Spontaneous Pubertal Development Research Articles

A Novel Homozygous BMP15 Mutation Causes Ovarian Dysgenesis and Primary Amenorrhea.

Despite a growing number of studies, the genetic etiology in many cases of ovarian dysgenesis is incompletely understood. This work aimed to study the genetic etiology causing absence of spontaneous pubertal development, hypergonadotropic hypogonadism, and primary amenorrhea in 2 sisters. Whole-exome sequencing was performed on DNA extracted from peripheral lymphocytes of 2 Palestinian sisters born to consanguineous parents. Following a BMP15 variant identification, confirming genetic segregation studies were performed in family members. Three-dimensional (3D) modeling for BMP15 dimer and BMP15-GDF-9 heterodimer were followed by functional studies in human ovarian COV434 granulosa cells cotransfected with plasmid harboring either the variant or a wild-type (WT) control, and a second plasmid harboring a luciferase-reporter-gene with a BMP-responsive element. A novel homozygous c.G959A/p.C320Y BMP15 mutation was identified in both sisters, and segregated with the disease in the family. By 3D-structure modeling, the mutations were predicted to damage a cysteine-knot motif, disrupt BMP15 dimerization, and severely impair activation of the BMP pathway. The homologous mutation C53Y occurring and identified spontaneously in sheep results in sterility in homozygotes, mimicking the human phenotype here. A 3.8-fold decrease in BMP15 signaling was observed in vitro in cells expressing the homozygous BMP15 mutant when compared to the WT control. The novel homozygous missense C320Y mutation is the first homozygous human BMP15 variant causing impaired signaling ability, which correlates with the predicted 3D-structural changes leading to ovarian dysgenesis. The homologous mutation in sheep mimics the human phenotype by infertility. Beyond genetic counseling, and considering ovarian preservation, the ovine model enables further elucidation and interventions in the BMP signaling.

Identification of novel variants and candidate genes in women with 46,XX complete gonadal dysgenesis

Background46,XX complete gonadal dysgenesis (46,XX-CGD) is a rare disorder of sexual development (DSD) characterized by primary amenorrhea and a lack of spontaneous pubertal development in individuals with a 46,XX karyotype despite the presence of female internal and external genitalia due to failure of bilateral ovarian development. The condition is genetically heterogeneous, and in most cases, its etiology is unknown. Determining the genetic cause would provide insights into potential targets for genetic diagnosis and counseling.MethodsTo clarify the molecular mechanisms of 46,XX complete gonadal dysgenesis in the population of China, whole-exome sequencing (WES) was performed on DNA samples from patients with 46,XX-CGD. In silico analysis was conducted to predict the pathogenicity of the variants.ResultsWe recruited 20 patients with 46,XX-CGD and identified 8 variants in 6 genes, including three homozygous variants in MCM9, POF1B, and PSMC3IP; compound heterozygous variants in TWNK; and three heterozygous variants in TP63 and INSRR, from 7 patients. These variants included 3 recurrent variants and 5 novel variants.ConclusionsThis study identified several novel variants, broadening the variant spectrum of 46,XX-CGD. 46,XX-CGD is a genetically heterogeneous condition, and WES is a powerful tool for determining its genetic etiology. The results of this study will aid researchers and clinicians in genetic counseling and suggest that WES is valuable for detecting 46,XX-CGD, which may lead to early interventions for patients.

