Query: Precocious Puberty breast

title: A Six Year Old Girl with Breast Development (Precocious Puberty)

title: Ultrasound assessment of breast development: distinction between premature thelarche and precocious puberty.
abstract: We analyzed the correlation between breast development and ultrasound measured breast bud diameter. We also evaluated different breast ultrasound findings in pediatric subjects with precocious puberty and premature thelarche while comparing bone age and hormone levels.  We performed a retrospective study with a sample of 90 girls (mean age, 7.8 years) who underwent breast ultrasound for evaluation of early breast development between March 2011 and February 2013. We evaluated breast ultrasound grade, bud diameter, and clinical characteristics including bone age and hormone levels. Among the 90 girls, 69 were up to 8 years old (mean age, 7.3 years) We divided them into healthy, precocious puberty, and premature thelarche groups and evaluated the clinicoradiologic findings for each group.  Breast ultrasound grade was correlated with age, bone age, bud diameter, luteinizing hormone (LH) follicle stimulating hormone (FSH) and estradiol (E2) Bud diameter was correlated with age, bone age, LH, FSH, and E2. However, the difference between bone age and chronological age was not correlated with ultrasound grade or bud diameter. Among 69 girls up to 8 years old, including 11 healthy girls (15.9% 26 girls with precocious puberty (37.7% (mean [SD] age, 7.3 years) and 32 girls with premature thelarche (46.4% (mean age, 7.2 years) there were no significant differences in other variables except values for bone age (p 0.001) and difference between bone age and chronological age (p 0.001) CONCLUSION. Breast ultrasound might be useful for evaluating sexual development with respect to bud diameter or ultrasound grade. However, its ability to distinguish precocious puberty from premature thelarche is limited.

title: Validation of an Accurate and Noninvasive Tool to Exclude Female Precocious Puberty: Pelvic Ultrasound With Uterine Artery Pulsatility Index.
abstract: The purpose of this study is to validate the accuracy of pelvic ultrasound (US) with the evaluation of uterine artery pulsatility index (PI) to exclude female precocious puberty.  Tanner breast development score, luteinizing hormone (LH) peak after gonadotropin releasing hormone (GnRH) stimulation, and uterine and ovarian volumes and diameters were assessed with pelvic US in 495 girls at a single institution. The study population was divided as follows: prepubertal (n 207) pubertal with physiologic activation of the hypothalamic pituitary ovarian axis (n 176) and central precocious puberty (CPP; n 112) PI was measured with spectral Doppler US at the ascending branches of the right uterine artery (50 Hz filter; time gain compensation, 73; pulse repetition frequency, 6.6) ROC analyses and t tests were performed.  The mean SD) PI values in the prepubertal, pubertal, and CPP groups were 6.3 1.4, 3.4 1.1, and 4.1 1.5, respectively (p 0.001) The best PI cutoff value to distinguish pubertal from prepubertal girls was 4.6 (sensitivity, 83% specificity, 94% positive predictive value, 95% negative predictive value, 80% accuracy, 87% ROC AUC values for LH peak (cutoff value, 5 mU/mL) and for spectral Doppler US PI plus longitudinal uterine diameter (i.e. the combination of a PI of 4.6 with a longitudinal uterine diameter of 35 mm) were 0.9272 and 0.9439, respectively (p 0.7925) The negative predictive values for LH peak and for PI plus longitudinal uterine diameter were 89% and 88% respectively.  A PI greater than 4.6 at spectral Doppler US combined with a longitudinal uterine diameter less than 35 mm allows noninvasive exclusion of female precocious puberty with comparable accuracy and lower costs compared to examination of LH peak after GnRH stimulation. Therefore, PI plus longitudinal uterine diameter might be used as a noninvasive first line test to exclude precocious puberty and thereby avoid further investigations.

title: Basal serum luteinizing hormone value as the screening biomarker in female central precocious puberty
abstract: Precocious puberty refers to the development of secondary sex characteristics before ages 8 and 9 years in girls and boys, respectively. Central precocious puberty (CPP) is caused by premature activation of the hypothalamus pituitary gonadal (HPG) axis and causes thelarche in girls before the age of 8. A gonadotropin releasing hormone (GnRH) stimulation test is the standard diagnostic modality for diagnosing CPP. However, the test cannot always be used for screening because it is expensive and time consuming. This study aimed to find alternative reliable screening parameters to identify HPG axis activation in girls <8 years old (CPP) and for girls 8 9 years old (early puberty, EP) Methods From January 2013 to June 2015, medical records from 196 girls younger than 9 years old with onset of breast development were reviewed, including 126 girls who had a bone age (BA) 1 year above their chronological age. All patients underwent a GnRH stimulation test, and 117 underwent pelvic sonography. The girls were divided into 4 groups based on age and whether the GnRH stimulation test showed evidence of central puberty. Subanalyses were also conducted within each group based on peak luteinizing hormone (LH) level quartiles.  Basal serum LH level was the most sensitive marker for screening CPP and EP. The cutoff values were 0.245 IU/L for CPP under 8 years old (P=0.049, area under the curve [AUC]=0.764, 88% sensitivity, 48% specificity) and 0.275 IU/L for EP between 8 9 years old (P=0.005, AUC=0.813, 79% sensitivity, 77% specificity) Peak LH level decreased as BMI z score among subgroups increased when there was no difference in BA; however, higher BA eliminated this effect.  Basal serum LH level is a useful screening parameter for diagnosing CPP and EP in girls. Peak LH levels were lower with increasing BMI z score, although older BA eliminated this effect.

