Molecular screening of a large cohort of Moroccan patients with congenital hypopituitarism

Fritez, Nabila; Sobrier, Marie-Laure; Iraqi, H.; Vié-Luton, Marie-Pierre; Netchine, Irène; Annas, Abdessamad El; Pantel, Jacques; Collot, Nathalie; Rose, Sophie; Piterboth, William; Legendre, M.; Chraibi, A.; Amselem, Serge; Kadiri, A.; Hilal, Latifa

doi:10.1111/cen.12706

Cited by 15 publications

(15 citation statements)

References 38 publications

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“…However, genetic counselling remains a challenge due to variable phenotypes with incomplete penetrance and wide spectrum of anterior pituitary dysfunctions ranging from isolated deficiency to evolving panhypopituitarism. To date, several cohorts of patients with hypopituitarism have been reported from national registries 3‐5,8‐10,24 or international studies 7 . However, few provided detailed phenotypic description of CPHD patients 4,7,8 .…”

Section: Discussionmentioning

confidence: 99%

“…Genetic screening of these transcription factors using a phenotype‐based strategy represents a rational way to identify aetiology of CPHD. However, defects in any of these genes have been found to date in a minority of such patients in national or international cohorts 2‐10 …”

Section: Introductionmentioning

confidence: 99%

“…However, defects in any of these genes have been found to date in a minority of such patients in national or international cohorts. [2][3][4][5][6][7][8][9][10] The GENHYPOPIT network is a multicentre study in international paediatric and adult endocrinology centres. It was launched to screen pituitary transcription factor genes and enrolled patients with primary hypopituitarism over the past two decades.…”

Section: Introductionmentioning

confidence: 99%

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Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort

Jullien

Saveanu

Vergier

et al. 2020

Clinical Endocrinology

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ContextThe international GENHYPOPIT network collects phenotypical data and screens genetic causes of non‐acquired hypopituitarism.AimsTo describe main phenotype patterns and their evolution through life.DesignPatients were screened according to their phenotype for coding sequence variations in 8 genes: HESX1, LHX3, LHX4, PROP1, POU1F1, TBX19, OTX2 and PROKR2.ResultsAmong 1213 patients (1143 index cases), the age of diagnosis of hypopituitarism was congenital (24%), in childhood (28%), at puberty (32%), in adulthood (7.2%) or not available (8.8%). Noteworthy, pituitary hormonal deficiencies kept on evolving during adulthood in 49 of patients. Growth Hormone deficiency (GHD) affected 85.8% of patients and was often the first diagnosed deficiency. AdrenoCorticoTropic Hormone deficiency rarely preceded GHD, but usually followed it by over 10 years. Pituitary Magnetic Resonance Imaging (MRI) abnormalities were common (79.7%), with 39.4% pituitary stalk interruption syndrome (PSIS). The most frequently associated extrapituitary malformations were ophthalmological abnormalities (16.1%). Prevalence of identified mutations was 7.3% of index cases (84/1143) and 29.5% in familial cases (n = 146). Genetic analysis in 449 patients without extrapituitary phenotype revealed 36 PROP1, 2 POU1F1 and 17 TBX19 mutations.ConclusionThis large international cohort highlights atypical phenotypic presentation of constitutional hypopituitarism, such as post pubertal presentation or adult progression of hormonal deficiencies. These results justify long‐term follow‐up, and the need for systematic evaluation of associated abnormalities. Genetic defects were rarely identified, mainly PROP1 mutations in pure endocrine phenotypes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort

Jullien

Saveanu

Vergier

et al. 2020

Clinical Endocrinology

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“…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%

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Wit

Oostdijk

Losekoot

et al. 2016

European Journal of Endocrinology

153

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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“…In contrast to sporadic cases, familial subjects from all countries should undergo genetic analysis if possible. In these familial cases, the likelihood of detecting a mutation within any of the transcription factor genes is much higher [ 10 – 16 , 19 , 20 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic screening of regulatory regions of pituitary transcription factors in patients with idiopathic pituitary hormone deficiencies

et al. 2017

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PurposeMutation frequencies of PROP1, POU1F1 and HESX1 in patients with combined pituitary hormone deficiencies (CPHD) vary substantially between populations. They are low in sporadic CPHD patients in Western Europe. However, most clinicians still routinely send DNA of their CPHD patients for genetic screening of these pituitary transcription factors. Before we can recommend against screening of PROP1, POU1F1 and HESX1 as part of routine work-up for Western-European sporadic CPHD patients, it is crucial to rule out possible defects in regulatory regions of these genes, which could also disturb the complex process of pituitary organogenesis.MethodsThe regulatory regions of PROP1, POU1F1 and HESX1 are not covered by Whole Exome Sequencing as they are largely located outside the coding regions. Therefore, we manually sequenced the regulatory regions, previously defined in the literature, of PROP1, POU1F1 and HESX1 among 88 Dutch patients with CPHD. We studied promoter SNPs in relation to phenotypic data.ResultsWe found six known SNPs in the PROP1 promoter. In the POU1F1 promoter, we found one new variant and two known SNPs. We did not find any variant in the HESX1 promoter.ConclusionAlthough the new POU1F1 variant might explain the phenotype of one patient, the general conclusion of this study is that variants in regulatory regions of PROP1, POU1F1 and HESX1 are rare in patients with sporadic CPHD in the Netherlands. We recommend that genetic screening of these pituitary transcription factors should no longer be part of routine work-up for Western-European, and especially Dutch, sporadic CPHD patients.Electronic supplementary materialThe online version of this article (10.1007/s11102-017-0850-6) contains supplementary material, which is available to authorized users.

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Molecular screening of a large cohort of Moroccan patients with congenital hypopituitarism

Cited by 15 publications

References 38 publications

Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort

Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Genetic screening of regulatory regions of pituitary transcription factors in patients with idiopathic pituitary hormone deficiencies

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