The phenotypic spectrum associated with OTX2 mutations in humans.

Objective: The transcription factor OTX2 is implicated in ocular, craniofacial, and pituitary development. Design: We aimed to establish the contribution of OTX2 mutations in congenital hypopituitarism patients with/without eye abnormalities, study functional consequences, and establish OTX2 expression in the human brain, with a view to investigate the mechanism of action. Methods: We screened patients from the UK (n = 103), international centres (n = 24), and Brazil (n = 282); 145 were within the septo-optic dysplasia spectrum, and 264 had no eye phenotype. Transactivation ability of OTX2 variants was analysed in murine hypothalamic GT1-7 neurons. In situ hybridization was performed on human embryonic brain sections. Genetically engineered mice were generated with a series of C-terminal OTX2 variants. Results: Two chromosomal deletions and six haploinsufficient mutations were identified in individuals with eye abnormalities; an affected relative of one patient harboured the same mutation without an ocular phenotype. OTX2 truncations led to significant transactivation reduction. A missense variant was identified in another patient without eye abnormalities; however, studies revealed it was most likely not causative. In the mouse, truncations proximal to aa219 caused anophthalmia, while distal truncations and the missense variant were tolerated. During human embryogenesis, OTX2 was expressed in the posterior pituitary, retina, ear, thalamus, choroid plexus, and partially in the hypothalamus, but not in the anterior pituitary. Conclusions: OTX2 mutations are rarely associated with hypopituitarism in isolation without eye abnormalities, and may be variably penetrant, even within the same pedigree. Our data suggest that the endocrine phenotypes in patients with OTX2 mutations are of hypothalamic origin.

Pituitary gland development: an update.

The embryonic development of the pituitary gland involves a complex and highly spatio-temporally regulated network of integrating signalling molecules and transcription factors. Genetic mutations in any of these factors can lead to congenital hypopituitarism in association with a wide spectrum of craniofacial/midline defects ranging from incompatibility with life to holoprosencephaly (HPE) and cleft palate and septo-optic dysplasia (SOD). Increasing evidence supports a genotypic overlap with hypogonadotrophic hypogonadal disorders such as Kallmann syndrome, which is consistent with the known overlap in phenotypes between these disorders. This chapter reviews the cascade of events leading up to the successful development of the pituitary gland and to highlight key areas where genetic variations can occur thus leading to congenital hypopituitarism and associated defects.

Prevalence of hematological abnormalities in patients with Sheehan's syndrome: response to replacement of glucocorticoids and thyroxine.

Anemia and other hematological abnormalities are common in patients with Sheehan's syndrome. The response of these abnormalities to replacement of thyroxine and glucocorticoids is not clear. The aim of the present study was to document the profile of hematological abnormalities and response to treatment in patients with Sheehan's syndrome. Forty patients of Sheehan's syndrome and an equal number of age and parity matched healthy controls were studied for prevalence of hematological abnormalities. Hemoglobin concentration, hematocrit, red cell, white cell and platelet count were significantly decreased in patients with Sheehan's syndrome compared to controls. Frequency of anemia, leucopenia, thrombocytopenia and pancytopenia was significantly higher in these patients compared to controls. After achieving euthyroid and eucortisol state, there was a complete recovery of these hematological abnormalities. We conclude that anemia and other cytopenias are common in patients with Sheehan's syndrome and replacement with thyroxine and glucocorticoids results in complete recovery of these abnormalities.

Novel mutations in LHX3 are associated with hypopituitarism and sensorineural hearing loss.

