Growth Hormone Deficiency Research Articles

Characterization of Somatotrope Cell Expansion in Response to GHRH in the Neonatal Mouse Pituitary.

In humans and mice, loss-of-function mutations in growth hormone-releasing hormone receptor (GHRHR) cause isolated GH deficiency. The mutant GHRHR mouse model, GhrhrLit/Lit (LIT), exhibits loss of serum GH, but also fewer somatotropes. However, how loss of GHRH signaling affects expansion of stem and progenitor cells giving rise to GH-producing cells is unknown. LIT mice and wild-type littermates were examined for differences in proliferation and gene expression of pituitary lineage markers by quantitative reverse transcription polymerase chain reaction and immunohistochemistry at postnatal day 5 (p5) and 5 weeks. At p5, the LIT mouse shows a global decrease in pituitary proliferation measured by proliferation marker Ki67 and phospho-histone H3. This proliferative defect is seen in a pituitary cell expressing POU1F1 with or without GH. SOX9-positive progenitors show no changes in proliferation in p5 LIT mice. Additionally, the other POU1F1 lineage cells are not decreased in number; rather, we observe an increase in lactotrope cell population as well as messenger RNA for Tshb and Prl. In the 5-week LIT pituitary, the proliferative deficit in POU1F1-expressing cells observed neonatally persists, while the number and proliferative proportion of SOX9 cells do not appear changed. Treatment of cultured pituitary explants with GHRH promotes proliferation of POU1F1-expressing cells, but not GH-positive cells, in a mitogen-activated protein kinase-dependent manner. These findings indicate that hypothalamic GHRH targets proliferation of a POU1F1-positive cell, targeted to the somatotrope lineage, to fine tune their numbers.

Growth Hormone Dosing Estimations Based on Body Weight Versus Body Surface Area

Both body weight (BW)- and body surface area (BSA)-based dosing regimens have been recommended for growth hormone (rhGH) replacement. The aim was to compare the two regimens to determine if either resulted in inadequate treatment depending on anthropometric factors. The retrospective study included children diagnosed with idiopathic isolated growth hormone deficiency. BW-based dosing in mcg/kg/day was converted to BSA in mg/m2/day to determine the equivalent amounts of the given rhGH. Those with a BW-to-BSA ratio of more than 1 were allocated to the “relatively over-dosed group”, while the remaining patients with a ratio of less than 1 were assigned to the “relatively under-dosed” group. Patients with a height gain greater than 0.5 standard deviation score (SDS) at the end of one year were classified as the height gain at goal (HAG), whereas those with a height gain of less than 0.5 SDS were assigned as the height gain not at goal (NHAG). The study included 60 patients (18 girls, 30%). Thirty-six (60%) patients were classified as HAG. The ratio of dosing based on BW-to-BSA was positively correlated both with the ages and body mass index (BMI) levels of the patients, leveling off at the age of 11 at a BMI of 18 kg/m2. The relative dose estimations (over- and under-dosed groups) differed significantly between the patients classified as HAG or NHAG. Fifty-six percent of NHAG compared to 44% of HAG patients received relatively higher doses, while 79% of HAG compared to 21% of NHAG received relatively lower doses (p=0.006). When the patients were subdivided according to their pubertal status, higher doses were administrated mostly to the pubertal patients in both the NHAG and HAG groups. In the pre-pubertal age group, 73% of NHAG compared to 27% of HAG received relatively higher doses, while 25% of NHAG compared to 75% of HAG received relatively lower doses (p=0.01). Dosing based on BW may be preferable in both prepubertal and pubertal children who do not show adequate growth responses. In prepubertal children, relatively lower doses calculated based on BW rather than BSA provide similar efficacy at lower costs.

Growth hormone receptor agonists and antagonists: from protein expression and purification to long-acting formulations.

Recombinant human growth hormone (rhGH) and GH receptor antagonists (GHAs) are used clinically to treat a range of disorders associated with GH deficiency or hypersecretion, respectively. However, these biotherapeutics can be difficult and expensive to manufacture with multiple challenges from recombinant protein generation through to development of long-acting formulations required to improve the circulating half-life of the drug. In this review, we summarise methodologies and approaches used for making and purifying recombinant GH and GHA protein, and strategies to improve pharmacokinetic and pharmacodynamic properties, including PEGylation and fusion proteins. Therapeutics that are in clinical use or are currently under development are also discussed. This article is protected by copyright. All rights reserved.

