Outcomes of Patients With Familial Central Precocious Puberty due to Mutations of MKRN3 Gene After Treatment With Gonadotropin-Releasing Hormone Agonist

Management and outcome of central precocious puberty

Central precocious puberty (CPP), the onset of sexual development before age 8 in girls, reflects early activation of the hypothalamic-pituitary-gonadal axis and currently is treated with a gonadotropin-releasing hormone analog (GnRHa). One of the goals of such treatment is to slow bone maturation and thereby increase final adult height. Some patients, however, grow at a less than optimal rate and become short-statured as a result. This open-label study was carried out in 20 girls with CPP who experienced marked growth deceleration (height velocity below the 25th centile for age) during GnRHa treatment. All of them continued to receive 3.75 mg Leuprorelina intramuscularly at monthly intervals. Ten girls (group 1) also received, by mouth, 0.06 mg/kg daily of the androgen oxandrolone (Ox). The remaining 10 girls (group 2) continued to receive only the GnRHa. The groups were matched for chronologic age, bone age, the duration of GnRH analog treatment (averaging 5 years), and the degree of growth deceleration. In both groups, plasma concentrations of luteinizing hormone and follicle-stimulating hormone remained suppressed, rising to appropriate levels within 18 months of the time that GnRHa treatment stopped. Menarche occurred an average of 16 and 18 months after treatment stopped in groups 1 and 2, respectively. Bone age progressed regularly in both groups. When GnRHa treatment began, predicted adult height (PAH) in patients in group 1 did not differ significantly from that recorded at the time Ox was added. At the end of combined treatment, PAH was significantly higher than at the time of diagnosis and at the start of GnRHa therapy. Final height significantly exceeded target height in patients in group 1, was similar to the PAH at the end of treatment, and was significantly higher than when GnRHa treatment began. In patients in group 2, PAH at the start of treatment did not differ significantly from that at the time GnRHA therapy ended. Their final height was similar to the PAH at both the beginning of treatment and its end. Target height was not reached and it significantly exceeded final height. The gap between pretreatment PAH and final height in patients in group 1 differed significantly from that in patients in group 2 (7.8 vs -3.8 cm). The same was the case for the difference between final height and target height (4.6 vs -4.2 cm). No adverse effects were noted in either treatment group. Treatment did not alter circulating levels of insulin-like growth factor I. Adding oxandrolone to GnRHa treatment in girls with idiopathic CPP whose growth has markedly decelerated improves final height without causing significant side effects. In the present study, combined treatment permitted the girls to reach a final height greater than the target height. This was not the case for girls who continued to receive only GnRHa whose final height was lower than target height.

<h3>Background</h3> Central precocious puberty (CPP) is defined by gonadotrophin-dependent development of secondary sex characteristics before the age of 8 in girls and 9 years in boys. Approximately 25% of CPP cases are familial, but its genetic cause often remains unknown. Mutations in makorin RING finger protein 3 gene (MKRN) are a common cause of familial CPP, being identified in 33-46 % of familial cases. We describe dizygotic twin sisters diagnosed with CPP and treated with gonadotrophin-releasing hormone agonists analog (GnRHa), in whom genetic analysis revealed the cause for CPP. <h3>Case Presentation</h3> A 6.4 year old girl presented with acne, pubic hair and body odour. Diagnosis of CPP was performed on the basis of clinical signs of central puberty (breast Tanner 2 and pubic hair Tanner 2), increased basal gonadotrophine hormones (LH 4.6 IU/L, FSH 3.7 IU/L, E2 109 pmol/L) and growth spurt (height on 1.6 SDS). Her bone age was assessed to be 7 years. Brain Magnetic Resonance (MRI) did not disclose any abnormality. Treatment with GnRHa was given subcutaneously once a month (triptorelin in a dose 3.75 mg). Girl's dizygotic twin sister developed signs of puberty at the age of 8 years. At presentation, she had breast Tanner 3 and pubic hair Tanner 1. Her bone age was 8.6 years, her height was on 0.8 SDS. Laboratory assessment confirmed CPP (LH 1.07 IU/L, FSH 3.9 IU/L, E2 187 pmol/L ) and after additional endocrinological and neuroradiological work-up, suppression of CPP started. Precocious puberty was well controlled by pharmacological therapy and both sisters reached their final height (163.8 and 159.1 cm) in accordance with midparental height (MPH 165cm, 0.6 SDS). As CPP was diagnosed in both dyzygotic twin sisters, we sought for a genetic cause. Coding regions of the MKRN3 gene and exon-intron boundaries were analyzed using Sanger sequencing. Pathologic heterozygous variant NM_005664.3:3:c.475_476insC (NP_005655.1:p.Ala162Glyfs) of MKRN3 gene was identified in both siblings. <h3>Conclusion</h3> We want to highlight the importance of genetic analysis in cases od familial CPP, providing grounds for genetic counseling in later life.

