ResearchPad - sexual-and-gender-development-in-the-pediatric-population Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[OR15-03 High Prevalence of Gene Variants in Boys of Prepubertal Age with Clinical Suspicion of Central Hypogonadism and Low AMH]]> Introduction: In boys of prepubertal age, the diagnosis of central hypogonadism may be difficult to ascertain since gonadotropins and testosterone are normally low. Sertoli cell markers, like AMH and inhibin B, may be useful. In recent years, with the development of next generation sequencing (NGS) technology, the number of genes associated with central hypogonadism has had an exponential increase. However, even with these advanced techniques, the gene variants with potential pathogenicity can be found at present in only 30-50% of the patients. Hypothesis of the study: Low serum AMH is an appropriate screening biomarker to select patients for NGS, in order to make a genetic diagnosis in boys of prepubertal age with suspected central hypogonadism. Patients and methods: All patients aged 1-10 yr referred between 2001 and 2018 with clinical suspicion of central hypogonadism (micropenis and cryptorchidism and/or microorchidism), with low serum AMH (<10th centile) were included. Serum AMH was determined by ELISA (Beckman-Coulter), and LH, FSH and testosterone (T) by ECLIA (Roche). NGS was performed with the TruSight™ One Sequencing Panel in a NextSeq® 500 sequencer (Illumina). Results are expressed as medians (range). Results: 13 patients were included. Age at first visit was 4.4 (0.1-9.2) yr. Cryptorchidism was present in all of them, micropenis in 10 and microorchidism in 11. Orchiopexy was required in 11 boys and the other 2 responded to hCG treatment. 4 patients had olfactory disturbances, 1 had sensory deafness and 1 had piebaldism. 2 patients had a family history of olfactory disturbances and/or central hypogonadism. 7 patients could be followed up to pubertal age, and the diagnosis of central hypogonadism was clinically confirmed. At age 6.1 yr (1.2-10), AMH was 159 pmol/L (65-363), LH was <0.1 IU/L in all, FSH was 0.61 IU/L (<0.1-1.9). 17 variants in 9 genes associated with central hypogonadism were found in 10 of 13 patients. 5 boys had 1 gene variant, while 4 had 2 gene variants and 1 had 3 gene variants indicating probable oligogenicity, in the following genes: FGFR1 (n:4), CHD7 (n:3), PROKR2 (n:2), SOX10 (n:2), AXL (n:2), HS6ST1 (n:1), AMHR2 (n:1), NSMF (n:1), DCC (n:1). Conclusion: A high prevalence of gene variants was found in boys of prepubertal age with a suspicion of central hypogonadism based on micropenis and cryptorchidism and/or microorchidism with low serum AMH.

<![CDATA[OR15-05 Gain in Near Adult Height Using the Combination of an LHRH Analogue and an Aromatase Inhibitor in Early Maturing Girls with Compromised Growth. The “Gail” Study ISRCTN11469487]]> Background. Third generation aromatase inhibitors (AI), as monotherapy, have never been used to increase predicted adult height in girls. Our previously published GAIL study has shown that the combination of anastrozole to an LHRH analogue for 24 months is safe and effective in ameliorating PAH in girls with early puberty +1.21 SDS (+7.51 cm) compared to inhibition of puberty alone +0.31 SDS (+1.92 cm), p=0.001 (1).

Objective and Hypotheses. We assessed the final height of the girls who participated in the GAIL study compared to the predicted after 24 months of combined treatment and additionally the efficacy of anastrozole monotherapy after completion of the combined treatment in further improving final height.

Methods. We measured adult (i.e. age 16.5 yrs) or near adult height (i.e. at bone age 14 yrs) of the 40 girls who participated in the GAIL study and were divided in two groups Group A (20 girls on anastrozole + leuprorelin) and Group B (20 girls on Leuprorelin alone). Group A was further randomized into two subgroups. Group A1 (10 girls), after completion of the combined therapy, received anastrozole 1 mg/day as monotherapy until bone age of 14 yrs with a 6-month follow-up. Group A2 (10 girls) had stopped the combined therapy at 24 months or 11 yrs of age and were recalled for adult (or near) height evaluation.

Results. Adult or near adult height (NAH) exceeded the predicted at the completion of the initial phase of the GAIL study in all three groups but the result was statistically significant only in Group A1: NAH-PAH = Group A1: +3.85 cm (+0,62 SDS) p=0.001, Group A2: +1,6 cm (+0,26 SDS) p=0.26, Group B: +1,7 cm (+0,3 SDS) p = 0.09. Gain in Group A1 was significantly greater to that of Group A2 (p=0.046) and Group B (p=0.035).

