This study aims to assess the effectiveness of pulsed gonadotropin-releasing hormone (GnRH) micropump replacement therapy in the treatment of hypogonadotropic hypogonadism (HH) caused by primary empty sella (PES).The efficacy of pulsed GnRH replacement therapy using the micropump was evaluated in a middle-aged male patient with HH who had experienced the loss of his only child. Relevant literature was also consulted to compare the differences between pulse GnRH treatment and conventional treatment in terms of the development of secondary sexual characteristics, sex hormone levels, sperm production rate, and sperm activity rate in male patient with HH.In this report, a 45-year-old male diagnosed with HH and PES presented with fatigue and decreased libido. The main characteristics included decreased follicle stimulating hormone (FSH) levels of 0.03 mIU/mL, luteinizing hormone (LH) levels of 0.02 mIU/mL, and testosterone (T) levels of 0.72 nmol/L. Magnetic resonance imaging (MRI) revealed an empty sella. Semen analysis showed a small number of normal sperm with reduced motility. During treatment with the micropump pulse GnRH, the patient experienced no side effects and showed improvements in fatigue, reduced libido, sexual urge, anxiety, and feelings of inferiority. LH, FSH, and T levels returned to normal, while sperm activity rate increased to 79.9%. Ultimately, the patient\'s spouse achieved a natural pregnancy.Pulsed gonadotropin delivery using the micropump demonstrates good efficacy and tolerability, and aligns more closely with the physiological rhythm of GnRH secretion in the human body.

BACKGROUND: Currently, there is a scarcity of cases and diagnostic data regarding ectopic adrenocortical adenomas, particularly in relation to their impact on gonadal function and localization diagnostic techniques. We report a typical case of ectopic adrenocortical adenomas and the data of treatment follow-up, and review the literature of 31 available cases of ectopic adrenocortical adenomas.
METHODS: A 27-year-old Chinese female patient was admitted to our hospital for hypertension, hyperglycaemia and primary amenorrhea. The patient was functionally diagnosed with ACTH-independent CS and hypogonadotropic hypogonadism. Radiological evaluations, including Computed Tomography (CT) and functional imaging, identified a mass at the left renal hilum. Histological assessments post-surgical excision confirmed the mass to be an ectopic adrenocortical adenoma. A subsequent 3-month follow-up showed no signs of disease recurrence, a swift recovery of the cortisol axis was observed, with a partial recuperation of the gonadal axis.
METHODS: Our literature review shows that the most common ectopic areas of cortisol adenomas are renal hilum and hepatic region. The most positive biomarker is Melan A, and only a few cases have been diagnosed with functional localization.
CONCLUSIONS: Ectopic adrenocortical adenomas may be asymptomatic in the early stage and can impact gonadal function. Physicians who treat hypogonadism must be aware of the need to test cortisol levels and perform functional localization in patients with lumps present.

X-linked adrenal hypoplasia congenita (AHC) is a rare disorder characterized by primary adrenal insufficiency (PAI) and hypogonadotropic hypogonadism (HH), with limited clinical and genetic characterization.
The clinical, biochemical, genetic, therapeutic, and follow-up data of 42 patients diagnosed with X-linked AHC were retrospectively analysed.
Hyperpigmentation (38/42, 90%), vomiting/diarrhoea (20/42, 48%), failure to thrive (13/42, 31%), and convulsions (7/42, 17%) were the most common symptoms of X-linked AHC at onset. Increased adrenocorticotropic hormone (ACTH) (42/42, 100%) and decreased cortisol (37/42, 88%) were the most common laboratory findings, followed by hyponatremia (32/42, 76%) and hyperkalaemia (29/42, 69%). Thirty-one patients presented with PAI within the first year of life, and 11 presented after three years of age. Three of the thirteen patients over the age of 14 exhibited spontaneous pubertal development, and ten of them experienced delayed puberty due to HH. Six patients receiving human chorionic gonadotropin (hCG) therapy exhibited a slight increase in testicular size and had rising testosterone levels (both P < 0.05). The testicular volumes of the three patients with pulsatile gonadotropin-releasing hormone (GnRH) therapy were larger than those of the six patients undergoing hCG therapy (P < 0.05), and they also exhibited some growth in terms of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone. Of the 42 patients, three had an Xp21 deletion, and 39 had an isolated DAX1 defect. Most patients (9/10) with entire DAX1 deletion accounting for 23.8% (10/42) of the total variants had early onset age of less than one year.
This study details the clinical features and genetic spectra of X-linked AHC. Patients with X-linked AHC show a bimodal distribution of the age of onset, with approximately 70% presenting within the first year of life. Pulsatile GnRH may be recommended for HH when hCG therapy is not satisfactory, although it is difficult to achieve normal testicular volume. The combination of clinical features and molecular tests provides information for an accurate diagnosis.

