scholarly journals Clinical and genetic features of patients with multiple anterior pituitary hormone deficiency caused by mutations in the PROP1 gene; the efficacy of recombinant growth hormone therapy

2017 ◽  
Vol 63 (2) ◽  
pp. 72-81 ◽  
Author(s):  
Anna E. Gavrilova ◽  
Elena V. Nagaeva ◽  
Tatiana Yu. Shiryaeva ◽  
Olga Yu. Rebrova ◽  
Anatoly N. Tiulpakov ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Gh Deficiency ◽  
Final Height ◽  
Gene Mutations ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Recombinant Growth Hormone ◽  
Secondary Hypothyroidism ◽  
Prop1 Gene ◽  
Secondary Hypogonadism

Rationale. One of the most common causes of multiple anterior pituitary hormone deficiency (MPHD) is genetic defects in the PROP1 gene. PROP1 deficiency leads to malfunction of somatotrophs, lactotrophs, thyrotrophs, corticotrophs, and gonadotrophs. Now, there is an opportunity to conduct large-scale population studies of patients with genetic MPHD, describe their clinical and genetic heterogeneity, and evaluate the efficacy of long-term therapy of these patients with a recombinant growth hormone (rGH). Aim. The study aim was to assess the spectrum of PROP1 gene mutations in the Russian population of MPHD patients, rate and expected age of hypopituitarism components, and efficacy of rGH therapy. Material and methods. We analyzed the data of 27 patients diagnosed with MPHD and genetically confirmed mutations in the PROP1 gene who were treated at the Institute of Pediatric Endocrinology of the Endocrinology Research Center (ERC) in 1978―2016. MPHD was diagnosed based on laboratory data and stimulatory tests characterizing the functional activity of the pituitary gland. The molecular genetic study was performed using high-performance parallel sequencing. We used a custom Ampliseq_HP primer panel developed at the Department of Hereditary Endocrinopathies of the ERC, which included coding regions of the following genes: ARNT2, GH1, GHRH, GHRHR, GHSR, GLI2, HESX1, LHX3, LHX4, OTX2, PAX6, POU1F1, PROP1, SHH, SOX2, and SOX3. All patients received rGH therapy at a growth-stimulating dose from the time of GH deficiency diagnosis until final height completion. We evaluated the efficacy of therapy by comparing the achieved final height with the genetically expected one. Results. Non-familial cases prevailed (N=23) in the study cohort of patients with MPHD caused by mutations in the PROP1 gene; only two patients were monochorionic twin sisters; the other two patients were siblings. An analysis of the distribution of PROP1 gene mutations revealed a hot-point mutation c.301_302delAG in 24 patients (89%, 95% CI 71%; 98%). A mutation in the c.150delA locus occurred in 11 patients (41%, 95% CI 22%; 61%). Two patients had other mutations (c.629delC and c.43_49delGGGCGAG). Total GH deficiency was detected in all patients. The rate of secondary hypothyroidism (SHT) in patients of the study sample was 78% (95% CI 58%; 91%) at the time of diagnosis of GH deficiency and 100% (95% CI 81%; 100%) at the time of final height. The rate of secondary hypogonadism (SHG) at the time of final height was 100% (95% CI 81%; 100%), and the rate of secondary hypocorticism (SHC) was 41% (95% CI 22%; 61%). The normal level of prolactin was detected in 83% (95% CI 65%; 94%) of patients. At the time of growth plate closure, patients receiving rGH therapy at the growth-stimulating dose achieved the genetically expected final height. Conclusion. According to our findings, the most common mutation in the PROP1 gene is a deletion of AG nucleotides in the 101 codon (c.301_302 delAG), which is found in 89% (95% CI 71%; 98) patients. Patients with MPHD caused by mutations in the PROP1 gene have total GH deficiency and are diagnosed with secondary hypothyroidism and secondary hypogonadism in 100% of cases. The possibility of delayed manifestation of hypopituitarism components requires regular screening of tropic hormone levels for the timely start of substitution therapy and prevention of life-threatening conditions. rGH therapy is highly effective for GH deficiency caused by PROP1 gene mutations and allows patients to achieve the genetically expected height in the case of early diagnosis of growth hormone deficiency.

