Pitfalls of diagnosing pituitary hypoplasia in the patients with short stature.

PURPOSE: Height age (HA) and bone age (BA) delay is well known in the patients with short stature. Therefore assessing pituitary hypoplasia based on chronological age (CA) might cause overdiagnosis of pituitary hypoplasia. We aimed to investigate the diagnostic and prognostic value of the PH and PV based on CA, HA, or BA in the patients with GHD. METHODS: Fifty-seven patients with severe and 40 patients with partial GHD and 39 patients with ISS assigned to the study. For defining the most accurate diagnosis of pituitary hypoplasia, PH and PV were evaluated based on CA, BA and HA. The relationship of each method with clinical features was examined. RESULTS: The mean PV was significantly larger in patients with ISS compared to the GH-deficient patients. PV was more correlated with clinical features including height SDS, stimulated GH concentration, IGF-1 and IGFBP-3 SDS, height velocity before and after rGH therapy. We found BA-based PV could discriminate GHD from ISS (Sensitivity: 17%, specificity: 98%, positive predictive value: 94%, negative predictive value: 39%), compared to the other methods based on PH or PV respect to CA and HA. 3% of patients with ISS, 17% of patients with GHD had pituitary hypoplasia based on PV-BA. CONCLUSION: PV based on BA, has the most accurate diagnostic value for defining pituitary hypoplasia. But it should be kept in mind that there might be still misdiagnosed patients by this method. PV is also a significant predictor for the rGH response.

A Japanese Boy with Dysmorphic Syndrome with Multiple Pituitary Hormone Deficiency and Gingival Fibromatosis Due to a Pathogenic KCNQ1 Variant.

A six-year-old boy presented with short stature and gingival fibromatosis (GF). Dysmorphic features included slant optic fissures, a high-arched palate, thick earlobes, and an edematous face. Laboratory tests showed low levels of serum insulin-like growth factor-1 and serum free thyroxine but normal serum thyrotropin levels. Provocative tests suggested growth hormone deficiency, central hypocortisolemia, and hypothalamic hypothyroidism. At 12 years old, hypogonadotropic hypogonadism was observed. Next-generation sequencing revealed a heterozygous missense variant, KCNQ1 p. (P369L), in the proband and mother. The coexistence of multiple pituitary hormone deficiencies and GF helps diagnose KCNQ1-variant dysmorphic syndrome through genetic testing.

Common and uncommon mouse models of growth hormone deficiency.

Mouse models of growth hormone deficiency (GHD) have provided important tools for uncovering the various actions of GH. Nearly 100 years of research using these mouse lines has greatly enhanced our knowledge of the GH/IGF-1 axis. Some of the shared phenotypes of the five "common" mouse models of GHD include reduced body size, delayed sexual maturation, decreased fertility, reduced muscle mass, increased adiposity, and enhanced insulin sensitivity. Since these common mouse lines outlive their normal-sized littermates - and have protection from age-associated disease - they have become important fixtures in the aging field. On the other hand, the twelve "uncommon" mouse models of GHD described herein have tremendously divergent health outcomes ranging from beneficial aging phenotypes (similar to those described for the common models) to extremely detrimental features (such as improper development of the CNS, numerous sensory organ defects, and embryonic lethality). Moreover, advancements in next generation sequencing technologies have led to the identification of an expanding array of genes that are recognized as causative agents to numerous rare syndromes with concomitant GHD. Accordingly, this review provides researchers with a comprehensive up-to-date collection of the common and uncommon mouse models of GHD that have been used to study various aspects of physiology and metabolism associated with multiple forms of GHD. For each mouse line presented, the closest comparable human syndromes are discussed providing important parallels to the clinic.

Post-traumatic pituitary stalk transection syndrome (PSTS) expeditiously manifested after a fall from a height combined with acute traumatic spinal cord injury: a rare case report with review of literature.