BackgroundThe primary aim of this study was to investigate the final adult height (FAH) of girls diagnosed with central precocious puberty (CPP) who were untreated.MethodsWe retrospectively analyzed the medical records of 36 girls diagnosed with CPP between 8 and 9 years of age who did not receive treatment, and 206 girls diagnosed with CPP within the same age range who received gonadotropin-releasing hormone (GnRH) agonist treatment. Midparental height (MPH), predicted adult height (PAH) obtained using height and bone age (BA) at the time of diagnosis (PAH for BA), and PAH obtained using the Bayley-Pinneau method (PAH by BP) were calculated. Additionally, height at the time of growth completion was compared with the predicted height.ResultsThe FAHs were 160.71±4.56 cm in the untreated group and 159.31±4.26 cm in the treated group. In the untreated group, the FAH was 0.99±4.50 cm shorter than the MPH but 4.29±3.33 cm and 3.46±3.93 cm greater than the PAH for BA and PAH by BP, respectively.ConclusionIn children diagnosed with CPP between 8 and 9 years of age who were untreated, FAH was greater than PAH for BA and PAH by BP at the time of diagnosis, indicating that the prognosis of FAH was not poor. Therefore, for girls diagnosed with CPP, it is recommended to consider various conditions, such as pubertal onset, height at diagnosis, BA, peak luteinizing hormone level, predicted height, and speed of puberty, when deciding whether to administer GnRH agonists.

PurposeThe aim of this study was to examine whether gonadotropin-releasing hormone (GnRH) agonist treatment is effective in preserving final height in patients with central precocious puberty (CPP) or early puberty (EP).MethodsThe medical records of 40 patients with CPP and 206 patients with EP who completed GnRH agonist treatment following diagnosis were analyzed retrospectively. Height and height standard deviation (height SDS) scores based on bone age (BA) were measured and calculated at baseline, after treatment completion, and at final follow-up to compare changes within and between groups. Predicted adult height (PAH) was estimated by the height corresponding to height SDS for BA in girls at 18 years 11 months of age based on the growth chart.ResultsPAH at baseline did not differ significantly between the CPP group (153.67±4.95) and the EP group (154.77±3.72). In the CPP group, PAH significantly increased at treatment completion (156.01±4.61) and at final follow-up (158.52±6.04) compared to baseline. In the EP group, PAH significantly increased at treatment completion (157.7±3.60) and at final follow-up (159.31±4.26) compared to baseline. The increase in PAH at all timepoints compared to baseline did not significantly differ between the CPP and EP groups.ConclusionsBoth CPP and EP groups had significantly greater PAH after treatment, with no difference in the amount of increase between groups. These results show that GnRH agonist treatment can help increase final height even in patients diagnosed with EP after the age of 8 years.

Recently, mutations of makorin RING-finger protein 3 (MKRN3) have been described in familial central precocious puberty. Serum levels of this protein decline before the pubertal onset in healthy girls and boys. The aim of the study is to investigate MKRN3 circulating levels in patients with central precocious puberty. We performed an observational cross-sectional study. We enrolled 17 patients with central precocious puberty aged 7 years (range: 2-8 years) and breast development onset <8 years; 17 prepubertal control age-matched patients aged 6.3 years (2-8.2); and 10 pubertal stage-matched control patients aged 11.4 years (9-14). Serum values of MKRN3, gonadotropins, (17)estradiol and Anti-Müllerian Hormone were evaluated and the MKRN3 genotyped in central precocious puberty patients. No MKRN3 mutation was found among central precocious puberty patients. MKRN3 levels were lower in patients with central precocious puberty compared to prepubertal age-matched ones (p: 0.0004) and comparable to those matched for pubertal stage. MKRN3 levels were inversely correlated to Body Mass Index Standard Deviations (r:-0.35; p:0.02), Luteinizing Hormone (r:-0.35; p:0.03), FSH (r:-0.37; p:0.02), and (17)estradiol (r: -0.36; p:0.02). We showed that girls with central precocious puberty had lower peripheral levels of MKRN3 compared to age-matched pairs and that they negatively correlated to gonadotropins, estrogen, and BMI. Our findings support the MKRN3 involvement in central precocious puberty also in absence of deleterious mutations, although our sample size is small. In addition our data suggest the role of MKRN3 in the complex mechanism controlling puberty onset and its interaction with other factors affecting puberty such as nutrition.

