ResearchPad - pediatric-sexual-differentiation-puberty-and-bone-biology Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[SUN-083 Screening of Vitamin D and Calcium Concentrations in Neonates of Mothers at High Risk of Vitamin D Deficiency]]> Objective: The aim of this study was to determine, retrospectively, the serum 25OHD and calcium concentrations of screened neonates of mothers at high risk of 25OHD deficiency (maternal 25OHD < 25 nmol/L or unknown vitamin D concentrations and risk factors for vitamin D deficiency) and critically analyse whether their measurements contributes to the management of these neonates.

Methods: Serum 25OHD and calcium concentrations from 600 samples of umbilical cord blood or venous blood collected from neonates over a 12-month period were analysed. 25OHD concentrations were reported for all while both the corrected calcium concentrations and vitamin D concentrations were available for 569 samples.

Results: There was little or no evidence of association between neonatal 25OHD concentrations and gender, gestational age or birth weight. There was a high prevalence of vitamin D insufficiency (27.6%, 30–50 nmol/L) and deficiency (21.3%, < 30 nmol/L) in neonates from high-risk maternal groups. There was a statistically positive but weak correlation (ρ = 0.22, P < 0.0001) between serum calcium and 25OHD concentrations. Only 7 neonates out of 569 (1.2%) had calcium levels in the hypocalcaemic range; however, a significant number (47.6%) were reported to be in the hypercalcaemic range. Nearly all of these were venous samples collected in first 24 hours after birth. We calculated the reference interval for corrected calcium from our data of venous samples in first 24 hours and the upper limit was significantly higher (2.38–3.04 mmol/L) than the standard reference range used.

Conclusion: Vitamin D deficiency is prevalent in neonates of high-risk mothers but the risk of hypocalcaemia due to vitamin D deficiency at birth is low. Screening neonates entails blood testing which can cause distress to neonates and their parents, substantial impost on staff and financial burden on the health care system. 25OHD deficiency is corrected relatively easily in neonates with supplementation and vitamin D supplementation of neonates from birth without routine screening appears to offer better value of care. Also, the data from this study suggest that the paediatric reference range for corrected calcium concentrations in neonates is higher and the paediatric reference range should be reconsidered.

<![CDATA[SUN-095 Understanding and Communication Around DSD According to the Mothers and Patients’ Perspectives]]> Communication around DSD is complex. It involves diagnosis and treatment aspects and is influenced by the psychological status of the individuals and the cultural context. An adequate understanding by patients and relatives is essential for approach of DSD. Objetive: To evaluate the DSD care setting in three Brazilian tertiary centers in order to identify the barriers to an adequate understanding and an optimal communication. Methods: A guide with 69 questions, assessing the level of knowledge, the main doubts and difficulties around DSD was developed and guided individual interviews with 100 mothers and 53 adult patients with DSD. The main doubts were clarified and a self-assessment was requested to them before and after the interview on a scale from 0 to 10. Results: Mothers and patients mean age were, respectevily, 35.2 and 36.5 years. Both of them had a satisfactory educational level. Although 48% (p<0.01) of mothers and 68% (p:0.02) of patients were satisfied/very satisfied about their knowledge related to the DSD, 78% and 58%, respectively, of them still had doubts. The doubts were related to diagnosis, karyotype, medications, appearance of genitalia, surgery, sexual activity, fertility, genetic counseling, consequences of the condition and treatment on general health and condition influence on the child’s behavior and personality The unsatisfied mothers cited as barriers to an optimal understanding the complexity of the conditions, the difficult terms and the psychological stress at diagnosis. Patients also cited as barriers the absence of dialogue about the condition at home and some of them chose not to know. About 55% of mothers and 62% of patients didn’t even know the name of the condition; but positively 88% of them knew the necessary treatment. Regarding communication, 68% of mothers and 89% of patients didn’t feel comfortable talking to people about the DSD condition and around 68% of them underwent negative comments. Although 73% of patients would prefer to be first informed about their condition at childhood, 29% of mothers think that childhood is the best age for it. Among mothers and patients, the most and least appropriate term to name the DSD condition is, respectively, genital malformation and disease (p<0.01). Both of them have the stigma as the main concern. Conclusion: Even in a tertiary center with a multidisciplinary team, the mothers and patient’s knowledge about DSD conditions is scarce. The proper choice of the term to refer to DSD conditions should consider the families and patients perspectives. Communication about DSD is prejudiced by the lack of knowledge and the stigma suffered by these patients and families. Thus, due to complexity of this topic, continued educational action must be instituted as a strategy to modify this scenario.