Post-traumatic pituitary stalk transection syndrome (PSTS) is an extremely rare cause of combined pituitary hormone deficiency (CPHD), affecting approximately 9 per 100,000 cases of traumatic brain injury. In contrast, pituitary stalk interruption syndrome (PSIS) is also a rare cause of CPHD. Importantly, these conditions are often confused due to their similar names and resembling findings on magnetic resonance imaging (MRI). PSIS has been thought to be a prenatal developmental event resulting from a couple of genetic aberrations. In typical PSIS, anterior pituitary hormone deficiencies are restricted to growth hormone (GH) and gonadotropin during the pediatric age, gradually and generally progressing to panhypopituitarism in most cases. In contrast, global deficiencies of the anterior pituitary hormones in PSTS are temporally associated with trauma. To the best of our knowledge, no case reports of PSTS combined with acute traumatic spinal cord injury have been reported. A 34-year-old female was transferred to our hospital after jumping from the fourth building floor. She was diagnosed as an acute traumatic spinal cord injury and underwent the operation of elective posterior spinal fusion. On postoperative day 7, the blood tests revealed considerable hyperkalemia, hyponatremia and eosinophilia. Notably, menstruation stopped after falling from a height. Pituitary function tests revealed GH deficiency, hypogonadism, hypothyroidism and hypoadrenocorticism. MRI revealed loss of the pituitary stalk, whilst the hyperintense signal from distal axon of hypothalamus was still identified. Based on these findings, she was diagnosed as PSTS. Our case highlights endocrinological landscape of transection of the pituitary stalk by acute trauma.

Increased Adrenocorticotropic Hormone Levels Predict Recovery of Consciousness in Patients With Disorders of Consciousness.

The potential influence of pituitary-related hormones (including both pituitary gland and target gland hormones) on functional recovery after traumatic brain injury has been observed. However, the relationship between these hormones and the recovery of consciousness in patients with disorders of consciousness (DOC) remains unclear. In this retrospective and observational study, 208 patients with DOC were recruited. According to the Glasgow Outcome Scale (GOS) scores after 6 months, patients with DOC were categorized into two subgroups: a favorable prognosis subgroup (n = 38) comprising those who regained consciousness (GOS score ≥3), and a poor prognosis subgroup (n = 156) comprising those who remained in DOC (GOS score <3). Comparative analyses of pituitary-related hormone levels between the two subgroups were conducted. Further, a binary logistic regression analysis was conducted to assess the predictive value of pituitary-related hormones for the patients' prognosis. The favorable prognosis subgroup showed a significant increase in adrenocorticotropic hormone (ACTH) levels (p = 0.036). Moreover, higher ACTH levels and shorter days since injury were significantly associated with a better prognosis, with odds ratios (ORs) of 0.928 (95% confidence interval [CI] = 0.873-0.985, p = 0.014) and 1.015 (95% CI = 1.005-1.026, p = 0.005), respectively. A subsequent receiver operating characteristic (ROC) analysis demonstrated the potential to predict patients' prognosis with an area under the curve value of 0.78, an overall accuracy of 75.5%, a sensitivity of 77.5%, and a specificity of 66.7%. Our findings indicate that ACTH levels could serve as a clinically valuable and convenient predictor for patients' prognosis.

Pituitary stalk interruption syndrome due to novel ROBO1 mutation presenting as combined pituitary hormone deficiency and central diabetes insipidus.

OBJECTIVES: The genetic causes of pituitary stalk interruption syndrome (PSIS) remain elusive in 95 % of cases. The roundabout receptor-1 gene (ROBO1) plays critical roles in axonal guidance and cell migration. Recently, mutations in the ROBO1 gene have been reported patients with PSIS. CASE PRESENTATION: We report a 2.9-year-old boy with PSIS who presented with combined pituitary hormone deficiency, central diabetes insipidus, and the classical triad of MRI findings. Through clinical exome sequencing using next-generation sequencing techniques, a previously unidentified novel heterozygous frame shift mutation in the ROBO1 gene was identified. This is the first report of ROBO1 mutation associated with posterior pituitary dysfunction. CONCLUSIONS: We conclude and emphasize that ROBO1 should be investigated in patients with PSIS. Our case is unique in the published literature in that we are first time reporting posterior pituitary dysfunction as manifestation of ROBO1 mutation. The full clinical spectrum of the mutations may not be fully known.

Current and Emerging Pharmacological Therapies for Cushing's Disease.