scholarly journals Genetic background of inherited multiple pituitary hormone deficiency. Mutations of PROP1 gene in Hungary

2011 ◽  
Vol 152 (6) ◽  
pp. 221-232
Author(s):  
Zita Halász
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Deficiency ◽  
Mutational Analysis ◽  
Hot Spot ◽  
Gene Mutations ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Multiple Pituitary Hormone Deficiency ◽  
Pituitary Hormone Deficiency ◽  
Prop1 Gene

In this work I analysed the outcome of growth hormone replacement treatment in patients with inherited form of multiple pituitary hormone deficiency and examined diseased-causing mutations of pituitary transcription factor genes which may underlie this disorder. The results showed that after treatment for a longer than 7-year period with a growth hormone preparation available under well-controlled distribution, the mean height of children with growth hormone deficiency reached the normal national reference range adjusted for age and sex. After establishment of clinical criteria for screening PROP1 gene mutations, I performed mutational analysis of all coding exons of this gene in 35 patients with inherited form of multiple pituitary hormone deficiency. With these studies, diseases-causing PROP1 gene mutations were detected in 15 of the 35 patients (43%). It was also found that more than 80% of mutant alleles were accounted for by those containing the 150delA and 301-302delGA mutations of the PROP1 gene. Importantly, these findings indicated a high relevance of mutational ”hot spots” of the PROP1 gene in Hungarian patients with inherited form of multiple pituitary hormone deficiency and they also offered an opportunity for the development of rational and cost-effective screening strategy. When clinical and hormonal findings of patients with and without PROP1 gene mutations were compared, results showed that growth hormone deficiency was diagnosed at earlier age of life in patients with PROP1 gene mutations, but the severity of growth retardation at the time of diagnosis of growth hormone deficiency or the age of patients at the time of manifestation of other pituitary hormone deficiencies (TSH, LH, FSH and ACTH) were similar in the two groups of patients. In 15 patients inherited form of multiple pituitary hormone deficiency who had no PROP1 gene mutations, exon 6 of the POU1F1 gene containing a mutational ”hot spot” was also examined but no mutations were found. Thus, these results do not support a significant role of the mutational ”hot spot” of the POU1F1 gene in Hungarian patients with inherited form of multiple pituitary hormone deficiency. Finally, I introduced a method for the detection of mutations of the PITX2 gene, a pituitary transcription factor that plays a role not only in pituitary development and differentiation but also in the lateralization of organs. With the use of this method, I performed mutational analysis of all coding exons of this gene in an exceptionally unique patient who had both situs inversus totalis and inherited form of multiple pituitary hormone deficiency, but no mutation was found. Thus, the findings in this patient failed to indicate that mutation of the PITX2 gene is involved in the pathomechanism of situs inversus totalis associated with inherited form of multiple pituitary hormone deficiency. Orv. Hetil., 2011, 152, 221–232.

Growth hormone replacement for patients with adult onset growth hormone deficiency—what have we learned?

2004 ◽  
Vol 16 (4) ◽  
pp. 1-6
Author(s):  
Monique Piersanti
Keyword(s):  
Growth Hormone ◽  
Gh Deficiency ◽  
Hormone Replacement ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Adult Onset ◽  
Gh Replacement ◽  
Term Benefit

Growth hormone (GH) deficiency is a condition recognized to occur in individuals who have had multiple pituitary hormone deficiencies as a result of pathological processes or neurosurgical interventions. The indications, benefits, and risks of GH replacement therapy will be reviewed with an emphasis on those patients who were adults with the deficiency first emerged. The results of this analysis indicate that, although a measurable improvement can be detected in the patient's quality of life, body composition, and some cardiovascular parameters, the larger questions of long-term benefit and patient selection currently remain unanswered.