7407 Normosmic Idiopathic Hypogonadotropic Hypogonadism in Women: A Case Report and Comprehensive Review

Abstract Disclosure: E.G. Bustamante: None. M. Sulehri: None. I. Patoli: None. A. Karunakaran: None. Normosmic Idiopathic Hypogonadotropic Hypogonadism (nIHH) in Women: A Case Report and Literature ReviewIntroduction: IHH is a rare genetic disorder affecting gonadotropic-releasing hormone (GnRH) production and/or action, resulting in diminished sex steroid levels. Characterized by the absence of spontaneous pubertal development. In women, it manifests with normal adrenarche but absent thelarche and menarche. Our case highlight a late diagnosis of IHH in a 34-year-old woman with primary amenorrhea. Case report: A 34 year old lady with a history of primary amenorrhea sought evaluation. At age 16, she underwent assessment for short stature and primary amenorrhea, denying anosmia, headache, visual disturbances. Evaluation revealed bone age concordant with chronological age and normal MRI Brain. Pelvic ultrasound (US) showed small premenarchal uterus and ovaries. She initiated oral contraceptive pills (OCP) and experienced regular menses. Seeking fertility assistance at age 24, a normal Hysterosalpingogram was followed by successful delivery of twins after ovarian stimulation. Post-delivery menses did not resume and OCP was not restarted. Family history revealed a sister with irregular periods requiring OCP.Subsequently workup at age 30 showed Estradiol 22 pg/ml, FSH/LH 4.1/2.3 mUI/mL; normal PRL, TFT, DHEAS, 17OHP. Repeat Pelvic US showed normal uterus, endometrial stripe normal at 0.24 cm and non-visualized ovaries. PCOS testing negative for hyperandrogenism. Progesterone challenge resulted in no withdrawal bleeding. Brain MRI demonstrated a 2.2 x 1.3 mm hypoenhancing ovoid mass in the pars Intermedia of the pituitary gland suggestive of pituitary microadenoma. Pituitary axis hormonal testing was normal. Karyotype revealed 46 XX (normal female). Genetic evaluation identified a pathogenic variant (p.R35C) in GNRH1 gene. Her final diagnosis: nIHH. Discussion HH is diagnosed in 5% of all women with primary amenorrhea and is divided into 2 major categories: Kallmann syndrome and nIHH. The majority of known causes of HH can be attributed to mutations in KAL1, FGFR1, or GNRHR. The p.R35C variant has been associated with autosomal dominant nIHH. Diagnosis involves clinical suspicious, low LH/FSH and sex steroid levels, normal hypothalamic–pituitary imaging, and exclusion of differentials.Treatment goal for female focus on regular breast and uterine development, as well as the capability to conceive. Use of hormonal replacement therapy and/or gonadotropins or pulsatile GnRH for ovarian stimulation are essential. ConclusionWhile IHH predominantly affects men, limited literature explores its manifestation in women and its impact on fertility. The identification of a GNRH1-related nIHH variant highlights the role of genetic testing in specific HH diagnoses. Failure to diagnose in adolescence may compromise women overall well-being Presentation: 6/1/2024

Clinical and genetic characteristics of 42 Chinese paediatric patients with X-linked adrenal hypoplasia congenita

BackgroundX-linked adrenal hypoplasia congenita (AHC) is a rare disorder characterized by primary adrenal insufficiency (PAI) and hypogonadotropic hypogonadism (HH), with limited clinical and genetic characterization.MethodsThe clinical, biochemical, genetic, therapeutic, and follow-up data of 42 patients diagnosed with X-linked AHC were retrospectively analysed.ResultsHyperpigmentation (38/42, 90%), vomiting/diarrhoea (20/42, 48%), failure to thrive (13/42, 31%), and convulsions (7/42, 17%) were the most common symptoms of X-linked AHC at onset. Increased adrenocorticotropic hormone (ACTH) (42/42, 100%) and decreased cortisol (37/42, 88%) were the most common laboratory findings, followed by hyponatremia (32/42, 76%) and hyperkalaemia (29/42, 69%). Thirty-one patients presented with PAI within the first year of life, and 11 presented after three years of age. Three of the thirteen patients over the age of 14 exhibited spontaneous pubertal development, and ten of them experienced delayed puberty due to HH. Six patients receiving human chorionic gonadotropin (hCG) therapy exhibited a slight increase in testicular size and had rising testosterone levels (both P < 0.05). The testicular volumes of the three patients with pulsatile gonadotropin-releasing hormone (GnRH) therapy were larger than those of the six patients undergoing hCG therapy (P < 0.05), and they also exhibited some growth in terms of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone. Of the 42 patients, three had an Xp21 deletion, and 39 had an isolated DAX1 defect. Most patients (9/10) with entire DAX1 deletion accounting for 23.8% (10/42) of the total variants had early onset age of less than one year.ConclusionsThis study details the clinical features and genetic spectra of X-linked AHC. Patients with X-linked AHC show a bimodal distribution of the age of onset, with approximately 70% presenting within the first year of life. Pulsatile GnRH may be recommended for HH when hCG therapy is not satisfactory, although it is difficult to achieve normal testicular volume. The combination of clinical features and molecular tests provides information for an accurate diagnosis.

