INTRODUCTION:Considering that testicular volume (TV) is probably not an adequate marker of pubertal onset in boys born small for gestational age (SGA), we aimed to describe the progression of pubertal clinical and biochemical characteristics, comparing the trajectory of TV with other parameters as markers of pubertal onset in boys born SGA. METHODS:We performed a retrospective, descriptive study of a cohort of boys born SGA with longitudinal follow-up. We determined the TV at the time when serum AMH decreased ≥30% or LH attained 0.35 IU/L. RESULTS:Thirty boys born SGA were included: 16 of 30 (53.3%) had LH ≥0.35 IU/L and 7 of 24 boys (29.2%) had a decline ≥30% in serum AMH with a TV <4 mL. LH ≥0.35 IU/L and AMH decrease ≥30% were observed at least 1 year before TV 4-5 mL in 11 of 22 (50%) and 3 of 19 (15.8%) boys, respectively. During follow-up, higher serum LH, FSH, and testosterone and lower AMH levels than those expected for TV were observed, indicating that some boys born SGA have a more advanced stage of puberty than their TV suggests. CONCLUSION:We identified a subgroup of boys born SGA in whom hormonal changes typical of initial puberty (serum LH ≥0.35 IU/L and AMH decline ≥30%) occurred before a clinical diagnosis of pubertal onset (TV ≥4 mL) was evident. These results indicate that TV 4 mL is not a reliable clinical sign of pubertal onset in all boys born SGA and that other biomarkers, such as serum LH and AMH, may need to be assessed.

CONTEXT:There is scarce information on the natural history of gonadal function of testicular disorders/differences of sex development (T-DSD) and ovotesticular DSD (OT-DSD). OBJECTIVE:To evaluate gonadal outcome in a large cohort of cases of T-DSD and OT-DSD. METHODS:A total of 29 cases of T-DSD and 32 cases of OT-DSD were identified from 20 centers across 13 countries in the I-DSD Registry. RESULTS:Male registration at birth occurred in 24 (83%) and 18 (56%) cases of T-DSD and OT-DSD, respectively. Of 42 cases registered as male, there were no cases of sex reassignment, while of 17 cases registered as female, 2 cases of T-DSD were reassigned within the first year of life. In male infants, stretched penile length (SPL) was <5th centile in 11/15 (73%) and similar in T-DSD and OT-DSD. However, in adolescence, median SPL in boys with OT-DSD (n, 5) and T-DSD (n, 4) was 5 cm (4.8, 7.5) and 9.5 cm (7.5, 12.5), respectively (P < .05). Of the 14 male and 4 female individuals who were aged >14 years, 7 (50%) and 2 (50%), respectively, had spontaneous puberty. In 8/9 (89%) male and 1/2 (50%) female adolescents and adults, serum gonadotropins were above reference range. However, in 8/9 (89%) males, serum testosterone was within the reference range. In 34 cases with available data, gonadal tumors had not been reported at a median age of 11.3 years (1 month, 35.5 years). CONCLUSION:In young adulthood, biochemical evidence of primary gonadal insufficiency is present in the majority of males and females with T-DSD and OT-DSD. In males with OT-DSD, micropenis may persist in young adulthood despite normal testosterone concentration.

Complex genetic syndromes represent a diagnostic challenge due to their diverse phenotypic presentations, which often evolve over time and may not be fully evident at birth. Disorders of sex development (DSD) comprise congenital conditions with discordance between chromosomal, gonadal, and/or genital sex. In 46,XY gonadal dysgenesis, undervirilisation or female-appearing genitalia may occur despite a normal karyotype, and diagnosis increasingly relies on genomic approaches. Prenatal and postnatal growth failure has been described in patients with syndromic 46,XY DSD. We report a male patient with SGA, lack of postnatal catch-up growth, and syndromic dysgenetic 46,XY DSD followed longitudinally from infancy to 11 years, in whom whole-exome sequencing (WES) reanalysis revealed a pathogenic 2.7 Mb microdeletion at 3q27.1q27.2. Systematic review of previously reported 3q27.1 deletions identified overlapping phenotypes but limited documentation of gonadal dysfunction. Curation of 71 genes within the deleted region highlighted DVL3 and CLCN2 as potential contributors to the gonadal phenotype, although functional evidence remains lacking. This case expands the phenotypic spectrum of 3q27.1 microdeletion syndrome, suggesting that 46,XY gonadal dysgenesis may represent an under-recognised feature. It also underscores the importance of copy number variant (CNV) analysis and periodic re-evaluation of sequencing data to increase diagnostic yield.