Culler-Jones syndrome is a rare clinical phenomenon with diverse manifestations and is prone to misdiagnosis. We report one patient who presented with a 10-year history of anosmia and a 1-year history of epididymal pain. Kallmann syndrome was suspected initially. The results of his laboratory tests, imaging, and genetic testing, however, combined to provide a conclusive diagnosis of Culler-Jones syndrome. With the aid of high-throughput sequencing technology, the GLI2 gene c.527A>G (p.Tyr176Cys) heterozygous mutation in the child was identified. No published works have yet described this mutation site. We described Culler-Jones syndrome in a child at length. We recommend that Culler-Jones syndrome be taken into account when considering the spectrum of disorders associated with abnormal growth and development in children. Once diagnosed, individualized hormone replacement treatment is required for each patient.

Hypogonadotropic hypogonadism (HH) is a disease defined by dysfunction of the hypothalamic- pituitary-gonadal hormone axis, leading to low sex hormone levels and impaired fertility. HH with anosmia or hyposmia is known as Kallmann syndrome (KS). Waardenburg syndrome (WS) is a rare autosomal dominant genetic disorder characterized by sensorineural hearing loss and abnormal pigmentation. In this report, we collected the clinical data of a patient with hypogonadotropic hypogonadism and congenital hearing loss of unknown cause. The patient had no obvious secondary sexual characteristics development after puberty, and had a heterozygous deletion (at least 419 kb) in 22q13.1 region (Chr.22:38106433-38525560), which covered the SOX10 gene. The abnormalities were not found in gene sequencing analysis of both the parents and sister of the proband. By summarizing and analyzing the characteristics of this case, we further discussed the molecular biological etiological association between HH and WS type 2. This case also enriches the clinical data of subsequent genetic studies, and provides a reference for the diagnosis and treatment of such diseases.
低促性腺激素性性腺功能减退症(hypogonadotropic hypogonadism, HH)是以下丘脑-垂体-性腺激素轴功能障碍为主要特征的一类疾病，可致性激素水平低和生育能力受损。伴随嗅觉丧失/减退的HH被称为Kallmann综合征(Kallmann syndrome, KS)。Waardenburg综合征(Waardenburg syndrome, WS)是一种罕见的常染色体显性遗传病，以感音神经性听力损失以及色素沉着异常为主要特征。本研究收集1例不明原因的低促性腺激素性性腺功能减退和先天性耳聋患者的临床资料，该患者进入青春期后无明显第二性征发育，在22q13.1区域(Chr.22:38106433-38525560)存在杂合缺失，至少419 kb，此区域覆盖了SOX10基因。患者父母、妹妹基因测序分析未见异常。通过总结分析该病例特点，分析探讨低促性腺激素性性腺功能减退症与Waardenburg综合征2型在分子生物学上的病因关联，丰富后续遗传学研究的临床资料，同时为此类疾病的诊疗措施提供参考。.

The aim of this study was to evaluate the diagnostic accuracy of different olfactory evaluation tools in congenital hypogonadotropic hypogonadism (CHH) patients.
Seventy-one CHH patients were prospectively recruited at Peking Union Medical College Hospital between November 2020 and July 2021. The Chinese Olfactory Function Test (COFT) and Self-reported Olfactory Scale (SROS) were adapted as the subjective tools for the evaluation of olfactory function, and magnetic resonance imaging of olfactory apparatus (MRI-OA) was the objective tool. The olfactory bulb volume (OBV) and the olfactory sulcus depth (OSD) were quantified.
Based on the COFT, 36 patients were categorized as having normosmic CHH (nCHH), and the other 35 patients were categorized as having Kallmann syndrome (KS). Among nCHH patients, 35 patients were classified as having normal olfaction and 1 patient had abnormal olfaction by SROS. For KS patients, there were 30 patients grouped into abnormal olfaction, while 5 patients had normal olfaction by SROS. For MRI-OA, 67% (18/27) of nCHH patients showed normal olfactory apparatus, and 33% (9/27) showed bilateral or unilateral olfactory bulb aplasia or hypoplasia. Among KS patients, 96% (27/28) of patients showed bilateral olfactory bulb hypoplasia or aplasia, and 4% (1/28) of patients showed normal olfactory apparatus. All six patients with unilateral olfactory bulb aplasia and three patients with bilateral olfactory bulb aplasia showed normal olfactory function. The accuracy of the SROS in the diagnosis of nCHH and KS was 91.5%, with a sensitivity of 0.857 and a specificity of 0.972, while the accuracy of MRI-OA is 92.7%, with a sensitivity of 0.964 and a specificity of 0.889.
SROS and MRI-OA both showed high accuracy to distinguish between KS and nCHH. The abnormal structure of the olfactory apparatus was relatively common in nCHH patients. CHH patients with unilateral olfactory bulb aplasia dysplasia usually had normal olfaction. Normal olfaction without apparent olfactory bulbs is rare but occurred in male CHH patients.

