A Novel Missense Mutation (P366T) of the LHX4 Gene Causes Severe Combined Pituitary Hormone Deficiency with Pituitary Hypoplasia, Ectopic Posterior Lobe and a Poorly Developed Sella Turcica

Tajima, Toshihiro; Hattori, Tsukasa; Nakajima, Takeo; Okuhara, Koji; Tsubaki, Junko; Fukui, Kenji

doi:10.1507/endocrj.k06-200

Cited by 55 publications

(28 citation statements)

References 24 publications

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“…7 In addition, ectopic posterior pituitary lobe has been reported in subjects with lim homeobox gene 4 (LHX4) and sry-box 3 gene (SOX3) mutations. 29,30 An ectopic posterior pituitary lobe presents a distinctive appearance on MRI, with the hyperintense posterior lobe characteristically seen at the median eminence in the floor of the third ventricle on unenhanced T1-weighted images. 31 Ectopic neurohypophysis has been rarely reported in association with other cortical malformations.…”

Section: Discussionmentioning

confidence: 99%

Bilateral Perysilvian Polymicrogyria With Cerebellar Dysplasia and Ectopic Neurohypophysis

et al. 2011

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Polymicrogyria (involving or not the sylvian scissure) with cerebellar cortical dysplasia or vermis hypoplasia has been reported in few cases. In addition, the association between ectopic neurohypophysis and other cortical malformations, including bilateral perisylvian polymicrogyria, has been documented. We describe a girl affected by focal epilepsy since the age of 2 years. Magnetic resonance imaging (MRI) at 11 and 22 years of age showed bilateral perisylvian polymicrogyria, dysplasia of the left cerebellar hemisphere, and ectopic neurohypophysis. Genetic tests, including fluorescent in situ hybridization 22q11.2 and array-comparative genomic hybridization, and pituitary hormones (at the age of 20 years) were normal. The patient is now 22 years old, and she is seizure free under therapy with lamotrigine and levetiracetam. To the best of our knowledge, this is the first description of this complex cerebral malformation. This finding confirms that bilateral perisylvian polymicrogyria can be associated with other cerebral malformations; cerebellum and neurohypophysis must be carefully evaluated in patients with polymicrogyria.

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Section: Discussionmentioning

confidence: 99%

Bilateral Perysilvian Polymicrogyria With Cerebellar Dysplasia and Ectopic Neurohypophysis

et al. 2011

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“…Although a family with GH, TSH, and ACTH deficiency due to a heterozygous mutation in the LHX4 gene has been described, the child was prepubertal, so gonadotropin levels were not investigated [148] . Recently, a second child was reported with a heterozygous LHX4 missense mutation [149] . Theoretically, LHX4 should also cause hypogonadotropic hypogonadism, but no pubertal aged children have yet been described.…”

Section: Sox2 and Sox3mentioning

confidence: 99%

Clinical Manifestations of Impaired GnRH Neuron Development and Function

2008

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Gonadotropin-releasing hormone (GnRH) and olfactory neurons migrate together in embryologic development, and disruption of this process causes idiopathic hypogonadotropic hypogonadism (IHH) with anosmia (Kallmann syndrome (KS)). Patients with IHH/KS generally manifest irreversible pubertal delay and subsequent infertility due to deficient pituitary gonadotropins or GnRH. The molecular basis of IHH/KS includes genes that: (1) regulate GnRH and olfactory neuron migration; (2) control the synthesis or secretion of GnRH; (3) disrupt GnRH action upon pituitary gonadotropes, or (4) interfere with pituitary gonadotropin synthesis or secretion. KS patients may also have midline facial defects indicating the diverse developmental functions of genes involved. Most causative genes cause either normosmic IHH or KS except FGFR1, which may cause either phenotype. Recently, several balanced chromosomal translocations have been identified in IHH/KS patients, which could lead to the identification of new disease-producing genes. Although there are two cases reported who have digenic disease, this awaits confirmation in future larger studies. The challenge will be to determine the importance of these genes in the 10–15% of couples with normal puberty who have infertility.

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“…A recent analysis suggested that the disease is likely a result of deficits in activation of pituitary genes such as PIT1/POU1F1 rather than a dominant negative effect (15). A second type of patient has a heterozygous mutation (P366T) affecting a residue in the carboxyl terminus of LHX4 (16). This patient has deficiencies of GH, prolactin, TSH, LH, FSH, ACTH, a hypoplastic anterior lobe, an ectopic posterior pituitary, a poorly developed sella turcica, Chiari malformation, and respiratory distress syndrome.…”

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confidence: 99%

Three Novel Missense Mutations within the LHX4 Gene Are Associated with Variable Pituitary Hormone Deficiencies

Pfaeffle

Hunter

Savage

et al. 2008

The Journal of Clinical Endocrinology &Amp; Metabolism

101

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Context:The LHX4 LIM-homeodomain transcription factor has essential roles in pituitary gland and nervous system development. Heterozygous mutations in LHX4 are associated with combined pituitary hormone deficiency.Objectives: Our objectives were to determine the nature and frequency of LHX4 mutations in patients with pituitary hormone deficiency and to examine the functional outcomes of observed mutations. Design:The LHX4 gene sequence was determined from patient DNA. The biochemical and gene regulatory properties of aberrant LHX4 proteins were characterized using structural predictions, pituitary gene transcription assays, and DNA binding experiments. Patients:A total of 253 patients from 245 pedigrees with GH deficiency and deficiency of at least one additional pituitary hormone was included in the study. Results:In five patients, three types of heterozygous missense mutations in LHX4 that result in substitution of conserved amino acids were identified. One substitution is between the LIM domains (R84C); the others are in the homeodomain (L190R; A210P). The patients have GH deficiency; some also display reductions in TSH, LH, FSH, or ACTH, and aberrant pituitary morphology. Structural models predict that the aberrant L190R and A210P LHX4 proteins would have impaired DNA binding and gene activation properties. Consistent with these models, EMSAs and transfection experiments using pituitary gene promoters demonstrate that whereas the R84C form has reduced activity, the L190R and A210P proteins are inactive. A fter early inductive events, the development of the specialized hormone-secreting cells of the anterior pituitary gland is dependent on the actions of multiple transcription factors such as LHX3, LHX4, PIT1 (POU1F1 gene), PROP1, PITX1, PITX2, SF1, and TPIT (1). Of these, the structurally related LHX3 and LHX4 proteins are members of the LIMhomeodomain (HD) family of transcription factors (2). LIM-HD proteins feature two amino-terminal LIM domains, required for Conclusions

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A Novel Missense Mutation (P366T) of the LHX4 Gene Causes Severe Combined Pituitary Hormone Deficiency with Pituitary Hypoplasia, Ectopic Posterior Lobe and a Poorly Developed Sella Turcica

Cited by 55 publications

References 24 publications

Bilateral Perysilvian Polymicrogyria With Cerebellar Dysplasia and Ectopic Neurohypophysis

Bilateral Perysilvian Polymicrogyria With Cerebellar Dysplasia and Ectopic Neurohypophysis

Clinical Manifestations of Impaired GnRH Neuron Development and Function

Three Novel Missense Mutations within the LHX4 Gene Are Associated with Variable Pituitary Hormone Deficiencies

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