnormality in bone scintigraphy screening.

A testicular ultrasonography showed a solid mass of a size of 2×2 mm in the right testicle. A surgical intervention was performed. During the operation, the testis was mobilized by inguinal incision and a 2×2 mass was detected. In cold ischemia conditions, the mass was excised by testis-saving procedure and sent for histopathological evaluation.

Q What is the treatment of GIPP in boys ?

  • For Tumor of Testis, adrenal or GCT: Surgery and/or other modes of therapy for the tumor
  • CAH- glucocorticoids
  • For other causes- anti-androgen therapy

Q What is bicalutamide ?

  • It is a pure androgen receptor antagonist
  • In GIPP – it is given in dose of 2 mg/kg

Q What is done if GIPP patients develop secondary CPP ?

  • GnRH agonist is given additionally

Q What is the treatment of Familial male limited precocious puberty (FMPP) or testitoxicosis ?

  • It is treated with bicalutamide + Anastazole
  • Ketoconazole and sprionolactone have also been used

Pathological examination revealed nodular Leydig cell hyperplasia. After surgery, serum total testosterone level did not decline

Anti-androgen treatment with bicalutamide (50 mg/day) and aromatase inhibition with anastrozole (1 mg/day) were initiated. A normal testosterone level could not be obtained and another surgery was planned. The same inguinal incision was performed and vascular pedicle was secured in cold ischemia conditions. The mass was not localized by visual examination. Intraoperative ultrasonography demonstrated a 3×3 mm mass and with the guidance of the probe, the mass was found and excised by another testis-saving procedure. Histopathological examination revealed the diagnosis of nodular Leydig cell hyperlasia again.

Q What are the typical histological findings of the testis seen in case of FMPP ?

  • Leydig cell hyperplasia is typical
  • Hyperplasia of Sertoli cell and spermatogenesis is also present because of increase intratesticular testosterone concentration.

Since the patient met the criteria for the diagnosis of testotoxicosis, a genetic analysis for LHCGR gene was performed.

Q What is the diagnostic criteria for FMPP ?

FMPP is a diagnosis of exclusion. The criteria are as follows:

  1. Family history with autosomal dominant mode of inheritance
  2. Limited to males
  3. Gondotropin independent precocity (LH response to GnRH agonist prepubertal)
  4. No CNS, Adrenal or testicular abnormality detected.
  5. Premature Leydig cell maturation

Sequence analysis of all coding regions and exon-intron boundaries were done by in house designed primers using Sanger sequencing technique and a novel mutation c.830G>T (p.S277I) (heterozygous) was described (Figure 1b). In silico evaluation tools including Mutation taster, SIFT and Polyphen 2 predict this variant as a disease-causing mutation. Parental analysis was normal, then this variation was most probably a de novo pathogenic variant. Screening of 200 healthy people for this variant was done and no one had this mutation.

Q What is the typical age of presentation of FMPP ?

  • They typically present between 1-3 years of age.
  • However in this case the onset was even before 1 year of age.
  • This may be because of the novel mutation found.
  • Such cases with earlier onset of FMPP have been reported in literature.

Q What is the mode of inheritance of Familial male limited precocious puberty (FMPP)  ?

  • FMPP has an autosomal dominant inheritence with more than 90% penetrance.

Cyproterone acetate was added to the treatment regimen because the suppression of pubertal progression and serum testosterone levels was not sufficient, but it was withdrawn in one month because of increases in liver enzymes which could not be associated with another cause; liver enzymes became normal after the cessation of the drug.

In the 20th month of treatment, GnRH stimulation revealed a pubertal response and a GnRH analogue was added to treatment.

Q Why do children who have GIPP also develop Central precocious puberty secondarily ?