The Growth Hormone Deficiency (GHD) Reversal Trial: effect on final height of discontinuation versus continuation of growth hormone treatment in pubertal children with isolated GHD—a non-inferiority Randomised Controlled Trial (RCT)

Background Growth hormone deficiency (GHD) is the commonest endocrine cause of short stature and may occur in isolation (I-GHD) or combined with other pituitary hormone deficiencies. Around 500 children are diagnosed with GHD every year in the UK, of whom 75% have I-GHD. Growth hormone (GH) therapy improves growth in children with GHD, with the goal of achieving a normal final height (FH). GH therapy is given as daily injections until adult FH is reached. However, in many children with I-GHD their condition reverses, with a normal peak GH detected in 64–82% when re-tested at FH. Therefore, at some point between diagnosis and FH, I-GHD must have reversed, possibly due to increase in sex hormones during puberty. Despite increasing evidence for frequent I-GHD reversal, daily GH injections are traditionally continued until FH is achieved.Methods/designEvidence suggests that I-GHD children who re-test normal in early puberty reach a FH comparable to that of children without GHD. The GHD Reversal study will include 138 children from routine endocrine clinics in twelve UK and five Austrian centres with I-GHD (original peak GH < 6.7 mcg/L) whose deficiency has reversed on early re-testing. Children will be randomised to either continue or discontinue GH therapy. This phase III, international, multicentre, open-label, randomised controlled, non-inferiority trial (including an internal pilot study) will assess whether children with early I-GHD reversal who stop GH therapy achieve non-inferior near FH SDS (primary outcome; inferiority margin 0.55 SD), target height (TH) minus near FH, HRQoL, bone health index and lipid profiles (secondary outcomes) than those continuing GH. In addition, the study will assess cost-effectiveness of GH discontinuation in the early retesting scenario.DiscussionIf this study shows that a significant proportion of children with presumed I-GHD reversal generate enough GH naturally in puberty to achieve a near FH within the target range, then this new care pathway would rapidly improve national/international practice. An assumed 50% reversal rate would provide potential UK health service cost savings of £1.8–4.6 million (€2.05–5.24 million)/year in drug costs alone. This new care pathway would also prevent children from having unnecessary daily GH injections and consequent exposure to potential adverse effects.Trial registrationEudraCT number: 2020-001006-39

Therapeutic effect of recombinant human growth hormone on children with growth hormone deficiency and different pituitary developmental conditions: a prospective study

To investigate the therapeutic effect of recombinant human growth hormone (rhGH) on children with growth hormone deficiency (GHD) and different pituitary developmental conditions. A prospective study was performed on 90 children with GHD who were admitted to Xuchang Maternity and Child Health Hospital from June 2020 to December 2021. According to pituitary height on the median sagittal plane, they were divided into three groups: pituitary dysplasia group (n=45), normal pituitary group (n=31), and enlarged pituitary growth group (n=14). The changes in body height, growth velocity, height standard deviation score and serum levels of insulin-like growth factor binding protein-3 (IGFBP-3) and insulin-like growth factor-1 (IGF-1) were examined after treatment in the above three groups, and the differences of the above indices before and after treatment were compared among the three groups. After treatment, all three groups had significant increases in body height, growth velocity, height standard deviation score, and the serum levels of IGFBP-3 and IGF-1 (P<0.05). Compared with the normal pituitary group, the pituitary dysplasia group and the enlarged pituitary growth group had significantly higher values in terms of the differences in body height, growth velocity, height standard deviation score, IGF-1, and IGFBP-3 before and after treatment (P<0.05). There was no significant difference in the incidence rate of adverse reactions among the three groups (P>0.05). In GHD children with different pituitary developmental conditions, rhGH can promote bone growth and increase body height, especially in children with pituitary dysplasia and pituitary hyperplasia, with good safety.

Reliability of Agreement between Insulin, Clonidine, and Glucagon Stimulation Tests for the Diagnosis of Growth Hormone Deficiency in Children: A Retrospective Cohort Study.