<![CDATA[SUN-091 Change in Sex of Rearing in Individuals with Disorders of Sex Development]]> Introduction: Differences of Sex Development (DSDs) encompass variations in formation of internal or external sex characteristics. Historically, sex assignment in children with DSDs depended on phenotype, and gender was thought to be malleable. Attention in DSD has recently shifted toward reducing gender dysphoria and preserving fertility potential. Our multidisciplinary DSD clinic was formed in 2008 with these goals and includes specialists from Endocrinology, Gynecology, Urology, Psychology, Social Work, Genetics, and Chaplaincy.

Subjects: A chart review was done on all patients seen in our DSD clinic between April 2008 and June 2019 to determine rates of sex reassignment and gender dysphoria. Two hundred patients were seen: 23 were found to not have DSDs; 61 were 46,XX; 66 were 46,XY; 31 had a sex chromosome DSD; 5 had gonadal dysgenesis without known chromosome mosaicism; and 14 had syndromic genital atypia. Mean age of follow-up is 8.77 years.

Results: Only 2 patients underwent sex reassignment at our institution. One was assigned male at birth, but was found to be 46,XX with 21-hydroxylase deficiency and was reassigned female at 1 month of age. The second was assigned male at birth and was found to be 46,XY with an NR5A1 variant. Sex was reassigned female at two months of age. Two additional patients had a sex reassignment outside our institution. One was born abroad and assigned male at birth. The patient was found to be 46,XY with an NR5A1 variant, and was reassigned female. The second patient was assigned male at birth, but was found to be 46,XX with P450 oxidoreductase deficiency. The parents changed the sex of rearing to female at 19 months of age. To date, none has signs of gender dysphoria.

A total of three patients experienced gender dysphoria and underwent transition. The first had genital ambiguity with sex chromosome mosaicism in the gonads and was assigned female at birth. We held care conferences with the family and discussed the possibility of gender dysphoria. At age 3, the patient declared that he was male, and parents socially transitioned him at that time. Two were assigned female after receiving the diagnosis of 46,XX 21-hydroxylase deficiency. Both declared male gender identity later, one at 12.5 years of age, and one at 20.5 years of age.

Conclusion: Whereas our patient population is still relatively young, it is reassuring that the overall rate of gender dysphoria is low. The rate in patients with CAH is similar to previous reports in the literature. Careful attention to sex assignment in early childhood may reduce the rates of gender dysphoria in children with DSDs.

<![CDATA[SUN-100 Mice Lacking Paternally Expressed DLK1 Reach Puberty at a Lower Body Weight Than Littermate Controls]]> Body fat content along with a variety of genetic, environmental and psychosocial factors are responsible for the development and maintenance of reproductive function, especially in females. Epidemiologic studies indicate a relationship between increased body mass index and earlier puberty in girls. In contrast, a significant delay in puberty and menarche is seen in girls who are very physically active and have markedly diminished body fat. This link between reproduction and metabolism was reinforced with the recent report of loss-of-function mutations in the Delta-like homolog 1 (DLK1) gene in girls with central precocious puberty (CPP) and increased body fat. DLK1 is a paternally expressed gene located on chromosome 14q32.2 in a locus associated with Temple syndrome (TS), an imprinting disorder caused mainly by maternal parental disomy (mUPD). Dlk1 knockout mice display pre- and postnatal growth retardation, a phenotype that overlaps with human mUPD14. However, precocious puberty, a common finding associated with TS, was not carefully characterized in these mice. We used a Dlk1 deficient mouse model to determine the effects of Dlk1 on pubertal maturation. We confirmed by RT-qPCR that Dlk1 mRNA was undetectable in the mediobasal hypothalamus, where kisspeptin and other regulators of puberty are expressed, of Dlk+/p- mice (which inherited the mutant allele from their father) whereas it was present in Dlk+/+ mice. As reported previously, body weight was significantly lower in juvenile male and female Dlk+/p- mice, compared to wild-type littermate controls. Interestingly, mutant and control female mice achieved vaginal opening, a marker of puberty onset, at a similar age (Dlk+/p-: 29.8 ± 1.5 days, n=11 vs. Dlk+/+: 29.1 ± 0.7 days, n=15, p=0.6) despite a considerably lower body weight in the Dlk1 deficient mice at the time of vaginal opening (Dlk+/p-: 10.1 ± 0.8 g vs. Dlk+/+: 14.3 ± 0.3 g, p<0.0001). Similarly, in the Dlk+/p- males, preputial separation occurred at a lower body weight than in controls (Dlk+/p-: 12.4 ± 0.3 g, n=9 vs. Dlk+/+: 14.1 ± 0.2 g, n=19, p<0.0001). We hypothesize that the lack of Dlk1 at the hypothalamic level may be attenuating the effect of the low body weight on determining pubertal onset. These findings suggest that DLK1 is an important link between body weight and pubertal development in mice, as has been shown in humans.

