Cause Of Growth Hormone Deficiency Research Articles

Beyond the bias! Sex distribution in paediatric growth hormone deficiency reexamined.

Various biases pertaining to stature account for a male sex predominance in growth hormone deficiency (GHD) cases diagnosed by endocrinology clinics. This manuscript will assess the sex distribution when biases are minimised. Retrospective chart review was conducted on patients diagnosed with GHD between 3 and 16 years of age. The sex distribution of cases was ascertained according to: (1) peak GH (pGH) by groups; based on growth hormone provocative testing, (2) pituitary gland imaging results, and (3) isolated GHD (IGHD) versus multiple pituitary hormone deficiencies (MPHD). The relative frequency of each sex was compared according to these subgroups with significance evaluated at α = .05 level. Of the 5880 clinic referrals for short stature, there were 3709 boys (63%) and 2171 girls (37%). Of these, 20% of boys (n = 745) and 15.3% of girls (n = 332) underwent provocative testing for GHD. Of those tested, 39.2% of boys (n = 292) and 32.2% of girls (n = 107) were diagnosed with GHD, all p < .001. There was a male predominance in GHD cases based on pGH or GHD severity. Though not significant, girls were more likely than boys to have MPHD (p = .056), even across pGH groups (p = .06). Both boys and girls had a similar distribution of imaging abnormalities. Stratifying by sex, we found similar percentages of pituitary imaging abnormalities (including tumours) and the number of pituitary hormone deficiencies in boys and girls as the cause of GHD. For these classifications, we did not find the historically reported male sex predominance.

Clinical and laboratory characteristics but not response to treatment can distinguish children with definite growth hormone deficiency from short stature unresponsive to stimulation tests.

It has been proposed that not all children with short stature displaying an inadequate response to tests for growth hormone (GH) secretion truly suffer from GH deficiency (GHD). Only children with a monogenic cause of GHD or an identifiable combined hormonal deficiency or anatomical anomaly in the hypothalamic-pituitary axis should be considered definite GHD (dGHD). The remaining patients can be defined as a separate group of patients, "short stature unresponsive to stimulation tests" (SUS). The aim of this proof-of-concept study, was to assess whether SUS patients treated with rhGH exhibit any differences compared to GHD patients undergoing the same treatment. Retrospective analysis on 153 consecutive patients with short stature and pathological response to two GH stimulation tests. Patients with dGHD were defined as those with a clear genetic or anatomical hypothalamic-pituitary anomaly, as well as those with combined pituitary hormone deficiencies and those with a known insult to the hypothalamic-pituitary axis (i.e. total brain irradiation) (n=38, 25%); those without any of the previous anomalies were defined as SUS (n=115, 75%). At diagnosis, dGHD and SUS populations did not differ significantly in sex (F 32% vs 28%, p=0.68), age (11.9 vs 12.1, p=0.45), height SDS at diagnosis (-2.2 vs. -2.0, p=0.35) and prevalence of short stature (height <-2 SDS) (56% vs 51%, p=0.45). IGF-1 SDS were significantly lower in dGHD (-2.0 vs -1.3, p<0.01). After 1 year of treatment, the prevalence of short stature was significantly reduced in both groups (31% in dGHD vs. 21% in SUS, p<0.01) without any significant differences between groups (p=0.19), while the increase in IGF-1 SDS for bone age was greater in the dGHD category (+1.9 vs. +1.5, p<0.01), with no further difference in IGF-1 SDS between groups. At the last available follow-up, 59 patients had reached the near adult height (NAH) and underwent retesting for GHD. No differences in NAH were found (-0.3 vs. -0.4 SDS, 0% vs. 4% of short stature). The prevalence of pathological retesting was higher in dGHD (60% vs. 10%, p<0.01) as well as of overweight and obesity (67% vs. 26%). Stimulation tests and the equivalent benefit from rhGH therapy, cannot distinguish between dGHD and SUS populations. In addition, lower IGF-1 concentrations at baseline and their higher increase during treatment in dGHD patients, and the lack of pathological retesting upon reaching NAH in SUS patients, are facts that suggest that deficient GH secretion may not be the cause of short stature in the SUS studied population.

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

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. 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. 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. 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.