The Cut-Off Value of Serum Anti-Müllerian Hormone Levels for the Diagnosis of Turner Syndrome with Spontaneous Puberty.

Preservation of fertility in Turner syndrome (TS) patients may be feasible through cryopreservation of ovarian tissue before follicles begin to disappear. Anti-Müllerian hormone (AMH) is said to be a predictive factor of spontaneous pubertal development in TS. We aimed to determine the cut-off values of AMH for the diagnosis of TS girls with spontaneous puberty. Design and methods: A total of 95 TS patients between 4 and 17 years were evaluated at the Department of Pediatric Genetic Metabolism and Endocrinology from July 2017 to March 2022. Serum AMH, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels were analyzed according to age, karyotype, pubertal development, and ultrasound ovarian visualization. Receiver-operating characteristic (ROC) curve analyzes were used to test the utility of AMH for the diagnosis of TS girls with spontaneous puberty. One-fourth of TS girls aged 8-17 years had spontaneous breast development, with the ratios as follows: 45, X (6/28, 21.4%), mosaicism (7/12, 58.3%), and mosaicism with structural X chromosome abnormalities (SCA) (2/13, 15.4%), SCA (1/13, 7.7%), and Y chromosome (1/3, 33.3%). The AMH cut-off value for the prediction of spontaneous puberty in TS patients was 0.07 ng/ml, with sensitivity and specificity both at 88%. FSH, LH levels, and Karyotypes could not be considered as markers of spontaneous puberty in TS (P > 0.05). A strong relationship was observed between serum AMH levels and spontaneous puberty or ultrasound bilateral ovarian visualization. The AMH cut-off value for the prediction of spontaneous puberty in TS girls aged 8-17 years was 0.07 ng/ml, with sensitivity and specificity both at 88%. However, spontaneous puberty in these patients is not predictable based on karyotype or FSH or LH levels.

GNRHR-related central hypogonadism with spontaneous recovery – case report

BackgroundCongenital hypogonadotropic hypogonadism (CHH) is a clinically and genetically heterogeneous disease characterized by absent or incomplete puberty and infertility. Clinical characteristics are secondary to insufficient gonadotropin secretion, caused by deficient gonadotropin-releasing hormone (GnRH) production, secretion, or action. Loss-of-function variants of the gonadotropin-releasing hormone receptor (GNRHR) are associated with CHH without anosmia. CHH was previously considered a permanent condition, but in the past two decades, cases of spontaneous recovery of CHH have been reported. The reversal of hypogonadism in CHH is currently unpredictable, and can happen unnoticed.Case presentationThe male proband was diagnosed with CHH due to compound heterozygosity for two previously reported pathogenic missense variants in the GNRHR gene, NM_000406.2:c.416G > A (NP_000397.1:p.Arg139His) and c.785G > A (p.Arg262Gln) at 16 years of age. In addition to arrested partial puberty, he had a low testosterone level, gonadotropins in the range of early puberty, and a normal inhibin B level. A therapy with increasing doses of intramuscular testosterone undecanoate was received for 2.5 years, while there was no change in testicular volume. At the age of 19 years, testosterone supplementation was interrupted. During the next two years, he had spontaneous pubertal development to achieve a testicular volume of 20 mL, with normal adult levels of gonadotropins and testosterone.ConclusionsGenetic diagnostics can help discriminate congenital hypogonadotropic hypogonadism, deserving therapeutic intervention, from the self-limited constitutional delay of growth and puberty (CDGP). Patients with GNRHR associated hypogonadism can experience spontaneous recovery of the hypothalamic-pituitary–gonadal axis. Spontaneous testis enlargement in patients with central hypogonadism not taking gonadotropins or pulsatile GnRH therapy can indicate recovery of hypogonadism.