Growth hormone (GH) deficiency (GHD) is a rare disorder. The diagnosis of GHD requires a combination of two provocative GH tests. This study aimed to find agreement between commonly used medications to determine which combined tests have high reliability of agreement. This retrospective cohort included 201 children who underwent GH provocation testing from January 2012 to December 2022. The insulin tolerance test (ITT) with the clonidine stimulation test (CST) or glucagon stimulation test (GST) with the CST were performed. We calculated Cohen's kappa to determine the agreement between the test medications by considering the post-stimulation peak GH level with a cut-off value of 10 ng/mL as the primary outcome. A total of 151 patients underwent the two provocative tests and were included in the analysis. Of these patients, 119 underwent the ITT and CST and 54 (45.3%) were diagnosed with GHD. However, 32 patients underwent the GST and CST and 18 (56.2%) were diagnosed with GHD. The kappa value for ITT and CST was 0.258 (25.8%), indicating fair agreement between clonidine and insulin (p = 0.005). However, the kappa value for CST and GST was 0.178 (17.8%), representing slight agreement. The correlation coefficient revealed a very strong relationship between ITT and CST. Clonidine has fair agreement and a very strong correlation coefficient with ITT when used to diagnose GHD in children. Among the commonly used pharmacological tests for GH provocation in our unit, the CST was considered the best pharmacological test in terms of safety and reduced parental anxiety.

Occult neurohypophyseal germinoma discovered during the course of long-term diabetes insipidus: illustrative case.

The authors report a case of occult neurohypophyseal germinoma detected in a patient with long-term diabetes insipidus. Central diabetes insipidus is the initial symptom in 95% of cases of neurohypophyseal germinoma. In occult neurohypophyseal germinomas, no abnormalities are seen on magnetic resonance imaging (MRI) at the onset of symptoms. It can take several months or even years for these changes to be detected on MRI. A 20-year-old male was diagnosed with central diabetes insipidus at the age of 17 years, and gonadal and adrenal corticosteroid insufficiency was noted at the age of 19 years. Head MRI showed an enlarged and enhanced pituitary stalk. He was referred to our department for a suspected neoplastic lesion. Endoscopic transsphenoidal biopsy indicated a pure germinoma. He was treated with chemotherapy and radiotherapy and then was discharged. In this case, new imaging findings appeared 19 months after the onset of diabetes insipidus, and the pathological diagnosis was made after almost 24 months. Because the patient had a history of growth hormone deficiency and had a positive test result for diabetes insipidus, occult neurohypophyseal germinoma was suspected, and periodic contrast-enhanced MRI monitoring was deemed essential.

Somatropin for Growth Hormone Deficiency

&#x0D; We identified 2 evidence-based guidelines that provide recommendations for the clinical management of children and adults with growth hormone deficiency.&#x0D; The American Association of Clinical Endocrinologists and American College of Endocrinology guideline provides recommendations on assessment, screening, diagnostic testing, treatment, and monitoring for a range of patients with different causes of adult growth hormone deficiency. The recommendations emphasize accurate diagnosis using appropriate growth hormone cut points for different growth hormone–stimulation tests and careful interpretation of serum growth hormone and insulin-like growth factor-1 levels. Treatment with recombinant human growth hormone should be carried out with consideration of the benefits and risks specific to each individual patient.&#x0D; The Pediatric Endocrine Society guideline provides recommendations for the clinical management of children and adolescents with growth failure due to growth hormone deficiency. The guideline lists various conditions for which growth hormone deficiency can be diagnosed by conventional approaches without growth hormone–stimulation testing. The treatment dose of growth hormone should be calculated based on weight and body surface area and not on insulin-like growth factor-1 levels. The guideline highlights that the initial growth hormone dose, subsequent dosing, and discontinuation of pediatric doses should be assessed based on each individual patient.&#x0D; Both guidelines recognize the uncertainty of long-term safety (i.e., posttreatment effects) of growth hormone treatment, which is a limitation of both guidelines.&#x0D;

Longitudinal assessment of bone health index as a measure of bone health in short-statured children before and during treatment with recombinant growth hormone.