Cushing's Disease (CD), hypercortisolism due to pituitary ACTH secreting neuroendocrine neoplasm, is associated with increased morbidity and, if untreated, mortality in about half of the affected individuals. Consequently, the timely initiation of effective treatment is mandatory. Neurosurgery is the first line and the only potentially curative treatment; however, 30% of patients will have persistent disease post-surgery. Furthermore, a small percentage of those initially controlled will develop hypercortisolism during long-term follow- up. Therefore, patients with persistent or recurrent disease, as well as those considered non-eligible for surgery, will need a second-line therapeutic approach, i.e., pharmacotherapy. Radiation therapy is reserved as a third-line therapeutic option due to its slower onset of action and its unfavorable profile regarding complications. During the past few years, the understanding of molecular mechanisms implicated in the physiology of the hypothalamus-pituitary-adrenal axis has evolved, and new therapeutic targets for CD have emerged. In the present review, currently available treatments, compounds currently tested in ongoing clinical trials, and interesting, potentially new targets emerging from unraveling molecular mechanisms involved in the pathophysiology of Cushing's disease are discussed.

Phenotype-Genotype Correlations of GH1 Gene Variants in Patients with Isolated Growth Hormone Deficiency or Multiple Pituitary Hormone Deficiency.

INTRODUCTION: Genetic forms of growth hormone deficiency (GHD) may occur as isolated GHD (IGHD) or as a component of multiple pituitary hormone deficiency (MPHD). This study aimed to present the clinical and molecular characteristics of patients with IGHD/MPHD due to the GH1 gene variants. METHODS: A gene panel accommodating 25 genes associated with MPHD and short stature was used to search for small sequence variants. Multiplex ligation-dependent probe amplification was performed in patients with normal panel results to investigate gross deletion/duplications. Segregation in the family was performed by Sanger sequencing. RESULTS: The GH1 gene variants were detected in 5 patients from four unrelated families. One patient had IGHD IA due to homozygous whole GH1 gene deletion and one had IGHD IB due to novel homozygous c.162C>G/p.(Tyr54*) variant. Two patients from a family had previously reported heterozygous c.291+1G>A/p.(?) variant in which clinical and genetic characteristics were compatible with IGHD II accompanying MPHD. One patient had clinical and laboratory characteristics of IGHD II with MPHD but the heterozygous c.468 C>T/p.(R160W) variant had conflicting results about the relationship with the phenotype. CONCLUSION: Expanding our knowledge of the spectrum of GH1 gene variants by apprehending clinical and molecular data of more cases, helps to identify the genotype-phenotype correlation of IGHD/MPHD and the GH1 gene variants. These patients must be regularly followed up for the occurrence of additional pituitary hormone deficiencies.

Genetic diagnosis of congenital hypopituitarism in Turkish patients by a target gene panel: novel pathogenic variants in GHRHR, GLI2, LHX4 and POU1F1 genes

ABSTRACT Objective: Congenital hypopituitarism (CH) is a rare disease characterized by one or more hormone deficiencies of the pituitary gland. To date, many genes have been associated with CH. In this study, we identified the allelic variant spectrum of 11 causative genes in Turkish patients with CH. Materials and methods: This study included 47 patients [21 girls (44.6%) and 26 boys (55.4%)] from 45 families. To identify the genetic etiology, we screened 11 candidate genes associated with CH using next-generation sequencing. To confirm and detect the status of the specific familial variant in relatives, Sanger sequencing was also performed. Results: We identified 12 possible pathogenic variants in GHRHR, GH1, GLI2, PROP-1, POU1F1, and LHX4 in 11 patients (23.4%), of which six were novel variants: two in GHRHR, two in POU1F1, one in GLI2, and one in LHX4. In all patients, these variants were most frequently found in GLI2, followed by PROP-1 and GHRHR. Conclusion: Genetic causes were determined in only 23.4% of all patients with CH and 63% of molecularly diagnosed patients (7/11) from consanguineous families. Despite advances in genetics, we were unable to identify the genetic etiology of most patients with CH, suggesting the effect of unknown genes or environmental factors. More genetic studies are necessary to understand the etiology of CH.

Comparison of clinical characteristics of a pediatric cohort with combined pituitary hormone deficiency caused by mutation of the PROP1 gene or of other origins.