  • Excess sex steroid exposure as in McCune albirght or CAH can lead to secondary CPP
  • Two theories
  1. Priming effect of sex steroids
  2. On reducing Sex steroid with treatment – there is loss of negative feedback à rebound activation of gonadotropin axis

In his follow-up at age 3.8 years, despite bicalutamide (100 mg/day), anastrozole (2 mg/day) and GnRH analogue treatments, sufficient suppression of puberty and decline in serum testosterone levels were not achieved (Table 2). Antiandrogen treatment with bicalutamide (androgen receptor antagonist) was changed to ketoconazole (androgen synthesis inhibitor) in a dose of 10 mg/kg/day. A treatment regimen of ketoconazole, anastrozole and a GnRH analogue led to a decline in serum testosterone level from 900 ng/dL to 490 ng/dL on the 3rd day of the treatment. At the 3rd month of ketoconazole (15 mg/kg/d) treatment, serum testosterone level decreased to 125 ng/dL without any sign of side effects; whether this benefit will be sustained or not needs to be evaluated in the long term.

Learning points

Familial male limited precocious puberty (Testitoxicosis) is an important cause of Gonadotropin independent precocious puberty (GIPP) in boys and generally present between ages 1-3 years but may present earlier.

Absence of testicular enlargement in presence of other features of Precocious puberty points towards GIPP, however FMPP may have mild testicular enlargement because of Leydig cell hyperplasia and/or hyperplasia of seminifeous tubules and sertoli cells due to intratesticular testosterone.

A Case of Prepubertal Gynecomastia

Original Case by Fatma Dursun,1 Şeyma Meliha Su Dur,2 Ceyhan Şahin,3 Heves Kırmızıbekmez,1 Murat Hakan Karabulut,4 and Asım Yörük5

1Ümraniye Training and Research Hospital, Pediatric Endocrinology, 34766 Istanbul, Turkey
2Ümraniye Training and Research Hospital, Radiology, Istanbul, Turkey
3Ümraniye Training and Research Hospital, Pediatric Surgery, Istanbul, Turkey
4Ümraniye Training and Research Hospital, Pathology, Istanbul, Turkey
5Göztepe Training and Research Hospital, Pediatric Oncology, Istanbul, Turkey

A 4-year-old boy was referred to pediatric endocrinology because of bilateral breast enlargement

Q What is importance of age of presentation of gynecomastia ?

  • During neonatal period, puberty and in elderly, gynecomastia is physiological.
  • Gynecomastia in prepubertal children and in young- middle age adults is unusual and pathlogical causes of gynecomastia must be sought in these patients.

Q What are the causes of Prepubertal gynecomastia ?

  1. Drug induced
  2. Aromatase excess syndrome
  3. Chronic liver disease
  4. Chronic renal disease
  5. Testicular tumor
  6. Adrenal tumors
  7. Hyperthyroidism

There was no history of a chronic disease, medication, or a familial disorder.

Q Name some common drugs that lead to gynecomastia ?

  • Spironolactone – used in hypertension and CCF
  • Finesteratide – 5 alpha reductase inhibitor used in BPH
  • Cimitidine- H2 receptor antagonist used in peptic ulcer management
  • Growth hormone
  • HCG
  • Anti-androgen – like flutamide- used in prostate cancer.

Height was 114 cm (+1.2 SDS), weight was 20 kg (+0.7 SDS), and physical examination revealed bilateral gynecomastia.

Breast development appeared as Tanner Stage-2 (Figure 1)

Q What is Tanner stage 2 of breast ?

  • Presence of breast bud is Tanner stage 2
  • Areola starts to develop with small amount of breast tissue.

axillary and pubic hair were absent, stretched penile length was 6 × 1.5 cm, and right testis was 2 mL and left testis was 5 mL 

Q What is unusual here ?

Asymmetrical testicular enlargement.

Q What is the mean streached penile length at this age ?

The mean SPL would be around 5.6 cm. Here it is around 6 cm , which is normal.

Q How will you evaluate this case further on from here ?

