Band 37, Heft 12

This study is to evaluate the efficacy and safety of aromatase inhibitors (AIs) in the treatment of short stature in male children and adolescents. Pooled estimates of final or near-final height, predicted adult height (PAH), bone age, and potential side effects were calculated using a random-effects model or fixed-effects model. Our search identified 11 studies with a total of 463 participants. AI was associated with a significant increase in final or near-final height (weight mean difference (WMD)=3.61 cm, 95 % CI: 0.96, 6.26; p<0.001) and PAH (WMD=2.52 cm, 95 % CI: 0.32, 4.72; p=0.025) compared to other treatment. The use of AI showed an increased risk of minor side effects (risk ratio (RR)=2.90, 95 % CI: 1.15, 7.33; p=0.025), but no severe adverse effects were reported. Subgroup analysis, stratified by patient disease, revealed that AI significantly enhanced final or near-final height in both patients with idiopathic short stature (ISS) and those with constitutional delay of growth and puberty (CDGP). AIs may contribute to height increase in male children and adolescents with short stature, without significantly advancing bone age. However, the increased risk of minor side effects indicates the need for careful monitoring during AI therapy.

Objectives Hybrid closed-loop (HCL) systems improve glycemic control in type 1 diabetes mellitus (T1D), but their effectiveness in young, poorly controlled populations is not established and requires study. Methods A pre–post study was performed using electronic health records of patients 3–24 years with baseline HbA 1c ≥9 % prescribed HCL within the New York City Health+Hospitals System assessing HbA 1c levels and hospitalizations before and after HCL initiation and factors associated with achieving HbA 1c <9 % after HCL initiation. Results Of 47 children and adolescents who met inclusion criteria, 4.68 % female, 95.72 % non-White, and 82.22 % covered by public insurance, with a baseline average HbA 1c  10.6 % (2.28 IQR). The most prevalent pump type was Omnipod 5 (70.21 %). The HbA 1c was significantly lower in the postperiod than baseline (HbA 1c before=median 10.6 (IQR2.28), HbA 1c after=median 9.33 (IQR 2.97), difference 1.00 (IQR 1.64), p<0.05) with a decrease in median diabetes-related hospitalizations (preperiod 1.00 (IQR 1.00), postperiod 0.00 (IQR 1.00), difference −1.00, IQR 2, p<0.05). Lower baseline HbA 1c levels made reaching HbA 1c <9 % more likely. Multivariable analysis showed that the odds of having HbA 1c of <9 % was 2.1 times less likely for every one point increase in baseline HbA 1c and 12.5 times less likely for those with a pump at (p<0.05). Conclusions HCL therapy improved glycemic control and decreased diabetes-related hospitalizations in youth with poorly controlled T1DM. Higher baseline HbA 1c levels predicted less success with HCL therapy so those who stand to benefit most benefit least.

Objectives To evaluate the long-term effectiveness of weekly vs. daily growth hormone (GH) administration in children with GH deficiency. Methods This study, part of the “LG Growth Study”, included a total of 996 children with GH deficiency (773 receiving daily GH and 193 receiving weekly GH). Anthropometric data were collected at baseline and every 12 months; clinical and laboratory data were collected at baseline and throughout the study. Results At baseline, the weekly GH group was older, shorter in mid-parental height (MPH), and had more pubertal boys compared to the daily GH group (age: 8.46 ± 3.44 vs. 7.46 ± 2.89 years, p<0.001; MPH: −0.88 ± 0.73 SD vs. −1.02 ± 0.84 SD, p=0.044; pubertal boys: 34.0 vs. 16.9 %, p=0.006). Height velocity and change in height SDS during the first 12 months were higher in the daily GH group (height velocity: 9.06 ± 1.72 vs. 8.67 ± 1.98 cm/year, p=0.028; height SDS change: 0.78 ± 0.39 vs. 0.61 ± 0.41, p<0.001). However, height SDS at 24 and 48 months were similar between groups. No significant differences in overall height velocity, annualized treatment continuation rate, and safety profile were observed over 48 months. Conclusions Weekly GH therapy appears to be an effective and safe alternative to daily GH treatment in children with GH deficiency over a 4-year period. Further research with larger sample sizes and longer follow-up is needed to confirm these findings and assess the extended safety and effectiveness of LAGH.