The aim of our study was the longitudinal assessment of bone health index (BHI) in short-statured children during growth hormone (GH) treatment to estimate changes in their bone health. 256 short-statured children (isolated GH deficiency (IGHD) n=121, multiple pituitary hormone deficiency (MPHD) n=49, intrauterine growth retardation (small for gestational age (SGA)) n=52, SHOX (short stature homeobox gene) deficiency n=9, Ullrich Turner syndrome (UTS) n=25) who started with GH between 2010 and 2018 were included. Annual bone ages (Greulich and Pyle, GP) and BHI were, retrospectively, analysed in consecutive radiographs of the left hand (BoneXpert software) from GH therapy start (T0) up to 10 years (T10) thereafter, with T max indicating the individual time point of the last available radiograph. The results are presented as the median (25 %/75 % interquartile ranges, IQR) and statistical analyses were performed using non-parametric tests as appropriate. The BHI standard deviation scores (SDS) were reduced (-0.97,-1.8/-0.3) as bone ages were retarded (-1.6 years,-2.31/-0.97) in all patients before start of GH and were significantly lower in patients with growth hormone deficiency (GHD) (-1.04,-1.85/-0.56; n=170) compared to non-GHD patients (-0.79,-1.56/-0.01; n=86; p=0.022). BHISDS increased to-0.17 (-1/0.58) after 1 year of GH (T1, 0.5-1.49, p<0.001) and to-0.20 (-1/-0.50, p<0.001) after 5.3 years (T max, 3.45/7.25). BHI SDS are reduced in treatment-naive short-statured children regardless of their GH status, increase initially with GH treatment while plateauing thereafter, suggesting sustained improved bone health.

Evaluating the Usefulness and Ease of Use of a Next-Generation-Connected Drug Delivery Device for Growth Hormone Therapy: Qualitative Study of Health Care Professionals' Perceptions.

Digital solutions targeting children's health have become an increasingly important element in the provision of integrated health care. For the treatment of growth hormone deficiency (GHD), a unique connected device is available to facilitate the delivery of recombinant human growth hormone (r-hGH) by automating the daily injection process and collecting injection data such that accurate adherence information is available to health care professionals (HCPs), caregivers, and patients. The adoption of such digital solutions requires a good understanding of the perspectives of HCPs as key stakeholders because they leverage data collection and prescribe these solutions to their patients. This study aimed to evaluate the third generation of the easypod device (EP3) for the delivery of r-hGH treatment from the HCP perspective, with a focus on perceived usefulness and ease of use. A qualitative study was conducted, based on a participatory workshop conducted in Zaragoza, Spain, with 10 HCPs experienced in the management of pediatric GHD from 7 reference hospitals in Spain. Several activities were designed to promote discussion among participants about predefined topics based on the Technology Acceptance Model and the Unified Theory of Acceptance and Use of Technology to provide their perceptions about the new device. Participants reported 2 key advantages of EP3 over previous easypod generations: the touch screen interface and the real-time data transmission functionality. All participants (10/10, 100%) agreed that the new device should be part of a digital health ecosystem that provides complementary functionalities including data analysis. This study explored the perceived value of the EP3 autoinjector device for the treatment of GHD by HCPs. HCPs rated the new capabilities of the device as having substantial improvements and concluded that it was highly recommendable for clinical practice. EP3 will enhance decision-making and allow for more personalized care of patients receiving r-hGH.

Incidence and Predictors for Oncologic Etiologies in Chinese Children with Pituitary Stalk Thickening.