  • This is clearly a case of prepubertal gynecomastia which is unusual.
  • I would consider endocrine evaluation as well as scrotal ultrasound to evaluate the asymmetrical testicular enlargement.
  • For the endocrine evaluation, I would order an LH, Testosterone, E2,  and HCG levels.
  • Additional I would ask for a bone age of the child.

Hormone levels were in normal ranges (Table 1); tumor markers were negative while scrotal ultrasonography (USG) exhibited a 8 × 12 mm solid lesion with cystic component in the left testis.

Q What is your interpretation of the  evaluation ?

  • Bone age is advanced.
  • There is a testicular mass which needs assessment.
  • LH and Testosterone are in Normal prepubertal range.
  • Other hormonal investigations are normal.

Q Which testicular tumors are associated with gynecomastia ?

  • HCG producing germ cell tumors of testis
  • Leydig cell tumor
  • Large calcifying Sertoli cell tumors typically seen in Carney’s complex or Peutz Jaghers syndrome.

Q What are DD of testicular mass ?

  1. Testicular adrenal rest tissue (TART)
  2. Testicular tumor
  3. Epididymitis
  4. Epidymoorchitis
  5. Varicocele
  6. Hernia
  7. Hydrocele
  8. Hematoma
  9. Spermatocele

Q Why is testicular biopsy not routinely performed for such lesion ?

This is because there is risk of seeding of the tissue and spreading of the malignant tissue

Q Which is the first and most important step in evaluation of a male with testicular mass ?

Scrotal ultrasound

Q What are the USG apperance of seminoma and non seminoma ?

  • Seminomas- well defined hypoechoic areas without cysts
  • Non seminomas- indistinct margins, calcification, cysts and inhomogenous

Q What is done is incidental testicular lesion is found in scrotal ultrasound ?

  • Go for tumor marker
  • If negative- ultrasound follow up is adequate

Q Which are the tumor markers for testicular Germ cell Tumors ?

  1. AFP
  2. LDH
  3. Beta HCG

Q What is the relation between type of cancer and the tumor markers ?

  • Non Seminomas- beta HCG and/or AFP is elevated in 80% of cases
  • Seminomas- beta HCG is elevated in 20% cases, AFP is not elevated

Q Are tumor makers alone sensitive to diagnose GCT ?

  • No
  • They are not sensitive enough to make a diagnosis without histological confirmation

Q Which is the gold standard for diagnosis of testicular GCT ?

  • Radical inguinal orchiectomy is the gold standard for diagnosis of testicular GCT
  • It gives histopathological confirmation
  • Neither ultrasound nor tumor markers can replace it

Q What is the next step for this child ?

The child has tumor marker for GCT which are negative.

  • However, since the child has gynecomastia and advanced bone age with this testicular mass, evaluation is required.
  • I would consider doing an orchidectomy of the involved testis.

The committee on tumoral diseases agreed on the decision to perform a testis-sparing surgery in the light of examination of frozen sections. However the large and cystic mass left no adequate testis tissue to conserve, so a left orchiectomy was performed.

Abdomen and thorax Computed Tomography (CT) imaging were normal. Histopathological investigation revealed a sertoli cell tumor which had positive staining with inhibin, vimentin, and calretinin. Gynecomastia regressed at the end of three months following the operation.

Q Sertoli cell tumors are associated with which conditions ?

  • Carney’s complex
  • Peutz Jeghers syndrome

Q What is the characteristic of these tumor in Carney’s complex ?

  • They are large cell calcifying Sertoli cell tumors
  • They generally appear in the 2nd decade
  • They are generally non hormonal producing

Q What is the feature of the tumor in Petz Jeghers ?

They have high aromatase activity and hence they often produce gynecomastia

Q What about Sertoli cell tumors which are not a part of the above disorders, are they hormonally active ?

No, They are not

Q Which is the most common testicular tumor in infants ?

  • Juvenile granulosa cell tumor is the most common testicular tumor in infants
  • It occurs in first few months of life
  • They generally have good prognosis
  • They rarely present with ambigious genitalia

Q What about adult granulosa cell tumors ?