CONTEXT:Survival after pediatric hematologic malignancies has improved substantially, increasing concern regarding endocrine sequelae. While gonadotoxic effects on germ cells are characterized in adult survivors, the early impact of cancer and chemotherapy on hypothalamic-pituitary-testicular axis during childhood and adolescence remains insufficiently studied. DESIGN:We conducted a prospective longitudinal cohort study including 63 boys and adolescents with acute lymphoblastic leukemia, acute myeloid leukemia, or non-Hodgkin lymphoma treated at a tertiary pediatric center in Argentina between 2013 and 2019. Hormonal markers of Sertoli cell (AMH, inhibin B, FSH) and Leydig cell function (testosterone, LH) were serially assessed from diagnosis, throughout chemotherapy, and up to 3 years after treatment completion. RESULTS:In prepubertal boys, Sertoli cell function was mildly impaired at diagnosis, with reduced AMH and FSH levels. AMH increased during induction chemotherapy, fluctuated during treatment, and normalized thereafter, remaining stable up to 3 years post-treatment. Transient FSH suppression coincided with exposure to high-dose corticosteroids. Boys entering puberty during follow-up showed persistently elevated AMH relative to pubertal stage, suggesting delayed Sertoli cell maturation. In pubertal patients, a transient seminiferous tubular dysfunction, reflected by increased FSH and decreased inhibin B occurred, with recovery by 3 years after treatment. Mild compensated Leydig cell dysfunction persisted, characterized by elevated LH despite normal testosterone concentrations. CONCLUSIONS:Testicular dysfunction associated with pediatric hematologic malignancies is mostly reversible. However, delayed Sertoli cell maturation and persistent compensated Leydig cell insufficiency indicate residual testicular vulnerability, underscoring the importance of long-term endocrine surveillance during and after the end of chemotherapy.

Abstract Disclosure: S.M. Suco: None. A.C. Keselman: None. M.G. Ballerini: None. M.E. Rodriguez: None. M.G. Ropelato: None. S. Rosenbrock: None. D. Braslavsky: None. R.A. Rey: None. R.P. Grinspon: None. Introduction: Some children born SGA have an earlier pubertal onset and more rapid progression. Therefore, it is essential to identify the onset of puberty to proceed in a timely and appropriate manner. As it has also been suggested that there may be some gonadal dysfunction, the classic markers of pubertal onset, for example, testicular volume ≥ 4ml, may not be appropriate in these cases. Objective: To describe the clinical and biochemical characteristics of pubertal maturation in boys born SGA and determine parameters that best identify pubertal onset. Methods: We perform a retrospective, descriptive study of a cohort of boys born SGA with longitudinal follow-up, at a tertiary pediatric public hospital in Buenos Aires, Argentina. The subjects were selected from 1997 to 2023. Main outcome measures were serum levels of LH and AMH and testicular volume (TV). Additionally, height velocity, bone age, IGF1 and HOMA-IR were also collected to analyze its association with puberty. Pubertal onset was defined as serum LH ≥ 0.3 U/L and/or a decrease in serum AMH ≥ 30%. Results: The cohort included 25 boys born SGA, 24% were born prematurely and 60% were referred for short stature. In 18 boys (72%) AMH decline occurred with testicular volume < 4ml, at a median age of 9.8 yr (IQR 8.3 – 11 yr), and with median TV of 2ml. In 5 boys, LH was ≥ 0.3 U/L when AMH decline >30%. In 14 boys (56%) TV was <4ml when serum LH was ≥ 0.3 U/L. The median age for LH ≥0.3 was 11.3yr (IQR 10.4 – 12.2 yr), with a median TV of 3ml. In 3 boys the decrease in AMH occurred concomitantly with the increase in LH, while in 6 it occurred before.Alongside with the AMH decline, acceleration of bone age was observed in 35%, increase in growth velocity in 29%, increase in IGF1 concentrations in 24% and an increase in HOMA-IR in 26% of the boys. Concomitantly with an LH ≥0.3 U/L, acceleration of bone age was observed in 19%, increase in growth velocity in 25%, increase in IGF1 concentrations in 30% and an increase in HOMA-IR in 50% of the boys. Conclusion: The increase in testicular volume to 4ml, a classic parameter used as a marker of pubertal onset, may not be appropriate in a subgroup of children born SGA. Probably other parameters such as the increase in serum LH or the decrease in AMH should be considered. Presentation: 6/1/2024