<![CDATA[SUN-092 Effect of Pubertal Induction with Gonadotropins and GnRH Therapy in Male Hypogonadotropic Hypogonadism: Meta-Analysis]]> Background: The use of gonadotropins is a recent strategy for inducing puberty in adolescent males with hypogonadotropic hypogonadism (HH). Testosterone use has been discouraged in patients who desire to preserve fertility. Human chorionic gonadotropin (hCG) has been recommended for inducing puberty in HH; however, several clinicians administer hCG in combination with other gonadotropins. The benefits of using combination gonadotropin therapies (hCG+) over hCG monotherapy in pre-pubertal adolescent males with HH has not been clearly established. We performed a meta-analysis to assess the outcomes of hCG compared to hCG+ in terms of virilizing effects and testicular growth in peripubertal boys with HH.

Methods: We evaluated for heterogeneity among studies. We calculated pooled means for the post-treatment mean testicular volume (MTV), testosterone (T) level, and penile length for the hCG monotherapy and hCG+ treatment groups. We performed a meta-regression analysis to examine the contribution of various factors to post-treatment outcomes including baseline T level, age, treatment duration, and study quality.

Results: The meta-analysis included seven studies. All participants were prepubertal (age range: 13.3–25.9 years), with weighted mean treatment durations of 10.95 months for hCG monotherapy and 28.2 months for hCG. There was significant heterogeneity in baseline age (Q = 121.71; df = 1; P < 0.001) and T levels (Q = 436.74; df = 1; P < 0.001) between the two treatment groups. The hCG+ group had a larger post-treatment MTV, but it was not significantly different between the two groups (6.60 mL [95% CI, 3.18–10.02] for hCG monotherapy vs. 10.02 mL [95% CI, 8.30–11.75] for hCG+; P = 0.079). Post-treatment T levels differed significantly between the two groups (101.89 ng/dL [95% CI, 50.7–153.08] for hCG monotherapy vs. 424.10 ng/dL [95% CI, 304.59–543.62] for hCG+; P < 0.0001). A meta-regression analysis of post-treatment T levels showed that baseline age, baseline T level, and study grade did not contribute significantly to the difference between treatment groups. Treatment duration explained 3.04% of the difference between the two groups (P < 0.0001). After adjusting for treatment duration, the post-treatment T level remained significantly higher in the hCG+ group compared to the hCG monotherapy group. The hCG+ was also associated with better outcomes for post-treatment penile length, although these findings relied on data from only three studies.

Conclusion: Our study indicates that hCG+ therapies provide potential benefits over hCG monotherapy for pubertal induction in males with HH, regarding T levels and penile growth, with no difference in testicular growth between treatments. Prospective pediatric studies are needed to assess the benefits of these therapies in patients with HH and, ultimately, to establish guidelines for gonadotropin therapy in the adolescent population.