Objectives Testicular adrenal rest tumours (TARTs) are a common cause of infertility in males with congenital adrenal hyperplasia (CAH). Ovarian adrenal rest tumours (OARTs) and polycystic ovaries (PCO) can impair ovarian function in female patients with CAH. We aim to detect gonadal changes in children and adolescents with CAH. Methods This study was conducted on 50 CAH patients (30 females and 20 males) with 21-hydroxylase deficiency (21-OHD), with a mean age of 10.35 ± 2.36 years. Testicular ultrasonography and pelvic magnetic resonance imaging (MRI) were done in males and females respectively. Glucocorticoid doses and biochemical data were obtained from the patients’ medical records. Results TARTs were detected in 10/20 male patients (50 %). There was a significant relation between presence of TARTs, body mass index (BMI) standard deviation score (SDS), and bone age (p=0.017 and 0.023; respectively). There was no significant relation between presence of TARTs, laboratory parameters, or treatment received (p>0.05). Of those subjected to genetic analysis, 48 % had I2 splice (c.290-13A/C>G) followed by P30L (c.89C>T) (40.7 %). P30L (c.89C>T) was the most common allele among the patients with TARTs (42.9 %). There was no significant relation between presence of TARTs, the genotype, alleles, or the genotype groups (p>0.05). Only one female patient had radiological evidence of bilateral polycystic ovaries and none had OARTs. Conclusions The prevalence of TARTs in our study was high (50 %). Screening for TARTs in males with CAH is crucial; however, routine ovarian imaging in CAH females is not indicated unless ovarian dysfunction is present.

Growth hormone deficiency (GHD) diagnosis still lacks a gold standard or ideal diagnostic marker. Unlike other epigenetic mechanisms, non-coding RNAs regulate post-transcriptional levels. The information on non-coding RNAs in the field of GHD is limited. Therefore, this study aimed to explore the role of hsa_circ_0002473 as a competitive endogenous RNA for has-miR-4645-3p in attenuating the inhibitory effect of has-miR-4645-3p on SSTR2. In this study, we screened three significantly expressed circular RNAs (circRNAs) in five children with GHD, and selected the highest expressed hsa_circ_0002473 as the study object, and screened has-miR-4645-3p, which is the most likely to bind to hsa_circ_0002473, according to the microRNA (miRNA)-circRNA regulatory network, to study the role and mechanism of has-miR-4645-3p as a competitive endogenous RNA of has-miR-4645-3p on GH3 cells. Somatostatin receptor 2 (SSTR2) inhibits GH3 cell proliferation, and miRNA binding to SSTR2 inhibits the latter expression. Both bioinformatics and dual-luciferase reporter analyses showed targeting relationships between hsa_circ_0002473 and has-miR-4645-3p and between has-miR-4645-3p and SSTR2. We constructed the hsa_circ_0002473/has-miR-4645-3p axis and transfected it into GH3 cells and found that overexpression of hsa_circ_0002473 inhibited the proliferation and growth hormone (GH) secretion of GH3 cells, and that hsa-miR-4645-3p promoted the proliferation and GH secretion of GH3 cells by targeting SSTR2. Co-culture revealed that the inhibitory effect of hsa_circ_0002473 was reversed by has-miR-4645-3p. In conclusion, our findings suggest that hsa_circ_0002473 can act as a competitive endogenous RNA for has-miR-4645-3p to regulate GH3 cell proliferation and secretion by targeting SSTR2.

Objectives Existing literature lacks data on a subgroup exhibiting psychiatric symptoms below the DSM-5 diagnostic threshold within differences of sexual development (DSD) cases. Our study aims to assess parental knowledge, attitudes toward DSD, and parental perceptions of emotional and behavioral states through a transdiagnostic perspective. Methods The study was conducted with a total of 35 parents of children with DSD. Two groups were established via k-means clustering, based on psychiatric symptomatology levels, derived from The Strength and Difficulties Questionnaire – Parent Form and The Revised Children’s Anxiety and Depression Scale – Parent Form: with one group exhibiting lower reported psychiatric symptoms (LPS=27) and the other demonstrating higher psychiatric symptoms (HPS=8) by parents. Results Our study found that many parents were hesitant to disclose DSD diagnoses to their children, believing them to be too young to comprehend the information (42.9 %) and that they were unaware of the available support that could be provided by the medical team in disclosing the diagnosis (25.7 %). Our study found no differences in DSM-5 diagnoses between HPS and LPS groups (p>0.05), with ADHD being the most prevalent diagnosis (21.7 %) and a significant overrepresentation of children with a discrepancy between assigned gender at birth and gender upbringing in the HPS group compared to the LPS group (p<0.001). Conclusions Our study emphasizes the necessity of a transdiagnostic approach in psychiatry to move beyond binary conceptualizations and better understand the complexities of individuals with DSD.