Clinical and StAR genetic characteristics of 33 children with congenital lipoid adrenal hyperplasia

Objective: To analyze the clinical and genetic characteristics of 33 children with congenital lipoid adrenal hyperplasia (CLAH) caused by StAR gene defects. Methods: The clinical, biochemical, genetic, and follow-up (until December 2021) data of 33 children diagnosed with CLAH from 2006 to 2021 were retrospectively analyzed in Xinhua Hospital, Shanghai Jiao Tong University School of Medicine. Results: Of the 33 children with CLAH, 17 had a karyotype of 46, XX and 16 had a karyotype of 46, XY; 31 were female and 2 were male by social gender. Classic type and non-classic type were found in 30 and 3 children respectively. The age at diagnosis was 9.0 (3.0, 34.5) months. All the 30 cases with classic CLAH presented within the first year of life with skin hyperpigmentation (28 cases, 93%), vomiting and(or) diarrhea (19 cases, 63%), no increase in body weight (8 cases, 27%), elevated adrenocorticotropic hormone levels (21cases (70%)>275 pmol/L), decreased cortisol levels (47 (31,126) nmol/L), hyponatremia ((126±13) mmol/L), hyperkalemia ((5.7±1.1) mmol/L), and normal 17α-hydroxyprogesterone levels (30 cases, 100%). All these with classic CLAH exhibited female external genitalia. Three children with non-classic CLAH (including 2 cases of 46, XY and 1 case of 46, XX) also showed signs and symptoms of adrenal insufficiency, but 2 of them had an age of onset later than 1 year of age, including 1 case of 46, XY with male external genitalia and 1 case of 46, XX with female external genitalia. The other 46, XY patient with non-classic CLAH presented with adrenal insufficiency at 2 months of age, showing micropenis and hypospadias. In the 17 females with 46, XX, 4 older than 10 years of age showed spontaneous pubertal development. A total of 25 StAR gene pathogenic variants were identified in 33 patients, with p.Q258* (18/66, 27%), p.K236Tfs*47 (8/66, 12%) and p.Q77* (6/66, 9%) being the common variantion. Six novel variants were found, including c.358T>G, c.713_714del, c.125del, c.745-1G>A, c.179-2A>C, and exon 1 deletion. Conclusions: Patients with classic CLAH typically present with signs and symptoms of primary adrenal insufficiency in the early infancy period and female external genitalia. p.Q258*, p.K236Tfs*47 and p.Q77* are common variants in CLAH patients.

FSH and bone: Comparison between males with central versus primary hypogonadism.

ObjectiveExperimental studies proposed a direct effect of follicle-stimulating hormone (FSH) on the skeletal metabolism, but results of human studies mainly conducted in females are controversial. The present study aims to investigate the possible role of FSH excess in male bone health, by comparing for the first time primary and central hypogonadism.Design and Methods119 men were enrolled in this cross-sectional observational study at the time of the first diagnosis of hypogonadism. All participants had spontaneous pubertal development. Regarding patients with hypergonadotropic hypogonadism (Hyper-H), Klinefelter syndrome (KS) patients were distinguished from the other forms (non-KS-Hyper-H) based on the onset of FSH elevation. Bone mineral density (BMD) at both lumbar spine (LS) and femoral neck (FN), as well as the prevalence of morphometric vertebral fractures (VFx), were assessed.ResultsAcross the whole cohort, higher LS and FN BMD were associated with older age at diagnosis and higher body mass index (BMI), respectively. After adjusting for potential confounders (age at diagnosis, BMI, smoking habits, degree of hypogonadism defined by calculated free testosterone, and 25OH vitamin D levels), non-KS-Hyper-H patients showed significantly lower LS BMD and tended to show lower FN BMD values, as compared to those with hypogonadotropic hypogonadism (Hypo-H). In KS men, LS BMD was significantly lower than in those with non-KS-Hyper-H. No significant differences in the prevalence of VFx were found between the groups.ConclusionsThese findings suggest a potential negative effect of FSH excess on the male bone mass, especially at spine. The duration of high FSH levels may also contribute to these findings.