Homozygous loss-of-function mutations in the transcription factor LHX3 have been associated with hypopituitarism with structural anterior pituitary defects and cervical abnormalities with or without restricted neck rotation. We report two novel recessive mutations in LHX3 in four patients from two unrelated pedigrees. Clinical evaluation revealed that all four patients exhibit varying degrees of bilateral sensorineural hearing loss, which has not been previously reported in association with LHX3 mutations, in addition to hypopituitarism including adrenocorticotropic hormone deficiency and an unusual skin and skeletal phenotype in one family. Furthermore, re-evaluation of three patients previously described with LHX3 mutations showed they also exhibit varying degrees of bilateral sensorineural hearing loss. We have investigated a possible role for LHX3 in inner ear development in humans using in situ hybridization of human embryonic and fetal tissue. LHX3 is expressed in defined regions of the sensory epithelium of the developing inner ear in a pattern overlapping that of SOX2, which precedes the onset of LHX3 expression and is known to be required for inner ear and pituitary development in both mice and humans. Moreover, we show that SOX2 is capable of binding to and activating transcription of the LHX3 proximal promoter in vitro. This study therefore extends the phenotypic spectrum associated with LHX3 mutations to encompass variable sensorineural hearing loss and suggests a possible interaction between LHX3 and SOX2 likely to be important for development of both the inner ear and the anterior pituitary in human embryonic development.

Molecular basis of pituitary development defects.

UNLABELLED: Over the last twenty years, the progress made in molecular biology have led to the identification of many transcription factor genes, whose mutations has been reported as causes of familial hypopituitarism. AIM: Based on a literature review, this study is intending to highlight the role of some transcription factors in the development of the anterior pituitary gland and to analyse the involvement of their dysfunction in some cases of congenital hypopituitarism. METHODS: Litterature review. RESULTS: These transcription factors are nuclear proteins expressed specifically in certain target cells, in order to control genes expression. Their role is fundamental in embryonic and foetal development, and particularly in pituitary ontogenesis. Together, they direct the formation of anterior pituitary gland, the differentiation, the expansion and the definitive function of the five pituitary cell types. In this report, after introducing the different stages of anterior pituitary development and differentiation of its cell lines, we will briefly highlight the clinical phenotypes associated with alterations of different transcription factor genes in both murine models and humans.

Transcription factors regulating pituitary development.

This review will address contributions of nuclear transcription factors to the embryologic development and definitive function of the anterior pituitary gland. The HESX1, PITX1, PITX2, PROP1 and POU1F1 genes are of particular interest because of their recognized or potential associations with human disease. Mutations of any of the first three genes produce complex disease phenotypes such as septo-optic dysplasia, Treacher Collins Franceschetti syndrome or Rieger syndrome that may include deficiency of one or more pituitary hormones. Mutations in PROP1 or POU1F1, or their mouse homologous, result in severe hypopituitarism as well as morphological abnormalities of the pituitary gland.

Aplasia of right internal carotid artery and hypopituitarism.

BACKGROUND: The pathogenesis of congenital hypopituitarism is unknown in many cases. OBJECTIVE: We report a case of congenital pan-anterior hypopituitarism in association with a complex vascular abnormality involving the central nervous system, nasal pyriform aperture stenosis, and a single central maxillary incisor. MATERIALS AND METHODS: MRI and MRA were used to define this patient's complex vascular anomaly. RESULTS: The vascular abnormality consists of absence of the right common carotid artery, the right internal carotid artery, the A1 segment of the right anterior cerebral artery, the anterior communicating artery, and partial absence of the M1 segment of the right middle cerebral artery. CONCLUSION: This unusual vascular anomaly may contribute to the pathogenesis of some cases of congenital hypopituitarism and related midline abnormalities, or may result from a common defect that causes pituitary insufficiency.

Targeted mutation in beta1,4-galactosyltransferase leads to pituitary insufficiency and neonatal lethality.