  • They are more likely to be hormonally active
  • They present in middle age with gynecomastia and feminizing features

Q Which important immunohistochemical is common in the various sex cord tumors ?

Inhibin Alpha


Q Why are sertoli cell tumors more likely to produce estrogen compared to Leydig cell tumors ?

  • Sertoli cell tumors have aromtase enzyme expressed in them.
  • Hence they are more likely to produce estrogen.
  • They mainly produce Estrone from androstenadione in prepubertal boys.

Learning points

  1. Sertoli cell tumors have high aromatase activity and hence can present with gynecomastia. However, most sertoli cell tumors occur in context of PJS or Carney’s complex and are often bilateral. Unilateral Sertoli cell tumor presenting with gynecomastia in prepubertal child without evidence of any syndrome is rare.
  2. Drugs are the most common cause of prepubertal gynecomastia.




Learning Objective- Sharpen Skills for bone age estimation

Q. What is the bone age of a male whose X ray is shown below ?
(You may use atlas method or Tanner Whitehouse)


Q. What is the approximate bone age based on clinical assessment ?

1. The epiphysis of the distal phlaxanx has fused – bone age is surely more than 14 years
2. The distal ulnar epiphysis has not fused – age is <17 year
3. 14-17 years is approximate bone age (wide variation- I would need Atlas of Tanner Whitehouse for perfect estimation)

Q. What is the bone age based on Tanner Whitehouse ?
• TWII- 14.9 years
• TWIII- 15.9 years

Q. What is the bone age by Greulich Pyle method ?
15- 16 years

Q. What is the bone age by Gaskin and Kahn atlas ?
It says 15 years 6 months

Q. Please give the explanation for the bone age based on the Atlas ?

1. The epiphysis of distal phalanges have fused
2. Fusion is about to begin in distal part of 2nd -5th epiphysis of metacarpals
3. 1st metacarpal epiphysis has fused
4. Distal ulnar epiphysis has not fused

Q. What is the key area here ?

The key differentiating feature is fusion of the 1st metacarpal epiphysis which fuses at 15 years and 6 months



CASE 18- A Case of extreme short stature with Delayed puberty

Original case by Deep Dutta et al


A 16-year-old girl presented with short stature noticed since 10 years of age along with lack of puberty. She had normal childhood, without any history of failure to thrive, head injury or polyuria. Maternal age of menarche was 14 years.

Q What are the differential diagnosis of short stature with primary amenorrhea at this age ?

  1. Constitutional delay
  2. Turner’s syndrome
  3. Other causes of Gonadal dysgenesis
  4. Hypogonadotrophic hypogonadism
  5. Panhypopituitarism

Q What are points against CDGP ?

Mother had menses at 14 years of age. CDGP generally have family history of delayed puberty.


Examination revealed significant short stature (Height 127.2cm; standard deviation. -6.06), multiple  facial nevi (Fig. 1a), cubitus valgus and goiter. Sexual maturity rating was pre-pubertal. Bone age (Greulich Pyle) was 10 years.

Q What is the definition of short stature based on Standard deviation ?

Short stature is defined as height of child 2 Standard deviation below the mean for the chronological age and sex of the child.

Q This SD corresponds to what percentile ?

This corresponds to 2.3 percentile.

Q Based on the clinical examination findings what is your differential diagnosis and why ?

The differential diagnosis goes strongly in favour of Turner’s syndrome after history and examination. The points in favour are:

  1. Patient has extreme short stature with absence of secondary sexual characteristics.
  2. Cubitus vulgus
  3. Presence of Goiter
  4. Delayed bone age

Q Are nevi common in patients with Turner’s syndrome ?

Yes. Nevi are more common in patients with Turner’s than in general population. However, melanoma risk is not increased.

Q Which rare skin neoplasm is common in Turner’s syndrome ?