Clinical Presentation of Hypogonadotropic Hypogonadism in 18-Year-Old Man: Case Report

The absence of spontaneous pubertal development characterized idiopathic hypogonadotropic hypogonadism (IHH) as a result of low levels of sex steroids and gonadotropins with normal pituitary function. An 18-year-old man came to the Andrology Poly of RSUD Dr Soetomo with complaints that his penis was small. After being examined, the result showed that he had pitched voice, lipomastia , penis length 4.5 cm, penis circumference 4 cm, and found coronal hypospadias. There was no publicity yet. The size of the right and left testes was ± 1cc with a supple consistency and was inside the scrotum. Karyotyping result was 46, XY. The result of the hormone indicated that the FSH, LH and testosterone levels were low. The results of testicular ultrasound showed that the right and left testes in the scrotum and on abdominal ultrasound had no visible picture of the uterus. The patient was diagnosed with IHH with coronal hypospadias. The patient was given counselling, information and education about the disease he suffered, a therapy plan to be given, and the need to make lifestyle modifications. This case report describes the clinical presentation of a male patient with hypogonadotropic hypogonadism. Keywords: Idiopathic hypogonadotropic hypogonadism, mikropenis, hipospadia coronal DOI: 10.7176/JHMN/85-01 Publication date: January 31 st 2021

Pubertal outcomes of children transplanted with allogeneic stem cells after myeloablative total body irradiation or busulfan: Influence of age and sex is confirmed, while a role of chronic graft-versus-host disease in delayed puberty onset is revealed.

Myeloablative conditioning before allogeneic HSCT during childhood exposes to serious long-term complications, especially gonadal dysfunction. Pubertal issues are less described than other post-HSCT sequelae in childhood. Pubertal development and biological gonadal parameters were assessed in a retrospective monocentric cohort of prepubertal patients who underwent HSCT after myeloablative conditioning with TBI or busulfan between 1981 and 2017. Seventy-four patients (28 girls and 46 boys) were included. No spontaneous pubertal development was found in 50% of girls and 10% of boys (P<.001), and delayed puberty or no spontaneous pubertal development was found in 57% of girls and 24% of boys (P=.009). HRT was used in 82% of girls and 24% of boys (P<.001). In univariate analysis, TBI conditioning (P=.05), female sex (P<.001), acute GVHD (P=.05), extensive chronic GVHD (P=.021), steroid treatment >6months (P=.016), and malignant diseases (P=.016) were associated with no spontaneous pubertal development, whereas TBI conditioning (P=.003) and extensive chronic GVHD (P=.005) were associated with delayed puberty. In multivariate analysis, factors independently associated with no spontaneous puberty onset were female sex (P=.001) and age >10years (P=.033). Factors independently associated with delayed puberty were extensive chronic GVHD (P=.041) and age >10years (P=.031). This study highlighted the toxicity of MAC in prepubescent children: TBI did worse, but this was especially true for the most susceptible patients (girls, leukemic patients, and patients older than 10years). It suggests a possible role of GVHD in delayed puberty.

Urogenital Abnormalities in Adenosine Deaminase Deficiency

BackgroundImproved survival in ADA-SCID patients is revealing new aspects of the systemic disorder. Although increasing numbers of reports describe the systemic manifestations of adenosine deaminase deficiency, currently there are no studies in the literature evaluating genital development and pubertal progress in these patients.MethodsWe collected retrospective data on urogenital system and pubertal development of 86 ADA-SCID patients followed in the period 2000–2017 at the Great Ormond Street Hospital (UK) and 5 centers in Italy. In particular, we recorded clinical history and visits, and routine blood tests and ultrasound scans were performed as part of patients’ follow-up.Results and DiscussionWe found a higher frequency of congenital and acquired undescended testes compared with healthy children (congenital, 22% in our sample, 0.5–4% described in healthy children; acquired, 16% in our sample, 1–3% in healthy children), mostly requiring orchidopexy. No urogenital abnormalities were noted in females. Spontaneous pubertal development occurred in the majority of female and male patients with a few cases of precocious or delayed puberty; no patient presented high FSH values. Neither ADA-SCID nor treatment performed (PEG-ADA, BMT, or GT) affected pubertal development or gonadic function.ConclusionIn summary, this report describes a high prevalence of cryptorchidism in a cohort of male ADA-SCID patients which could represent an additional systemic manifestation of ADA-SCID. Considering the impact urogenital and pubertal abnormalities can have on patients’ quality of life, we feel it is essential to include urogenital evaluation in ADA-SCID patients to detect any abnormalities, initiate early treatment, and prevent long-term complications.

