Idiopathic central precocious puberty with Prader–Willi syndrome: pubertal development with discontinuation of gonadotropin-releasing hormone analog

Background

Prader–Willi syndrome (PWS) is a common obesogenic syndrome caused by the absence of the expression of paternally active genes on chromosome 15q11–q13. Hypogonadism is one of the main clinical features of PWS, which is characterized by normal luteinizing hormone (LH), high follicle-stimulating hormone (FSH), low testosterone, low inhibin B, and relatively low anti-Müllerian hormone (AMH) levels compared with those in normal males, which suggest both hypothalamic and primary hypogonadism (1). A few cases of central precocious puberty (CPP) with PWS have been reported. Although loss-of-function mutations of the makorin RING finger protein (MKRN3) gene at 15q11–q13 are responsible for familial CPP (2), the pathophysiology of CPP with PWS remains unknown (3). The gonadal function of CPP with PWS who received gonadotropin-releasing hormone analog (GnRHa) therapy has not fully been identified.

This article aims to reveal the pubertal development with GnRHa therapy discontinuation in patients with CPP with PWS.

Case presentation

Our patient was born at 37 weeks of gestation weighing 1944 g to a healthy Portuguese mother and a Brazilian father and displayed poor feeding, poor weight gain, and hypotonia during the neonatal period. He visited our hospital due to obesity and cryptorchidism at 3 years of age. Bilateral orchidopexy was performed. Afterward, he did not visit our hospital for a while.

He was referred to our hospital due to precocious puberty at 7.2 years of age. His height, height SDS, weight, BMI, and BMI SDS were 115.0 cm, −1.4 SDS, 26.0 kg, 19.7 kg/m², and +1.6 SDS, respectively. His hands and feet were relatively small, and his skin color was transparent. His bilateral testicular volume was 6 mL, with Tanner stage 3 pubic hair.

Investigation

His bone age was 12.5 years according to the Greulich and Pyle method. A GnRH test revealed pubertal LH and FSH levels (basal, peak: 0.5, 29.7 mIU/mL and 5, 22.6 mIU/mL, respectively) and testosterone was 0.41 ng/mL. Adrenal hyperplasia was excluded, although 17-hydroxyprogesterone (17-OHP), DHEA sulfate, and urinary pregnanetriolone levels were 2.7 (normal: 0.93 ± 0.81) ng/mL, 1990 (normal: 52–1080) ng/mL, and 0.034 (normal: 0.000–0.038) mg/gCr, respectively. Adrenocorticotrophic hormone test was not be performed for high 17-OHP. Abdominal CT did not detect a tumor in the adrenal gland, liver, or testis. Brain MRI did not reveal an enlarged pituitary gland. He had never been prescribed steroid hormone and had never received radiation. He was diagnosed with idiopathic CPP.

Treatment

The patient was prescribed a GnRHa (leuprorelin acetate of 0.94 mg s.c. injection every 1 month) because his bone age accelerated for his chronological age. During therapy, his testicular volume reduced in size (2 mL), LH and testosterone were suppressed, and bone age stagnated (Fig. 1 and Table 1).

View Full Size

Growth chart of the patient on the 2000 Nation Growth Survey on Preschool Children and School Health Statics Research. Black circles represent height and weight and open triangles represent bone age. The first, second, and third arrows indicate the age at the start of GnRHa therapy, discontinuation of GnRHa therapy, and the start of GH therapy, respectively.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2022, 1; 10.1530/EDM-22-0244

• Download Figure
• Download figure as PowerPoint slide

Outcome and follow-up

PWS was suspected because of his history and developmental deficits at 10 years of age. Chromosome 15q11.2 deletion was identified using the fluorescent in situ hybridization analysis. GnRHa therapy was discontinued at 11.3 years of age because pubertal progression could be adequately suppressed and primary hypogonadism was of concern attributable to PWS. His right and left testicular volume was 3 mL and 4 mL, respectively, and bone age was 13.0 years 2 months after discontinuation (Table 1). Additionally, hormonal examination was evaluated 2 months after GnRHa therapy discontinuation and revealed the following: GnRH test demonstrated prepubertal levels of LH and FSH (peak; 6.9 mIU/mL and 7.3 mIU/mL, respectively); human chorionic gonadotropin (hCG) test showed normal testosterone levels (basal and peak; 0.17 ng/mL and 2.98 ng/mL, respectively); and AMH level was slightly low (22 ng/mL) for his prepubertal stage according to his LH level on the GnRH test (Table 1). His pituitary gland was slightly small for his chronological age on brain MRI.

His inadequate growth became remarkable (height: 130.2 cm, −2.0 SDS) at 11.3 years of age. The insulin test suggested growth hormone (GH) deficiency (basal and peak: 0.06 ng/mL and 1.07 ng/mL, respectively) at 11.5 years of age. GH therapy (0.23 mg/kg/week) was started at 12.0 years of age (height: 133.4 cm, −2.1 SDS). He grew close to his final height of 146.5 cm (−3.2 SDS) at 15.1 years of age. The right and left testicular volume was 10 mL and 15 mL, respectively, with Tanner stage 5 pubic hair and LH, FSH, testosterone, and AMH levels were 4.6 mIU/mL, 19.9 mIU/mL, 1.54 ng/mL, and 2.92 ng/mL, respectively (Table 1).

