Contribution of LHX4 Mutations to Pituitary Deficits in a Cohort of 417 Unrelated Patients

Cohen, Enzo; Maghnie, Mohamad; Collot, Nathalie; Léger, Juliane; Dastot, Florence; Polak, Michel; Rose, Sophie; Touraine, Philippe; Duquesnoy, Philippe; Tauber, Maïté; Copin, Bruno; Bertrand, Anne Marie; Brioude, Frédéric; Larizza, Daniela; Edouard, Thomas; Briceño, Laura González; Netchine, Irène; Oliver‐Petit, Isabelle; Sobrier, Marie-Laure; Amselem, Serge; Legendre, M.

doi:10.1210/jc.2016-3158

Cited by 22 publications

(19 citation statements)

References 36 publications

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“…There were no other changes reported for this gene, which is not surprising since other mutations are ultrarare and contribute to a minority of patients (5,32). The other disruptive variants affecting POU1F1, LHX3, and LHX4, contribute only occasionally to the pituitary phenotype (33)(34)(35).…”

Section: Discussionmentioning

confidence: 83%

SEMA3A and IGSF10 Are Novel Contributors to Combined Pituitary Hormone Deficiency (CPHD)

et al. 2020

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Background: The mutation frequencies of pituitary transcription factors genes in patients with combined pituitary hormone deficiencies (CPHD) vary substantially between populations. However, apart from PROP1 the mutation rate of other genes is low and for almost half of the patients with CPHD the routine sequencing of known genes is unsuccessful in the identification of genetic causes.Methods: A cohort of 66 sporadic and nine familial CPHD cases (80 patients in total) were subjected to initial testing of the genes PROP1, POU1F1, LHX3, LHX4, and HESX1 using a targeted gene panel and MLPA. In patients who tested negative, a whole exome sequencing approach was employed.Results: In nine of the familial cases and 32 of the sporadic patients mutations in the PROP1 gene were found (the common pathogenic variants included c.301_302delAG and c.150delA). Mutations were also found in genes so far not related directly to CPHD. A unique homozygous and clinically relevant variant was identified in the SEMA3A gene, which may contribute to neural development and his phenotypic spectrum including short stature and isolated hypogonadotropic hypogonadism (IHH). Another pathogenic variant p.A1672T was found in the IGSF10 gene reported to be responsible for delayed puberty and neuronal migration during embryogenesis. Several suspected novel but predicted benign variants were also identified for the CHD7, WDR11 and FGF17 genes. Conclusion:Although PROP1 defects account for a majority of CPHD patients, identification of rare, less frequent variants constitutes a big challenge. Multiple genetic factors responsible for CPHD are still awaiting discovery and therefore the usage of efficient genomic tools (i.e., whole exome sequencing) will further broaden our knowledge regarding pituitary development and function.

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Section: Discussionmentioning

confidence: 83%

SEMA3A and IGSF10 Are Novel Contributors to Combined Pituitary Hormone Deficiency (CPHD)

et al. 2020

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“…Genetic alteration of LHX4, involved in pituitary primordium ontogenesis (Rathke's pouch), is responsible for phenotypical variability: LHX4 mutations were found to be associated with variable expressivity, and most of them with incomplete penetrance and variable pituitary hormone deficiencies and MRI abnormalities (17,27,28). Heterozygous mutations causing LHX4 haploinsufficiency are responsible for PSIS with poorly developed sella turcica, inconstant pituitary hypoplasia and brain malformations (27).…”

Section: Single Pituitary-specific Genesmentioning

confidence: 99%

DIAGNOSIS OF ENDOCRINE DISEASE: Pituitary stalk interruption syndrome: etiology and clinical manifestations

Vergier

Castinetti

Saveanu

et al. 2019

European Journal of Endocrinology

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Pituitary stalk interruption syndrome (PSIS) is a congenital pituitary anatomical defect. This syndrome is an antenatal developmental defect belonging to the holoprosencephaly phenotype spectrum. It is heterogeneous regarding clinical, biological and radiological presentation and is characterized by the following triad: thin (<1 mm) or interrupted pituitary stalk connecting the hypothalamus to the pituitary gland, no eutopic posterior lobe, and hypoplasia or aplasia of the anterior lobe. This review reports current knowledge about the composite pathogenesis, for which underlying mechanisms remain unclear. Current data suggest genetic origins involving early developmental gene mutations with complex inheritance patterns and environmental influence, placing PSIS at the crossroads between Mendelian and multifactorial diseases. The phenotype associated with PSIS is highly heterogeneous with a high incidence of various combinations of hormonal deficiencies, sometimes associated with extra-pituitary birth defects. The age at onset is variable, but typical presentation is evolutive combined anterior pituitary hormone deficiencies at pediatric age, which progress even during adulthood to panhypopituitarism. Therefore, patients’ follow-up throughout life is essential for adequate management.

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“…In another study, heterozygous missense mutations in LHX4 resulting in the substitution of amino acids resulted in GH deficiency, +/-reductions in LH, TSH, FSH or ACTH and aberrant pituitary morphology [25]. Screening of 417 unrelated patients with isolated growth hormone deficiency or combined protein deficiency associ-ated with ectopic posterior pituitary and/or sella turcica anomalies demonstrated seven heterozygous variations in LHX4 [26].…”

Section: Lhx3 and Lhx4mentioning

confidence: 98%

Genetic causes of hypopituitarism

Parkin

Kapoor

Bhat

et al. 2020

aoms

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Hypopituitarism in neonates is rare, but has life-threatening complications if untreated. This review describes the features of hypopituitarism and the evidence for which infants in whom a genetic cause should be suspected. Importantly, neonates are often asymptomatic or present with non-specific symptoms. Hypopituitarism can be due to abnormal gland development as a result of genetic defects, which result from mutations in gene coding for transcription factors which regulate pituitary development. The mutations can be divided into those causing isolated hypopituitarism or those causing syndromes with associated hypopituitarism. The latter involve mutations in transcription factors which regulate pituitary, as well as extra-pituitary development. There is a paucity of evidence as to which patients should be investigated for genetic mutations, but detailed clinical and biochemical phenotyping with magnetic resonance imaging of the pituitary gland could help target those in whom genetic investigations would be most appropriate.

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Contribution of LHX4 Mutations to Pituitary Deficits in a Cohort of 417 Unrelated Patients

Cited by 22 publications

References 36 publications

SEMA3A and IGSF10 Are Novel Contributors to Combined Pituitary Hormone Deficiency (CPHD)

SEMA3A and IGSF10 Are Novel Contributors to Combined Pituitary Hormone Deficiency (CPHD)

DIAGNOSIS OF ENDOCRINE DISEASE: Pituitary stalk interruption syndrome: etiology and clinical manifestations

Genetic causes of hypopituitarism

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