Does Basal Morning Luteinizing Hormone (bLH) Predict Central Precocious Puberty (CPP) in Girls?

Background and Objectives: bLH is considered an excellent biochemical predictor of CPP. However, its utilization in clinical practice shows some uncertainties. This study aims to evaluate the diagnostic power of bLH and propose a diagnostic algorithm for CPP. Materials and Methods: We conducted a monocentric cohort retrospective study evaluating all females referred for suspicion of CPP between 1 January 2017 and 31 December 2020 who underwent a GnRH test. Auxological, hormonal, and instrumental data were collected, including pelvic ultrasonography and bone age (BA) assessment. Simple linear regression, t-test, and ROC tests were utilized to study the diagnostic value of basal hormone levels. Two hundred thirteen girls were included in the study. They were subdivided into two groups according to the results of the GnRH test: Group 1, with LH peak > 5 IU/L (pubertal) and 79 patients (37%), and Group 2, with an LH peak ≤ 5 IU/L (prepubertal) and 134 patients (63%). Results: The ROC curve showed that bLH level > 1.5 Ul/L best predicts a pubertal response to the GnRH test (AUC 0.8821, accuracy 82%), with low sensitivity (34%). The multivariate analysis found that bLH > 0.5 IU/L, basal FSH (bFSH) > 3.5 IU/L, bLH/bFSH ratio > 0.16, BA advancement > 1.7 years, uterine volume > 3.6 mL, longitudinal uterine diameter > 41 mm, and the presence of endometrial rhyme were significantly associated with a pubertal response at the GnRH test. An algorithm based on these features was created, and its application would reduce the number of GnRH tests by 34%. Overall, 96.2% of Group 1 patients reached the LH peak at the 30th minute of the GnRH test, supporting the hypothesis that the GnRH test duration could be reduced to 30 min. Conclusions: Morning bLH > 1.5 IU/L could be carefully used as a diagnostic predictor of CPP. The GnRH test, even reduced to 30 min, could be reserved for girls who show low intermediate morning bLH and specific clinical signs of pubertal development.

Testicular Adrenal Rest Tumors in Congenital Adrenal Hyperplasia: Study of a Cohort of Patients from a Single Italian Center.

Testicular adrenal rest tumors (TARTs) are a common complication in male patients with congenital adrenal hyperplasia (CAH). The aim of our cross-sectional cohort study is to estimate the frequency of TARTs with the correlation of genotype and disease control on tumor development. Thirty-five male patients, aged 14-26 years, were included in the study, all followed by the same center of pediatric endocrinology in Bologna. We studied genotypes, hormonal profiles at different time intervals and testicular ultrasound. A logistic regression model with multivariant analysis was developed for the statistical analysis. TARTs were detected in 31.4% of the cases, 90.9% of them had a classic form with salt wasting, while 9.1% had a non-classic form. Additionally, a significant correlation between the incidence of TARTs and severity of genotype was detected. Patients with TARTs had markedly worse metabolic control on average (p = 0.027), reflected by high ACTH, 17OH progesterone, and overall delta4-androstenedione. In conclusion, a screening tool is mandatory, especially (but not exclusively) in patients with the most severe forms of CAH and poor endocrine control of the disease.

Cystathionine Beta-Synthase Deficiency: Three Consecutive Cases Detected in 40 Days by Newborn Screening in Emilia Romagna (Italy) and a Comprehensive Review of the Literature.