Purpose There are few reports on the therapeutic effects of gonadotropin-releasing hormone agonists in boys with central precocious puberty, and studies reported in Korea are very rare. We aimed to assess the significance of clinical factors and the effects of gonadotropin-releasing hormone agonist treatment on final adult height in boys diagnosed with central precocious puberty.Methods We retrospectively evaluated the medical records of 18 boys treated for idiopathic central precocious puberty between 2007 and 2018 at Chosun University Hospital. Gestational age, birth weight, and parental height were assessed at the initial visit. Chronological age, bone age, bone age/chronological age ratio, height and height standard deviation scores, predicted adult height, body mass index, and hormone levels were assessed during the treatment period.Results At the time of diagnosis, the chronological age was 9.9±0.6 years, the bone age was 11.6±1.0 years, and the bone age/chronological age ratio was 1.20±0.1. The bone age/chronological age ratio decreased significantly to 1.12±0.1 at the end of treatment (P<0.05). The luteinizing hormone/follicular stimulating hormone ratios were 3.4±1.2, 0.6±0.4, and 0.6±1.0 at the start of treatment, after 1 year of treatment, and at the end of treatment, respectively. After gonadotropin-releasing hormone agonist treatment, the final adult height reached 172.0±4.8 cm compared to the target height range of 171.0±4.0 cm.Conclusions In boys with central precocious puberty, gonadotropin-releasing hormone agonist treatment improved growth potential.

Objective To observe the final adult height of 20 boys with idiopathic central precocious puberty (ICPP) treated with slow-releasing gonadotropin-releasing hormone analogue(GnRHa).Methods Twenty boys with ICPP were treated with GnRHa for( 20.0 ± 6.1 ) months.At the beginning of therapy,mean chronological age and bone age was( 11.4 ± 1.0 ) years and ( 13.0 ± 0.4 ) years,respectively,GnRHa was discontinued when the boys reached the chronological age and bone age of( 13.2 ± 1.1 ) years and ( 13.7 ± 0.6 ) years,respectively.After the end of treatment,all the boys had been followed up for( 3.3 ± 1.5 ) years and had achieved adult height.Comparisons were made among their predicted adult height ( PAH ),final adult height ( FAH ),and target height ( THt ).The long-term outcome of final adult height in boys with ICPP was investigated after GnRHa treatment.Results All the boys reached target height range.Final height was similar to the target height [ ( 169.8 ± 5.8 vs 167.8 ± 4.6 ) cm,P＞0.05 ].The height gain,defined as the difference between predicted adult height at the start of treatment using the height SDS for bone age and actual adult height was( 3.62 ± 3.57 ) cm with the residual growth capacity of ( 11.82 ±3.99)cm,PAH significantly improved after GnRHa treatment compared with before treatment [ ( 169.0 ± 5.0 vs166.2 ± 4.2 ) cm,P＜0.01 ].There were no differences among PAH,FAH,and THt.Conclusion GnRHa treatment improves final height within the range of target height in boys with central precocious puberty. Key words: Gonadotropin-releasing hormone ; Puberty, precocious ; Adult height

ObjectiveGonadotropin-releasing hormone agonist (GnRHa) treatment improves the potential for gaining height in patients with central precocious puberty (CPP). However, most studies have focused on girls because CPP in boys is relatively rare. Therefore, we aimed to determine the effect of GnRHa treatment on auxological outcomes in boys with CPP.MethodsEighty-five boys with CPP were treated with leuprolide or triptorelin acetate 3.75 mg over 2 years. Anthropometry, bone age, sexual maturity rating, and predicted adult height (PAH) were assessed every 6 months. Furthermore, 20 boys were followed up after treatment discontinuation until achievement of the final adult height (FAH).ResultsThe mean chronological age (CA) and bone age (BA) of the patients with CPP at treatment initiation were 9.5 ± 0.5 years and 11.7 ± 0.9 years, respectively. The mean duration of treatment was 2.87 ± 0.63 years. The PAH at treatment initiation was 172.1 cm (-0.23 ± 1.05 PAH standard deviation score). The PAH at treatment discontinuation (176.2 ± 6.6 cm) was significantly higher than the pretreatment PAH. In addition, the mean final adult height in the 20 boys who were followed up after discontinuation of treatment was 173.4 ± 5.8 cm, which was significantly higher than the initial PAH (170.1 ± 4.5 cm; p = 0.006). In multivariate analysis, the height gain (the difference between the FAH and PAH at treatment initiation) significantly correlated with the target height.ConclusionLong-term GnRHa treatment significantly improved the growth potential and FAH in boys with CPP.