Objectives Parents of children with differences of sex development (DSD) are known to suffer from psychological distress at the time of diagnosis and thereafter. We analyzed the prevalence of anxiety and depression in Indian parents of children with DSD and its associated risk factors, as well as their experiences, perceptions and expectations from the healthcare system. Methods This cross-sectional study included parents of children aged ≤6 years with atypical genitalia. Data was collected through face-to-face semi-structured interview using specially designed questionnaire. Depression and anxiety have been assessed using PHQ9 (Patient Health Questionnaire) and GAD-7 (Generalized Anxiety Disorder Scale), respectively. Results The current mean age of the 43 children (46,XY=26, 46,XX=16 and chromosomal DSD=1) was 36.5 ± 21.4 months with a median age of diagnosis of 5 months (range- 0–60 months). 68 parents (35 mothers and 33 fathers) were interviewed. The score was above the cut-off for clinically significant depression in 27.2 and 25.7 % of the fathers and mothers, respectively; and for clinically significant anxiety in 15.1 and 28.6 % of the fathers and mothers, respectively. The most significant factor associated with psychological distress was rearing a boy with lower EMS in fathers and lower literacy levels (with higher perception of stigma) in mothers. Absence of family support was associated with high levels of distress in both parents. Conclusions There is a high level of depression and anxiety amongst Indian parents of children born with atypical genitalia and requirement for psychological support and counseling.

Objectives We describe a male with adrenal hypoplasia congenita (AHC) caused by a novel mutation in NR0B1 , who was noted at 9 months of age to have central precocious puberty (CPP). Case presentation A 3-week-old full-term male presented with hypothermia and lethargy, and a 0.3 kg weight loss since birth. Labs were consistent with adrenal crisis, he was stabilized with stress dose hydrocortisone (HC), insulin, and antibiotics, and he was admitted to the Pediatric Intensive Care Unit. Subsequent labs revealed primary adrenal insufficiency with abdominal ultrasound remarkable for nonvisualization of the adrenal glands. Genetic testing identified a novel pathogenic c.707G>A [p.Trp236ter] nonsense variant in the DNA-binding domain of NR0B1 (DAX-1) confirming AHC. The patient was discharged with HC, fludrocortisone, and sodium supplementation with good tolerance and interval weight gain and normal electrolytes. At 9 months of age, the patient developed signs of precocious puberty, which failed to self-resolve or diminish with increased dosing of HC, and by the age of 15 months, he was treated with leuprolide acetate. Conclusions Historically, hypogonadotropic hypogonadism has been observed in 76 % of adolescent patients with AHC who have alterations in NR0B1 . CPP has been infrequently described in AHC, and the natural history and management of CPP in this setting is not established. Our observations may contribute to the understanding of factors influencing normal and abnormal puberty in infants. Increased awareness of the possibility of CPP in AHC will aid clinicians in the earlier clinical and laboratory detection of this complication.

Objectives Steroid 5α-reductase type 2 deficiency (5α-RD2) is an autosomal recessive disorder caused by mutations in the SRD5A2 gene. This condition is characterized by reduced enzymatic activity of the 5α-reductase type 2 enzyme. Individuals with mutations in the SRD5A2 gene may exhibit various symptoms of under-masculinization in 46, XY individuals. We conducted a comprehensive analysis of the SRD5A2 gene in a patient with disorder of sex development (DSD). Case presentation We describe a patient with a homozygous Gly183Ser variant in the SRD5A2 gene. Their sibling also carries this variant in homozygosity, while both parents have it in a heterozygous state. The patient presents with predominantly female traits and was raised as a girl. Although the siblings exhibit distinct phenotypic characteristics, both have assumed a male gender identity. Conclusions This study reveals different phenotypes for the two siblings, highlighting the complexity of establishing a genotype-phenotype correlation in the SRD5A2 gene. It is noteworthy that the Gly183Ser variant seems to be more prevalent among individuals of African descent, aligning with our patient’s ethnic background.

