Kisspeptin and DLK1 levels for monitoring treatment of girls with central precocious puberty.

BACKGROUND: Kisspeptin and delta-like 1 homolog (DLK1) are neuropeptides that reportedly play an important role in pubertal timing by activating and inhibiting the hypothalamic-pituitary-gonadal axis, respectively. Consequently, serum kisspeptin and DLK1 levels may be novel biomarkers for differentiating between central precocious puberty (CPP) and premature thelarche (PT) in girls and used to monitor CPP treatment. PURPOSE: To compare baseline serum kisspeptin and DLK1 levels in girls with CPP at diagnosis and after treatment to age-matched girls with PT. METHODS: This prospective longitudinal study included girls with precocious puberty and girls with PT who experienced breast development before 8 years of age and peak luteinizing hormone levels of ≥6 versus <6 IU/L after a gonadotropin-releasing hormone (GnRH) stimulation test. Serum kisspeptin and DLK1 levels were determined in both groups at baseline and after 6 months of GnRH analog treatment in the CPP group and analyzed by enzyme-linked immunosorbent assay. RESULTS: The study divided a total of 48 girls into CPP (n=24; mean age, 7.7±0.7 years) and PT (n=24; mean age, 7.4±0.8 years) groups. The baseline median serum kisspeptin levels were 50.5 pg/mL (range, 38.2-77 pg/mL) and 49.5 pg/mL (range, 39.7-67.6 pg/mL), respectively (P=0.89), while the baseline median serum DLK1 levels were 6.5 ng/mL (range, 5.9-7.5 ng/mL) and 6 ng/mL (4.4-14.4 ng/mL), respectively (P=0.68). After 6 months of GnRH analog treatment in the CPP group, the median serum kisspeptin level was lower (46.4 ng/mL; range, 37.1-60 ng/mL) than that at baseline (P=0.002), while the median serum DLK1 level was higher (7 ng/mL; range, 6.7-8.9) than that at baseline (P=0.002). CONCLUSION: Our findings suggest that baseline serum kisspeptin and DLK1 levels are not reliable biomarkers for differentiating between CPP and PT. However, significant changes in serum kisspeptin and DLK1 levels may be used to monitor CPP treatment.

Effectiveness of leuprolide acetate administered monthly compared to three-monthly in the treatment of central precocious puberty: evaluation at the end of treatment.

Introduction: Gonadotropin-releasing hormone (GnRH) analogs are the standard treatment for central precocious puberty (CPP). Although there are numerous varieties of GnRH agonists, the effectiveness of 1-monthly compared with 3-monthly Leuprolide acetate is still restricted. The objective of this study was to evaluate the outcomes of CPP treatment with Leuprolide acetate at a 1-monthly dosage of 3.75 mg, in comparison to a dosage of 11.25 mg administered every 3 months. Method: This retrospective cohort study involved 143 girls diagnosed with CPP with 72 of them receiving the monthly treatment regimen and 71 receiving the 3-monthly treatment regimen. Anthropometric measurements were compared at the start and end of the therapy. The rates and level of LH suppression were assessed six months after therapy. Results: The regimen administered every 3 months showed more significant suppression of LH. The 3-monthly group showed lower actual height and degree of bone age advancement at the end of therapy. However, the predicted adult height (PAH) remained comparable in both groups. Conclusion: The 3-monthly treatment showed greater hormonal and growth suppression effects, but there was no significant difference in PAH between the two groups.

The utilization of basal luteinizing hormone in combination with the basal luteinizing hormone and follicle-stimulating hormone ratio as a diagnostic tool for central precocious puberty in girls.

