Analysis of clinical phenotype and genotype of Chinese children with disorders of sex development / 中华儿科杂志

Objective: To explore the heterogeneity and correlation of clinical phenotypes and genotypes in children with disorders of sex development (DSD). Methods: A retrospective study of 1 235 patients with clinically proposed DSD in 36 pediatric medical institutions across the country from January 2017 to May 2021. After capturing 277 DSD-related candidate genes, second-generation sequencing was performed to analyzed the heterogeneity and correlation combined with clinical phenotypes. Results: Among 1 235 children with clinically proposed DSD, 980 were males and 255 were females of social gender at the time of initial diagnosis with the age ranged from 1 day of age to 17.92 years. A total of 443 children with pathogenic variants were detected through molecular genetic studies, with a positive detection rate of 35.9%. The most common clinical phenotypes were micropenis (455 cases), hypospadias (321 cases), and cryptorchidism (172 cases) and common mutations detected were in SRD5A2 gene (80 cases), AR gene (53 cases) and CYP21A2 gene (44 cases). Among them, the SRD5A2 mutation is the most common in children with simple micropenis and simple hypospadias, while the AMH mutation is the most common in children with simple cryptorchidism. Conclusions: The SRD5A2 mutation is the most common genetic variant in Chinese children with DSD, and micropenis, cryptorchidism, and hypospadias are the most common clinical phenotypes. Molecular diagnosis can provide clues about the biological basis of DSD, and can also guide clinicians to perform specific clinical examinations. Target sequence capture probes and next-generation sequencing technology can provide effective and economical genetic diagnosis for children with DSD.

Relationship between body mass index and sexual development in Chinese children / 中华儿科杂志

Objective: To investigate the relationship between body mass index (BMI) and sexual development in Chinese children. Methods: A nationwide multicenter and population-based large cross-sectional study was conducted in 13 provinces, autonomous regions and municipalities of China from January 2017 to December 2018. Data on sex, age, height, weight were collected, BMI was calculated and sexual characteristics were analyzed. The subjects were divided into four groups based on age, including ages 3-<6 years, 6-<10 years, 10-<15 years and 15-<18 years. Multiple Logistic regression models were used for evaluating the associations of BMI with sexual development in children. Dichotomous Logistic regression was used to compare the differences in the distribution of early and non-early puberty among normal weight, overweight and obese groups. Curves were drawn to analyze the relationship between the percentage of early puberty and BMI distribution in girls and boys at different Tanner stages. Results: A total of 208 179 healthy children (96 471 girls and 111 708 boys) were enrolled in this study. The OR values of B2, B3 and B4+ in overweight girls were 1.72 (95%CI: 1.56-1.89), 3.19 (95%CI: 2.86-3.57), 7.14 (95%CI: 6.33-8.05) and in obese girls were 2.05 (95%CI: 1.88-2.24), 4.98 (95%CI: 4.49-5.53), 11.21 (95%CI: 9.98-12.59), respectively; while the OR values of G2, G3, G4+ in overweight boys were 1.27 (95%CI: 1.17-1.38), 1.52 (95%CI: 1.36-1.70), 1.88 (95%CI: 1.66-2.14) and in obese boys were 1.27 (95%CI: 1.17-1.37), 1.59 (95%CI: 1.43-1.78), and 1.93 (95%CI: 1.70-2.18) (compared with normal weight Tanner 1 group,all P<0.01). Analysis in different age groups found that OR values of obese girls at B2 stage and boys at G2 stage were 2.02 (95%CI: 1.06-3.86) and 2.32 (95%CI:1.05-5.12) in preschool children aged 3-<6 years, respectively (both P<0.05). And in the age group of 6-10 years, overweight girls had a 5.45-fold risk and obese girls had a 12.54-fold risk of B3 stage compared to girls with normal BMI. Compared with normal weight children, the risk of early puberty was 2.67 times higher in overweight girls, 3.63 times higher in obese girls, and 1.22 times higher in overweight boys, 1.35 times higher in obese boys (all P<0.01). Among the children at each Tanner stages, the percentage of early puberty increased with the increase of BMI, from 5.7% (80/1 397), 16.1% (48/299), 13.8% (27/195) to 25.7% (198/769), 65.1% (209/321), 65.4% (157/240) in girls aged 8-<9, 10-<11 and 11-<12 years, and 6.6% (34/513), 18.7% (51/273), 21.6% (57/264) to 13.3% (96/722), 46.4% (140/302), 47.5% (105/221) in boys aged 9-<10, 12-<13 and 13-<14 years, respectively. Conclusions: BMI is positively correlated with sexual development in both Chinese boys and girls, and the correlation is stronger in girls. Obesity is a risk factor for precocious puberty in preschool children aged 3-<6 years, and 6-<10 years of age is a high risk period for early development in obese girls.