With the increasing use of magnetic resonance imaging (MRI) in the evaluation of children with endocrine disorders, pituitary stalk thickening (PST) poses a clinical conundrum due to the potential for underlying neoplasms and challenges in obtaining a tissue biopsy. The existing literature suggests Langerhans cell histiocytosis (LCH) to be the commonest (16%) oncologic cause for PST, followed by germ cell tumors (GCTs, 13%) (CCLG 2021). As the cancer epidemiology varies according to ethnicity, we present herein the incidence and predictors for oncologic etiologies in Hong Kong Chinese children with PST. Based on a territory-wide electronic database, we reviewed patients aged < 19 years who presented to three referral centers with endocrinopathies between 2010 and 2022. Records for patients who underwent at least one MRI brain/pituitary were examined (n = 1670): those with PST (stalk thickness ≥ 3 mm) were included, while patients with pre-existing cancer, other CNS and extra-CNS disease foci that were diagnostic of the underlying condition were excluded. Twenty-eight patients (M:F = 10:18) were identified. The median age at diagnosis of PST was 10.9 years (range: 3.8-16.5), with central diabetes insipidus (CDI) and growth hormone deficiency (GHD) being the most frequent presenting endocrine disorders. At a median follow-up of 4.8 years, oncologic diagnoses were made in 14 patients (50%), including 13 GCTs (46%; germinoma = 11, non-germinoma = 2) and one LCH (4%). Among patients with GCTs, 10 were diagnosed based on histology, two by abnormal tumor markers and one by a combination of histology and tumor markers. Three patients with germinoma were initially misdiagnosed as hypophysitis/LCH. The cumulative incidence of oncologic diagnoses was significantly higher in boys and patients with PST at presentation ≥6.5 mm, CDI or ≥2 pituitary hormone deficiencies at presentation and evolving hypopituitarism (all p < 0.05 by log-rank). A higher rate of GCTs was observed in Chinese children with endocrinopathy and isolated PST. The predictors identified in this study may guide healthcare providers in Asia in clinical decision making. Serial measurement of tumor markers is essential in management.

Pituitary function before and after surgery for nonfunctioning pituitary adenomas - Data from the Swedish Pituitary Register.

Data on pre- and postoperative pituitary function in nonfunctioning pituitary adenomas (NFPA) are not consistent. We aimed to investigate pituitary function before and up to five years after transsphenoidal surgery with emphasis on the hypothalamic-pituitary-adrenal axis (HPA). Data from the Swedish Pituitary Register was used to analyze anterior pituitary function in 838 patients with NFPA diagnosed between 1991 and 2014. Patients who were reoperated or had received radiotherapy were excluded. Preoperative ACTH, TSH, LH/FSH and GH deficiencies were reported in 31% (236/755), 39% (300/769), 51% (378/742) and 28% (170/604) of the patients, respectively. Preoperative median tumor volume was 5.0 (2.4-9.0) cm3. Amongst patients with preoperative, one year and five years postoperative data on the HPA axis (n=428), 125 (29%) were ACTH-deficient preoperatively. One year postoperatively, 26% (32/125) of them had recovered ACTH function while 23% (70/303) patients had developed new ACTH deficiency. Thus, one year postoperatively 163 (38%) patients were ACTH-deficient (P <0.001 vs. preoperatively). No further increase was seen five years postoperatively (36%, P=0.096). At one year postoperatively recoveries in the TSH- and LH/FSH-axes were reported in 14% (33/241) and 15% (46/310), respectively, and new deficiencies in 22% (88/403) and 29% (83/288), respectively. ACTH deficiency increased significantly at one year postoperatively. Event though not significant, some patients recovered from or developed new deficiency between one and five years postoperatively. This pattern was seen in all axes. Our study emphasizes that continuous individual evaluations are needed during longer follow-up of patients operated for NFPA.

A rare case of SCHMID metaphyseal chondrodysplasia associated with hypothyroidism,growth hormone deficiency and celiac disease: case report.

The authors present a rare case of 4-year-2-month-old boy referred to our Unit for harmonious short stature, he had a waddling gait, subtle micromelia, and hyperlordosis, no special facies. The skeletal scan made the diagnosis of SCHMID metaphyseal chondrodysplasia. The first laboratory workup showed elevated thyroid stimulating hormone and anti-tissue transglutaminase immunoglobulin A. The duodenal biopsies confirmed the diagnosis of coeliac disease. Treatment of levothyroxine was initiated with a gluten-free diet .6 years later, his re-evaluation showed a low insulin-like growth factor 1 and low growth hormone peaks confirming the diagnosis of growth hormone deficiency, Growth hormone therapy was initiated with an adjusted dose of levothyroxine. Other causes of short stature should not be missed when diagnosing chondrodysplasia, and further investigations should be carried out to detect other concomitant disorders since metaphyseal chondrodysplasia is a rare cause for short stature while hypothyroidism and coeliac disease are relatively common.

Endocrine disorders associated with obesity.

