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,*

Abbreviations

  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.

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