title: SAT 304 Unexplained Asymptomatic Hyperestrogenism in Central Precocious Puberty Patient Treated with Gonadotropin Releasing Hormone Agonist
abstract: In Central precocious puberty(CPP) the gonadotropin releasing hormone(GnRH) agonist competes with LHRH in the pituitary gland to desensitize and downregulate the response of gonadotropin releasing hormone receptors, effectively inhibiting the secretion of sex hormones in the gonad to prepubertal levels. During the treatment, the bone age progression is slowed, the progression of secondary growth is stopped, and the secretion of sex hormones is maintained as prepubertal levels. We report a case of CPP patient who was treated with GnRH agonist, but abnormally elevated in estradiol level without changes in FSH and LH levels, and slowly normalized without any other abnormal clinical symptoms or laboratory findings. A 5 year and 10 months old girl visited our clinic with breast development which was examined as Tanner stage 2 3. Anthropometric datas were as follows: Her height was 127.3 cm(100th percentile) body weight was 29kg(100th percentile) and BMI was 17.9 kg/cm2. Her bone age was asessed to be 9.7 years by TW3 method. In the abdominopelvic ultrasonography, her uterus showed a pubertal status and no other abnormal findings were noted. LHRH stimulation test showed a pubertal response (peak LH level: 12.1 IU/L after 30min) She was confirmed as central precocious puberty, but brain MRI could not be perfomed due to refusal of the patient's parents. Suppressive treatment was initiated with leuprorelin acetate 3.75mg(Lorelin depo, Dongkuk pharm) There was no further progression of secondary sexual characteristics after the treatment, and we noticed the downregulation of gonadotropin(FSH,LH) and estradiol in initial follow up hormonal assessment. However, second follow up study which was perfomed after 6 months of the treatment showed a feature of peripheral precocious puberty (FSH:1.0 IU/L(normal<2) LH:0.5 IU/L(normal<0.3) Estradiol: 68.6 pg/mL(normal<10) There was no changes in secondary sexual characteristics of the patient, and no specific abnormal finding was found in her pelvic ultrasonography. On consecutive serial follow up studies, only the estradiol level was elevated gradually, and reached 162.2 pg/mL after 12 months of the treatment. There was no estrogenic effect such as acceleration of height gain, progression of secondary sexual characteristics, uterine enlargement, or rapid bone age progression. The duration of elevated hormonal status of the estradiol was nearly 48 months. Bone age was advanced from 9.7 to 10.4 years in this period. No abnormal skin lesion including cafe au lait spot was appeared. However, after this period, estradiol level was gradually decreased and normalized on consecutive follow up studies. In conclusion, estrogen elevation could be shown during the GnRH agonist treatment in CPP patients, however, there is an uncommon possibility of rising and normalizing estrogen levels without evidence of disinhibition in being treated CPP patients.