The most commonly identified genetic cause of combined pituitary hormone deficiency (CPHD) is PROP1 gene mutations. The aim of the study was to compare selected clinical features of patients with CPHD caused by variants of the PROP1 gene (CPHD-PROP1) and patients with inborn CPHD of other etiology (CPHD-nonPROP1). MATERIAL AND METHODS: The retrospective analysis included childhood medical records of 74 patients (32 female) with CPHD, including 43 patients (23 female) with the mutation in the PROP1 gene. RESULTS: Patients with CPHD-PROP1 compared to the CPHD-nonPROP1 presented with the following: significantly higher median birth weight (0.21 vs. - 0.29 SDS, p = 0.019), lower growth velocity within 3 years preceding growth hormone administration (- 2.7 vs. - 0.8 SDS, p < 0.001), higher mean maximal blood concentration of growth hormone within the stimulation process (1.2 vs. 1.08 ng/mL, p = 0.003), lower TSH (1.8 vs. 2.4 µIU/mL, p < 0.001), significantly lower prolactin concentrations (128 vs. 416.3 µIU/mL, p < 0.001), and less frequent typical signs of hypogonadism at birth in boys (n = 6; 30% vs. n = 12, 54%, p < 0.001). Secondary adrenal insufficiency was less frequent in CPHD-PROP1 (20 vs. 25 cases, p = 0.006) and occurred at a later age (13.4 vs. 10.4 years). MRI of the pituitary gland in CPHD-PROP1 revealed a small pituitary gland (21 cases), pituitary gland enlargement (eight cases), and one pituitary stalk interruption and posterior lobe ectopy, while it was normal in nine cases. CONCLUSION: Patients with the PROP1 mutations present a clinical picture significantly different from that of other forms of congenital hypopituitarism. Certain specific clinical results may lead to the successful identification of children requiring diagnostics for the PROP1 gene mutation.

Diagnosing and treating anterior pituitary hormone deficiency in pediatric patients.

Hypopituitarism, or the failure to secrete hormones produced by the anterior pituitary (adenohypophysis) and/or to release hormones from the posterior pituitary (neurohypophysis), can be congenital or acquired. When more than one pituitary hormone axis is impaired, the condition is known as combined pituitary hormone deficiency (CPHD). The deficiency may be primarily due to a hypothalamic or to a pituitary disorder, or concomitantly both, and has a negative impact on target organ function. This review focuses on the pathophysiology, diagnosis and management of anterior pituitary hormone deficiency in the pediatric age. Congenital hypopituitarism is generally due to genetic disorders and requires early medical attention. Exposure to toxicants or intrauterine infections should also be considered as potential etiologies. The molecular mechanisms underlying the fetal development of the hypothalamus and the pituitary are well characterized, and variants in the genes involved therein may explain the pathophysiology of congenital hypopituitarism: mutations in the genes expressed in the earliest stages are usually associated with syndromic forms whereas variants in genes involved in later stages of pituitary development result in non-syndromic forms with more specific hormone deficiencies. Tumors or lesions of the (peri)sellar region, cranial radiation therapy, traumatic brain injury and, more rarely, other inflammatory or infectious lesions represent the etiologies of acquired hypopituitarism. Hormone replacement is the general strategy, with critical periods of postnatal life requiring specific attention.

Genetic diagnosis of congenital hypopituitarism in Turkish patients by a target gene panel: novel pathogenic variants in GHRHR, GLI2, LHX4 and POU1F1 genes.

Objective: Congenital hypopituitarism (CH) is a rare disease characterized by one or more hormone deficiencies of the pituitary gland. To date, many genes have been associated with CH. In this study, we identified the allelic variant spectrum of 11 causative genes in Turkish patients with CH. Materials and methods: This study included 47 patients [21 girls (44.6%) and 26 boys (55.4%)] from 45 families. To identify the genetic etiology, we screened 11 candidate genes associated with CH using next-generation sequencing. To confirm and detect the status of the specific familial variant in relatives, Sanger sequencing was also performed. Results: We identified 12 possible pathogenic variants in GHRHR, GH1, GLI2, PROP-1, POU1F1, and LHX4 in 11 patients (23.4%), of which six were novel variants: two in GHRHR, two in POU1F1, one in GLI2, and one in LHX4. In all patients, these variants were most frequently found in GLI2, followed by PROP-1 and GHRHR. Conclusion: Genetic causes were determined in only 23.4% of all patients with CH and 63% of molecularly diagnosed patients (7/11) from consanguineous families. Despite advances in genetics, we were unable to identify the genetic etiology of most patients with CH, suggesting the effect of unknown genes or environmental factors. More genetic studies are necessary to understand the etiology of CH.