OBJECTIVE:The hypothalamic-pituitary-testicular axis is characterised by the existence of major functional changes from its establishment in fetal life until the end of puberty. The assessment of serum testosterone and gonadotrophins and semen analysis, typically used in the adult male, is not applicable during most of infancy and childhood. On the other hand, the disorders of gonadal axis have different clinical consequences depending on the developmental stage at which the dysfunction is established. This review addresses the approaches to evaluate the hypothalamic-pituitary-testicular axis in the newborn, during childhood and at pubertal age. DESIGN:We focused on the hormonal laboratory and genetic studies as well as on the clinical signs and imaging studies that guide the aetiological diagnosis and the functional status of the gonads. RESULTS:Serum gonadotrophin and testosterone determination is useful in the first 3-6 months after birth and at pubertal age, whereas AMH and inhibin B are useful biomarkers of testis function from birth until the end of puberty. Clinical and imaging signs are helpful to appraise testicular hormone actions during fetal and postnatal life. CONCLUSIONS:The interpretation of results derived from the assessment of hypothalamic-pituitary-testicular in paediatric patients requires a comprehensive knowledge of the developmental physiology of the axis to understand its pathophysiology and reach an accurate diagnosis of its disorders.

OBJECTIVE:to describe the marked variability in clinical and biochemical patterns that are associated with a p.R209H GH1 missense variant in a large Argentinean pedigree, which makes the diagnosis of GHD elusive.DESIGN:We describe a non-consanguineous pedigree composed by several individuals with short stature, including 2 pediatric patients with typical diagnosis of isolated growth hormone deficiency (IGHD) and 4 other siblings with severe short stature, low serum IGF-1 and IGFBP-3, but normal stimulated GH levels, suggesting growth hormone insensitivity (GHI) in the latter group.RESULTS:Patients with classical IGHD phenotype carried a heterozygous variant in GH1: c.626G>A (p.R209H). Data from the extended pedigree suggested GH1 as the initial candidate gene, which showed the same pathogenic heterozygous GH1 variant in the four siblings with short stature and a biochemical pattern of GHI.CONCLUSIONS:We suggest considering GH1 sequencing in children with short stature associated to low IGF-1 and IGFBP-3 serum levels, even in the context of normal response to growth hormone provocative testing (GHPT).

Isolated growth hormone deficiency (IGHD) is most frequently caused by mutations in the GH1 gene. Pathogenic mutations in the GHRHR and GHSR have also been reported to cause IGHD. Individuals with IGHD type II present with variable clinical phenotype. Autosomal dominant GH1 p.R209H variant impairs GH secretion despite normal GH synthesis. The aim of this work is to expand the clinical and biochemical phenotype of heterozygous GH1 p.R209H missense mutation (previously known as p.R183H) in a large Argentinean pedigree. We report a non-consanguineous 4 generation pedigree. Two affected members showed classical IGHD phenotype: short stature (height -4.13 and -2.6 SD), low GH peak after arginine/clonidine provocative tests (3.6 and 2.6 ng/ml, cut-off value 4.7 ng/ml, GH IS 98/574, Immulite), non-detectable IGF-1, and low IGFBP-3 (-2.83 and -2.28 SD). Brain MRI showed anterior pituitary gland of 3.3 mm and 2.5 mm, respectively. The use of a customized panel for congenital hypopituitarism using single molecule molecular inversion probes sequencing (smMIPS) revealed a c.626G>A transition in GH1 gene, predicted to result in p.R209H mutation. The variant was subsequently confirmed by Sanger sequencing. Parents affected with the same variant presented either short (-1.91 SDS) or normal stature (-0.72 SDS). The patients’ response to rhGH treatment was adequate (Δ heights were 2.49 and 1.37 SDS in 2.4 and 1.0 year of treatment, respectively). Additionally, 4/9 siblings within this pedigree had short stature (mean height -2.48 ± 0.62 SD) with mild or no clinical phenotype of GHD, normal GH response to provocative pharmacologic tests (maximum GH peaks 5.46 to 10.9 ng/ml), associated to low serum IGF-1 (mean -3.27 ± 0.89 SD) and IGFBP3 (mean -2.61 ± 0.42 SD), resembling a pattern of growth hormone insensitivity (GHI). IGF-1 generation tests (GH dose 33 µg/kg.day) showed a mean increment in IGF-1 of 3.25 times over basal, confirming adequate GH sensitivity. Despite the absence of complete GHD phenotype, data from the extended pedigree suggested GH1 as the initial candidate gene, identifying the same pathogenic GH1 variant in these four siblings. Brain MRI showed normal height of the anterior pituitary gland (range 3.9 to 4.6 mm). Their affected father had normal stature (-1.69 SDS) with low serum IGF-1 (64 ng/mL). We have shown that members of a large pedigree affected with the p.R209H GH1 variant showed either a classical clinical and biochemical pattern of GHD or an initial biochemical pattern resembling GHI. This variability could lead in certain cases to an elusive diagnosis of GHD when the classical phenotype is absent. Therefore, these results highlight the need to explore GH1 gene in children with short stature associated to low IGF-1 and IGFBP-3 serum levels even when GH response to pharmacological tests is normal.