Despite much attention, the function of oligosaccharide chains on glycoproteins and glycolipids remains largely unknown. Our understanding of oligosaccharide function in vivo has been limited to the use of reagents and targeted mutations that eliminate entire classes of oligosaccharide chains. However, most biological functions for oligosaccharides have been attributed to specific terminal sequences on these glycoside chains; yet, there have been few studies that examine the consequences of modifying terminal oligosaccharide structures in vivo. To address this issue, mice were created bearing a targeted mutation in beta1,4-galactosyltransferase (GalTase), an enzyme responsible for elaboration of many of the proposed biologically active carbohydrate epitopes. Most GalTase-null mice died within the first few weeks after birth and were characterized by stunted growth, thin skin, sparse hair, and dehydration. In addition, spermatogenesis was delayed, the lungs were poorly developed, and the adrenal cortices were poorly stratified. The few surviving adults had puffy skin (myxedema) and difficulty delivering pups at birth (dystocia) and failed to lactate (agalactosis). All of these defects are consistent with endocrine insufficiency, which was confirmed by markedly decreased levels of serum thyroxine. The polyglandular nature of the endocrine insufficiency is indicative of a failure of the anterior pituitary gland to stimulate the target endocrine organs. Previous in vitro studies have suggested that incomplete glycosylation of anterior pituitary hormones leads to the creation of hormone antagonists, which down-regulate subsequent endocrine function, producing polyglandular endocrine insufficiency. In GalTase-null mice, the anterior pituitary acquired a normal secretory phenotype during neonatal development indicative of normal glycoprotein hormone synthesis and secretion. However, as expected, the gland was devoid of GalTase activity. These results support a requirement for terminal oligosaccharide sequences for anterior pituitary hormone function. The fact that approximately 10% of the GalTase-null mice survive the neonatal period indicates the presence of a previously unrecognized compensatory pathway for glycoprotein hormone glycosylation and/or action.

Auxological, clinical and neuroradiological findings in infants with early onset growth hormone deficiency.

Sixteen infants less than 2 years of age with apparently idiopathic hypopituitarism were studied. At birth, 11 of 16 patients (69%) had subnormal length associated with relative adiposity and 10 of 16 (62%) showed significant deterioration in length deficiency from birth onwards. These findings suggest that: (a) growth hormone deficiency, in a number of patients, had started well before delivery; (b) growth hormones may play a role in intrauterine growth; and (c) growth hormone may also be involved in early postnatal growth. Magnetic resonance imaging in these patients was very similar to that described in hypopituitarism of later onset. This suggests that even in the latter case, hypopituitarism may have a prenatal onset. Finally, the severity of growth failure and the coexistence of other hypopituitary symptoms at the time of diagnosis in 31% of our patients indicate that early clinical screening of hypopituitarism is possible.

Hypopituitarism with invisible pituitary stalk: two case reports of males with micropenis suggesting fetal onset of hypopituitarism.

The presence of hypopituitarism and invisible pituitary stalk on a magnetic resonance image (MRI) is commonly attributed to birth trauma. Two patients with severe hypopituitarism and invisible pituitary stalk are presented. One was born by breech delivery, the other by Cesarean section. The presence of a micropenis since early infancy in these two patients suggested that their hypopituitarism might have begun during early fetal life thus effecting penile growth during the second and third triministers of gestation. These findings raise the possibility that the association of hypopituitarism and invisible pituitary stalk may have multiple etiologies including hormonal abnormalities during early fetal life.

Fetal hypopituitarism: perinatal endocrine and morphological studies in two cases.

We report two infants with congenital absence of the anterior pituitary gland, documented by magnetic resonance imaging (MRI) or autopsy. In cord plasma obtained at birth from both infants, prolactin (PRL), pituitary growth hormone (hGH), placental growth hormone (hPGH) and thyrotropin (TSH) were undetectable; cortisol was low; thyroxine (T4) was 31 nmol/l in one infant and 85 nmol/l in the other infant who had been treated prenatally with intra-amniotic L-T4 administration. In maternal plasma at birth, PRL, hPGH and T4 were normal and hGH was undetectable. These observations suggest that plasma hGH and PRL in the fetus are exclusively of fetal pituitary origin, hPGH is secreted into the maternal circulation and is not transferred to the fetus and fetal growth can be normal in the absence of hGH, hPGH and PRL in fetal plasma.

[Tooth and face abnormalities associated with pituitary growth hormone insufficiency]. / Les malformations dentaires et faciales associées à l'insuffisance hypophysaire en hormone de croissance.

Dental and facial examination has been performed in sixty-two children with idiopathic or congenital growth hormone deficiency. Fourteen (22%) had a malformation of the upper incisors and/or of the naso-frontal bud or of the eyes, associated in five with a malformation of the brain in the prosencephalon-derived areas. Moreover, fourteen patients had some facial abnormality in an area situated near that derived from the naso-frontal bud. These associations are to be considered as a clinical marker able to call for pituitary investigation in short children. They suggest that some cases of so-called idiopathic hypopituitarism relate in fact to congenital and malformative causes.