Clinico-radiological correlation of pituitary stalk interruption syndrome in children with growth hormone deficiency.

PURPOSE: To analyze the clinical, hormonal, and radiological characteristics of Pituitary stalk interruption syndrome (PSIS) in children with growth hormone deficiency (GHD). METHODS: This is a prospective cross-sectional study, conducted over a period of three years in a short stature clinic of tertiary care referral hospital. 57 severe short stature children with proven GHD were included in the study. RESULTS: Among 57 children with GHD, 14 (24%) were diagnosed as PSIS. The mean age at diagnosis was 11.8 ± 2.6years. The male to female ratio was 2.5:1. Nine (64%) children had multiple pituitary hormone deficiency (MPHD) and 5 (36%) had isolated growth hormone deficiency (IGHD). In spite of absent or ectopic posterior pituitary (EPP)in Magnetic Resonance Imaging (MRI) of PSIS cohorts, only one had Arginine vasopressin (AVP) deficiency. EPP was seen near median eminence in 6 (44%), elsewhere in 4 (28%), and absent in 4 (28%)children. The height gain following growth hormone therapy was better in PSIS cohorts as compared to non-PSIS. CONCLUSION: Male gender, breech presentation, external congenital anomalies like cryptorchidism, midline defects and nystagmus were more common in children with PSIS. MPHD were more frequently seen in PSIS whereas IGHD in non-PSIS cohort. AVP deficiency is very rare in PSIS despite of absent or ectopic posterior pituitary in MRI. High index of clinical suspicion in all severe short stature may lead to early diagnosis and prompt initiation of growth hormone treatment for better outcome.

PROKR2 Mutations in Patients with Short Stature Who Have Isolated Growth Hormone Deficiency and Multiple Pituitary Hormone Deficiency

Objective: Recent reports have indicated the role of the prokineticin receptor 2 gene (PROKR2) in the etiology of pituitary hormone deficiencies, suggesting a potential role for the PROK2 pathway in pituitary development, in addition to its role in gonadotropin releasing hormone-expressing neuron development. Here, we present the clinical and molecular findings of four patients with PROKR2 mutations. Methods: Next-generation targeted sequencing was used to screen 25 genes in 59 unrelated patients with multiple pituitary hormone deficiency (MPHD), isolated growth hormone (GH) deficiency, or idiopathic short stature. Results: Two different, very rare PROKR2 missense alterations classified as pathogenic (NM_144773.4:c.518T>G; NP_658986.1:p. (Leu173Arg)) and likely pathogenic (NM_144773.4:c.254G>A; NP_658986.1:p.(Arg85His)) were identified in four patients in heterozygous form. Patient 1 and Patient 2 presented with short stature and were diagnosed as GH deficiency. Patient 3 and Patient 4 presented with central hypothyroidism and cryptorchidism and were diagnosed as MPHD. No other pathogenic alterations were detected in the remaining 24 genes related to short stature, MPHD, and hypogonadotropic hypogonadism. Segregation analysis revealed asymptomatic or mildly affected carriers in the families. Conclusion: PROKR2 dominance should be kept in mind as a very rare cause of GH deficiency and MPHD. Expressional variation or lack of penetrance may imply oligogenic inheritance or other environmental modifiers in individuals who are heterozygous carriers.

Combined pituitary hormone deficiency harboring CHD7 gene missense mutation without CHARGE syndrome: a case report.

BACKGROUND: Heterozygous loss-of-function mutations in the chromodomain helicase DNA-binding protein 7 (CHD7) gene cause CHARGE syndrome characterized by various congenital anomalies. A majority of patients with CHARGE syndrome present with congenital hypogonadotropic hypogonadism (HH), and combined pituitary hormone deficiency (CPHD) can also be present. Whereas CHD7 mutations have been identified in some patients with isolated HH without a diagnosis of CHARGE syndrome, it remains unclear whether CHD7 mutations can be identified in patients with CPHD who do not fulfill the criteria for CHARGE syndrome. CASE PRESENTATION: A 33-year-old woman was admitted to our hospital. She had primary amenorrhea and was at Tanner stage 2 for both pubic hair and breast development. She was diagnosed with CPHD (HH, growth hormone deficiency, and central hypothyroidism), and a heterozygous rare missense mutation (c.6745G > A, p.Asp2249Asn) in the CHD7 gene was identified. Our conservation analysis and numerous in silico analyses suggested that this mutation had pathogenic potential. She had mild intellectual disability, a minor feature of CHARGE syndrome, but did not fulfill the criteria for CHARGE syndrome. CONCLUSIONS: We report a rare case of CPHD harboring CHD7 mutation without CHARGE syndrome. This case provides valuable insights into phenotypes caused by CHD7 mutations. CHD7 mutations can have a continuous phenotypic spectrum depending on the severity of hypopituitarism and CHARGE features. Therefore, we would like to propose a novel concept of CHD7-associated syndrome.

