Development of the Pituitary Gland.

The development of the anterior pituitary gland occurs in distinct sequential developmental steps, leading to the formation of a complex organ containing five different cell types secreting six different hormones. During this process, the temporal and spatial expression of a cascade of signaling molecules and transcription factors plays a crucial role in organ commitment, cell proliferation, patterning, and terminal differentiation. The morphogenesis of the gland and the emergence of distinct cell types from a common primordium are governed by complex regulatory networks involving transcription factors and signaling molecules that may be either intrinsic to the developing pituitary or extrinsic, originating from the ventral diencephalon, the oral ectoderm, and the surrounding mesenchyme.

Partial Loss of Function of the GHRH Receptor Leads to Mild Growth Hormone Deficiency.

Objective: Recessive mutations in GHRHR are associated with severe isolated growth hormone deficiency (IGHD), with a final height in untreated patients of 130 cm ± 10 cm (-7.2 ± 1.6 SDS; males) and 114 ± 0.

Recent advances in central congenital hypothyroidism.

Central congenital hypothyroidism (CCH) may occur in isolation, or more frequently in combination with additional pituitary hormone deficits with or without associated extrapituitary abnormalities. Although uncommon, it may be more prevalent than previously thought, affecting up to 1:16 000 neonates in the Netherlands. Since TSH is not elevated, CCH will evade diagnosis in primary, TSH-based, CH screening programs and delayed detection may result in neurodevelopmental delay due to untreated neonatal hypothyroidism.

Novel application of luciferase assay for the in vitro functional assessment of KAL1 variants in three females with septo-optic dysplasia (SOD).

KAL1 is implicated in 5% of Kallmann syndrome cases, a disorder which genotypically overlaps with septo-optic dysplasia (SOD). To date, a reporter-based assay to assess the functional consequences of KAL1 mutations is lacking. We aimed to develop a luciferase assay for novel application to functional assessment of rare KAL1 mutations detected in a screen of 422 patients with SOD.

Autosomal Dominant Growth Hormone Deficiency (Type II).

Isolated growth hormone deficiency (IGHD) is the commonest pituitary hormone deficiency resulting from congenital or acquired causes, although for most patients its etiology remains unknown. Among the known factors, heterozygous mutations in the growth hormone gene (GH1) lead to the autosomal dominant form of GHD, also known as type II GHD. In many cohorts this is the commonest form of congenital isolated GHD and is mainly caused by mutations that affect the correct splicing of GH-1.

SOX3 deletion in mouse and human is associated with persistence of the craniopharyngeal canal.

Context: SOX3 is an early developmental transcription factor involved in pituitary development. In humans, over- and underdosage of SOX3 is associated with X-linked hypopituitarism with variable phenotypes ranging from isolated GH deficiency (GHD) to panhypopituitarism, with or without mental retardation and, in most cases, with reported pituitary imaging, an ectopic/undescended posterior pituitary.

Patient: We present a young patient with hemophilia B and developmental delay who had a 2.

Isolated growth hormone deficiency (GHD) in childhood and adolescence: recent advances.

The diagnosis of GH deficiency (GHD) in childhood is a multistep process involving clinical history, examination with detailed auxology, biochemical testing, and pituitary imaging, with an increasing contribution from genetics in patients with congenital GHD. Our increasing understanding of the factors involved in the development of somatotropes and the dynamic function of the somatotrope network may explain, at least in part, the development and progression of childhood GHD in different age groups. With respect to the genetic etiology of isolated GHD (IGHD), mutations in known genes such as those encoding GH (GH1), GHRH receptor (GHRHR), or transcription factors involved in pituitary development, are identified in a relatively small percentage of patients suggesting the involvement of other, yet unidentified, factors.

Variations in PROKR2, but not PROK2, are associated with hypopituitarism and septo-optic dysplasia.

Context: Loss-of-function mutations in PROK2 and PROKR2 have been implicated in Kallmann syndrome (KS), characterized by hypogonadotropic hypogonadism and anosmia. Recent data suggest overlapping phenotypes/genotypes between KS and congenital hypopituitarism (CH), including septo-optic dysplasia (SOD).

Objective: We screened a cohort of patients with complex forms of CH (n = 422) for mutations in PROK2 and PROKR2.

Phenotype-genotype correlations in congenital isolated growth hormone deficiency (IGHD).

Isolated growth hormone deficiency (IGHD) may be congenital, often due to genetic mutations, or acquired as a result of other factors such as cranial irradiation. The commonest genes implicated in its genetic etiology are those encoding growth hormone (GH1) and the receptor for GH-releasing hormone (GHRHR). Rarely, IGHD may be caused by mutations in transcription factors (HESX1, SOX3, OTX2) or be the first presentation before the development of other pituitary hormone deficiencies.

SOX2 haploinsufficiency is associated with slow progressing hypothalamo-pituitary tumours.