Conclusion. In early maturing girls with compromised growth, treatment for 2 yrs or until the age of 11 yrs with LHRH analogue plus anastrozole 1mg/day, the gain is +9.7cm in total when treated with anastrozole monotherapy until they reach NAH, whereas it is +7.4 cm if they do not continue with the monotherapy and only +3.6 cm when treated with an LHRHa only. As a result, the combination therapy continued with anastrozole monotherapy, ends in the shortest distance from target height. This implies that the addition of the anastrozole to an LHRHa apart from being safe, is effective in ameliorating substantially Near Adult Height making the intervention meaningful.


(1) Papadimitriou DT, Dermitzaki E, Papagianni M, Papaioannou G, Papaevangelou V, Papadimitriou A. Anastrozole plus leuprorelin in early maturing girls with compromised growth: the “GAIL” study. Endocrinol Invest. 2016 Apr;39(4):439-46]

<![CDATA[OR15-06 Integrative and Analytical Review of the 5 Alpha Reductase Type 2 Deficiency Worldwide]]> Introduction: The conversion of testosterone into dyhidrotestosterone is catalyzed by the 5 α reductase type 2 enzyme which plays a crucial role in the external genitalia virilization. It is encoded by the SRD5A2 gene. Allelic variants (AV) in this gene cause a 46,XY DSD with no genotype-phenotype relationship. It was firstly reported at early 70’s from isolated clusters. Since then, several cases have been reported. Putting together, it will expand the knowledge about the molecular bases of androgen regulation. Methods: We searched for SRD5A2 AV in the literature (Pubmed, EMBASE, Medline) and websites (ensemble, HGMD, ClinVar). Only cases with AV in both alleles, either in homozygous (HM) or compound heterozygous state (CH) and 5ARD2 phenotype were included. The AV were analyzed according to ethnicity, exon, domain, aminoacid (aa) conservation, age at diagnosis, sex assignment, gender change, external genitalia virilization and functional studies. External genitalia virilization was scored using Sinnecker scale. Conservation analysis was carried out using CONSURF platform. For categorical variables we used X2 test and Cramer’s V. Continuous variables were analyzed by t test or ANOVA. Concordance was estimated by Kappa. Results: We identified 434 cases of 5ARD2 deficiencies from 40 countries. Most came from Turkey (23%), China (17%), Italy (9%), and Brazil (7%). 69% were assigned as female. There were 70% of AV in HM and 30% in CH state. Most were missense variants (76%). However, small indels (11%), splicing (5%) and large deletions (4%) were all reported. They were distributed along all exons with exon 1 (33%) and exon 4 (25%) predominance. AV in the exon 4 (NADPH-binding domain) resulted in lower virilization (F=10.5; p<.0001). The positions 55, 65, 196, 235 and 246 are hotspots making up, 25% of all AV. Most AV (76%) were located at conserved aa. However, AV at non-conserved aa were more frequently indels (28% vs 6%; p<.01). The overall rate of gender change from female to male ranged from 16% to 70%. The lowest rate of gender change occurred in Turkey and the highest in Brazil. Virilization was similar between those who changed and kept their gender. The gender change rate was significantly different across the countries (V=0.44; p<.001) even with similar virilization scores. There was no concordance between genotype and phenotype in all recurrent AV (196, 235 and 246; k 0.6, 0.12 and 0.19). Conclusion: 5ARD2 deficiency has a worldwide distribution. AV at NADPH-ligand region cause lower virilization. Genitalia virilization influenced sex assignment but not gender change which was influenced by cultural aspects across the countries.

<![CDATA[OR15-02 Mental Health Implications and Determinants of When Youth Present to a Gender Clinic]]> Background/Aims: Gender incongruent (GI) youth experience high rates of mental health comorbidities. While gender-affirming medical care (GAMC) provides psychological benefit, GI youth often present to care at older ages. The goals of this study were to 1) assess the relationship between age at presentation to GAMC and rates of mental health comorbidities, 2) identify factors influencing when youth present to GAMC, and 3) determine whether older presenting youth face more barriers to care.

Methods: We performed a cross-sectional chart review of patients presenting to GAMC. Subjects were classified a priori as younger presenting youth (YPY): <15 years of age at presentation or older presenting youth (OPY): > 15 years of age. Self-reported rates of mental health comorbidities and medication use were compared between groups. Binary logistic regression analysis was used to identify determinants of mental health comorbidities. Covariates included pubertal stage at presentation, social transition status, and assigned sex. Next, we performed a sequential exploratory mixed-methods study. Factors influencing age at presentation to GAMC were explored through 24 semi-structured interviews with OPY, YPY, and their caregivers (OPY-C and YPY-C). Thematic analysis identified themes with differential representation between OPY/OPY-C and YPY/YPY-C. From these themes, a questionnaire was designed and distributed to youth and caregivers presenting for follow-up. Responses were compared between OPY and YPY and between OPY-C and YPY-C.