FRI340 Growth Hormone Deficiency Post Carbon Monoxide Poisoning

Abstract Disclosure: A.Y. Ghamlouche: None. O. Alzohaili: None. A.H. Elkadry: None. Carbon monoxide (CO) is the poisonous byproduct of combustion of fossil fuels, that is odorless and tasteless. In toxic levels CO leads to the impaired functioning of red blood cell’s ability to transport oxygen to tissues.1 Following CO toxicity, white matter demyelination and necrosis of the Globus pallidus that further results in other neurologic disorders, is common.2 A novel and underrecognized consequence of CO poisoning is growth hormone deficiency (GHD). GHD is the most common pituitary hormone deficiency following a traumatic brain injury.3 Four cases of GHD were described following an event of CO poisoning. Recommended GHD diagnosis criteria of less than 5.0 ng/mL was used with these patients. The Insulin Tolerance Test (ITT) and Glucagon stimulation test (GST) were administered. All patients had no causes of GHD in their medical history prior to their encounters with CO poisoning. A 44-year-old male with exposure in 2020, came for an evaluation in January of 2022 complaining of memory impairment, brain fog, mental fatigue, cognitive decline, anxiety, poor libido, and neuropathy. showed a GH peak of 1.1 ng/mL during the ITT a peak of 1.0 ng/mL during the GST. A 51-year-old male with exposure in 2016, came for an evaluation in December of 2020 complaining of memory impairment, blurry vision, fatigue, physical weakness, mood changes, and stuttered speech. Results showed a GH peak of 4.4 ng/mL during ITT and a GH peak of 0.157 ng/mL during the GST.A 43-year-old female with exposure in 2017, came for an evaluation in January of 2022 complaining of memory loss, attention issues, anxiety, depression, fatigue, weight gain and neuropathy. Results showed a GH peak of 1.7 ng/mL during ITT and a GH peak of 2.6 ng/mL during the GST. A 42-year-old male with exposure in 2018, came for an evaluation in November of 2019 complaining of memory impairment, headaches, tremors, fatigue, anxiety, depression, declining cognition, insomnia, poor libido, lack of concentration, and poor vision. Results showed a GH peak of 3.6 ng/mL during ITT and a GH peak of 0.109 ng/mL during the GST. All 4 patients were started on GH replacement therapy following their tests. All patients responded well, and showed significant improvements in quality of life. A possible connection can be drawn between pituitary gland damage and hypoxia from CO poisoning.

Growth hormone (GH) deficiency and GH replacement therapy in patients previously treated for Cushing's disease.

Several complications associated with active Cushing's disease may persist even years after complete and successful therapeutic remission of hypercortisolism. Growth hormone deficiency (GHD) shares many clinical features seen in patients with Cushing's disease, and its presence after disease remission (GHD-CR) might negatively influence and potentially worsen the systemic complications caused by previous hypercortisolism. GHD-CR is more prevalent in women, and compared to other causes of GHD, patients are younger at the onset of the pituitary disease, at diagnosis of GHD-CR and at start of GH therapy; prevalence of pituitary macroadenomas and visual abnormalities are lower, while prevalence of diabetes, hypertension, low bone mass, fractures, and worst quality of life, are higher. Serum IGF-1 levels are not useful for the diagnosis of GHD-CR and the application of GH stimulating tests requires some special attention in addition to the general recommendations for detecting GHD from other etiologies. In patients with active hypercortisolism, GH secretion is completely suppressed, but it may spontaneously and progressively recover over the years following successful therapy, meaning that GH testing may be performed at an appropriate time after remission for the correct diagnosis. Moreover, if the patient presents concomitant adrenal insufficiency, GH testing should only be carried out under adequate cortisol replacement therapy. GH therapy in children with GHD-CR improves adult height in the majority of patients, while GH therapy in adults has been associated with improvements in body composition, lipid profile and quality of life, but also with worsening of glucose metabolism.

Evaluation of Growth Hormone Deficiency in Children with Cystic Fibrosis.

Background:Due to chronic respiratory and gastrointestinal problems, growth failure is a common issue in patients with cystic fibrosis (CF). The present study aimed to investigate the prevalence of growth hormone deficiency (GHD) in CF children with stable gastrointestinal and respiratory conditions.Materials and Methods:In this study, the growth indicators of all 4–16-year-old children referred to two CF clinics were monitored over 3 years. Children without severe gastrointestinal or pulmonary symptoms with weight <3% percentile or whose height increase were two standard deviations below their expected height growth over 6 months were selected for the growth hormone (GH) stimulation test by clonidine and L-dopa test. Some of the children without CF, who were also referred for height growth disorders and matched the CF group, were considered the control group. They underwent the GH stimulation test, and the results were compared.Results:From 150 patients with CF, growth failure was observed in 24 patients with stable gastrointestinal and respiratory conditions; in 10 of them, the GH stimulation test was deficient. The prevalence of GHD was 6.6% in CF patients. In the control group of 30 children without CF, but with growth failure, the GH was deficient in nine cases, implying no significant difference with the case group (P = 0.37).Conclusion:In our study, the prevalence of GHD was 6.6% in CF patients, whereas the prevalence GHD in the normal population of childhood is <1%. Therefore, further studies should be designed to investigate the cause of GHD in CF patients.