This study aimed to compare clinical parameters, including final adult height (FAH), in girls with central precocious puberty treated with gonadotropin-releasing hormone agonists (GnRHa) with and without growth hormone (GH). This retrospective study reviewed data of 210 girls with precocious puberty who had reached FAH in a long-term trial of GnRHa treatment. The subjects were divided into the GnRHa treatment group (n = 188), and the combined GnRHa + GH treatment group (n = 22). Chronological age, bone age, height, height standard deviation score, predicted adult height (PAH), FAH, Tanner stage, and hormone levels were assessed during the treatment period. At the start of treatment, PAH was 156.35 ± 6.34 cm in the GnRHa monotherapy group and 150.41 ± 5.32 cm in the GnRHa + GH group (P < 0.001). At the end of treatment, PAH was 166.25 ± 5.26 cm in the GnRHa group and 164.07 ± 4.99 cm in the combined GnRHa + GH treatment group, which had increased compared to the start of treatment. The FAH in the GnRHa group and GnRHa + GH combination group were 161.07 ± 4.78 cm and 159.63 ± 3.8 6 cm, respectively, without significant difference. In addition, the height gain (FAH–PAH) was significantly higher in the GnRHa + GH group than the GnRHa group (9.22 ± 6.03 cm vs. 4.72 ± 5.01 cm, P < 0.001). In girls with central precocious puberty, the height gain in the FAH compared to PAH at the start of treatment was significantly higher with the GnRHa + GH combination treatment.

Background: Recently, mutations of makorin RING finger protein 3 (MKRN3) have been identified in familial central precocious puberty (CPP). Serum levels of this protein decline before the pubertal onset in healthy girls and boys and are lower in patients with CPP compared to prepubertal matched pairs. The aim of our study was to investigate longitudinal changes in circulating MKRN3 levels in patients with CPP before and during GnRH analogs (GnRHa) treatment. Methods: We performed a longitudinal prospective study. We enrolled 15 patients with CPP aged 7.2 years (range: 2–8) with age at breast development onset < 8 years and 12 control girls matched for the time from puberty onset (mean age 11.8 ± 1.2 years). Serum values of MKRN3, gonadotropins, and 17β-estradiol were evaluated before and during treatment with GnRHa (at 6 and 12 months). The MKRN3 gene was genotyped in CPP patients. In the girls from the control group, only basal levels were analyzed. Results: No MKRN3 mutations were found among CPP patients. MKRN3 levels declined significantly from baseline to 6 months of GnRHa treatment (p = 0.0007) and from 6 to 12 months of treatment (p = 0.003); MKRN3 levels at 6 months were significantly lower than in the control girls (p < 0.0001). Conclusions: We showed that girls with CPP had a decline in peripheral levels of MKRN3 during GnRHa treatment. Our data suggest a suppression of MKRN3 by continuous pharmacological administration of GnRHa.

Genetic studies of familial central precocious puberty (CPP) have suggested that makorin ring finger protein 3 (MKRN3) is the primary inhibitor of gonadotropin-releasing hormone (GnRH) secretion. Obesity in girls can cause early puberty by affecting the hypothalamic-pituitary-gonadal (HPG) axis. This study evaluated the serum MKRN3 level of patients with CPP and its relationship with body mass index (BMI). The study included 92 CPP and 86 prepubertal healthy controls (HC) aged 6-10 years. The CPP and HC groups were divided into obese and non-obese subgroups to evaluate whether BMI affects MKRN3. Patients' presenting complaints, chronological age, height age, bone age, Tanner stage, standard deviation scores for weight, height, and BMI, levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and MKRN3, and pelvic ultrasonography findings were recorded. The serum MKRN3 levels were lower in the CPP group and lowest in the CPP-obese subgroup. There were significant differences in MKRN3 levels between the CPP-obese and CPP-normal weight (p=0.02), CPP-obese and HC-obese (p<0.001), and CPP-obese and HC-normal weight (p=0.03) groups. MKRN3 and BMI were negatively correlated in all cases (r=-0.326, p<0.001). The negative correlation between BMI and MKRN3, and lower MKRN3 levels in CPP-obese patients, suggests that adipose tissue has a role in the onset of puberty. More comprehensive studies are needed to determine the relationship between MKRN3 and adipose tissue.