Cysthiatonine beta-synthase (CBS) deficiency (CBSD) is an autosomal recessive rare disorder caused by variations on CBS that leads to impaired conversion of homocysteine (Hcy) to cystathionine. Marked hyperhomocysteinemia is the hallmark of the disease. The administration of pyridoxine, the natural cofactor of CBS, may reduce total plasma Hcy. Patient phenotype is classified on pyridoxine responsivity in two groups: pyridoxine-responsive and non-responsive patients. Ectopia lentis, bone deformities, developmental delay, and thromboembolism are the classic signs and symptoms of the disease. Early diagnosis and treatment impact patients' natural history. Therapy aims to lower promptly and maintain Hcy concentrations below 100 µmol/L. Depending on the patient's phenotype, the treatment goals could be obtained by the administration of pyridoxine and/or betaine associated with a methionine-restricted diet. CBSD could be diagnosed in the early days of life by expanded newborn screening (ENS), however, the risk of false negative results is not negligible. In Emilia-Romagna (Italy), during the first 10 years of screening experience, only three cases of CBSD identified have been diagnosed, all in the last two years (incidence 1:118,000 live births). We present the cases and a comprehensive review of the literature to emphasize the role of ENS for early diagnosis of CBSD and its potential pitfalls, reiterating the need for a more effective method to screen for CBSD.

Transient central precocious puberty: a new entity among the spectrum of precocious puberty?

OBJECTIVE: Recently, we observed some cases of Precocious Puberty (PP) with a partial central activation of hypothalamic-pituitary-gonadal (HPG) axis that tended to normalized in 6-12 months. To evaluate the frequency of this form within the spectrum of forms of PP, we retrospectively assessed the clinical, hormonal and ultrasound characteristics of patients attending to our Center for signs of PP, between 2007 and 2017. To hypothesize some causes of this "pubertal poussée" a questionnaire about environmental data was provided to patients. METHODS: 96 girls were recruited for the study and divided into three Groups. Group 1: 56 subjects with Central PP (CPP) requiring treatment with GnRH analogue; Group 2: 22 subjects with transient activation of pubertal axis, that tended to normalize, "Transient CPP"(T-CPP); Group 3: 18 subjects with Isolated Thelarche (IT). RESULTS: Mean age at diagnosis was 6.8 ± 1.0 years in Group 1, 5.9 ± 1.3 years in Group 2 and 5.6 ± 1.5 years in Group 3. A significant increase of diagnosis of T-CPP was observed over the study period. Significantly higher use of some homeopathic medicines and potential exposure to pesticides was reported in Group 2 vs Group 1. CONCLUSIONS: To our knowledge, we first reported a form defined as T-CPP, characterized by partial activation in the HPG axis normalizing over time. An increased use of homeopathic medicines and exposure to environmental pollutants in these patients was evidenced.

Surgical Practice in Girls with Congenital Adrenal Hyperplasia: An International Registry Study.

In this article international trends in surgical practice in girls with congenital adrenal hyperplasia (CAH) are evaluated. All cases that had been classified in the I-CAH/I-DSD registry as 46,XX CAH and who were born prior to 2017 were identified. Centers were approached to obtain information on surgical decision making. Of the 330 included participants, 208 (63.0%) presented within the first month of life, and 326 (98.8%) cases were assigned female. Genital surgery had been performed in 250 (75.8%). A total of 64.3, 89.2, and 96.8% of cases residing in Europe, South America and Asia, respectively, had at least one surgery. In a logistic regression model for the probability of surgery before the second birthday (early surgery) over time an increase of probability for early vaginal surgery could be identified, but not for clitoral surgery or both surgeries combined. Genitoplasty in girls with CAH remains controversial. This large international study provides a snapshot of current practice and reveals geographical and temporal differences. Fewer surgeries were reported for Europe, and there seems to be a significant trend towards aiming for vaginal surgery within the first 2 years of life.

Prevalence and ultrasound patterns of testicular adrenal rest tumors in adults with congenital adrenal hyperplasia.