<![CDATA[SUN-081 High Throughput Genetic Analysis Revealed Novel Genomic Loci and Candidate Genes Involved in Central Precocious Puberty Associated with Complex Phenotypes]]> <![CDATA[SUN-087 FGFR-Selective Tyrosine Kinase Inhibitors, Such as Infigratinib, Show Potency and Selectivity for FGFR3 at Pharmacologically Relevant Doses for the Potential Treatment of Achondroplasia]]> <![CDATA[SUN-LB16 Clitoromegaly in Premature Infants: Is It Truly Pathologic?]]> 9 mm or clitoral width >6 mm. Patients not meeting these criteria or those with clitoral edema, prominent clitoral hood were classified under false clitoromegaly. In the ‘no formal consult’ group, the documented discharge examination was used to assess persistence of clitoromegaly. Uni- and multi-variable logistic regression were used to determine factors that increased the likelihood of a formal consult. Results: 29 patients met inclusion criteria; 15 in the ‘formal consult’ group and 14 in the ‘no formal consult’ group. No significant differences were found between the groups in terms of birth weight, gestational age, race, ethnicity and maternal factors. History of IUGR (intrauterine growth restriction) was more common in the ‘formal consult’ group (60%) vs. ‘no formal consult’ group (21%) (p=0.04). Only 3/15 patients in the ‘formal consult’ group had true clitoromegaly; all 3 had normal 17-hydroxyprogesterone levels, and only 1 patient had transient elevation in androgen levels (androstenedione, deoxycortisol and testosterone). Of the ‘no formal consult’ group, only 3/14 patients had clitoromegaly noted on discharge; outcome was unknown for 1. Multi-variable logistic regression showed that lower gestational age (p=0.04) and history of IUGR (p=0.03), even after adjusting for birth weight, increased the likelihood of a formal consult. Conclusion: In summary, the majority of perceived clitoromegaly in premature infants is not associated with hormonal dysfunction. Lower gestational age and a history of IUGR increase the likelihood of a formal consult for clitoromegaly in these patients. Approximately half of the patients were noted to have false clitoromegaly indicating inconsistencies in examination technique and need for provider education. ]]> <![CDATA[SUN-084 A Quantitative-PCR Based Rapid and Cost-Effective Diagnostic Method for Turner Syndrome and Its Variants]]> 95% sensitivity and specificity. SHOX gene primer was the best to diagnose TS of all karyotypes combined and also classical TS(XO) from normal females. qPCR could also identify non-classical TS with >92% sensitivity and specificity,the best primer being ARSE, for detecting both mosaics and isochromosomes. The cut-offs determined from our study corroborates with past similar studies.1,2 qPCR using an appropriate panel of primers on the short and long arms of X chromosomes can be a rapid and cheaper alternative to karyotyping to diagnose TS of different karyotypes. The choice of primers should be guided by the need for a more sensitive or specific test depending on the clinical scenario. If used as a neonatal screening test, SHOX should be the best primer. For diagnostic purposes, when the pre-test probability is low, a more specific primer like SHOX would be more appropriate. However, when the pre-test probability is high, a sensitive primer for ruling out TS like VAMP7 is better. In case there is a high pre test probability of the patient having a non-classic TS rather than classic TS, ARSE should be used. This is the first study to show good sensitivity of qPCR in detecting non-classic TS of different karyotypes in addition to classic TS. References: 1. Ibarra-Ramírez M, Martínez-de-Villarreal LE. Clinical and genetic aspects of Turner’s syndrome. Medicina universitaria. 2016 Jan 1;18(70):42-8. 2 .Rocha MN et al. Applicability of real-time PCR methodology in the neonatal detection of Turner syndrome. Hormone and metabolic research. 2010 Aug;42(09):677-81. ]]> <![CDATA[SUN-086 Pilot Study Using Aromatase Inhibitor in Puberty of Boys With Partial Androgen Insensitivity: Report of Three Cases]]> <![CDATA[SUN-099 Seasonal Variations of 25-Hydroxy Vitamin D3, Parathyroid Hormone, and Alkaline Phosphatase in School-Aged Children]]> <![CDATA[SUN-093 Prospective Clinical Assessment Study in Children with Achondroplasia: The PROPEL Trial]]> <![CDATA[SUN-090 Investigation of Imprinting Defects in MKRN3 and DLK1 in Children with Idiopathic Central Precocious Puberty Through Specific DNA Methylation Analysis]]> <![CDATA[SUN-096 Incidentally Found Severe Hypercalcemia in a Pediatric Patient, Diagnostic Challenge]]> <![CDATA[SUN-101 Support for a New Therapeutic Approach of Using a Low-Dose FGFR Tyrosine Kinase Inhibitor (Infigratinib) for Achondroplasia]]> <![CDATA[SUN-LB17 The Association of Growth Hormone Treatment in Children With Short Stature With Idiopathic Scoliosis]]> <![CDATA[SUN-097 Gonadotropins Levels Measurement in First Morning