Diagnosis and Incidence of Congenital Combined Pituitary Hormone Deficiency in Denmark-A National Observational Study.

CONTEXT: Congenital combined pituitary hormone deficiency (cCPHD) is the loss of ≥2 pituitary hormones caused by congenital factors. OBJECTIVE: We aimed to estimate the national incidence of cCPHD diagnosed before age 18 years and in subgroups. METHODS: Patients with cCPHD were identified in the Danish National Patient Registry and Danish hospital registries in the period 1996-2020. Hospital files were reviewed and incidences calculated using background population data. Incidence was the main outcome measure. RESULTS: We identified 128 patients with cCPHD; 88 (68.8%) were males. The median (range) age at diagnosis was 6.2 (0.01-19.0) years. The median (25th;75th percentile) number of hormone deficiencies at diagnosis was 3 (3; 4) at <1 year vs 2 (2; 2) at 1-17 years, P < .0001. Abnormal pituitary magnetic resonance imaging findings were seen in 70.3% (83/118). For those born in Denmark aged <18 years at diagnosis (n = 116/128) the estimated national incidence (95% CI) of cCPHD was 10.34 (7.79-13.72) per 100 000 births, with an annual incidence rate of 5.74 (4.33-7.62) per million. In subgroup analysis (diagnosis <1 vs 1-17 years), the incidence was highest in the 1-17 years subgroup, 7.97 (5.77-11.00) vs 1.98 (1.39-2.84) per 100 000 births, whereas the annual incidence rate was highest at <1 year, 19.8 (13.9-28.4) vs 4.69 (3.39-6.47) per million births. CONCLUSION: cCPHD had the highest incidence rate and the most hormone deficiencies in those diagnosed at <1 year. The incidence was highest in the 1-17 years age group, underscoring the need for multiple pituitary hormone investigations throughout childhood and adolescence in children with only 1 hormone deficiency.

Prevalence of pituitary dysfunction after aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis.

BACKGROUND: Pituitary dysfunction (PD) is a common complication after aneurysmal subarachnoid hemorrhage (aSAH). The prevalence of PD varies widely at a global level and no recent meta-analysis is available. Therefore, the aim of our systematic review and meta-analysis was to summarize the updated estimates of worldwide prevalence of PD after aSAH. METHODS: Scopus, Embase, Web of Science, and PubMed databases were used to comprehensively search the appropriate literature and a random-effects meta-analysis on the results of the available studies was performed. The heterogeneity in the prevalence estimates was evaluated by subgroup analysis in terms of types of PD, and acute and chronic phases of aSAH. The onset of PD within 6 months after aSAH was considered as acute, while that after 6 months was considered as chronic. RESULTS: Twenty-seven studies with 1848 patients were included in this analysis. The pooled prevalence of PD in the acute phase was 49.6% (95% CI, 32.4-66.8%), and 30.4% (95% CI, 21.4-39.4%) in the chronic phase. Among the hormonal deficiencies, growth hormone dysfunction was the most prevalent in the acute phase, being 36.0% (95% CI, 21.0-51.0%), while hypoadrenalism was the most prevalent in the chronic phase, being 21.0% (95% CI, 12.0-29.0%). Among the six World Health Organization regions, the South-East Asia Region has the highest prevalence of PD in the acute phase (81.0%, 95%CI, 77.0-86.0%, P < 0.001), while the European Region had the highest prevalence of PD in the chronic phase (33.0%, 95%CI, 24.0-43.0%, P < 0.001). Moreover, single pituitary hormonal dysfunction occurred more frequently than the multiple one, regardless of acute or chronic phase. CONCLUSIONS: Almost half (49.6%) of the included patients with aSAH developed PD complication in the acute phase, while 30.4% of the patients developed them in the chronic phase. Although prevalence varies globally, the high healthcare burden, morbidity and mortality require greater awareness among clinicians.