Kearns-Sayre syndrome – rare cause of growth hormone deficiency

Kearns-Sayre syndrome – rare cause of growth hormone deficiency

MON-LB014 Autosomal Dominant Growth Hormone Deficiency Due to a Novel c.178g&amp;gt;A Mutation in the GH1 Gene Is Caused by Alternative Splicing to Produce a Small GH Isoform

Introduction: Growth hormone (GH) plays a vital role in human physiology. Mutations in GH1 cause isolated growth hormone deficiency (GHD). The most frequent cause of familial growth hormone deficiency is Type II autosomal dominant GHD (isolated GHD type II) due to several heterozygous GH1 mutations. These mutations have been shown to (a) produce shorter isoforms of GH that do not bind to growth hormone receptors, (b) cause diminished secretion of GH, or (c) result in misfolded GH protein. Methods: Genomic DNA from patients with familial GHD was enriched for the coding exons using hybrid capture technology, and GH1 was sequenced using Next Generation Sequencing technology. The p.A34T mutant protein was expressed in bacteria, and binding to GHR was studied by surface plasmon resonance technology. Computational prediction of transcription indicated that alternative splicing is likely to produce a shorter GH variant with skipping of exon 3 in GH1. Mammalian cell-based studies incorporating transfection of whole GH1 gene containing exons/introns were used to study transcriptional effects. RNA was isolated from cells transfected with WT and mutant GH1 gene and analyzed by RT PCR using primers in the second and fifth exons of GH1 that could identify all possible isoforms of GH1 mRNA. Results: GHD was identified in three female siblings aged 3.25-6.33 years (Ht SDS -3.21 to -1.13, peak GH 2.9-6.6 ng/mL); their mother had previously been diagnosed with GHD at age 12.33 years (Ht SDS -3.44, GH peak < 2 ng/mL). Sequencing of GH1 identified a novel heterozygous variant (c.178G>A; p.Ala34Thr) not found in the Broad ExAc dataset representing >60,000 children without the severe childhood-onset disease. Functional studies using whole gene transfection showed that the c.178G>A mutation leads to alternate splicing resulting in increased production of the shorter 17.5kD isoform of GH due to exon 3 skipping. Results were confirmed by quantitative RT-PCR as well as GH secretion assays, which showed a lower level of GH production from cells transfected with the GH1 gene containing the c.178G>A mutation. The SPR based receptor binding assay and cell proliferation assay using bacterially expressed proteins showed that once produced, the GH protein with the A34T mutation behaves similar to WT GH protein. All these results confirm that the cause of GHD due to the c.178G>A mutation in GH1 is due to altered transcription leading to the production of the shorter 17.5 kD isoform of GH protein and not due to the amino acid change A34T that is caused by the mutation. Conclusion: The presence of a heterozygous GH1 variant (c.178G>A, p.Ala34Thr) in four individuals with GHD suggests that this is a novel cause of IGHD type II. Production of the smaller 17.5 kD GH isoform results in reduced overall GH secretion and loss of binding to GHR due to competition with the normal GH protein, explaining the dominant-negative phenotype.

SAT-LB19 Is There a Need to Use Gadolinium Contrast for Pituitary MRI in the Evaluation of Pediatric Short Stature and Growth Hormone Deficiency?

SAT-LB19 Is There a Need to Use Gadolinium Contrast for Pituitary MRI in the Evaluation of Pediatric Short Stature and Growth Hormone Deficiency?

