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Objective: 17β-Hydroxysteroid dehydrogenase 3 deficiency (17β-HSDD) and 5α-reductase type 2 deficiency (5α-RD) are rare 46,XY differences of sex development (DSD). This study aims to enlarge the limited knowledge on long-term gonadal function and gonadal pathology in these conditions., Design: Retrospective multicentre cohort study., Methods: Data on phenotype, laboratory results, and hormone treatment were collected from patients aged ≥16 years at time of data collection with genetically confirmed 17β-HSDD and 5α-RD from 10 centres via the I-DSD Registry. If gonadectomy or gonadal biopsy had been performed, pathology reports and/or gonadal tissue or images were collected., Results: All 16 patients with 17β-HSDD were raised female; 1 (6%) changed to male gender at age 14. Three females were treated with gonadotrophin-releasing hormone agonists (GnRHa) to prevent virilisation. Thirteen underwent gonadectomy at median age 8 (range 0-17). None had germ cell (pre)malignancies. Of 14 patients with 5α-RD, 10 (71%) were raised female. Five changed gender at age 7-23, of whom 4 to male gender. One was treated with GnRHa. Six underwent gonadectomy at median age 10 (range 0-31). None had germ cell (pre)malignancies. With gonads in situ, puberty spontaneously progressed. Three were treated with dihydrotestosterone., Conclusions: A significant percentage of individuals with 17β-HSDD and 5α-RD changed gender, and some were treated with GnRHa to prevent virilisation before making a definitive decision about gonadectomy. When left in situ, spontaneous puberty occurs and germ cell (pre)malignancies seem uncommon at least until early adulthood. Together, these data support delaying a decision about gonadectomy until late adolescence in these conditions., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2025. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Background: Hereditary hypophosphatemia (HH), is a rare condition related to decreased renal tubular phosphate reabsorption. Although X-linked hypophosphatemia or PHEX gene variant is the most frequent cause of HH, recent advances in next-generation sequencing (NGS) techniques enable the identification of genetic etiologies as a whole., Objective: To identify genetic causes of HH using various genetic testing methods and to compare clinical features between FGF23-dependent and FGF23-independent HH groups., Design and Methods: Fifty patients (24 males) from 39 unrelated families were included. Based on initial evaluation, PHEX gene sequencing was performed in patients with clinical and biochemical findings suggestive of FGF23-dependent HH. If sequencing showed no alterations, multiplex ligation-dependent probe amplification (MLPA) analysis for PHEX was conducted. Initially, a specific gene panel was performed for FGF23-independent HH or those in whom PHEX gene showed no genetic alteration., Results: Genetic etiology was revealed in 43 patients from 33 families. PHEX gene variants were identified (four novel) in 24 patients from 19 unrelated families (50%). SLC34A3 was the second most common (16.6%) and the rest were rarer causes of hypophosphatemia (DMP1 n=3, SLC34A1 n=2, CLCN5 n=2, OCRL n=2, FAM2°C n=1, SLC2A2 n=1). When the genetically proven FGF23-dependent (n=28) and FGF23-independent (n=15) HH groups were compared for clinical and biochemical features; lower phosphate and TmP/GFR SDSs and higher ALP SDS with more severe clinical rickets were detected in FGF23-dependent group, whereas, higher serum and urine calcium and lower PTH levels were detected in FGF23-independent group., Conclusions: The application of MLPA provided an additional explanatory value of 10% to the molecular etiology. However, 10% of the cases of HH still remain unexplained even after a comprehensive genetic work-up. Biochemical findings suggest distinct biochemical profiles between FGF23-dependent and FGF23-independent HH groups., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Purpose: 17α Hydroxylase/17,20 lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia, typically diagnosed in late adolescence with symptoms of pubertal delay and hypertension. This study aimed to determine the clinical and laboratory characteristics of 17OHD cases and gather data on disease management., Methods: Data from 97 nationwide cases were analyzed using the CEDD-NET web system. Diagnostic, follow-up findings, and final heights of patients were evaluated., Results: Mean age at admission was 13.54 ± 4.71 years, with delayed puberty as the most common complaint. Hypertension was detected in 65% at presentation; hypokalemia was present in 34%. Genetic analysis revealed Exon 1-6 homozygous deletion as the most frequent mutation, identified in 42 cases. Hydrocortisone replacement was universal; pubertal replacement was administered to 66 cases. Antihypertensive treatment was required in 57 (90%) patients. Thirty-seven cases reached final height, with an average SD of 0.015 in 46,XX and -1.43 in 46,XY. Thelarche and pubarche did not develop properly in some cases despite estradiol treatment., Conclusion: This study represents the largest cohort of pediatric cases of 17-hydroxylase deficiency (17OHD) documented in the literature. Hypertension and hypokalemia can serve as guiding indicators for early diagnosis.The final height is typically considered to be normal. The relationship between genotype and phenotype remains elusive. The initial genetic test for exon 1-6 deletions may be MLPA in our region., (© 2024. The Author(s).)