scholarly journals Final height in isolated GH deficiency type 1A: effects of 5-year treatment with IGF-I

2001 ◽  
pp. 379-383 ◽  
Author(s):  
MF Messina ◽  
F De Luca ◽  
M Wasniewska ◽  
M Valenzise ◽  
F Lombardo ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Gh Deficiency ◽  
Final Height ◽  
Phenotypic Expression ◽  
Hormone Deficiency ◽  
Target Height ◽  
Igf I ◽  
Puberty Onset ◽  
The One ◽  
Deficiency Type

Data concerning final height (FH) in isolated growth hormone deficiency type 1A (IGHD1A) are scanty and controversial. In this paper we report the FH outcome of two girls with IGHD1A who were treated either with GH only (first patient) or with GH during the first 8 years and successively with IGF-I (second patient). In the first patient, FH was only slightly subnormal and slightly taller with respect to target height (TH). Surprisingly, FH was severely subnormal and very far from TH in the patient who underwent IGF-I therapy for >5 years: an auxological outcome similar to the one recently reported in the only two cases in the literature of patients with IGHD1A who have been treated with IGF-I until near FH achievement. We conclude that IGHD1A could have a very heterogeneous phenotypic expression in terms of FH and that IGF-I therapy, even though initiated some years before puberty onset and prolonged for more than 5 years, may not be able to ensure the normalization of height prognosis and the achievement of an FH close to TH.

scholarly journals Four Novel Mutations of the LHX3 Gene Cause Combined Pituitary Hormone Deficiencies with or without Limited Neck Rotation

2007 ◽  
Vol 92 (5) ◽  
pp. 1909-1919 ◽  
Author(s):  
Roland W. Pfaeffle ◽  
Jesse J. Savage ◽  
Chad S. Hunter ◽  
Christina Palme ◽  
Martina Ahlmann ◽  
...  
Keyword(s):  
Dna Binding ◽  
Gh Deficiency ◽  
Gene Activation ◽  
Gene Mutations ◽  
Biochemical Properties ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Molecular Defects ◽  
Recessive Mutations ◽  
Neck Rotation

Abstract Context: The Lhx3 LIM-homeodomain transcription factor gene is required for development of the pituitary and motoneurons in mice. Human LHX3 gene mutations have been reported in five subjects with a phenotype consisting of GH, prolactin, TSH, LH, and FSH deficiency; abnormal pituitary morphology; and limited neck rotation. Objective: The objective of the study was to determine the frequency and nature of LHX3 mutations in patients with isolated GH deficiency or combined pituitary hormone deficiency (CPHD) and characterize the molecular consequences of mutations. Design: The LHX3 sequence was determined. The biochemical properties of aberrant LHX3 proteins resulting from observed mutations were characterized using reporter gene and DNA binding experiments. Patients: The study included 366 patients with isolated GH deficiency or CPHD. Results: In seven patients with CPHD from four consanguineous pedigrees, four novel, recessive mutations were identified: a deletion of the entire gene (del/del), mutations causing truncated proteins (E173ter, W224ter), and a mutation causing a substitution in the homeodomain (A210V). The mutations were associated with diminished DNA binding and pituitary gene activation, consistent with observed hormone deficiencies. Whereas subjects with del/del, E173ter, and A210V mutations had limited neck rotation, patients with the W224ter mutation did not. Conclusions: LHX3 mutations are a rare cause of CPHD involving deficiencies for GH, prolactin, TSH, and LH/FSH in all patients. Whereas most patients have a severe hormone deficiency manifesting after birth, milder forms can be observed, and limited neck rotation is not a universal feature of patients with LHX3 mutations. This study extends the known molecular defects and range of phenotypes found in LHX3-associated diseases.