Voided Urine as a Diagnostic Tool for Central Precocious Puberty]]> 5 IU/L. FMV urinary Gn were compared between CPP and premature thelarche (PT) groups. The correlation between serum and urinary Gn were assessed and the cutoff value of urinary Gn to diagnose CPP was established. FMV urinary Gn of 480 Thai school girls (control) were also collected to determine the reference values according to their breast Tanner (BT) stages. Results: FMV ULH level in girls with CPP was significantly higher than that of PT (2.46 VS 0.8 IU/L; median, P <0.001). However, the level of ULH in PT group was not different from control group with BT1. FMV ULH and ULH: UFSH were well correlated with basal serum LH (r=0.63 and 0.73, respectively, Ps<0.001) and peak serum LH (r=0.44 and 0.54, respectively, Ps<0.001). Base on receiver operating characteristics analysis, basal serum LH was the best parameter to differentiate CPP from PT (area under the curve 0.797–0.926). ULH levels at ≥ 1.13 IU/L and ≥ 1.52 provide optimal sensitivity (72.3 and 68.1 %, respectively) and specificity (85.7 and 100 %, respectively). Combined ULH level ≥ 1.13 IU/L with ULH: UFSH ≥ 0.17 increased specificity from 85.7 to 92.9 % for predicting a positive GnRH agonist test. (peak LH ≥ 5 IU/L) Conclusions: First morning voided urinary Gn levels measurement is a highly potential method for the diagnosis of CPP in girls due to its good correlation with GnRH agonist test. Further study in a larger number of patients with close monitoring of clinical outcome is required before recommending as a standard investigation in CPP. ]]> <![CDATA[SUN-LB19 Novel Homozygous Mutation in BMP1 Causing Osteogenesis Imperfecta]]> 10 min, with difficulty running and climbing stairs. There was no family history of musculoskeletal disorders.Stature was consistently between 10-15th% for age. Subtle facial dysmorphism included micrognathia and small chin, with patchy blue-gray sclerae, and normal dentition. The lumbar spine was tender to percussion. Gait was slow and antalgic with external rotation of the right hip.Laboratory evaluation revealed normal serum calcium, iPTH, magnesium, phosphate, 25-hydroxyvitamin D and alkaline phosphatase for age. P1NP was slightly high (193 µg/L, 30-110 µg/L) and CTX was slightly low (554 pg/mL, n: 574-1849 pg/mL), the latter being atypical for OI. Total hip BMD (adjusted for height Z-score) was normal (Z-score = 1.76) and adjusted femoral neck BMD was high (Z-score = 2.67). VCFs precluded assessment of lumbar spine BMD. Genomic analysis revealed a homozygous missense mutation in exon 4 of BMP1 resulting in an amino acid substitution (c. C505T; p.Arg169Cys) in both the bone morphogenetic protein 1 and mTLD gene products of BMP1. The mutation is predicted to be damaging to both proteins, and associated with this rare form of OI. Conclusion: We report a novel homozygous mutation in BMP1 identified in a child with autosomal recessive OI. Unlike most forms of OI, patients with type XIII often have normal or increased BMD [1], making a correlation between BMD and fracture risk difficult. While bisphosphonates (BP) may help reduce recurrent fractures and provide symptomatic relief, the broad phenotypic spectrum and concern for further increasing BMD complicate management. A high resolution peripheral quantitative CT scan to assess bone microarchitecture and quality may aid in the decision of BP therapy. As evidence is limited on the effectiveness of BP in this rare form of OI, it is important to consider each case individually.1.Sangsin, A., et al., Two novel compound heterozygous BMP1 mutations in a patient with osteogenesis imperfecta: a case report. BMC Med Genet, 2017. 18(1): p. 25. ]]> <![CDATA[SUN-098 Low-Dose Infigratinib Treatment Does Not Lead to Changes in Phosphorous Preclinically in Mice]]> <![CDATA[SUN-LB18 Serum 25-Hydroxyvitamin D Is Not Associated With the Type of Central Precocious Puberty in Girls]]> 30 ng/mL). (2) No significant difference in serum 25OHD levels between RP-CPP group and SP-CPP group (F =0.809, p=0.369) was found. There is no correlation of BMD and disease course between the two groups (p>0.1). Bone age, BMI, LHP/FSHP and IGF1 levels in RP-CPP group were higher than SP-CPP group (P<0.05). Logistic regression analysis showed that BMI, LHP/FSHP and IGF1 were the independent risk factors for CPP (OR 2.690, 1.005, 3.288, respectively). (3) There were significant differences among different serum 25OHD levels as for season, disease course and IGF1 (p<0.05). The correlation with the season was the highest (r=0.402, p<0.001). [Conclusions] (1) Vitamin D levels are generally insufficient in CPP girls and are not related to different types of CPP. (2) The higher BMI, IGF1, LHP/FSHP levels are, the easier CPP girls will transfer to RP-CPP, but not associated with vitamin D levels. (3) CPP girls suffer from vitamin D deficiency in seasons of winter and spring easilier. ]]>