Similar cases were identified in published literature, and the features of 16 patients (7 male patients and 9 female patients) having PWS with CPP, including our patient, were summarized (Table 2) (4, 5, 6, 7, 8, 9, 10, 11, 12, 13). Cases with premature adrenarche were excluded. Molecular pathogenesis was clear only in five patients. LH level was increased in 11 patients (case 1, 4, 5, 8, 10, 11, 12, 13, 14, 15, and 16). Nine patients were treated with GnRHa (5 male patients: cases 1, 8, 12, 13, and 16; 4 female patients: cases 9, 10 or 11, 14, and 15), two patients were not treated with GnRHa (1 male patient and 1 female patient), and five patients were not mentioned whether treated or not. Cases 1, 13, 14, and 16, who were treated with GnRHa, were assessed for pubertal development after discontinuation at 13.0 years of age or older, with Tanner stage 3 or 4 in all of them. Case 4, who was not treated with GnRHa, was assessed for pubertal development at 13.0 years of age, Tanner stage 3–4. Cases 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, and 15 were assessed for pubertal development under 13.0 years of age, and age at the last visit was not mentioned.

Out of 9 patients who were treated with GnRHa, 5 had GH therapy (cases 1, 13, 14, 15, and 16), 2 had not performed GH therapy (cases 8 and 9), and 2 patients had not mentioned GH therapy. The external genitalia development was Tanner stage 3–4 in 5 patients who were treated with GH (cases 1, 13, 14, 15, and 16); pubertal development was incomplete in 2 who were not treated with GH (cases 8 and 9).

Discussion

Here, we presented a rare case of male CPP with PWS confirmed by chromosome 15q11.2 deletion after GnRHa therapy initiation. Our patient fulfilled all CPP diagnostic criteria, that is, testicular enlargement, advanced bone age, high androgen level, and LH pubertal response to GnRH test. He also presented with PWS features, hypotonia, insufficient weight gain, and cryptorchidism in the newborn period and obesity, developmental disability, and learning disability in school age. However, the absence of short stature and delayed puberty, which are characteristic manifestations of PWS, were masked by CPP.

The re-evaluated gonadal function after GnRHa therapy revealed an incomplete gonadotropin response for the GnRH test, while testosterone showed a normal response for the hCG test. . However, the gonadal function was well in LH and testosterone levels, and Sertoli cells have been kept active after GnRHa therapy because the AMH level was not significantly low. Patients with PWS commonly do not complete puberty, which may correlate with prolonged AMH activity (1).

Patient with PWS commonly have delayed or incomplete puberty, and premature adrenarche is occasionally reported with increased adrenal androgen secretion, induced by adiposity as well as healthy obese children, but true precocious puberty is extremely rare. Therefore, we identified a case series of patients with PWS who presented with CPP in the published literature and summarized the features of 16 cases, including our patient’s (Table 2) (4, 5, 6, 7, 8, 9, 10, 11, 12, 13). We could not clarify the correlation between the frequency of CPP and molecular pathogenesis because only five cases mentioned molecular pathogenesis. CPP was considered to be caused by hypothalamic–pituitary acceleration by increased LH levels in 11 patients, and 9 patients were treated with GnRHa. Four patients showed external genitalia maturation with discontinuation of GnRHa therapy; it is considered to be restored to pubertal development. And pubertal development without GnRHa therapy was confirmed in 1 patient (case 4). Pubertal development in patients with PWS with CPP is considered to be going well with or without GnRHa therapy. Furthermore, GH therapy probably may help the pubertal development after GnRHa therapy discontinuation (14, 15).

Loss-of-function mutations of the MKRN3 gene, located on chromosome 15q11–q13 in the critical PWS region, are reported as responsible for familial CPP (2). Normally, MKRN3 is thought to prevent the onset of puberty at high levels in the brain before adolescence. A paternally derived MKRN3 allele deletion in PWS can cause puberty to start at an inappropriately young age. Alternatively, 17-hydroxyprogesterone and DHEA sulfate levels were high in our patient at CPP diagnosis, which may indicate increased adrenal androgen levels as previously reported in PWS. Thus, precocious puberty may occur in our patient as a combination of paternally derived MKRN3 allele deletion, basal adrenarche, and hypothalamic–pituitary acceleration. Other findings support the hypothesis that GnRHa therapy showed good clinical and laboratory response, that is, adequate puberty blockage evaluated by decreasing testicular volume, decreasing gonadotropin and testosterone, and bone age stabilization, which was restored after GnRHa discontinuation.

In conclusion, CPP is considered even if the patient was already diagnosed with PWS. GnRHa therapy may be beneficial, especially for male patients, because the male pubertal signs were identifiable due to the increased adrenal androgen levels in PWS as previously reported. Accumulating cases that are examined post-GnRHa gonadal function is desirable to assess the long-term effects of GnRHa therapy for CPP in PWS.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This study did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Patient consent

Written informed consent has been obtained from the patient for publication of this article and accompanying images.

Author contribution statement

Mami Kobayashi wrote the manuscript. Hideaki Yagasaki is the primary physician of the patient. Kei Tamaru and Yumiko Mitsui managed the patient’s genetic testing and treatment. Takeshi Inukai supervised and all authors approved the final version of the manuscript.