A procedure in mice to obtain intact pituitary-infundibulum-hypothalamus preparations: a method to evaluate the reconstruction of hypothalamohypophyseal system.

PURPOSE: The histopathological study of brain tissue is a common method in neuroscience. However, efficient procedures to preserve the intact hypothalamic-pituitary brain specimens are not available in mice for histopathological study. METHOD: We describe a detailed procedure for obtaining mouse brain with pituitary-hypothalamus continuity. Unlike the traditional methods, we collect the brain via a ventral approach. We cut the intraoccipital synchondrosis, transection the endocranium of pituitary, broke the spheno-occipital synchondrosis, expose the posterior edge of pituitary, separate the trigeminal nerve, then the intact pituitary gland was preserved. RESULT: We report an more effective and practical method to obtain continuous hypothalamus -pituitary preparations based on the preserve of leptomeninges. COMPARED WITH THE EXISTING METHODS: Our procedure effectively protects the integrity of the fragile infundibulum preventing the pituitary from separating from the hypothalamus. This procedure is more convenient and efficient. CONCLUSION: We present a convenient and practical procedure to obtain intact hypothalamic-pituitary brain specimens for subsequent histopathological evaluation in mice.

Effects of Osmotic Stress on the mRNA Expression of prl, prlr, gr, gh, and ghr in the Pituitary and Osmoregulatory Organs of Black Porgy, Acanthopagrus schlegelii.

In euryhaline teleost black porgy, Acanthopagrus schlegelii, the glucocorticoid receptor (gr), growth hormone receptor (ghr), prolactin (prl)-receptor (prlr), and sodium-potassium ATPase alpha subunit (α-nka) play essential physiological roles in the osmoregulatory organs, including the gill, kidney, and intestine, during osmotic stress. The present study aimed to investigate the impact of pituitary hormones and hormone receptors in the osmoregulatory organs during the transfer from freshwater (FW) to 4 ppt and seawater (SW) and vice versa in black porgy. Quantitative real-time PCR (Q-PCR) was carried out to analyze the transcript levels during salinity and osmoregulatory stress. Increased salinity resulted in decreased transcripts of prl in the pituitary, α-nka and prlr in the gill, and α-nka and prlr in the kidney. Increased salinity caused the increased transcripts of gr in the gill and α-nka in the intestine. Decreased salinity resulted in increased pituitary prl, and increases in α-nka and prlr in the gill, and α-nka, prlr, and ghr in the kidney. Taken together, the present results highlight the involvement of prl, prlr, gh, and ghr in the osmoregulation and osmotic stress in the osmoregulatory organs (gill, intestine, and kidney). Pituitary prl, and gill and intestine prlr are consistently downregulated during the increased salinity stress and vice versa. It is suggested that prl plays a more significant role in osmoregulation than gh in the euryhaline black porgy. Furthermore, the present results highlighted that the gill gr transcript's role was solely to balance the homeostasis in the black porgy during salinity stress.

Association of Homozygous PROP1 Mutation in a Saudi Family with Combined Pituitary Hormone Deficiency.

Background and Objectives: Combined pituitary hormone deficiency (CPHD) is a rare heterogeneous disease. It is characterized by the deficiency of growth hormone (GH) and shortage of at least one or more other hormones of the pituitary gland including thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin. Rare pathogenic variants in nearly 30 genes have been identified as an underlying cause of CPHD pathogenicity. Among these genes, paired-like homeobox 1 (PROP1) has been reported to be the most common cause of CPHD. Materials and Methods: In the present study, we investigated a large family of Saudi origin with three adult sisters suffering from short stature in combination of secondary amenorrhea. Results: Whole-exome sequencing followed by Sanger sequencing shows a homozygous missense variant (NM_006261.5; c.211C > T; p.R71C) in the PROP1 gene segregating with the disease phenotype within the family. In silico analysis studies show that this variant is highly conserved among several orthologues and is predicted as likely pathogenic using various bioinformatics tools. Conclusions: Our finding presents the first Saudi familial case of autosomal recessive form of CPHD caused by the PROP1 variant.