Autosomal Dominant Growth Hormone Deficiency Due to a Novel c.178G&gt;A Mutation in the GH1 Gene is Caused by Alternative Splicing to Produce a Small GH Isoform

IntroductionGrowth hormone (GH) is a member of the somatotropin/prolactin family of hormones and plays a vital role in human physiology. Mutations in GH1 cause isolated growth hormone deficiency. Several disease‐causing mutations have been reported in patients with IGHD. The most frequent cause of familial growth hormone deficiency (GHD) is Type II autosomal dominant GHD (isolated GHD type II) due to several heterozygous GH1 mutations. These mutations have been shown to (a) produce shorter isoforms of GH that do not bind to growth hormone receptors, (b) cause diminished secretion of GH, or (c) result in misfolded GH protein.MethodsGenomic DNA from patients with familial GHD was enriched for the coding exons using hybrid capture technology, and GH1 was sequenced. The p.A34T mutant protein was expressed in bacteria, and binding to GHR was studied by Surface Plasmon Resonance technology. Computational prediction of transcription indicated that alternative splicing is likely to produce a shorter GH variant with skipping of exon 3 in GH1. Mammalian cell‐based studies incorporating transfections of the whole GH1 gene containing all exons and introns, were used to study transcriptional effects. RNA was isolated from cells transfected with WT and mutant GH1 gene and analyzed by RT PCR using primers in the second and fifth exons of GH1 that could identify all possible isoforms of GH1 mRNA.ResultsGHD was identified in three female siblings aged 3.25–6.33 years (Ht SDS −3.21 to −1.13, peak GH 2.9–6.6 ng/mL); their mother had previously been diagnosed with GHD at age 12.33 years (Ht SDS −3.44, GH peak &lt; 2 ng/mL). Sequencing of GH1 identified a novel heterozygous variant (c.178G&gt;A; p.Ala34Thr) not found in the Broad ExAc dataset representing &gt;60,000 children without the severe childhood‐onset disease. Functional studies using whole gene transfection showed that the c.178G&gt;A mutation leads to alternate splicing resulting in increased production of the shorter 17.5kD isoform of GH due to exon 3 skipping. Results were confirmed by quantitative RT‐PCR as well as GH secretion assays, which showed a lower level of GH production from cells transfected with the GH1 gene containing the c.178G&gt;A mutation. The SPR based receptor binding assay and cell proliferation assay using bacterially expressed proteins showed that once produced, the GH protein with the A34T mutation behaves similar to WT GH protein. All these results confirm that the cause of GHD due to the c.178G&gt;A mutation in GH1 is due to altered transcription leading to the production of the shorter 17.5 kD isoform of GH protein and not due to the amino acid change A34T that is caused by the mutation.ConclusionThe presence of a heterozygous GH1 variant (c.178G&gt;A, p.Ala34Thr) in four individuals with GHD suggests that this is a novel cause of IGHD type II. Production of the smaller 17.5 kD GH isoform results in reduced overall GH secretion and loss of binding to GHR due to competition with the normal GH protein, explaining the dominant‐negative phenotype.Support or Funding InformationUnrestricted research grants from Novo Nordisk AG, &amp; Sandoz Pharmaceuticals AG, Switzerland.

Ectopic neurohypophysis: an unusual cause of growth hormone deficiency

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Incidence and Outcomes of Pituitary Microadenomas in Children with Short Stature/Growth Hormone Deficiency

Background/Aims: Patients with short stature (SS)/growth hormone deficiency (GHD) and precocious puberty (PP) undergo brain MRI to evaluate for structural brain abnormalities or pituitary lesions, and pituitary microadenomas are a common finding. Theoretically, a mass effect from these lesions could cause GHD and growth hormone treatment could cause them to enlarge, but they should not cause PP, at least in females. Methods: We investigated if pituitary microadenomas cause GHD by comparing their incidence in patients with SS/GHD to that in females with PP. We performed a retrospective chart review of patients with these disorders who had a brain MRI between 2000 and 2013. Results: The incidence of microadenoma was high in both groups, 18.5% for SS (n = 346) and 21.1% for PP females (n = 194), but did not differ between groups (p = 0.46). In patients with microadenomas, repeat imaging showed resolution in 58% (SS, n = 33) and 67% (PP females, n = 21). Importantly, none of the lesions grew, even in patients treated with growth hormone. Conclusions: Pituitary microadenomas are common in children with GHD/SS and PP, but it does not appear that they are a cause of GHD. They appear to be of limited clinical significance and should not be considered a contraindication to growth hormone therapy.

Serum Lipid and Leptin Concentrations in Patients with Sheehan Syndrome.