Pilomatricoma. This is a rare skin neoplasm arising from cells of the hair follicles. They present as asymptomatic papules.


Ultrasonography revealed infantile uterus with lack of visualization of ovaries. Karyotype was 45,X. Height plotted on Turner syndrome specific growth chart (TSGC) was <5thpercentile. Hormonal evaluation revealed secondary hypothyroidism and hypogonadism (low basal and post GnRH analogue stimulated LH).  Serum electrolytes were normal.

Anti thyroid peroxidase antibody titer was elevated (224 U/mL; normal <35 U/mL). Serum IgA antitissue transglutaminase antibody levels were normal (0.2 AU/mL; normal <8 AU/mL).

Hormonal profile (Table)

Q The patient has hypothyroidism. What is unusual about it ?

Primary hypothyroidism , mainly autoimmune is not uncommon in Turner’s syndrome. However, as per the case report the patient has secondary hypothyroidism which is unusual.  Also the LH and FSH are generally elevated in patients with Turner’s syndrome. In this case they are low.

Q Why are is anti TTg done in this case ?

To rule out Celiac disease. Again, celiac is not uncommon in patient with Turner’s syndrome.

Q What is the interpretation of the clonidine stimulation and insulin tolerance test in this case ?

They are suggestive of GH deficiency.

Q What is the importance of Turner specific growth chart ?

The patient is having short stature even as per the Turner specific growth chart. This means the patient potentially has other causes of short stature which need to be ruled out. If a patient has <  3rd percentile on Turner specific growth chart than additional evaluation for short stature etiology is mandated.

Q Is growth hormone stimulation test routinely necessary in patients with Turner’s syndrome ?

No. It is not routinely advised.

Levothyroxine was started at 50 μg/day. Evaluation of GH status 4 weeks later revealed GH deficiency (Web Table I). Magnetic resonance imaging (MRI) of brain revealed empty sella with ectopic neurohypophysis near tuber cinerium.

Q What is the MRI features of Congenital hypopituitarism ?

  1. Ectopic posterior pituitary
  2. Small anterior pituitary (or empty sella)
  3. Deviated anterior pituitary stalk

Q Why was the GH stimulation test done after correcting the hypothyroidism ?

The response of GH to stimulation may be subnormal if patient is having hypothyroidism. Hence thyroid should be corrected before GH stimulation testing.

Q What is the normal response of GH on stimulation ?

Generally GH >10 ug/l is considered to be normal on stimulation.


GH was started at 3 U/night subcutaneously, increased to 4.5U/night after three months.

Q What is the dose of GH in patients with Turner’s syndrome ?

The dose is generally 50 ug/kg/day ie 0.375 mg/kg/week Q How will you convert dose of GH from  milligram to International units ?

3 IU = 1 mg of Growth hormone. The dose in Turner would be 0.16 units/kg/day

Ethinyl-estradiol 2.5 μg/day was also started, along with calcium and vitamin-D. Reassessment was done 6 monthly. Ethinyl-estradiol was increased by 2.5 μg every 6 months.

  1. How is Pubertal induction and Estrogen therapy administered in patients with Turner’s syndrome ?
  2. Age of 12
    1. Start estrogen therapy
    2. Ethinyl estradiol preferred – PROGYNOVA (or T. EVALON) 0.25 mg (1/4th tablet) once a day
    3. If Progynova not available then Conjugated estrogen – PREMARIN – 0.625 mg once a day may be given as alternative
    4. Gradually increase the dose every 3-6 months till age of 14 years
      1. T Progynova- 0.25 mg increase every 3 month 0.25 – 0.5 mg -1 mg – 1.25 mg – 1.5 mg – 1.75 mg – 2 mg. Scoring of tablet may be difficult so you can increase by ½ tablet (0.5 mg) every 6 months
      2. T. Premarin – 0.625 mg increase every 6 months- 0.625 mg – 1.25 mg – 1.875 mg- 2.5 mg
    5. 14 years of age
      1. Patient now receives adult dose of Estrogen. Estrogen generally given from days 1-25.
      2. Progesterone may be added cyclically (may be added earlier if breakthrough bleeding occurs)
        1. C. ALGEST / ENDOGEST – 200 mg on day 20-30 of cycle
        2. T. MEPRATE (Medroxyprogesterone) –2.5- 5 mg on days 20-30