Expanding the mutational spectrum of monogenic hypogonadotropic hypogonadism: novel mutations in ANOS1 and FGFR1 genes

BackgroundCongenital hypogonadotropic hypogonadism (CHH) is a rare disease, triggered by defective GnRH secretion, that is usually diagnosed in late adolescence or early adulthood due to the lack of spontaneous pubertal development. To date more than 30 genes have been associated with CHH pathogenesis with X-linked recessive, autosomal dominant, autosomal recessive and oligogenic modes of inheritance. Defective sense of smell is present in about 50–60% of CHH patients and called Kallmann syndrome (KS), in contrast to patients with normal sense of smell referred to as normosmic CHH.ANOS1 and FGFR1 genes are all well established in the pathogenesis of CHH and have been extensively studied in many reported cohorts. Due to rarity and heterogenicity of the condition the mutational spectrum, even in classical CHH genes, have yet to be fully characterized.MethodsTo address this issue we screened for ANOS1 and FGFR1 variants in a cohort of 47 unrelated CHH subjects using targeted panel sequencing. All potentially pathogenic variants have been validated with Sanger sequencing.ResultsSequencing revealed two ANOS1 and four FGFR1 mutations in six subjects, of which five are novel and one had been previously reported in CHH. Novel variants include a single base pair deletion c.313delT in exon 3 of ANOS1, three missense variants of FGFR1 predicted to result in the single amino acid substitutions c.331C > T (p.R111C), c.1964 T > C (p.L655P) and c.2167G > A (p.E723K) and a 15 bp deletion c.374_388delTGCCCGCAGACTCCG in exon 4 of FGFR1. Based on ACMG–AMP criteria reported variants were assigned to class 5, pathogenic or class 4, likely pathogenic. Protein structural predictions, the rarity of novel variants and amino acid conservation in case of missense substitutions all provide strong evidence that these mutations are highly likely to be deleterious.ConclusionsDespite the fact that ANOS1 and FGFR1 are classical CHH genes and were thoroughly explored in several CHH cohorts we identified new, yet undescribed variants within their sequence. Our results support the genetic complexity of the disorder. The knowledge of the full genetic spectrum of CHH is increasingly important in order to be able to deliver the best personalised medical care to our patients.

OR17-5 Clinical and Genetic Features of Constitutional Delay of Growth and Puberty

Constitutional delay of growth and puberty (CDGP) is the most prevalent cause of delayed puberty in both sexes. It has a strong family history, however, its genetic basis is still poorly understood. Objective: To characterize the clinical and genetic features of a CDGP cohort. Methods: 59 unrelated probands with CDGP were selected. They underwent careful and long-term clinical evaluation. Genetic analysis was performed using a custom DNA target enrichment panel (NextSeq 500 next-generation sequencing, Illumina Inc) designed to capture 36 known and candidate genes implicated with delayed puberty. Results: All CDGP patients had spontaneous pubertal development or it was induced by a transient sexual steroid replacement. Male predominance (81%), short stature (91%) associated with delayed bone age and positive family history (59%) were the major clinical features of this cohort. Genetic analyses revealed 16 rare heterozygous predicted to be deleterious variants in 15 CDGP patients (25%) in 8 distinct genes (HS6ST1, IGSF10, GHSR, CHD7, SEMA3A, IL17RD, SPRY4 and WDR11). IGSF10 and GHSR were the most prevalent affected genes in this group (3 variants in 4 patients each one). The vast majority of variants were missense. We identified a stop-gain variant, likely pathogenic, in HS6ST1 gene (p.Cys27X) in a male proband with no family history of delayed puberty. 5% of the subjects had oligogenicity (variants in more than one gene). Conclusions: The classic phenotype of CDGP has as clinical features short stature in the prepubertal period, higher prevalence in males and more than a half of the individuals had a positive family history. Genetic heterogeneity was demonstrated in typical CDGP phenotype.