scholarly journals Molecular analysis of the PROP1 and HESX1 genes in patients with septo-optic dysplasia and/or pituitary hormone deficiency

2010 ◽  
Vol 54 (5) ◽  
pp. 482-487 ◽  
Author(s):  
Juliana B. Cruz ◽  
Vania S. Nunes ◽  
Sueli A. Clara ◽  
Denise Perone ◽  
Peter Kopp ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Genetic Alterations ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Pituitary Hormone Deficiency ◽  
Exon 1 ◽  
Genetic Mechanisms ◽  
Direct Sequence Analysis ◽  
Prop1 Gene ◽  
Pathogenic Process

OBJECTIVE: The present study aimed at evaluating the PROP1 and HESX1 genes in a group of patients with septo-optic dysplasia (SOD) and pituitary hormone deficiency (combined - CPHD; isolated GH deficiency - GHD). Eleven patients with a clinical and biochemical presentation consistent with CPHD, GHD or SOD were evaluated. SUBJECTS AND METHODS: In all patients, the HESX1 gene was analyzed by direct sequence analysis and in cases of CPHD the PROP1 gene was also sequenced. RESULTS: A polymorphism (1772 A > G; N125S) was identified in a patient with SOD. We found three patients carrying the allelic variants 27 T > C; A9A and 59 A > G; N20S in exon 1 of the PROP1 gene. Mutations in the PROP1 and HESX1 genes were not identified in these patients with sporadic GHD, CPHD and SOD. CONCLUSION: Genetic alterations in one or several other genes, or non-genetic mechanisms, must be implicated in the pathogenic process.

scholarly journals Partial Loss of Function of the GHRH Receptor Leads to Mild Growth Hormone Deficiency

2016 ◽  
Vol 101 (10) ◽  
pp. 3608-3615 ◽  
Author(s):  
Louise Cheryl Gregory ◽  
Kyriaki Sandy Alatzoglou ◽  
Mark James McCabe ◽  
Peter Christopher Hindmarsh ◽  
Jose William Saldanha ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Deficiency ◽  
Gh Deficiency ◽  
Final Height ◽  
Fold Increase ◽  
Hormone Deficiency ◽  
Loss Of Function ◽  
Partial Loss ◽  
Mild Phenotype ◽  
Partial Activity

Objective: Recessive mutations in GHRHR are associated with severe isolated growth hormone deficiency (IGHD), with a final height in untreated patients of 130 cm ± 10 cm (−7.2 ± 1.6 SDS; males) and 114 ± 0.7 cm (−8.3 ± 0.1 SDS; females). Design: We hypothesized that a consanguineous Pakistani family with IGHD in three siblings (two males, one female) would have mutations in GH1 or GHRHR. Results: Two novel homozygous missense variants [c.11G>A (p.R4Q), c.236C>T (p.P79L)] at conserved residues were identified in all three siblings. Both were absent from control databases, aside from pR4Q appearing once in heterozygous form in the Exome Aggregation Consortium Browser. The brothers were diagnosed with GH deficiency at 9.8 and 6.0 years (height SDS: −2.24 and −1.23, respectively), with a peak GH of 2.9 μg/liter with low IGF-1/IGF binding protein 3. Their sister presented at 16 years with classic GH deficiency (peak GH <0.1 μg/liter, IGF-1 <3.3 mmol/liter) and attained an untreated near-adult height of 144 cm (−3.0 SDS); the tallest untreated patient with GHRHR mutations reported. An unrelated Pakistani female IGHD patient was also compound homozygous. All patients had a small anterior pituitary on magnetic resonance imaging. Functional analysis revealed a 50% reduction in maximal cAMP response to stimulation with GHRH by the p.R4Q/p.P79L double mutant receptor, with a 100-fold increase in EC50. Conclusion: We report the first coexistence of two novel compound homozygous GHRHR variants in two unrelated pedigrees associated with a partial loss of function. Surprisingly, the patients have a relatively mild IGHD phenotype. Analysis revealed that the pP79L mutation is associated with the compromise in function, with the residual partial activity explaining the mild phenotype.