PURPOSE: Intravenous gonadotropin-releasing hormone (IV GnRH) testing is the gold standard for confirming a central precocious puberty (CPP) diagnosis. However, this test is not widely available commercially. Therefore, our study aim was to establish cutoff values for basal gonadotropin level and gonadotrophin responses to a 100-µg subcutaneous IV GnRH test that can distinguish between CPP and premature thelarche (PT) to discover a simple method to detect CPP. METHODS: Girls between the ages of 6 and 8 years who attended the pediatric endocrinology outpatient clinic at our tertiary hospital between 2019 and 2022 were included in this study. They were evaluated for breast development, and a subcutaneous 100-µg GnRH test was administered by measuring the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in blood samples at baseline and then 30, 60, 90, and 120 minutes after injection. CPP is characterized by increased height velocity, advanced bone age, and progression of breast development. The cutoff value for diagnosis of CPP was determined using a receiver operating characteristic (ROC) analysis. RESULTS: In 86 Thai girls (56 with CPP and 30 with PT), the ROC analysis showed 71.4% and 100% sensitivity and specificity, respectively, for basal LH (cutoff ≥ 0.2 IU/L) plus the basal LH/FSH ratio (cutoff ≥ 0.1). The optimal cutoff values for peak LH (cutoff ≥ 7 IU/L) demonstrated a sensitivity of 94.6% and a specificity of 100%, whereas the LH value at 30 and 60 minutes after injection (cutoff ≥ 6 IU/L) demonstrated sensitivities of 92.9% and 94.6% and a specificity of 100%, respectively. CONCLUSION: Combining the basal LH (cutoff: 0.2 IU/L) and the basal LH/FSH ratio (cutoff: 0.1) can easily and cost-effectively diagnose CPP in a girl in breast Tanner stage II.

Coexistence of Graves' disease with acute rheumatic fever treated as thyroid storm in young Thai patient.

OBJECTIVES: This report presents a case of acute onset of chorea, concurrent Graves' disease, and acute rheumatic fever in an 8-year-old female patient. CASE PRESENTATION: The child had intermittent involuntary movement of all extremities and both eyes for 4 days, with a previous history of increased appetite, weight lost, and heat intolerance over a period of two months. Physical examination revealed fever, tachycardia, exophthalmos, eyelid retraction, as well as diffused thyroid enlargement. Initial clinical features and thyroid function testing suggested a thyroid storm due to Graves' disease. Methimazole, propranolol, potassium iodide (SSKI), and dexamethasone were prescribed. Congestive heart failure developed after propranolol and cardiovascular re-evaluation and Revised Jones criteria suggested acute rheumatic fever. Chorea was successfully treated with pulse methylprednisolone. CONCLUSIONS: We reported Graves' disease patients with acute rheumatic fever simulating a thyroid storm. The underlying cardiac disease must be considered, especially where chorea and congestive heart failure are present.

Novel Variants and Phenotypes in NEUROG3-Associated Syndrome.

CONTEXT: Biallelic pathogenic variants in the NEUROG3 gene cause malabsorptive diarrhea, insulin-dependent diabetes mellitus (IDDM), and rarely hypogonadotropic hypogonadism. With only 17 reported cases, the clinical and mutational spectra of this disease are far from complete. OBJECTIVE: To identify the underlying genetic etiology in 3 unrelated Thai patients who presented with early-onset malabsorptive diarrhea, endocrine abnormalities, and renal defects and to determine the pathogenicity of the newly identified pathogenic variants using luciferase reporter assays and western blot. METHODS: Three unrelated patients with congenital diarrhea were recruited. Detailed clinical and endocrinological features were obtained. Exome sequencing was performed to identify mutations and in vitro functional experiments including luciferase reporter assay were studied to validate their pathogenicity. RESULTS: In addition to malabsorptive diarrhea due to enteric anendocrinosis, IDDM, short stature, and delayed puberty, our patients also exhibited pituitary gland hypoplasia with multiple pituitary hormone deficiencies (Patient 1, 2, 3) and proximal renal tubulopathy (Patient 2, 3) that have not previously reported. Exome sequencing revealed that Patient 1 was homozygous for c.371C > G (p.Thr124Arg) while the other 2 patients were homozygous for c.284G > C (p.Arg95Pro) in NEUROG3. Both variants have never been previously reported. Luciferase reporter assay demonstrated that these 2 variants impaired transcriptional activity of NEUROG3. CONCLUSIONS: This study reported pituitary gland hypoplasia with multiple pituitary hormone deficiencies and proximal renal tubulopathy and 2 newly identified NEUROG3 loss-of-function variants in the patients with NEUROG3-associated syndrome.

Sex-specific ranges and ratios for anogenital distance among Thai full-term newborns.