Background: Assessment of breast development by physical examination can be difficult in the early stages and in overweight girls., Objective: To investigate ultrasonography (US) for evaluation of early breast development., Materials and Methods: In a prospective study, 125 girls (age 7.1 ± 1.5 years) with breast development before 8 years underwent US breast staging, breast volume, and elastography, in addition to clinical/hormonal evaluation for precocious puberty. Accuracy of US for determining breast development and predicting progression to central precocious puberty was investigated., Results: Physical examination revealed glandular breast enlargement in 100 and predominantly lipomastia in 25. Breast US in the former confirmed glandular breast development in 92 (group 1, physical examination and US positive), but not in 8 (group 2, physical examination positive, US negative). Comparison of the two groups demonstrated lower Tanner and US staging, bone age/chronological age, basal luteinizing hormone (LH), breast volume, and uterine volume in group 2. In the 25 lipomastia patients, US demonstrated no breast tissue in 19 (group 3, physical examination and US negative), but US stage ≥ II in 6 (group 4, physical examination negative, US positive) without differences in clinical parameters. After follow-up of 19.8 ± 4.2 months, 46/125 subjects were diagnosed with precocious puberty. US stage, total breast volume, and shear-wave speeds were significantly higher in these 46 patients. Multivariate analyses demonstrated breast volume > 3.4 cc had odds ratio of 11.0, sensitivity of 62%, and specificity of 89, in predicting progression to precocious puberty, being second only to stimulated LH for all variables., Conclusion: Breast US is a useful predictive tool for diagnosis of precocious puberty in girls. Higher US stages and higher breast volume on US increased the likelihood of eventual diagnosis of precocious puberty., (© 2024. The Author(s).)

Although hypothalamo-pituitary-gonadal axis is active during mini-puberty, its relationship with somatic growth and the role on the development of external genitalia has not been fully elucidated. We aimed to evaluate the effects of somatic growth and reproductive hormones on the development of external genitalia during mini-puberty. Anthropometric data, pubertal assesment, serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone sulfate (DHEAS), androstenedione (A4), sex-hormone binding globulin (SHBG), estradiol (E2) and inhibin-B, testosterone (T), and anti-Mullerian Hormone (AMH) of healthy infants aged 1-4 months were evaluated. Free sex hormone index was calculated as T/SHBG for boys and E2/SHBG for girls. The mean age of 148 (74 female) infants included in the study was 2.31 ± 0.76 months. Tanner stage 2-3 sex steroid and gonadotropin levels were observed. A statistically significant difference was found between the weight, height, BMI, weight gain and serum FSH, LH, and A4 measurements of girls and boys (p < 0.05). Penile length was associated with weight (r = 0.24, p = 0.03), height (r = 0.25, p = 0.02), and AMH (r = 0.3, p = 0.01), but not with testosterone (p = 0.56 respectively). A negative correlation was found between weight and serum LH (r =  - 0.26, p = 0.2) and T/SHBG levels in males (r =  - 0.38, p = 0.015 respectively). Weight-SDS was negatively correlated with testosterone in males (r =  - 0.25, p = 0.02). Testicular size and breast stage did not correlate with any of the hormonal and anthropometric parameters.  Conclusions: External genitalia in males during mini-puberty is related more to somatic growth rather than reproductive hormones. Similar to pubertal developmental stages, both total and free testosterone are negatively associated with higher weight during mini-puberty. What is Known: • Mini-puberty allows early assessment of HPG axis function in infancy. • There is an inverse relationship between the amount of adipose tissue and circulating testosterone levels in males during puberty and adulthood. • The potential effect of somatic growth and reproductive hormones on external genital development during mini-puberty remains unclear. What is New: • During mini-puberty, males' external genitalia is more related to somatic growth than to reproductive hormones, but this relationship is not observed in girls. • Both total and free testosterone are negatively associated with higher weight during mini-puberty, similar to the pubertal developmental stages., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Central precocious puberty (CPP) develops as a result of early stimulation of the hypothalamic-pituitary-gonadal (HPG) axis. The loss-of-function mutations in the Makorin-ring-finger3 (MKRN3) gene appear to be the most common molecular cause of familial CPP. We aimed to identify MKRN3 gene mutations in our CPP cohort and to investigate the frequency of MKRN3 mutations., Methods: 102 patients with CPP included. 53 of them had family history of CPP in the first and/or second-degree relatives. MKRN3 gene was analyzed by next-generation sequencing., Results: Possible pathogenic variants were found in 2/53 patients with family history of CPP (3.8%) and 1/49 patient without family history (2%). A novel heterozygous c.1A>G (p.Met1Val) mutation, a novel heterozygous c.683&#95;684delCA (p.Ser228*) and a previously reported c.482dupC (Ala162Glyfs*) frameshift variations were detected. The two novel variants are predicted to be pathogenic in silico analyses., Conclusions: In our cohort, possible pathogenic variants in MKRN3 gene were detected in 2.9% of the total cohort, 3.8% of the familial and 2% of the nonfamilial cases, slightly lower than that reported in the literature. Two novel variants detected contribute to the molecular repertoire of MKRN3 defects in CPP. Classical pattern of paternal inheritance has been demonstrated in all three cases. However, the father of the patient 3 did not have history of CPP suggesting that the father inherited this variant from his mother and had phenotype skipping. Therefore, we emphasize that the absence of history of CPP in the father does not exclude the possibility of a MKRN3 mutation., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)