Several endocrine disorders, including diabetes, insulinoma, Cushing syndrome, hypothyroidism, polycystic ovarian syndrome, and growth hormone deficiency, are associated with obesity. The mechanisms underlying the development of obesity vary according to the abnormalities of endocrine function. The primary actions of insulin, glucocorticoids (GCs), thyroid hormone, and growth hormone are associated with energy metabolism in the liver, muscle, adipose tissue, and other tissues. This chapter describes the pathogenesis of obesity and metabolic dysfunction associated with excess insulin or GCs and the deficiency of thyroid hormone or growth hormone.

Combined growth hormone stimulation testing: Could the tests be shortened?

IntroductionGrowth hormone stimulation tests (GHST) remain the cornerstone for diagnosing growth hormone deficiency (GHD), yet they can be lengthy and costly. We aimed to examine whether the combined clonidine and glucagon stimulation test (CGST) and l-dopa and glucagon stimulation test (LDGST) can be shortened without compromising the test's specificity. Material and methodsWe retrospectively analyzed the baseline characteristics, auxological and laboratory data of children with short stature who had undergone a CGST and an LDGST for GHD. We compared the diagnostic accuracy for the standard test and shortened test, eliminating time points of 0 and 210 min. ResultsWe reviewed 830 charts (8.17 ± 2.92 years old; 56.27% males), with 431 (57.0%) children in the CGST group, and 38 (51.35%) in the LDGST group who tested negative for GHD. The peak and maximum GH levels occurred at the 60-min time point for both the CGST and LDGST. Eliminating the 0-min time point was the only time that did not affect the specificity of the CGST, with a false-positive rate of 2 (2.99%), specificity of 0.99 (0.99–0.99), and p value of 0.25. Eliminating the 0- and 210-min time points did not affect the specificity of the LDGST, with a false-positive rate of 2 (5.26%), specificity of 0.95 (0.95–0.95), and p value of 0.24. ConclusionsWe concluded that 0-min time point could be eliminated without compromising the combined GHST diagnostic value, thus resulting in cost reduction. Larger studies are needed for the combined LDGST to explore whether the 30- and 210-min time points could be eliminated, thus resulting in cost and time savings.

Hepatomegaly and fatty liver disease secondary to central hypothyroidism in combination with macrosomia as initial presentation of IGSF1 deficiency syndrome.

IGSF1 deficiency syndrome (immunoglobulin superfamily member 1) is considered the most common sex-linked cause of secondary congenital hypothyroidism and is characterized by a wide variety of other clinical and biochemical features, including hypoprolactinemia, transient and partial growth hormone deficiency, early/normal timing of testicular enlargement but delayed testosterone rise in puberty, and adult macro-orchidism. Congenital central hypothyroidism is a rare disease (1:65,000 births); the detection of which may be delayed and missed by neonatal screening programs since most neonatal screening programs are based on TSH determination in dried blood spots only. Untreated hypothyroidism may cause abnormal liver biochemistry and non-alcoholic fatty liver disease. Our aim is to report a case of secondary hypothyroidism in an infant with an uncommon initial presentation. A 3-month-old male baby was referred to our hospital due to elevated alpha-fetoprotein levels, hypercholesterolemia, and macrosomia. Initial investigations revealed enlarged fatty liver and central hypothyroidism. Pituitary insufficiency was biochemically excluded and a pituitary MRI showed normal findings. Upon genetic analysis, a hemizygous variant NM_001170961.1:c.2422dup, p.(His808Profs*14), in IGSF1 gene was detected, establishing the diagnosis of the IGSF1 deficiency syndrome. In our patient, no other clinical findings were identified. Treatment with levothyroxine led to the remission of liver disease. Liver disease may be the initial presentation of secondary hypothyroidism in neonates and infants. Macrosomia in patients with isolated secondary central hypothyroidism is a strong indicator of IGSF1 syndrome.

Retracted: Effect of Vitamin D Combined with Recombinant Human Growth Hormone in Children with Growth Hormone Deficiency.

[This retracts the article DOI: 10.1155/2022/7461958.].