Clinical analysis of the recombinant human growth hormone combined with letrozole in the treatment of short pubertal boys / 中国实用儿科杂志

OBJECTIVE: To explore the therapeutic effects and adverse reactions of a combination treatment of recombinant human growth hormone(rh GH)with letrozole,compared with rh GH alone,in short pubertal boys. METHODS: Fifty-five short pubertal boys were divided into two groups,one group was treated with rh GH(rh GH group,n=24),and the other group was treated with the combination of rh GH and letrozole(combination group,n=31). All boys had completed the over one year of treatment. The advancement of bone age(BA),height standard deviation score by bone age(Ht SDSBA),body mass index standard deviation(BMI SDS),glucose and lipid metabolism,and the changes of the external genitalia and adverse reactions were evaluated. RESULTS: The age of two groups was(12.72±0.99)years and(12.90±1.36)years,respectively(P>0.05).The treatment periods were(1.71±0.55)years and(1.58±0.46)years,respectively(P>0.05).Their BA increased(0.96±0.27)years/year and(0.50±0.20)years/year during treatment,respectively(P0.05)respectively during treatment. There were no statistically significant difference in BMI SDS,glucose or lipid metabolism between the two groups.Three boys in combination group suffered from fractures during the treatment. Ultrasound bone density scan showed serious shortage of bone mineral density;after supplemental calcium and calcitriol,bone density increased within 3 to 6 months,and there was no recurrence of fracture. CONCLUSION: Combination of rh GH and letrozole in short pubertal boys could inhibit BA progression and ameliorate HtSDSBA,without affecting the normal sexual development,but bone density may be affected,and long-term follow-up is needed.

Effects of gonadotropin releasing hormone analog and growth hormone on height in girls with idiopathic central precocious puberty / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To determine the effect of gonadotropin releasing hormone agonist (GnRHa), by itself alone or in combination with recombinant human growth hormone (rhGH), on height in young girls (bone age≥10 years) with idiopathic central precocious puberty (ICPP).</p><p><b>METHODS</b>Eighty girls with ICPP (9.0±0.7 years old) from six medical centers across Southeast and Southwest China participated in this study. They were allocated to treatment with GnRHa+rhGH (n=31) and GnRHa (n=49) respectively. Girls in the GnRHa+rhGH group (bone age 11.18 ±0.53 years) were treated with GnRHa for 25.29±6.92 months and rhGH for 12.87±7.02 months. Girls in the GnRHa group (bone age 11.03 ±0.50 years) were treated with GnRHa for 25.96±8.95 months. The height standard deviation for bone age (HtSDS-BA), predicted adult height, near-adult height and net height increase before and after treatment were recorded for girls in both groups.</p><p><b>RESULTS</b>HtSDS-BA was significantly improved after treatment for both groups (P<0.01) and the HtSDS-BA value was superior in the GnRHa+rhGH group over the GnRHa group (P<0.01). Values in near adult height (157±6 cm vs 157±4 cm), net height increase after treatment (4.68 cm vs 3.89 cm), and predicted adult height after drug withdrawal (161±5 cm vs 158±5 cm) were higher in the GnRHa+rhGH group than the GnRHa group, but the differences were not significant.</p><p><b>CONCLUSIONS</b>Both GnRHa plus rhGH and GnRHa alone can improve the near adult height in girls with ICPP with a bone age ≥10 years to a similar extent. Adult height predicted based on bone age in ICPP girls following drug withdrawal is usually overestimated and precautions should be taken when this parameter is used.</p>