Background:Sheehan syndrome (SS) refers to the occurrence of hypopituitarism after parturition. Hypopituitary adults with growth hormone (GH) deficiency have abnormal body composition with increased fat mass. As leptin is secreted almost exclusively by fat cells and the circulating leptin level is proportional to total fat mass, it is expected that abnormal elevations of leptin concentrations are found in GH deficient hypopituitary patients. The present study was undertaken to evaluate the anthropometric, lipid and leptin levels in patients with SS.Materials and Methods:Thirty patients with SS and 30 age and body mass index (BMI) matched controls were part in this study. All patients were stable on conventional replacement therapy for at least 6 months before the study. The subjects underwent detail clinical, biochemical, and hormone analysis.Results:Patients with SS on conventional replacement therapy showed significantly higher mean triglyceride, total cholesterol, low density lipoprotein cholesterol and lower high density cholesterol concentrations. The leptin levels were significantly raised in the patients with SS on standard replacement therapy compared with controls. The difference was more marked in obese cases versus obese controls than in lean cases and controls (P = 0.001).Conclusion:SS, a cause of GH deficiency. Our study demonstrated that patients with SS have an abnormal lipid profile, and raised leptin levels as compared to age and BMI matched controls.

Postoperative growth hormone dynamics in clinically nonfunctioning pituitary adenoma.

Growth hormone deficiency (GHD) is an endocrine disorder characterized by insufficient production of growth hormone (GH). Non-functioning pituitary adenoma (NFPA) is one of common causes of GHD. Although most patients with NFPA have transsphenoidal surgery, the time-dependent changes in GH after operation have yet to be investigated. In this study, we analyzed patients with NFPAs that underwent transsphenoidal surgery. Postoperatively, GH secretion was evaluated in response to GH-releasing peptide-2 (GHRP2) infusion. We also investigated how several factors affected GH dynamics. Of 119 patients analyzed, 94 (79.0%) had peak GH levels less than 9.0 ng/mL and were diagnosed with severe GHD (sGHD) immediately after surgery. Of those patients, 27 (28.7%) recovered from sGHD within 1-2 years after surgery. Univariate analyses confirmed that sGHD recovery improved significantly in patients that were younger, had only undergone a single primary surgery, had not had anterior hormone deficiency except GH, and had cystic adenoma or normal insulin-like growth factor-1 (IGF1) standard deviation score (SD-S) levels immediately after surgery. Multivariate analyses confirmed that younger age and absence of hormone replacement therapy significantly predicted sGHD recovery within 1-2 years after surgery. Taken together, our results indicated that postoperative sGHD should be assessed by GHRP2 infusion, regardless of IGF1 SD-S levels. Furthermore, recovery from sGHD occurs more frequently at 1-2 years after surgery especially in younger patients and/or those with GH deficiency alone. These patients, therefore, should be reassessed for GHD by appropriate tests including GHRP2 test at 1-2 years after surgery.

Lessons from monogenic causes of growth hormone deficiency

Through the multicentric international GENHYPOPIT network, 10 transcription factor genes involved in pituitary development have been screened in more than 1200 patients with constitutional hypopituitarism over the past two decades. The present report summarizes the main lessons learned from this phenotype-based genetic screening: (1) genetically determined hypopituitarism does not necessarily present during childhood; (2) constitutional hypopituitarism may be characterized by a pure endocrine phenotype or by various combinations of endocrine deficits and visceral malformations; (3) syndromic hypopituitarism may also be observed in patients with POU1F1 or PROP1 mutations; (4) in cases of idiopathic hypopituitarism, extensive genetic screening identifies gene alterations in a minority of patients; (5) functional studies are imperfect in determining the involvement of an allelic variant in a specific pituitary phenotype.

Growth hormone releasing hormone receptor codon 72 mutation in a cohort of Sri Lankan patients with growth hormone deficiency.

Growth hormone releasing hormone receptor (GHRH-R) codon 72 mutation is recognised as a common genetic cause of growth hormone deficiency (GHD) in the Indian subcontinent resulting in a characteristic lean phenotype. Genetic studies have not been previously carried out in Sri Lankans with GHD. Patients with GHD presenting to a tertiary care referral centre were studied for GHRH-R codon 72 mutation by PCR amplification and sequencing. The phenotype of the cohort was described as the BMI SDS (Body mass index standard deviation score) based on the anthropometric data at the time of diagnosis. Among 91 patients from 88 families studied, eight (6 boys) carried the codon 72 mutation. The presence of this mutation was low among the Sinhalese ethnicity (3 out of 68) than among Tamil and Moor ethnicities. BMI SDS of <-2 was seen in 71% of mutation positive and 45.8% of mutation negative patients. Prevalence of GHRH-R codon 72 mutation in this group of GH deficient patients was 8.8%. The lean phenotype observed in 71% of the mutation positive patients was not a significant association when compared to a similar phenotype in 45.8% of the mutation negative patients.