TaqI polymorphism of the vitamin D receptor gene in children with growth hormone deficiency

Background. The nuclear receptor for vitamin D mediates most of the biological functions of this vitamin. It belongs to the steroid hormone receptor family, the gene for which (vitamin D receptor — VDR) is located on chromosome 12q13.1. Genetic variability has been reported in the VDR gene, in which more than 470 single nucleotide polymorphisms have been identified. One of the most common polymorphisms in the VDR gene is rs731236 (TaqI). The purpose was to study the TaqI polymorphism of the VDR gene in children with growth hormone deficiency (GHD). Materials and methods. The TaqI polymorphism of the VDR gene (rs731236) was determined using the polymerase chain reaction, followed by analysis of the length of restriction fragments detected by agarose gel electrophoresis in 28 prepubescent children with GHD. Results. In the group of patients with GHD, the proportion of heterozygotes for T/C TaqI polymorphism of the VDR gene (rs731236) is 1.28 times higher than among healthy individuals. There were 0.68 and 0.90 times fewer patients carrying T/T and C/C genotypes than in the control group. The presence of a homozygous TT genotype increases the risk of developing GHD, but not significantly (odds ratio (OR) = 1.89, 95% confidence interval (CI) 0.66–5.39; p = 0.23), and the presence of a homozygous CC genotype is protective (OR = 0.75, 95% CI 0.17–3.22; p = 0.70). When analyzing alleles in patients with GHD, the following data were obtained: carriage of the T allele for the polymorphic loci TaqI rs731236 of the VDR gene is associated with the risk of GHD (OR = 1.24, 95% CI 0.65–2.36; p = 0.52) but not significantly. The ratio of allele (pТ = 0.554, qС = 0.446) frequencies practically does not differ from 1 : 1, which indicates the preservation of allele frequencies in the Ukrainian population. Conclusions. In children with GHD, the proportion of the T/C genotype is 1.28 times higher than in the group of healthy persons. The presence of a homozygous TT genotype increases the risk of developing GHD but not significantly (OR = 1.89, 95% CI 0.66–5.39; p = 0.23). Carriage of the T allele for the polymorphic locus TaqI rs731236 of the VDR gene is associated with the risk of the growth hormone deficiency (OR = 1.24, 95% CI 0.65–2.36; p = 0.52) but not significantly.

A Novel RNPC3 Gene Variant Expands the Phenotype in Patients with Congenital Hypopituitarism and Neuropathy

Introduction: Pathogenic biallelic RNPC3 variants cause congenital hypopituitarism (CH) with congenital cataracts, neuropathy, developmental delay/intellectual disability, primary ovarian insufficiency, and pituitary hypoplasia. Here, we aimed to evaluate the clinical and molecular characteristics of 2 patients with CH and neuropathy. Materials and Methods: Proband was evaluated by clinical, laboratory, and radiological exams, followed by exome sequencing (ES). Clinical investigation of an affected sibling and variant segregation in the family was performed by Sanger sequencing. A three-dimensional protein model study was conducted to predict the effect of the variant on the function of the RNPC3 peptide. Results: Proband was a 16-month-old girl who was referred for the evaluation of failure to thrive. Her height, weight, and head circumference were 55.8 cm (−7.6 SDS), 6.5 kg (−3.6 SDS), and 41.8 cm (−3.82), respectively. She had a developmental delay and intellectual disability. Central hypothyroidism, growth hormone, and prolactin deficiencies were identified, and MRI revealed pituitary hypoplasia. Electroneuromyography performed for the gait abnormality revealed peripheral neuropathy. A homozygous novel variant c.484C>T/p.(Pro162Ser) in the RNPC3 was detected in the ES. Her brother had the same genotype, and he similarly had pituitary hormone deficiencies with polyneuropathy. Conclusion: Expanding our knowledge of the spectrum of RNPC3 variants, and apprehending clinical and molecular data of additional cases, is decisive for accurate diagnosis and genetic counseling.

Robinow syndrome and its response to growth hormone treatment: a case report and review of the literature.

Robinow syndrome is a rare disease with short stature, characteristic phenotypical abnormalities, and intellectual integrity in most cases. We present the case of a 13-year and one-month-old male who came for medical consultation at 3 years of age due to short stature. Additionally, the patient showed craniofacial dysmorphia, congenital heart disease, and growth hormone deficiency. As per family history, the mother presented the same phenotype. The genetic study identified an unreported variant of the WNT5A gene. The patient initiated growth hormone treatment at a dose of 0.7 U/kg/week at 4 years of age with favorable results, increasing his height from the < 1st percentile to the 44th percentile.