Heterozygous defects in PAX6 gene and congenital hypopituitarism

Takagi, Masaki; Nagasaki, Keisuke; Fujiwara, Ikuma; Ishii, Tomohiro; Amano, Nobuyuki; Asakura, Yumi; Muroya, Koji; Hasegawa, Yukihiro; Adachi, Masanori; Hasegawa, Tomonobu

doi:10.1530/eje-14-0255

Cited by 18 publications

(20 citation statements)

References 26 publications

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“…The authors also reported a second patient with isolated GH deficiency diagnosed at the age of three, and a 310 kb deletion of PAX6 enhancer gene. MRI was normal except for the anterior pituitary, which was hypoplastic (18).…”

Section: Novel Aetiologies Involving Actors Known To Be Associated Wimentioning

confidence: 98%

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 Aetiologies Involving Actors Known To Be Associated Wimentioning

confidence: 98%

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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“…Its expression controls the established sharp boundaries of somatotrope, lactotrope, and thyrotrope cell types, based on the inhibition of SHH ventral signals. There is a wide phenotypic spectrum in PAX6 heterozygous mutation carriers, from severely impaired eye and pituitary development with PSIS to apparently normal phenotype (26).…”

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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“…Congenital hypopituitarism (CH) can be associated with varied eye malformations such as microphthalmia, optic nerve hypoplasia, and coloboma. The reported genetic etiologies of this association include heterozygous loss of function mutations of OTX2, SOX2, BMP4, and PAX6 (2)(3)(4)(5)(6). Optic nerve hypoplasia and retinal coloboma associated with CH have also been described in patients homozygous for mutations of the pituitary transcription factor HESX1 (7,8).…”

mentioning

confidence: 99%

“…Hence, clinically, although CH can be associated with various eye or craniofacial anomalies, the co-occurrence of CH, anophthalmia, cleft palate, and diabetes insipidus has seldom been described (6,10).…”

mentioning

confidence: 99%

Truncating RAX Mutations: Anophthalmia, Hypopituitarism, Diabetes Insipidus, and Cleft Palate in Mice and Men

Brachet

Kozhemyakina

Boros

et al. 2019

The Journal of Clinical Endocrinology &Amp; Metabolism

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ORCiD numbers: 0000-0001-7955-2534 (C. Brachet).Context: The transcription factor RAX is a paired-type homeoprotein that plays a critical role in eye and forebrain development of vertebrate species. RAX knockout mice have anophthalmia, cleft palate, and an abnormal hypothalamus and display perinatal lethality. In humans, homozygous or compound heterozygous RAX mutations have been reported to cause bilateral microphthalmia or anophthalmia without consistent associated features. Congenital hypopituitarism can be associated with various eye or craniofacial anomalies; however, the co-occurrence of congenital hypopituitarism, anophthalmia, cleft palate, and diabetes insipidus has been very rare. Results:We report the case of a child with anophthalmia, congenital hypopituitarism, diabetes insipidus, and bilateral cleft lip and palate who had a homozygous frameshift truncating mutation c.266delC (p.Pro89Argfs*114) in exon 1 of the RAX gene. Rax knockout mice show loss of ventral forebrain structures, pituitary, and basosphenoid bone and palate and a misplaced anterior pituitary gland along the roof of the oral cavity.Conclusions: Our patient's phenotype was more severe than that reported in other patients. Although most of the previously reported patients with RAX mutations showed either a missense or some less severe mutation in at least one of their RAX alleles, our patient was homozygous for truncating mutations that would yield a severe, null protein phenotype. The severity of the genetic defect, the precise match between the knockout mouse and the patient's endocrine phenotypes, and the prominent roles of RAX in eye and pituitary development and diencephalic patterning suggest that the RAX null mutations could fully account for the observed phenotype. (J Clin Endocrinol Metab

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Heterozygous defects in PAX6 gene and congenital hypopituitarism

Cited by 18 publications

References 26 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

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

Truncating RAX Mutations: Anophthalmia, Hypopituitarism, Diabetes Insipidus, and Cleft Palate in Mice and Men

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