GPR101 Mutations are not a Frequent Cause of Congenital Isolated Growth Hormone Deficiency.

Patients with Xq26.3 microduplication present with X-linked acrogigantism (X-LAG) syndrome, an early-childhood form of gigantism due to marked growth hormone (GH) hypersecretion from mixed GH-PRL adenomas and hyperplasia. The microduplication includes GPR101, which is upregulated in patients' tumor tissue. The GPR101 gene codes for an orphan G protein coupled receptor that is normally highly expressed in the hypothalamus. Our aim was to determine whether GPR101 loss of function mutations or deletions could be involved in patients with congenital isolated GH deficiency (GHD). Taking advantage of the cohort of patients from the GENHYPOPIT network, we studied 41 patients with unexplained isolated GHD. All patients had Sanger sequencing of the GPR101 gene and array comparative genome hybridization (aCGH) to look for deletions. Functional studies (cell culture with GH secretion measurements, cAMP response) were performed. One novel GPR101 variant, c.589 G>T (p.V197L), was seen in the heterozygous state in a patient with isolated GHD. In silico analysis suggested that this variant could be deleterious. Functional studies did not show any significant difference in comparison with wild type for GH secretion and cAMP response. No truncating, frameshift, or small insertion-deletion (indel) GPR101 mutations were seen in the 41 patients. No deletion or other copy number variation at chromosome Xq26.3 was found on aCGH. We found a novel GPR101 variant of unknown significance, in a patient with isolated GH deficiency. Our study did not identify GPR101 abnormalities as a frequent cause of GH deficiency.

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature.

The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFκB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T3/T4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in ∼3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.

Growth hormone deficiency after mild combat-related traumatic brain injury.

Traumatic brain injury (TBI) has been recognized as a cause of growth hormone deficiency (GHD) in civilians. However, comparable data are sparse in veterans who incurred TBI during combat. Our objective was to determine the prevalence of GHD in veterans with a history of combat-related TBI, and its association with cognitive and psychosocial dysfunction. Single center prospective study. Twenty male veterans with mild TBI incurred during combat 8-72 months prior to enrollment. GHD was defined by a GH peak <3 μg/L during glucagon stimulation test. Differences in neuropsychological, emotional, and quality of life of the GHD Veterans were described using Cohen's d. Large effect sizes were considered meaningful. Mean age was 33.7 years (SD 7.8) and all subjects had normal thyroid hormone and cortisol levels. Five (25%) exhibited a subnormal response to glucagon. Sixteen participants (80%) provided sufficient effort for valid neuropsychological assessment (12 GH-sufficient, 4 GHD). There were large effect size differences in self-monitoring during memory testing (d = 1.46) and inhibitory control (d = 0.92), with worse performances in the GHD group. While fatigue and post-traumatic stress disorder were comparable, the GHD group reported more depression (d = 0.80) and lower quality of life (d = 0.64). Our study found a 25% prevalence of GHD in veterans with mild TBI as shown by glucagon stimulation. The neuropsychological findings raise the possibility that GHD has adverse effects on executive abilities and mood. Further studies are needed to determine whether GH replacement is an effective treatment in these patients.

Glucagon Stimulation Testing in Adult Growth Hormone Deficiency— A 2014 Update

Growth hormone deficiency (GHD) is a well-recognized clinical syndrome in adults, and its diagnosis is established through one or more GH stimulation tests. The decision to perform GH stimulation testing should be based on medical history and clinical findings, and using appropriate GH stimulation test/s for biochemical confirmation. The insulin tolerance test (ITT) remains the diagnostic test of choice; however, this test is labor intensive, contraindicated in the elderly and in adults with seizure disorders and ischemic heart disease, can be unpleasant for the patient, and is potentially hazardous. With the discontinuation of the growth hormone releasing hormone (GHRH) analog (Geref®) in the US in 2008, the glucagon stimulation test (GST) has gained increasing popularity as the alternative test to the ITT because of its availability, reproducibility, safety, lack of influence by gender and hypothalamic cause of GH deficiency (GHD), and relatively few contraindications. In this article, recommendations for performing this test, the potential drawbacks in conducting and caveats in interpreting this test, and its future perspectives are discussed.