She gained 5 cm height in first 6 months, 3 cm in next 6 months, and 3 cm in next 1 year when GH was stopped. Two years after diagnosis, her height was 138.2 cm (Fig. 1c), had B3 breast development, and was on 10 μg of ethinyl-estradiol.

Following breakthrough bleeding, patient has been receiving monthly medroxypro-gesterone along with ethinyl-estradiol for the last three months, ensuring regular menses.


Q What is the typical GH profile in patients with Turner’s syndrome ?

They have

  1. Increased IGFBP3
  2. Reduced IGF1
  3. Normal GH stimulation

Q What are the indications for stopping GH Therapy in Turner’s syndrome ?

Therapy with GH is  continued till growth potential remains. Stopped when:

  1. Bone age >14 years
  2. Growth velocity <2 cm / year

Q Should oxandrolone have been added to this case ?

Yes. Turner’s patients with age >9 years have additional benefit with Oxandrolone.

Q Which additional evaluation should have been done for this patient ?

Cardiovascular evaluation at baseline must be done in all Turner’s patient. This includes:

Baseline evaluation

  1. All four limb blood pressure measurement
  2. ECG at baseline
  3. Echocardiography at baseline
  4. Older girls and adults also need to get done cardiac MRI
  5. If anything abnormal- refer to cardiologist
  6. If everything normal – follow up
  1. Which other investigations must be asked for in Child with Turner’s syndrome ?
  1. Ultrasound KUB – to rule out urinary tract abnormality
  2. ENT reference for assessment of hearing function
  3. Ophthalmology reference for visual assessment
  4. Child growth and psychological assessment must be done

They have problems in visuospatial, social cognition and non-verbal problem solving

Learning Points from this case

All children with Turner’s syndrome should have their height plot on Turner specific growth chart. If the chart shows height <  3rd percentile than additional evaluation for other causes of short stature is required


Original case by Betty Korljan Jelaska

We present the case of a 23-year-old female who was diagnosed with GSD type Ia shortly after birth.

Q What is the other name of GSD type 1a  ?

It is also known as Von Gierke’s disease.

Q What is the defect in Von Gierke’s disease?

It is a glycogen storage disorder with absence of Glucose – 6 phosphatase enzyme.

Q What are the clinical features of this disease ?

Glucose 6 phosphatase enzyme is required by both the Gluconeogenesis pathway and glycogenolysis pathway for production of glucose. Since the patient has absent glucose-6-phosphatase enzyme the patient generally develops fasting hypoglycemia which can be severe along with metabolic acidosis during infancy. Apart from this there is accumulation of glycogen in liver, leading to hepatomegaly and renal enlargement. There is also shunting to the uric acid pathway leading to hyperuricemia. There is also elevated triglycerides.

Q What are the difference in GSD Ia and Ib ?

Type 1b is mainly because of defect in translocase enzyme that transfer the glucose-6-phosphtase across the microsomal membrane. Apart the clinical symptoms described above these people also have neutropenia and increase risk of bacterial infections.


She was hospitalized for the first time at the age of 6 months for hypoglycaemia and metabolic acidosis that occurred during a respiratory infection. She had a doll-like facial appearance, hepatomegaly and kidney enlargement. She had been repeatedly hospitalized for episodes of enormous hypoglycaemia during infancy and adolescence.

Q What is the management of hypoglycemia is patient with GSD 1a ?

Hypoglycemia is generally managed by frequent feeding especially using uncooked corn-starch.

Q What is the role of uncooked corn-starch in endocrinology ?