Analysis of a family affected with familial male-limited precocious puberty due to a Ala568Val mutation in LHCGR gene / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>Familial male-limited precocious puberty (FMPP) is due to constitutive activation of a mutant luteinizing hormone/choriogonadotropin receptor (LH/CGR) leading to elevated testosterone synthesis in testicular Leydig cells. In the present study, we have analyzed the LHCGR gene for members of a Chinese FMPP family.</p><p><b>METHODS</b>Physical examinations have included assessment of penile length, testicular volume and pubic hair. Bone age assessment, levels of testosterone and gonadotropin-releasing hormone (GnRH) stimulations tests were measured. DNA was extracted from blood samples of the proband and his parents using an QIAGEN Blood DNA Mini Kit. The 11 exons of LHCGR gene were amplified using an AmpliTaq PCR system, and the PCR products were sequenced using an ABI3130xl Genetic Analyzer.</p><p><b>RESULTS</b>The affected boy was 3 year and 1 month old and showed typical clinical manifestation of peripheral precocious puberty. His height was 116.8cm (+5.1s) and Tanner stages were PH 2. Testicular volume was 8 mL bilaterally, penile was 8.5 cm × 2.5 cm. Basal testosterone was 2310 ng/L and bone age was 9 years. GnRH stimulation test revealed a prepubertal response to gonadotropin. The peak of LH was 2.66 IU/L, and the peak of FSH was 1.03 IU/L. Upon sequencing exon 11 of the LHCGR, a heterozygous point mutation of nucleotide 1703 from C to T was detected, which resulted in an amino acid transition from Ala (GCC) to Val (GTC) at position 568. Thus the mutation of LHCGR gene was confirmed to be constitutively active. After treating with aromatase inhibitors for half a year, the patient showed an increase in bone age and height by half a year and 4 cm, respectively. The same point mutation was detected in the patient's father, but did not have any influence on his puberty development.</p><p><b>CONCLUSION</b>A novel point mutation of the LHCGR gene has been identified in a family affected with FMPP. The c.1703C>T mutant LHCGR was confirmed to be constitutively active, which has led to maturation and proliferation of Leydig cells. The variable phenotype within the family suggested variable expressivity of the disease.</p>

Etiology and prognosis of peripheral precocious puberty in children / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To study the causes and prognosis of peripheral precocious puberty.</p><p><b>METHODS</b>The levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2) were detected by a simplified gonadotrophin-releasing hormone (GnRH) stimulation test. The etiologies of 125 children with peripheral precocious puberty were explored by ultrasound scans and bone age assessment. A total of 102 cases were followed up for 3 months to 7.5 years.</p><p><b>RESULTS</b>The etiological distribution of these children was as follows: exogenous hormones intake (n=80), ovarian cyst (n=11), McCune-Albright syndrome (n=11), congenital adrenal hyperplasia (CAH) (n=5), ovarian teratoma (n=1), masculine adrenal tumor (n=1), feminine adrenal tumor (n=1), and handle pituitary tumor (n=1). The causes in 14 cases were unknown. Follow-up showed that the sexual characteristics of 72 cases due to exogenous hormones intake subsided after 1-6 months. Of 11 cases with ovarian cysts, the sexual characteristics subsided spontaneously in 8 cases after 1 to 4 months, but one case was transformed to central precocious puberty after 2 years and three months. One child with ovarian cysts underwent an operation and than the sexual characteristics subsided. The sexual characteristics of the patient who had an ovarian teratoma subsided after operation. The clinical symptoms of children with McCune-Albright syndrome or CAH were alliaviated partly after treatment, and 7 cases were transformed to central precocious puberty. The clinical symptoms of 2 cases of adrenal tumors subsided after operation. One child with handle pituitary tumor died one year after operation.</p><p><b>CONCLUSIONS</b>Varied causes may contribute to peripheral precocious puberty and therefore must be carefully identified through history taking, physical examination, and auxiliary examinations. The prognosis may differ for patients with different etiologies of peripheral precocious puberty.</p>

Clinical Analysis of 38 Cases of Pseudoprecocious Puberty / 实用儿科临床杂志

Objective To study the causes, clinical feature,diagnoses and prognosis of pseudoprecocious puberty. Methods Thirty-eight cases with pseudoprecocious puberty were diagnosed by the serum LH and FSH of GnRHa stimulation test, pelvic ultrasonography and bone age assessment; they were treated and followed up. Results Peaks of LH were(0.49?0.48) IU/L, peaks of FSH were(0.54?0.78) IU/L, the level of E2 in 26 cases increased (36.11?15.70) ng/L,17-hydroxyprogesterone of 1 case was beyond 266 nmol/L. All cases showed hysterauxesis (3.98?1.18) mL. Cases of wrong contraceptive intake were 29,5 cases of McCune-Albright syndrome,2 cases of ovarian cyst, 1 case of ovarian granular cell tumor,1 case of congenital adrenal hyperplasia. Conclusions The causes of pseudoprecocious puberty are multifactors. Early diagnosis,therapy,follow-up are very important for prognosis.