Results: Of 300 youth, there were184 OPY and 116 YPY. Upon presentation, more OPY than YPY reported a diagnosis of depression (46% vs. 30%), had self-harmed (40% vs. 28%), had considered suicide (52% vs. 40%), had attempted suicide (17% vs. 9%), and required psychoactive medications (36% vs. 23%), all p < .05. After controlling for covariates, late puberty (Tanner stage 4 or 5) was associated with depressive disorders (OR 5.49 [95% CI: 1.14, 26.32]) and anxiety disorders (OR 4.18 [95% CI: 1.22, 14.49]) while older age remained associated only with psychoactive medication use (OR 1.31 [95% CI: 1.05, 1.63]). Six themes were identified from interviews that influenced age at first clinic visit, including individual, environmental, and healthcare system factors. 101/152 youth and 102/147 caregivers completed questionnaires. While OPY/OPY-C did not endorse more barriers to care than YPY/YPY-C, more OPY than YPY had religious families (54% vs 28%, p=.01) while more YPY than OPY had LGBTQ+ family members (46% vs. 20%, p=.006).

Conclusions: Older age and late pubertal stage are associated with worse mental health among GI youth presenting to GAMC. Our findings emphasize the importance of timely access to GAMC for GI youth and highlight familial environment as a factor that influences when youth present to gender-affirmative care.

<![CDATA[OR15-01 Blockers and Bones: Loss of Absolute Bone Mineral Density Is Common in Trans- and Gender- Diverse Adolescents Treated with GnRHa]]> Background: The expected pubertal accrual of bone mineral density (BMD) may be disrupted in trans and gender diverse (TGD) adolescents who undergo pubertal suppression with Gonadotropin Releasing Hormone agonists (GnRHa)1. The extent of this effect remains unclear and is confounded by varying methods used to assess BMD1.

While BMD Z-scores in GnRHa-treated TGD adolescents may be expected to decline relative to pubertal peers, this measure provides no information on actual changes in BMD. Annualised, percent change in BMD (%BMD velocity, %BMDV) provides a standardised measure of accrual or loss, but has not been reported in this context.

Aims: (1) To evaluate bone accrual or loss using %BMDV in a cohort of GnRHa-treated TGD adolescents; (2) to explore associations between baseline characteristics (BMD Z score, Vitamin D status and Tanner Stage) and %BMDV.

Methods. Retrospective 10yr audit at tertiary pediatric gender service. Bone densitometry data were collected at baseline and 12-24monthly during GnRHa. Areal BMD values and Z-scores for lumbar spine (LS) and total hip (TH) were obtained. %BMDV between baseline and final scan was calculated for LS and TH. Population data for %BMDV before and during puberty were derived from the BMD in Childhood Study2. Results are reported as mean (±SD) or mean difference (MD; 95% confidence interval).

Results. Data from 28 patients (20 transfemale; 8 transmale) who commenced GnRHa at 13.3 (±2.0) yrs and were observed over 23.2 (±11.5) mo were included. Mean (±SD) %aBMDV during GnRHa therapy was -0.66 (±4.54) %/yr for TH and +1.91 (±4.23) %/yr for LS, both substantially lower than %aBMDV in pre-pubertal population controls (~+3-4%/year). 53% of GnRHa-treated youth exhibited negative %aBMDV, indicating bone loss, at TH and/or LS. %aBMDV was lower in (i) Vitamin D deficient youth, with MD at TH (-6.07; -9.00, -3.13); and LS (-4.93; -9.56, -0.30) relative to Vitamin D sufficient peers and (ii) youth who were Tanner stage 4+ at baseline, with MD at TH (-4.1; -7.7, -0.44) and LS (-3.6; -7.2, 0.01) relative to Tanner stage 2-3 peers. Height-adjusted Z scores declined from baseline with GnRHa treatment in >95% of patients and were not predictive of %aBMDV.

Conclusion. GnRHa-treated TGD adolescents in this cohort exhibited lower BMD accrual rates than pre-pubertal population controls. Over half of our cohort lost BMD, which is a significant concern in adolescence. Vitamin D deficiency and more advanced pubertal stage at GnRHa initiation were associated with greater bone loss during treatment. These data highlight the need to monitor and optimise bone health in GnRHa-treated TGD young people. We recommend routine annual densitometry and %BMDV evaluation regardless of baseline Z-scores as well as routine screening and treatment of vitamin D deficiency while on GnRHa.



Chew D., et al., Pediatrics, 2018. 141: p.e20173742.


Zemel B.S., et al., JCEM, 2011. 96 p.3160-9.

<![CDATA[OR15-07 Novel Genes Involved in Sex Differentiation Identified by Whole-Exome Sequencing in a Cohort of Children with Disorders of Sex Development]]> <![CDATA[OR15-04 Central Precocious Puberty without Central Nervous System Lesions: Is It Really Idiopathic?]]>