Objectives To present the clinical journey and management of a 15-year-old female with SHORT syndrome, highlighting the diagnostic challenges and the novel genetic mutation identified. Case presentation A 15-year-old Filipino female was initially seen in a dermatology clinic at 9 years old for axillary skin darkening, indicative of acanthosis nigricans. Early evaluations revealed elevated blood glucose levels, resulting in a pediatric diabetes diagnosis without the usual hyperglycemic symptoms. Her medical history was notable for premature birth, intrauterine growth restriction, a cardiac murmur from patent ductus arteriosus and a bicuspid aortic valve, delayed teething, and distinct dysmorphic features. Genetic testing identified a novel PIK3R1 gene mutation. Treatment with metformin significantly improved her glycemic control and lipid profiles. The patient also displayed delayed puberty and polycystic ovary syndrome-like symptoms, but growth hormone deficiency was excluded. Endocrine evaluation for her short stature and lipodystrophy confirmed the presence of the PIK3R1 mutation. Conclusions This case highlights the importance of thorough endocrine and genetic evaluations in patients with complex clinical presentations like SHORT syndrome. The identification of a novel PIK3R1 gene mutation expands the understanding of the genetic basis of this syndrome and underscores the need for individualized treatment approaches.

Objectives Congenital adrenal hyperplasia (CAH) is an uncommon genetic disorder which affects cortisol production in the adrenal glands. It is usually treated with glucocorticoids. We present a case of non-classical CAH caused by the partial deficiency of 11 beta-hydroxylase (11βOH) which was treated with aldosterone antagonist (eplerenone) monotherapy. Case presentation An adolescent male was diagnosed with 11 beta-hydroxylase deficiency (11βOHD) at 13 years of age when he presented with hypertension, fatigue and headaches. He was initially treated with glucocorticoids, but requested an alternative therapy. Eplerenone was commenced at 25 mg with subsequent dose increases to 100 mg daily. His hypertension was controlled on this regimen, achieving a 24 h average blood pressure of 124/81 mmHg. Conclusions CAH caused by 11βOHD is a known cause of hypertension. It is usually managed with glucocorticoids, and antihypertensives are added if blood pressure remains uncontrolled. In this case, glucocorticoid therapy was not tolerated and treatment with aldosterone antagonist monotherapy was effective in controlling his hypertension.

Objectives Spondylo-epimetaphyseal dysplasia-aggregan (SEMD-ACAN) is a rare form of osteo-chondrodysplasia that includes vertebral, epiphyseal and metaphyseal dysplasia. It occurs as a result of loss-of-function mutations in the ACAN gene, which encodes aggregan protein, which is the basic component of the extracellular matrix in cartilage. It results in disproportionately short stature and skeletal abnormalities. Here, we aimed to present the fourth SEMD-ACAN report in the literature. Case presentation A 9-year-old girl was admitted to our clinic with growth retardation. She was born from a first-degree cousin marriage with severe short stature (41 cm; −3.54 SDS). Her mother also had severe short stature. Her height was 110 cm (−4.6 SDS); she had midface hypoplasia, low-set ears, short neck, short limbs, and central obesity. Biochemical and hormonal tests were normal. Skeletal survey showed moderate platyspondylia, thoracolumbar scoliosis, lumbar lordosis, bilateral femoro-acetabular narrowing, and advanced bone age (10 years). The patient’s brother was 100 cm (−3.97 SDS). He had similar but milder clinical findings. Biallelic ACAN variation (c.512C>T; p. Ala171Val) was detected in two siblings by next-generation sequencing. The parents were heterozygous carriers. Before, the heterozygous form of this variant has been reported in a 15-year-old boy with short stature, advanced bone age, and dysmorphic features. Conclusions SEMD-ACAN is a rare genetic condition that affects bone growth and development and can cause physical and developmental abnormalities. This article highlights the importance of considering genetic testing in characteristic symptoms associated with SEMD-ACAN, such as severe growth retardation and skeletal abnormalities.