Expanding the Spectrum of Mutations in GH1 and GHRHR: Genetic Screening in a Large Cohort of Patients with Congenital Isolated Growth Hormone Deficiency

Alatzoglou, Kyriaki S.; Turton, James; Kelberman, Daniel; Clayton, Peter E.; Mehta, Ameeta; Buchanan, Charles; Aylwin, Simon; Crowne, Elisabeth C.; Christesen, Henrik Thybo; Hertel, Niels Thomas; Trainer, Peter J; Savage, Martin O.; Raza, Jamal; Banerjee, Kausik; Sinha, Sunil; Ten, Svetlana; Mushtaq, Talat; Brauner, Raja; Cheetham, Timothy; Hindmarsh, Peter C.; Mullis, Primus Ε.; Dattani, Mehul

doi:10.1210/jc.2008-2783

Cited by 109 publications

(90 citation statements)

References 35 publications

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“…Our observations confirm the longstanding recommendation that indefinite follow-up for additional pituitary deficiencies is required, even among children currently diagnosed as idiopathic IGHD in routine clinical practice (14). The most frequent additional deficiency observed was TSH deficiency, which may reduce the response to GH therapy (15).…”

Section: Discussionsupporting

confidence: 82%

Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with idiopathic isolated GH deficiency

Blum

Deal

Zimmermann

et al. 2014

European Journal of Endocrinology

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Objective: We assessed the characteristics of children initially diagnosed with idiopathic isolated GH deficiency (IGHD) who later developed additional (multiple) pituitary hormone deficiencies (MPHD). Design: Data were analyzed for 5805 pediatric patients with idiopathic IGHD, who were GH-naïve at baseline and GH-treated in the multinational, observational Genetics and Neuroendocrinology of Short Stature International Study. Methods: Development of MPHD was assessed from investigator diagnoses, adverse events, and concomitant medications. Analyses were performed for all patients and for those who developed MPHD within 4.5 years or had R3.5 years, follow-up and continued to have IGHD (4-year cohort). Results: MPHD developed in 118/5805 (2.0%) children overall, and in 96/1757 (5.5%) in the 4-year cohort. Patients who developed MPHD had more profound GHD, with decreased height SDS, IGF1 SDS and peak stimulated GH, and greater height decrement vs target, compared with children who continued to have IGHD (P!0.001 for each variable). Delivery complications, congenital anomalies, and perinatal/neonatal adverse events occurred more frequently in patients who developed MPHD. The most frequent additional deficiency was TSH (82 patients overall); four patients developed two pituitary hormone deficiencies and one developed three deficiencies. Multivariable logistic regression indicated that years of follow-up (odds ratio 1.55), baseline age (1.17), baseline height SDS (0.69), and peak stimulated GH (0.64) were associated with the development of MPHD. Conclusions: MPHD is more likely to develop in patients with more severe idiopathic IGHD. Older baseline age, lower baseline height SDS, and longer follow-up duration are associated with increased risk of development of MPHD.

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Section: Discussionsupporting

confidence: 82%

Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with idiopathic isolated GH deficiency

Blum

Deal

Zimmermann

et al. 2014

European Journal of Endocrinology

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“…Other causes of CPHD include mutations in GLI3, FGF8, FGFR1, PROKR2, HMGA2, and GRP161 (Table 1). Isolated GHD mutations in the genes encoding GH (GH1) or GH releasing hormone receptor (GHRHR) can be found in up to 34% in familial cases (28). GH1 mutations can either lead to classical GHD (types IA, IB, and II) or bioinactive GH syndrome.…”

Section: Genetic Defects Of the Gh-insulin-like Growth Factor 1 Axismentioning

confidence: 99%

“…GH1 mutations can either lead to classical GHD (types IA, IB, and II) or bioinactive GH syndrome. While in the past the latter diagnosis was used without good experimental evidence, recent reports have shown that this is a real condition, characterized by normal or even elevated circulating GH levels, and in some cases also associated with partial GHI (28,29,30).…”

Section: Genetic Defects Of the Gh-insulin-like Growth Factor 1 Axismentioning

confidence: 99%

“…However, several other aberrations of GH1 have been described. The less severe type IB GHD is caused by mutations of GH1 or GHRHR, and a dominant form of GHD (type II) is usually caused by skipping of exon 3 resulting in production of a 17.5-kDa isoform of GH with a dominant negative effect (28). The X-linked type III GHD is associated with agammaglobulinaemia, and has been associated with mutations in BTK (31) and SOX3 (32).…”

Section: Gh Deficiencymentioning

confidence: 99%

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MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Wit

Oostdijk

Losekoot

et al. 2016

European Journal of Endocrinology

141

132

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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 NFkB 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 T 3 /T 4 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 w3% 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.

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“…All patients of this study were either Hindus or from an inbred Moor community. In a large series of growth hormone deficient patients of multiple ethnicities, only 3.7% carried GHRH-R mutations [9]. Among them codon 72 mutation was the commonest being present in eight patients from two Asian and one Somalian pedigree in homozygosity and in two patients from one Asian pedigree in compound heterozygosity.…”

Section: Growth Hormone (Gh) Is Under Stimulatory and Inhibitory Contmentioning

confidence: 99%

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

et al. 2016

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

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Expanding the Spectrum of Mutations in GH1 and GHRHR: Genetic Screening in a Large Cohort of Patients with Congenital Isolated Growth Hormone Deficiency

Abstract: IGHD patients with severe growth failure and a positive family history should be screened for genetic mutations; the evolving endocrinopathy observed in some of these patients suggests the need for long-term follow-up.

Cited by 109 publications

References 35 publications

Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with idiopathic isolated GH deficiency

Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with idiopathic isolated GH deficiency

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

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

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