It is a complex carb that is slowly broken down over 2-6 hrs. If taken at night time- it can prevent nocturnal hypoglycemia. EXTEND BAR is a popular preparation of uncooked corn-starch.

The patient was treated out of hospital with frequent meals rich in carbohydrates during the day and every 2–3 h during the night and as a result she developed obesity. Besides nutritional therapy, she was also treated with allopurinol for hyperuricaemia.

Q What are the long term complications of Von Gierke’s disease ?

  1. Short stature
  2. Delayed puberty
  3. PCOS like morphology in ovaries (without hirsutism and hyperandrogenism)
  4. Menorrhagia
  5. Risk of hepatic adenoma and hepatocellular carcrinoma
  6. Risk of proteinuria and renal failure.
  7. Dyslipidemia
  8. Osteoporosis
  9. Nephrocalcinosis
  10. Gout
  11. Risk of pancreatitis

She came to our clinic at the age of 22 years for the diagnostic evaluation of arterial hypertension and dyslipidaemia. Her weight was initially 80 kg, height was 157 cm and BMI was 32.5. The levels of uric acid were 425 nmol/l, LDL 3 mmol/l, HDL 0.8 mmol/l, cholesterol 5.2 mmol/l and TG 2 mmol/l. Her in-office blood pressure measurement repeatedly showed raised values (160/90 mmHg in average). We carried out a 24-h ambulatory blood pressure monitoring, which revealed normal daily and average 24-h values of both systolic and diastolic pressure, but also the non-dipping pattern of systolic pressure during the night. The latter can be attributed to excessive nocturnal eating and consequently disturbed sleeping pattern.

The patient used to control glycaemia with self-measurements, mostly in preprandial periods, and results were recorded in a blood glucose diary. The self-measurements were made only during the daytime and revealed no abnormal excursions of glucose levels in either direction.

It has been shown previously that glucose levels obtained by continuous subcutaneous glucose monitoring (CGM) correspond to those obtained by venous blood sampling or self-measurements. To evaluate the actual prevalence of eventual hypoglycaemic episodes, we proposed CGM during a 72-h period.

Glucose levels <3 mmol/l with symptoms that are relieved promptly when glucose levels are raised document hypoglycaemia. The results of CGM revealed no episodes of hypoglycaemia (the sensor was calibrated to the glucose range between 3.5 and 8.5 mmol/l). Instead, several episodes of postprandial hyperglycaemia were recorded (Fig. 2a, b and c).

The patient was advised by the nutritionist to change her dietary regimens. She reduced the quality and quantity of meals and cut out the candy syrup that she was using frequently for many years because of the fear of hypoglycaemia. She was advised to use cornstarch instead.

She used 400 g of cornstarch initially and only 250 g/day later on.

Q Apart from the corn-starch which is other way of preventing nocturnal hypoglycemia in such children ?

We can insert a nasogastric tube and start a continuous nocturnal gastric drip to prevent nocturnal hypoglycemia.

The patient came to our clinic at the age of 22 years for the diagnostic evaluation of arterial hypertension and dyslipidaemia. Her BMI was 32.5 at the time. The results of 72-h CGM revealed fluctuations in her blood glucose levels and allowed us to advise her to change her dietary regimens. She reduced the number and quantity of meals and lost 11 kg with a consequent decrease in BMI from 32.5 to 28 within a year.

Her lipid status also improved with an increase in the levels of HDL (1.2 mmol/l) and a decrease in the levels of TG (1.8 mmol/l), cholesterol (5 mmol/l), LDL (2.8 mmol/l) and uric acid (366 nmol/l).

Learning points from this case

  1. Fasting hypoglycemia is a clinical feature of Von Gierke’s disease
  2. Uncooked corn-starch can be used to prevent nocturnal hypoglycemia
  3. Patient with Von Gierke’s disease can develop serious problems in adulthood which include obesity, PCOS, gout, osteoporosis, dyslipidemia, hepatic adenomas, renal failure etc.