Growth hormone-releasing activity of growth hormone-releasing peptide-1 (a synthetic heptapeptide) in children and adolescents

1993 ◽  
Vol 129 (5) ◽  
pp. 424-426 ◽  
Author(s):  
Zvi Laron ◽  
Cyril Y Bowers ◽  
Daniel Hirsch ◽  
Antonio Selman Almonte ◽  
Moshe Pelz ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Children And Adolescents ◽  
Normal Values ◽  
Gh Deficiency ◽  
Clinical Applications ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Pituitary Insufficiency ◽  
Healthy Children ◽  
Plasma Prolactin

The heptapeptide growth hormone-releasing peptide-1 (GHRP-1 ), one of a series of recently synthesized small growth hormone (GH)-releasing peptides, was administered as an iv bolus (1 μg/kg) to 15 (six prepubertal, nine pubertal) short but healthy children and adolescents and to eight juvenile patients with pituitary insufficiency (four with isolated growth hormone deficiency, two with multiple pituitary hormone deficiencies, one with partial GH deficiency and one with GH-releasing hormone (GHRH) deficiency). Eleven out of 23 subjects also underwent an iv GHRH (1–29) test (1 μg/kg). All the healthy children responded with a progressive rise in plasma human GH (hGH) peaking at 15–30 min, with a significantly higher rise (p<0.05) in the pubertal than prepubertal group. The hGH response to GHRH (1–29) in these children was similar or slightly higher. Six hypopituitary patients had no response to either GHRP-1 or GHRH; the patient with partial GH deficiency had a hGH peak of 6.5 μg/l (at 5 min) to GHRP-1 and 9.2 μg/l (at 1 5 min) to GHRH. One patient had no response of hGH to hypoglycemia, clonidine and GHRP-1, but the plasma hGH rose to 10 μg/l after GHRH. Following the GHRP-1 bolus there was a significant (p <0.01) rise in plasma free thyroxine and a decrease of thyrotropin (p <0.01), both in the limits of normal values. There was also a transitory rise of plasma cortisol (p <0.05). Plasma prolactin, luteinizing hormone and follicle-stimulating hormone did not change. It is concluded that GHRP-1 is a potent GH-releasing drug because it acts also when administered orally and has great pharmaceutical and clinical applications.

scholarly journals Growth hormone - 20 years of clinical practice

2011 ◽  
Vol 57 (1) ◽  
pp. 71-79
Author(s):  
E V Nagaeva
Keyword(s):  
Growth Hormone ◽  
Intrauterine Growth Retardation ◽  
Final Height ◽  
Dna Recombination ◽  
Hormone Deficiency ◽  
Recombinant Growth Hormone ◽  
Intrauterine Growth ◽  
Pathological Conditions ◽  
System Therapy

Recombinant growth hormone (rGH) synthesized by the DNA recombination technology is available commercially since 1985. The advent of this product has greatly promoted a wider application of growth hormone therapy throughout the world and gave a powerful impetus to the investigations of its clinical efficiency, improved dosing schedules and methods of administration, facilitated reaching a final height, resulted in marked amelioration of the patients' quality of life, and extended the range of indications for the use of growth hormone preparations. A vast experience with the clinical use of rGH for the treatment of a variety of pathological conditions has been gained for the last 20 years. These include growth hormone deficiency in children and adults, syndromal and idiopathic short stature, intrauterine growth retardation, chronic renal insufficiency, juvenile idiopathic arthritis, and diseases of the hematopoietic system. Therapy with recombinant growth hormone is generally recognized to be efficacious and safe although the experience with its application for the treatment of certain diseases is insufficient and further accumulation of relevant data is needed.

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