Different Clinical Presentations and Management in Complete Androgen Insensitivity Syndrome (CAIS).

Complete androgen insensitivity syndrome (CAIS) is an X-linked recessive genetic disorder resulting from maternally inherited or de novo mutations involving the androgen receptor gene, situated in the Xq11-q12 region. The diagnosis is based on the presence of female external genitalia in a 46, XY human individual, with normally developed but undescended testes and complete unresponsiveness of target tissues to androgens. Subsequently, pelvic ultrasound or magnetic resonance imaging (MRI) could be helpful in confirming the absence of Mullerian structures, revealing the presence of a blind-ending vagina and identifying testes. CAIS management still represents a unique challenge throughout childhood and adolescence, particularly regarding timing of gonadectomy, type of hormonal therapy, and psychological concerns. Indeed this condition is associated with an increased risk of testicular germ cell tumour (TGCT), although TGCT results less frequently than in other disorders of sex development (DSD). Furthermore, the majority of detected tumoral lesions are non-invasive and with a low probability of progression into aggressive forms. Therefore, histological, epidemiological, and prognostic features of testicular cancer in CAIS allow postponing of the gonadectomy until after pubertal age in order to guarantee the initial spontaneous pubertal development and avoid the necessity of hormonal replacement therapy (HRT) induction. However, HRT is necessary after gonadectomy in order to prevent symptoms of hypoestrogenism and to maintain secondary sexual features. This article presents differential clinical presentations and management in patients with CAIS to emphasize the continued importance of standardizing the clinical and surgical approach to this disorder.

Anti-Müllerian hormone levels in patients with turner syndrome: Relation to karyotype, spontaneous puberty, and replacement therapy.

Most girls with Turner syndrome (TS) suffer from incomplete sexual development, premature ovarian failure, and infertility due to abnormal ovarian folliculogenesis. Serum anti-Müllerian hormone (AMH) levels reflect the ovarian reserve in females, even in childhood. Thus, we aimed to assess serum AMH levels in girls with TS and its relation to karyotype, spontaneous puberty, and growth hormone (GH) therapy. Fifty TS were compared to 50 age- and sex-matched controls. All subjects were subjected to history, anthropometric assessment, Tanner pubertal staging and measurement of serum follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and AMH. Karyotype results were obtained from patients' records. Serum AMH was measurable in 12 TS patients (24%). The lowest frequency of measurable AMH was in patients with a karyotype of 45,X. The measurable AMH was associated with spontaneous breast development (p = .003) and spontaneous menarche (p = .001). AMH correlated negatively with FSH (r = -.846, p = .000) and LH (r = -.83, p = .034). GH therapy increased the odds of having measurable AMH in TS girls (p = .002). In conclusion, AMH was associated with karyotype, spontaneous pubertal development, LH, and FSH in TS girls and may serve as a useful marker of ovarian function and ongoing follicular development in prepuberty.

Clinical, Cytogenetic, and Histopathologic Profile of a Case Of 46,XY Gonadal Dysgenesis

ABSTRACT Objective: This case report will highlight the importance of histopathologic analysis of the gonads to differentiate ovotesticular disorder of sexual development (OT-DSD) from mixed gonadal dysgenesis. Both disorders may have the same clinical and cytogenetic presentation, but the latter presents high risk for gonadal malignancy, hence there is usually a need for early gonadectomy, while the former has a low risk for malignancy. Therefore OT-DSD patients may have the opportunity for spontaneous pubertal development and fertility with regular tumor surveillance. Methods: We report the case of a 22-year-old patient reared as a male with a 46,XY karyotype diagnosed as OT-DSD by gonadal biopsy. The patient presented with microphallus with chordee, penoscrotal hypospadias, poor virilization, and development of gynecomastia at puberty. Results: Histopathologic examination of the single tubule biopsy of the left gonad showed seminiferous tubules lined by Sertoli cells and Leydig cells in the interstitia...

Diversity of Pubertal Development in Cartilage-Hair Hypoplasia; Two Illustrative Cases.