title: SAT 292 Superimposed Peripheral Precocious Puberty Caused by Autonomous Ovarian Follicular Cyst in Being Treated Central Precocious Puberty Patient: Underlying Condition of Herlyn Werner Wunderlich Syndrome
abstract: Autonomous ovarian follicular cysts are known as the most common cause of peripheral precocious puberty(PPP) in prepubertal girls, and relapses of autonomous ovarian cysts resulting in prolonged estrogen exposure can precipitate early maturation of the hypothalamic pituitary gonadal axis, resulting in progression from PPP to central precocious puberty(CPP) which is called "combined precocious puberty" an evolution which may require GnRH therapy. In present case, PPP caused by autonomous ovarian follicular cyst was developed concomitantly during the treatment course of CPP, with suppressed status of hypothalamic hypophyseal axis. In addition, a rare congenital Mullerian anomaly known as Herlyn Werner Wunderlich syndrome(HWWS) consisting of uterus didelphys, obstructed hemivagina and unilateral renal agenesis was incidentally diagnosed as an underlying condition. A 7 year old girl was presented to our clinic with the development of breast buds which was examined as Tanner stage 2 3. Right renal agenesis was diagnosed in infancy. Her bone age was advanced as 10 years of age, and Luteinizing hormone(LH) showed pubertal response in LHRH stimulation test. The pelvic US revealed absence of right kidney and uterine enlargement. Brain MRI showed no specific abnormalities. Based on these results, We diagnosed idiopathic central precocious puberty. Thereafter, we commenced the treatment with Leuprolide acetate 3.75mg every 4 weeks. After the 11th injection of Leuprolide acetate, however, the patient complained of sudden breast engorgement and vagnal bleeding. Being considered as unsuccessful suppression of HPG axis, Leuprolide acetate was boosted. Hormonal analysis results revealed an extremely elevated level of estradiol and suppressed baseline gonadotropin levels. The pelvic US revealed double uterus, which had not been detected to that point. Abdominopelvic MRI demonstrated right renal agenesis and uterus didelphys with clearly separated uterine body, cervix and vagina. About 3cm sized cystic lesion with several internal daughter cysts is also discovered in left adnexa area. Based on all examinations, we concluded that PPP caused by autonomous ovarian cyst was superimposed on treatment course of CPP and HWWS was incidentally found as underlying disease. Maintaining GnRH agonist treatment, the progression of secondary sexual characteristics was halted and left ovarian cyst disappeared. In couclusion, clinician should be aware of possibility of autonomous ovarian follicular cyst when sudden progression of secondary sexual characteristics is shown in being treated CPP patients, and discriminate PPP from unsuccessfully treated CPP. Additionally, careful suspicion for HWWS that is tied to indications of renal agenesis in children may be the key for successful early diagnosis and immediate treatment intervention, which could prevent long term complications.

title: SAT 290 Expanded Phenotype Associated with RNF135 Intragenic Deletion in a Girl with Peripheral Precocious Puberty
abstract: RNF135 gene is located within the 17q11.2 region and is often deleted in the NF1 contiguous microdeletion syndrome. Six individuals with suspected pathogenic mutations of RNF135 have been described with similar phenotypes including facial dysmorphism (downslanted palpebral fissures, elongated philtrum, broad nasal tip, thin upper lip, broad forehead) macrocephaly, tall stature, overgrowth, and learning disabilities. We present the first reported case of a patient with RNF135 intragenic deletion and precocious puberty.  Patient had ambiguous genitalia at birth, suspicious for CAH. Laboratory evaluation was normal. At age 2, she presented with breast and pubic hair development over the previous year. Leuprolide stimulation test was not consistent with central precocious puberty. Pelvic ultrasound revealed a paraovarian cyst that was drained at age 4 and pubertal development stabilized. At age 6, had progression of puberty with Tanner III breasts. MRI pelvis showed a large cyst of the left ovary and a post pubertal appearing uterus. Patient underwent left oophorectomy for numerous ovarian cysts and concern for progression of precocious puberty. Pathology showed a serous cystadenoma and pubertal ovary. At age 7 years 5 months, she had torsion of the right ovary and underwent laproscopic detorsion. Biopsy showed extensively hemorrhagic tissue with foci of ovarian stroma. Pubertal development was stable until age 7 years 10 months, when she presented with Tanner IV breasts and Tanner II pubic hair. MRI pelvis showed a multicystic right ovary with follicles. Since age 2, patient had tall stature, with height Z score ranging 3.45 4.47. She was diagnosed with focal epilepsy at age 3.5 years and had a PDA that was coiled at age 4. At age 7, chromosomal microarray showed an 88 base pair deletion at chromosome 17q11.2, including part of the RNF135 gene. Patient has dysmorphic facial features, including hypertelorism, upslanted palpebral fissures, bilateral epicanthal folds, flat nasal bridge, malar hypoplasia, high arched palate. Other dysmorphic body features include dolichocephaly and sandal gap between toes 1 and 2. Patient has fine motor, gross motor, and speech delays.  Mutations in the RNF135 gene are rare, with phenotypes only described in 6 individuals to date. Our patient exhibits many phenotypic features seen in described patients with pathogenic variants in this gene, including dysmorphic facial features, developmental delay, and tall stature. This is the first reported case of a patient with RNF135 intragenic deletion presenting with peripheral precocious puberty, cystic ovaries, and focal epilepsy. This case describes several new clinical features that are thought to be associated with a rare RNF135 related overgrowth syndrome.

