Novel Lethal Form of Congenital Hypopituitarism Associated With the First Recessive<i>LHX4</i>Mutation

Gregory, LC; Humayun, Khadija Nuzhat; Turton, James; McCabe, Mark J.; Rhodes, Simon J.; Dattani, Mehul

doi:10.1210/jc.2014-4484

Cited by 30 publications

(15 citation statements)

References 19 publications

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“…The family reported by Gregory et al (12) carried a novel homozygous missense variant (c.377COT, p.T126M): two children died after 3 weeks of age with severe panhypopituitarism despite optimal replacement therapy; the patients were also carrying mid-facial hypoplasia and lung anomalies. Surprisingly, functional studies, performed in an in vitro heterologous system, did not reveal any difference with WT LHX4 in the activation of target promoters.…”

Section: Novel Mode Of Transmissionmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

Castinetti¹,

Reynaud²,

Saveanu³

et al. 2016

European Journal of Endocrinology

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Over the last 5 years, new actors involved in the pathogenesis of combined pituitary hormone deficiency in humans have been reported: they included a member of the immunoglobulin superfamily glycoprotein and ciliary G protein-coupled receptors, as well as new transcription factors and signalling molecules. New modes of inheritance for alterations of genes encoding transcription factors have also been described. Finally, actors known to be involved in a very specific phenotype (hypogonadotroph hypogonadism for instance) have been identified in a wider range of phenotypes. These data thus suggest that new mechanisms could explain the low rate of aetiological identification in this heterogeneous group of diseases. Taking into account the fact that several reviews have been published in recent years on classical aetiologies of CPHD such as mutations of POU1F1 or PROP1, we focused the present overview on the data published in the last 5 years, to provide the reader with an updated review on this rapidly evolving field of knowledge.

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Section: Novel Mode Of Transmissionmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

Castinetti¹,

Reynaud²,

Saveanu³

et al. 2016

European Journal of Endocrinology

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“…Of note, 4 patients also presented respiratory distress [20][21][22] and one presented heart defect [21]. A recent reported homozygous mutation has been associated with a lethal phenotype (severe panhypopituitarism associated with pituitary aplasia and posterior ectopia, mild facial hypoplasia, undescended testes and respiratory distress) [22]. In a very large cohort of 417 unrelated patients with hypopituitarism the prevalence of LHX4 mutations was 1.4 % [23].…”

Section: Hypopituitarism With Cerebellar Abnormalities And/or Lung Dementioning

confidence: 99%

“…In humans, 15 sporadic or familiar LHX4 mutations have been reported with variable hypopituitarism (ranging from isolat-ed GH deficiency to complete panhypopituitarism) [15] and brain abnormalities (pituitary hypoplasia, ectopic posterior pituitary and poorly developed sella turcica as well as corpus callosum hypoplasia or Chiari syndrome) [12,[16][17][18][19]. Of note, 4 patients also presented respiratory distress [20][21][22] and one presented heart defect [21]. A recent reported homozygous mutation has been associated with a lethal phenotype (severe panhypopituitarism associated with pituitary aplasia and posterior ectopia, mild facial hypoplasia, undescended testes and respiratory distress) [22].…”

Section: Hypopituitarism With Cerebellar Abnormalities And/or Lung Dementioning

confidence: 99%

Congenital Hypopituitarism: Various Genes, Various Phenotypes

et al. 2019

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The ontogenesis and development of the pituitary gland is a highly complex process that depends on a cascade of transcription factors and signaling molecules. Spontaneous mutations and transgenic murine models have demonstrated a role for many of these factors, including HESX1, PROP1, PIT1, LHX3, LHX4, SOX2, SOX3, OTX2, PAX6, FGFR1, SHH, GLI2, and FGF8 in the etiology of congenital hypopituitarism. Genetic mutations in any of these factors can lead to congenital hypopituitarism, which is characterized by the deficiency in one or more pituitary hormones. The phenotype can be highly variable, consisting of isolated hypopituitarism or more complex disorders. The same phenotype can be attributed to different gene mutations; while a given gene mutation can induce different phenotypes. This review highlights the genetic variations that lead to congenital hypopituitarism and their associated defects. The overall incidence of mutations in known transcription factors in patients with hypopituitarism is low; therefore many gene mutations or even gene- epigenetic interactions have to be unraveled in the future to explain the vast majority of still unclear cases of congenital hypopituitarism.

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“…In addition, patients display abnormalities in the sella turcica of the central skull base, severe respiratory disease, and hypoglycemia. A homozygous mutation of LHX4 is associated with a lethal form of congenital hypopituitarism (Gregory et al, ). The patients are born small for gestational age with a small phallus, undescended testes, and mid‐facial hypoplasia, and died within the first week of life.…”

Section: Introdutionmentioning

confidence: 99%

Generation and characterization of Lhx4^tdT reporter knock‐in and Lhx4^loxP conditional knockout mice

Dong

Xie

Guo

et al. 2019

Genesis

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LHX4 is a LIM-homeodomain transcription factor essential for the development of spinal cord and pituitary gland. Mice with homozygous Lhx4-null mutation suffer early postnatal death from lung defect. In this study, to facilitate the research on Lhx4 function, we designed a targeting construct to generate two novel Lhx4 mouse lines:Lhx4 loxP conditional knockout and Lhx4 tdT reporter knock-in mice. Lhx4 tdT/+ , Lhx4 loxP/+ , and Lhx4 loxP/loxP were viable, fertile, and did not display any gross abnormalities.By breeding Lhx4 loxP line with Cre-expressing mice, the Exon 3 of Lhx4 was efficiently removed, resulting in a shift in the reading frame and the inactivation of Lhx4. The expression of tdTomato knock-in reporter recapitulated the endogenous LHX4 expression and was detected in the retina, spinal cord, pituitary gland, and hindbrain of Lhx4 tdT mice. Thus, Lhx4 tdT and Lhx4 loxP mouse lines provide valuable tools for unraveling the tissue-specific role of Lhx4 at postnatal stages in mice. K E Y W O R D S homeobox, LIM-homeodomain, pituitary gland, retina, spinal cord

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Novel Lethal Form of Congenital Hypopituitarism Associated With the First RecessiveLHX4Mutation

Abstract: We report, for the first time to our knowledge, a novel homozygous mutation in LHX4 associated with a lethal phenotype, implying that recessive mutations in LHX4 may be incompatible with life.

Cited by 30 publications

References 19 publications

MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

Congenital Hypopituitarism: Various Genes, Various Phenotypes

Generation and characterization of Lhx4^tdT reporter knock‐in and Lhx4^loxP conditional knockout mice

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Novel Lethal Form of Congenital Hypopituitarism Associated With the First RecessiveLHX4Mutation

Abstract: We report, for the first time to our knowledge, a novel homozygous mutation in LHX4 associated with a lethal phenotype, implying that recessive mutations in LHX4 may be incompatible with life.

Cited by 30 publications

References 19 publications

MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

Congenital Hypopituitarism: Various Genes, Various Phenotypes

Generation and characterization of Lhx4tdT reporter knock‐in and Lhx4loxP conditional knockout mice

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Product

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Generation and characterization of Lhx4^tdT reporter knock‐in and Lhx4^loxP conditional knockout mice