Cartilage-hair hypoplasia (CHH) is a rare chondrodysplasia, including disproportionate short stature, hypoplastic hair, immunodeficiency, and increased risk of malignancies. Absent pubertal growth spurt and absent pubic hair complicate monitoring of pubertal development in these patients. Two CHH patients with delayed puberty and excessive growth failure are described. One of the girls had hypogonadotropic hypogonadism whereas the other had hyponormogonadotropic hypogonadism with no spontaneous pubertal development and slow response to estrogen therapy, both requiring permanent replacement therapy. Careful follow-up of pubertal development in individuals with CHH and other growth-restricting bone diseases is needed. In delayed pubertal development timely hormone therapy is essential to ensure maximal growth and well developed secondary sex characteristics.

Сlinical and genetic variants of Turner syndrome and the rationale for the choice of their treatment

Background. The main clinical manifestation of Turner syndrome (TS) is short stature, which is observed in 98-100% of patients. In cases of karyotype 45,X girls do not develop puberty, different degrees of developmental delay can also occur in cases of mosaicism. The phenotype of TS have different variants that makes it difficult to diagnose, especially in case of mosaicism. In the available literature there is no data on the individual approach to the therapy with recombinant growth hormone (rGH) in girls with TS. Objective . To determine the clinical and genetic variants of TS girls before puberty and of puberty age, and especially their physical and pubertal development, growth hormone function in order to determine the individual indications for hormonal treatment of growth and puberty disorders. Materials and methods . We performed analysis of registry, which includes 566 children with TS during 12 years. Also we carried out a detailed survey of 150 girls with TS, during which the phenotypic features, parameters of physical and sexual development, growth hormone status of function, efficiency of treatment with rGH in children of different ages were assessed. Results and discussion . We identified clinical and genetic variants of girls with TS before puberty and of puberty age. The largest proportion of patients with TS before puberty age have dwarfism in conjunction with phenotypic features of high importance and karyotype 45,X, the smallest share – growth retardation in combination with phenotypic features of low significance and karyotype 45,X/46,XX. The greatest proportion of patients with TS of puberty age have dwarfism and lack of signs of the spontaneous pubertal development and karyotype 45,X, and the lowest – delayed growth and spontaneous puberty. Partial or complete deficiency of growth hormone was detected in 35,65% of patients with TS of different ages belonging to the clinical and genetic variants with dwarfism. Conclusions . Clinical and genetic variants of TS can be used for early diagnosis, as well as the choice of individual approach to rGH therapy. In girls with TS of puberty age in the presence of dwarfism and without spontaneous pubertal development as well as with dwarfism and spontaneous puberty appointment rGH for the treatment of short stature is justified, even in the case of late initiation. In contrast, it is inappropriate to start rGH treatment in puberty age patients with TS in cases of normal function of the pituitary growth hormone with dwarfism and with spontaneous pubertal development as well as those with growth retardation in presence or without of spontaneous pubertу because delayed initiation of rGH does not lead to effective increase in growth.

Pubertal Development

Pubertal Development

Concomitant occurrence of Turner syndrome and growth hormone deficiency.

Turner syndrome (TS) is a genetic disorder in phenotypic females that has characteristic physical features and presents as partial or complete absence of the second sex chromosome. Growth hormone deficiency (GHD) is a condition caused by insufficient release of growth hormone from the pituitary gland. The concomitant occurrence of TS and GHD is rare and has not yet been reported in Korea. Here we report 2 cases of TS and GHD. In case 1, GHD was initially diagnosed. Karyotyping was performed because of the presence of the typical phenotype and poor response to growth hormone therapy, which revealed 45,X/45,X+mar. The patient showed increased growth velocity after the growth hormone dose was increased. In case 2, a growth hormone provocation test and chromosomal analysis were performed simultaneously because of decreased growth velocity and the typical TS phenotype, which showed GHD and a mosaic karyotype of 45,X/46,XX. The patient showed spontaneous pubertal development. In female patients with short stature, it is important to perform a throughout physical examination and test for hormonal and chromosomal abnormalities because diagnostic accuracy is important for treatment and prognosis.