title: An intriguing case of precocious puberty due to an ovarian mass in an infant.
abstract: We present a rare occurrence of precocious puberty (PP) probably due to an autonomous ovarian cyst in a 15 month old girl who presented to us with growth spurt, breast and pubic hair development, and vaginal bleeding over the last few months. The clinical presentation was suggestive of central precocious puberty (CPP) However, the rapid progression of pubertal changes and occurrence of menarche at breast Tanner stage 2 indicated peripheral precocious puberty (PPP) Due to uncertainty of clinical diagnosis, investigations were conducted for CPP as well as PPP. The basal and peak stimulated LH concentrations were 0.3 IU/l and 2 IU/l, respectively, indicating PPP. However, the peak LH FSH ratio was 1, which is consistent with CPP. Abdominal imaging revealed an ovarian mass, which was laparoscopically excised, but the true nature of the mass could not be ascertained because the excised specimen showed only haemorrhage and features of ovarian torsion on histopathological examination. Regression of pubertal development occurred over a three month period postoperatively.

title: Precocious puberty and Chiari I malformation with syrinx: a case report of an unusual presentation of Costello syndrome
abstract: BackgroundCostello syndrome (CS) is a rare RASopathy causing developmental delays, short stature and classically, delayed puberty. We present a patient with CS and central precocious puberty (CPP).Case presentationA female patient with CS presented at 6 years 10 months of age with breast development. CPP was biochemically confirmed at 7 years 1 month of age, no additional pituitary dysfunction was noted and puberty progressed at follow up. Brain magnetic resonance imaging (MRI) revealed a Chiari I malformation with a syrinx, requiring surgical decompression. The patient was successfully treated with histrelin.ConclusionsAlthough recent publications do not recommend routine brain MRI in girls with isolated CPP over 6 years of age, in those with CS actionable MRI findings are more likely and imaging should be performed. It is unclear whether the cerebral malformation in the patient contributed to CPP or was an incidental syndromic finding.

title: Comparison of clinical characteristics between peripheral and central precocious puberty girls with basal luteinizing hormone less than 0.1 IU/L
abstract: To compare the clinical characteristics of peripheral precocious puberty (PPP) and central precocious puberty (CPP) girls with a basal luteinizing hormone (LH) level less than 0.1 IU/L to guide the reasonable clinical diagnosis of precocious puberty by the gonadotropin releasing hormone (GnRH) stimulating test.  From February 2016 to August 2018, PPP girls (263 cases) and CPP girls (20 cases) with a basal LH value<0.1 IU/L who visited the Subei Hospital of Clinical Medical College of Yangzhou University were studied. Data were compared between groups, and logistic regression analysis was perform to identify the relevant risk factors and ROC curve was used to evaluate the diagnostic value of related indicators.  There were no significant differences between the PPP group and the CPP group in breast development age, age at visit, height at visit, body mass index, genetic target height, growth rate, endometrium appearance, proportion of>4 mm follicles, or basal FSH value. There were significant differences between the two groups in advanced bone age (3.7+ 9.8) months vs (15.3+ 9.6) months, t= 4.908, P<0.001] ovary volume [1.1 (0.7, 1.7) ml vs 1.8 (1.3, 2.4) ml, Z= 3.916, P<0.001] uterine length [18 (16, 20) cm vs 21 (16, 24) cm, Z= 2.309, P=0.021] uterine volume [0.9 (0.6, 1.4) ml vs 1.3 (0.8, 2.4) ml, Z= 3.227, P=0.001] estradiol [18.4 (18.3, 25.3) pmol/L vs 33.3 (18.4, 43.0) pmol/L, Z= 3.182, P=0.001] and predicted compromised adult height (PAH TH) 0.4+ 7.4) cm vs (5.5+ 5.7) cm, t=1.223, P=0.001] Logistic regression analysis demonstrated that the months of advanced bone age (OR=0.844) and uterine volume (OR=0.330) were two independent risk factors for the diagnosis of CPP. ROC curve analysis showed that the area under the curve (AUC) of advanced bone age and uterine volume was 0.830 and 0.716, respectively. When the cutoff value for advanced bone age was 11.5 months, the sensitivity and specificity for diagnosis of CPP were 80.0% and 82.9% respectively. When the cutoff value for uterine volume was 2.085 mL, the sensitivity and specificity for diagnosis of CPP were 45.0% and 95.1% respectively.  The hypothalamic pituitary gonadal axis (HPGA) activation cannot be completely ruled out if basal LH is less than 0.1 IU/L. In these girls, GnRH stimulation test should be conducted to exclude CPP if the bone age is more than 11.5 months ahead or the uterine volume is greater than 2.085 ml.  Luteinizing hormone; Hypothalamic pituitary gonadal axis; Peripheral precocious puberty; Central precocious puberty; Girls