INTRODUCTION: Anogenital distance (AGD) is a marker of prenatal androgen exposure and a tool for assessment of differences of sex development. Data for AGD in newborns have been published, but these findings may not be applicable to Thai newborns. AIM: To provide the sex-specific ranges for AGD in Thai full-term newborns. METHODS: A cross-sectional study was conducted in term newborns in Thailand, during 2016-2018. AGD was measured from anus to anterior base of penis (AGDAP) and to perineoscrotal junction (AGDAS) in males and from anus to clitoris (AGDAC) and to posterior fourchette (AGDAF) in females. AGD ratio is defined as AGDAS divided by AGDAP in males and AGDAF divided by AGDAC in females. RESULTS: A total of 364 newborns were studied (male 51.4%). The mean AGDAS, AGDAP and AGD ratio in males were 25.20 ± 4.80, 52.60 ± 6.90 and 0.48 ± 0.08 mm, respectively. The mean AGDAF, AGDAC, and AGD ratio in females were 16.50 ± 3.90, 42.60 ± 6.20 and 0.39 ± 0.08 mm, respectively. There were significant differences between AGDAS and AGDAF, AGDAP and AGDAC, and AGD ratio between males and females (p < 0.001). The AGDAS, AGDAP, AGDAF, AGDAC were correlated with birth weight and length, but AGD ratio showed no correlation. CONCLUSION: The sex-specific ranges for AGD in Thai full-term newborns were determined. AGD ratio is a useful marker of prenatal androgen exposure since it differs between sexes, but constant between races and did not vary by body size.

A patient with combined pituitary hormone deficiency and osteogenesis imperfecta associated with mutations in LHX4 and COL1A2.

Genetic disorders have been shown to co-occur in individual patient. A Thai boy with features of osteogenesis imperfecta (OI) and combined pituitary hormone deficiency (CPHD) was identified. The causative mutations were investigated by whole exome and Sanger sequencing. Pathogenicity and pathomechanism of the variants were studied by luciferase assay. The proband was found to harbor a novel de novo heterozygous missense mutation, c.1531G > T (p.G511C), in COL1A2 leading to OI and a heterozygous missense variant, c.364C > T (p.R122W), in LHX4. The LHX4 p.R122W has never been reported to cause CPHD. The variant was predicted to be deleterious and found in the highly conserved LIM2 domain of LHX4. The luciferase assays revealed that the p.R122W was unable to activate POU1F1, GH1, and TSHB promoters, validating its pathogenic effect in CPHD. Moreover, the variant did not alter the function of wild-type LHX4, indicating its hypomorphic pathomechanism. In conclusion, the novel de novo heterozygous p.G511C mutation in COL1A2 and the heterozygous pathogenic p.R122W mutation in LHX4 were demonstrated in a patient with OI and CPHD. This study proposes that the mutations in two different genes should be sought in the patients with clinical features unable to be explained by a mutation in one gene.

Higher phthalate concentrations are associated with precocious puberty in normal weight Thai girls.

BACKGROUND: The cause of precocious puberty may be associated with genetics and other conditions such as central nervous system (CNS) insults, or the exposure to endocrine disrupting chemicals (EDCs). Phthalates is known to be one of the EDCs and have estrogenic and antiandrogenic activities, and may be associated with advanced puberty. The objective of the study was to determine the association between urinary phthalate metabolites and advanced puberty. METHODS: A cross-sectional study was conducted in patients with precocious puberty (breast onset <8 years, n=42) and early puberty (breast onset 8-9 years, n=17), compared to age-matched controls (n=77). Anthropometric measurements, estradiol, basal and gonadotropin releasing hormone (GnRH)-stimulated follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels, uterine sizes, ovarian diameters and bone ages (BA) were obtained. Urine samples were collected and mono-methyl phthalate (MMP) and mono-ethyl phthalate (MEP) were analyzed by high performance liquid chromatography (HPLC) and adjusted with urine creatinine. RESULTS: The median adjusted-MEP concentration in girls with precocious puberty, was greater than in normal girls (6105.09 vs. 4633.98 µg/g Cr: p<0.05), and had the same trend among early puberty and normal puberty (5141.41 vs. 4633.98 µg/g Cr: p=0.4), but was not statistically significant. CONCLUSIONS: Precocious puberty girls had an association with increased MEP concentration. This is the first report of the association between urinary phthalate levels and precocious puberty in Thai girls.