Adrenal hypoplasia congenita (AHC) is a rare X-linked recessive disease caused by mutations in the nuclear receptor subfamily 0, group B, member 1 (NR0B1) gene, which is also referred to as dosage-sensitive sex-reversal, adrenal hypoplasia congenita, in the critical region of the X chromosome, gene 1 (DAX1). This gene is expressed in the hypothalamus, anterior pituitary and steroidogenic tissues, including the gonads and adrenal cortex. Adult-onset forms of X-linked AHC are a significant cause of concern. In the present study, the case of a 21-year-old male who exhibited adrenal insufficiency and hypogonadotropic hypogonadism was described. The patient initially presented with nausea, vomiting, fatigue and dizziness. The laboratory results demonstrated that the patient had hyponatremia, a low basal cortisol concentration and increased adrenocorticotropic hormone levels. Molecular genetic examination revealed a novel frameshift mutation (c.1005delC, p.V336Cfs*36). Following steroid supplementation, the patient\'s vomiting, fatigue and dizziness rapidly improved. To the best of our knowledge, the present study was the first case report of adult-onset X-linked AHC with this novel frameshift mutation. Furthermore, the present study highlighted differences in the clinical presentation of adult-onset forms of X-linked AHC. This may therefore alert medical professionals to the need to perform genetic analysis for DAX1 mutations in adolescents and adults with primary adrenal insufficiency and hypogonadotropic hypogonadism.

Nuclear receptor subfamily 0 group B member 1 gene (NR0B1) encodes an orphan nuclear receptor that plays a critical role in the development and regulation of the adrenal gland and hypothalamic-pituitary-gonadal axis. In this study, we report a novel mutation in NR0B1 that led to adult-onset adrenal hypoplasia congenita (AHC) and pubertal development failure in a male adult. Clinical examinations revealed hyponatremia, elevated adrenocorticotropic hormone levels, reduced testosterone and gonadotropin levels, and hyper-responses to gonadotropin-releasing hormone and human chorionic gonadotropin stimulation tests. Whole-exome sequencing and Sanger sequencing were performed to identify the potential causes of AHC. Candidate variants were shortlisted based on the X-linked recessive models. Sequence analyses identified a novel hemizygous variant of c.1034delC in exon 1 of NR0B1 at Xp21.2, resulting in a frameshift mutation and premature stop codon formation. The c.1034delC/p.Pro345Argfs*27 in the NR0B1 gene was detected in the hemizygous state in affected males and in the heterozygous state in healthy female family carriers. These results expand the clinical features of AHC as well as the mutation profile of the causative gene NR0B1. Further studies are needed to elucidate the biological effects of the mutation on the development and function of the adrenal gland and the hypothalamic-pituitary-gonadal axis.

Camurati-Engelmann Disease (CED) is a rare sclerosing bone disease, sometimes associated delayed puberty. The treatment effect of glucocorticoid and angiotensin II receptor blocker (ARB) in bone health and puberty development remain unclear. We report a case of an 18-year-old girl who presented for a history of an enlarged head, pain of lower limbs, and no menstrual onset or breast development. Radiographs revealed thickening of skull and cortices in the diaphysis but sparse bone trabeculae in the spine and metaphysis. Sanger sequencing detected a mutation of c. 652C>T (p. R218C) in the gene TGFB1 and confirmed the diagnosis of CED. After treatment of a medium-to-small dosage of prednisone and losartan for 28 months, we observed improvement of bone mass in spine and hip and body fat mass and found initiation of puberty development. By a systemic review of current treatment strategies in patients with CED, we found that most cases reported relief of bone pain with treatment of glucocorticoid or ARB, but none has reported the outcome of hypogonadotropic hypogonadism. We propose that long-term use of glucocorticoid combined with ARB may inhibit the activation of TGFβ1 in CED, improve adipogenesis, and thus initiate puberty development and improve the bone mass in spine and hip.

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder, resulting from impaired production, secretion, or action of gonadotropin-releasing hormone (GnRH). Variants of the KISS1R gene can result in CHH. Herein we describe a Chinese boy with CHH, caused by a novel, compound heterozygous variant in KISS1R. A male infant presented to the pediatric urological surgeon at three months of age for micropenis. Laboratory investigations done at this time revealed low levels of serum gonadotropins and testosterone, suggesting a lack of minipuberty. Topical application of dihydrotestosterone gel was recommended, but the parents refused treatment. The child was brought to our hospital at 3.3 years of age for the same complaint. A diagnosis of CHH was considered, and next generation sequencing revealed a compound heterozygous variant including a novel c.182C>A (p.S61*) and a c.418C>T (p.R140C) in KISS1R. We describe a novel compound heterozygous variant in the KISS1R in a boy with CHH, born to non-consanguineous Chinese parents. This report adds to the spectrum of variants in KISS1R seen in children with CHH.