Loss-of-function mutations of makorin RING finger protein 3 (MKRN3) are the most common monogenic cause of familial central precocious puberty (CPP). To describe the clinical and hormonal features of a large cohort of patients with CPP due to MKRN3 mutations and compare the characteristics of different types of genetic defects. Multiethnic cohort of 716 patients with familial or idiopathic CPP screened for MKRN3 mutations using Sanger sequencing. A group of 156 Brazilian girls with idiopathic CPP (ICPP) was used as control group. Seventy-one patients (45 girls and 26 boys from 36 families) had 18 different loss-of-function MKRN3 mutations. Eight mutations were classified as severe (70% of patients). Among the 71 patients, first pubertal signs occurred at 6.2 ± 1.2 years in girls and 7.1 ± 1.5 years in boys. Girls with MKRN3 mutations had a shorter delay between puberty onset and first evaluation and higher follicle-stimulating hormone levels than ICPP. Patients with severe MKRN3 mutations had a greater bone age advancement than patients with missense mutations (2.3 ± 1.6 vs 1.6 ± 1.4 years, P = .048), and had higher basal luteinizing hormone levels (2.2 ± 1.8 vs 1.1 ± 1.1 UI/L, P = .018) at the time of presentation. Computational protein modeling revealed that 60% of the missense mutations were predicted to cause protein destabilization. Inherited premature activation of the reproductive axis caused by loss-of-function mutations of MKRN3 is clinically indistinct from ICPP. However, the type of genetic defect may affect bone age maturation and gonadotropin levels.

Background: Gonadotropin-releasing hormone agonists (GnRHa) represent the gold-standard treatment for central precocious puberty (CPP). In CPP children, GnRHa treatment slows bone age progression and preserves adult height (Ht) by suppressing sexual steroid secretion. In some patients, however, GnRHa induce an inappropriate growth deceleration impairing Ht outcome. Furthermore, slowly progressive CPP (spCPP) forms were reported which do not need GnRHa treatment. Methods: We evaluated the growth outcome of 26 spCPP girls treated with triptorelin (TR) and 21 with leuprorelin acetate (LA) for 36.5 ± 0.7 months. Results: GnRHa treatment induced a progressive growth deceleration in both spCPP groups. No difference in bone maturation was detected (p > 0.05; TR vs. LA group), however compared to LA, TR treatment resulted in significantly higher Ht after 24 months (p < 0.05; LA vs. TR group). Although target height (TH) standard deviation score (SDS) and predicted adult height (PAH)-SDS at diagnosis were similar in both spCPP groups (p > 0.05; LA vs. TR group), final height (FH-SDS) was lower in LA-treated subjects (p < 0.05; LA vs. TR group). In both spCPP groups, FH-SDS was significantly lower than TH-SDS (p < 0.001) but not lower than PAH-SDS at diagnosis (p > 0.05). Ht-SDS correlated with 17β-estradiol (E₂) blood levels in both spCPP groups (p < 0.0001) throughout GnRHa treatment, and E₂ values were higher in the TR- than in the LA-treated patients during the 12 months after GnRHa administration (p < 0.05; LA vs. TR group). GnRHa-induced E₂ secretion and Ht-SDS at GnRHa withdrawal correlated positively with FH (p < 0.01 and p < 0.001, respectively). Conclusions: The effectiveness of GnRHa treatment in improving FH in spCPP girls was doubtful.

We explored the clinical effect of gonadotropin-releasing hormone agonists for the treatment of children patients with central precocious puberty. From March 2012 to October 2015, 100 cases of children patients with central precocious puberty were enrolled in this study. Intramuscular injection of acetic acid triptorelin (50 to 100 pLg/kg) was made once every 4 weeks, and the treatment lasted for 4 months. Patients' bone age/height differentials (DBA/DCA), bone age (BA), growth velocity (GV) and predicted adult height (PAH) were determined before and after treatment (after 6, 12, 24, 36 months). Differences before and after treatment were analyzed. DBA/DCA, BA and PAH values 6, 12, 24, 36 months after treatment were significantly different compared with those before treatment. Sexual development symptoms in children patients were significantly improved 4 months after treatment (p<0.05). All patients completed the treatment, without any adverse drug reaction or severe complication. After one course of treatment (4 months), patients' uterus and ovarian volumes shrank, FSH level peaked, and LH level was reduced, compared to those before treatment. Acetate acid triptorelin is safe and reliable for treating central precocious puberty. We achieved the excellent clinical curative effect and were able to delay the growth rate in children patients. The predicted height and final height were improved.