BACKGROUND: Testicular adrenal rest tumors (TARTs) are benign neoplasms affecting patients with congenital adrenal hyperplasia (CAH). The prevalence of TART in adult patients with CAH is not well known. Ultrasonography (US) is the main tool for diagnosing TART and the role of contrast-enhanced US (CEUS) is never investigated. The aim of this study was to evaluate the TART prevalence in adults with CAH, by stratifying patients according to disease phenotype and assessing the diagnostic performance of US, color Doppler (CD) US and CEUS. METHODS: Male patients >16 years old with certain diagnosis of CAH who underwent US for TARTs, between December 2015 and September 2019 were prospectively enrolled. The control group included patients without CAH affected by testicular lesions at US other than TARTs. RESULTS: TARTs were identified in 16 of 52 patients (31%), of whom 15 (93.8%) displayed the salt-wasting (SW) form (P<0.001). The prevalence of TARTs in patients with the SW form was 54%. One patient with the non-classic (NC) form (6%) showed TART (likely the first documented case). The mean age of patients upon detection of TARTs was significantly younger compared with the control group (P<0.001); moreover, TARTs were bilateral in 15/16 patients (93.8%; P<0.001) and the largest lesion was more frequent in the medium third of testis in the TART group (87.5%), statistically different from the control group (P=0.013). CONCLUSIONS: TARTs almost exclusively affected patients with the SW form of CAH. Age at diagnosis and bilateralism are useful factors for achieving a correct diagnosis of TARTs in CAH adult patients.

Clinical but Not Histological Outcomes in Males With 45,X/46,XY Mosaicism Vary Depending on Reason for Diagnosis.

CONTEXT: Larger studies on outcomes in males with 45,X/46,XY mosaicism are rare. OBJECTIVE: To compare health outcomes in males with 45,X/46,XY diagnosed as a result of either genital abnormalities at birth or nongenital reasons later in life. DESIGN: A retrospective, multicenter study. SETTING: Sixteen tertiary centers. PATIENTS OR OTHER PARTICIPANTS: Sixty-three males older than 13 years with 45,X/46,XY mosaicism. MAIN OUTCOME MEASURES: Health outcomes, such as genital phenotype, gonadal function, growth, comorbidities, fertility, and gonadal histology, including risk of neoplasia. RESULTS: Thirty-five patients were in the genital group and 28 in the nongenital. Eighty percent of all patients experienced spontaneous pubertal onset, significantly more in the nongenital group (P = 0.023). Patients were significantly shorter in the genital group with median adult heights of 156.7 cm and 164.5 cm, respectively (P = 0.016). Twenty-seven percent of patients received recombinant human GH. Forty-four patients had gonadal histology evaluated. Germ cells were detected in 42%. Neoplasia in situ was found in five patients. Twenty-five percent had focal spermatogenesis, and another 25.0% had arrested spermatogenesis. Fourteen out of 17 (82%) with semen analyses were azoospermic; three had motile sperm. CONCLUSION: Patients diagnosed as a result of genital abnormalities have poorer health outcomes than those diagnosed as a result of nongenital reasons. Most patients, however, have relatively good endocrine gonadal function, but most are also short statured. Patients have a risk of gonadal neoplasia, and most are azoospermic, but almost one-half of patients has germ cells present histologically and up to one-quarter has focal spermatogenesis, providing hope for fertility treatment options.

The inconspicuous penis in children.

The term 'inconspicuous penis' refers to a group of anatomical abnormalities in which the penis looks smaller than is expected. Micropenis can be defined as 'true micropenis'--which results from a defect in the hypothalamic-pituitary-gonadal axis--and 'micropenis secondary to congenital anatomical anomalies of the surrounding and overlying structures'--also known as 'concealed penis'. The different forms of concealed penis include webbed penis, congenital megaprepuce and partially hidden penis caused by prepubic adiposity. This disorder can also have iatrogenic causes resulting from adhesions that are secondary to circumcision--this type of concealed penis is known as 'trapped penis'. However, in both groups, micropenis is defined as a stretched penile length that is at least 2.5 SD below the mean for the patient's age, but without any other penile defects. Patients with true micropenis can be managed with testosterone, which has demonstrated good penile elongation results in the long term. Surgery also has a pivotal role in reconstruction for elongating the penis and for correction of anatomical abnormalities in concealed penis.