SOX2 is an early developmental transcription factor and marker of stem cells that has recently been implicated in the development of the pituitary gland. Heterozygous SOX2 mutations have been described in patients with hypopituitarism and severe ocular abnormalities. In the majority of published cases, the pituitary gland is either small or normal in size.

Novel FGF8 mutations associated with recessive holoprosencephaly, craniofacial defects, and hypothalamo-pituitary dysfunction.

Context: Fibroblast growth factor (FGF) 8 is important for GnRH neuronal development with human mutations resulting in Kallmann syndrome. Murine data suggest a role for Fgf8 in hypothalamo-pituitary development; however, its role in the etiology of wider hypothalamo-pituitary dysfunction in humans is unknown.

Objective: The objective of this study was to screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47).

Absence of GH-releasing hormone (GHRH) mutations in selected patients with isolated GH deficiency.

Context: Although numerous reports of mutations in GH1 and GHRHR (GHRH receptor) causing isolated GH deficiency (IGHD) have been published, mutations in GHRH itself have not been hitherto reported but are obvious candidates for GH deficiency.

Objective: The aim of this study was to identify mutations in GHRH in a large cohort of patients with IGHD.

Patients And Methods: DNA was isolated from 151 patients diagnosed with IGHD at national and international centers.

Septo-optic dysplasia and other midline defects: the role of transcription factors: HESX1 and beyond.

Septo-optic dysplasia (SOD) is a highly heterogeneous condition comprising variable phenotypes including midline and forebrain abnormalities, optic nerve and pituitary hypoplasia. Most instances of SOD are sporadic and several aetiologies including drug and alcohol abuse have been suggested to account for the pathogenesis of the condition. However, a number of familial cases have been described with an increasing number of mutations in developmental transcription factors including HESX1, SOX2, SOX3 and OTX2 being implicated in its aetiology.

Increased transactivation associated with SOX3 polyalanine tract deletion in a patient with hypopituitarism.

Background And Aims: Correct gene dosage of SOX3 is critical for the development of the hypothalamo-pituitary axis. Both overdosage of SOX3, as a result of gene duplication, and loss of function resulting from expansion of the first polyalanine (PA) tract are associated with variable degrees of hypopituitarism, with or without mental retardation. The aim of this study was to further investigate the contribution of SOX3 in the etiology of hypopituitarism and the mechanisms involved in the phenotypic variability.

Genetic causes and treatment of isolated growth hormone deficiency-an update.

Isolated growth hormone deficiency is the most common pituitary hormone deficiency and can result from congenital or acquired causes, although the majority of cases are idiopathic with no identifiable etiology. Known genes involved in the genetic etiology of isolated growth hormone deficiency include those that encode growth hormone (GH1), growth-hormone-releasing hormone receptor (GHRHR) and transcription factor SOX3. However, mutations are identified in a relatively small percentage of patients, which suggests that other, yet unidentified, genetic factors are involved.

Two cases of myomectomy complicated by intravascular hemolysis and renal failure: disseminated intravascular coagulation or hemolytic uremic syndrome?

Objective: To present two cases of myomectomy complicated by intravascular hemolysis leading to acute renal failure and discuss the differential diagnosis and possible mechanism.

Design: Case report.

Setting: Minimally Invasive Therapy Unit, University Department of Obstetrics and Gynecology.

Genetic forms of hypopituitarism and their manifestation in the neonatal period.

The anterior pituitary gland is a central regulator of growth, reproduction and homeostasis. The development of the pituitary gland depends on the sequential temporal and spatial expression of transcription factors and signalling molecules. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of congenital hypopituitarism.

Acanthosis nigricans and insulin sensitivity in patients with achondroplasia and hypochodroplasia due to FGFR3 mutations.

Background And Aims: Acanthosis nigricans (AN) has been reported in association with severe skeletal dysplasias due to activating mutations in FGFR3, including thanatophoric dysplasia, severe achondroplasia (ACH) with developmental delay and AN (SADDAN syndrome), and Crouzon syndrome with AN. There are isolated reports of patients with ACH and AN. In this series, we report clinical and biochemical data on five male patients, four with ACH and one with hypochondroplasia (HCH), who developed AN without SADDAN.

Expanding the spectrum of mutations in GH1 and GHRHR: genetic screening in a large cohort of patients with congenital isolated growth hormone deficiency.

Context: It is estimated that 3-30% of cases with isolated GH deficiency (IGHD) have a genetic etiology, with a number of mutations being reported in GH1 and GHRHR. The aim of our study was to genetically characterize a cohort of patients with congenital IGHD and analyze their characteristics.

Patients And Methods: A total of 224 patients (190 pedigrees) with IGHD and a eutopic posterior pituitary were screened for mutations in GH1 and GHRHR.

The role of SOX proteins in normal pituitary development.

Pituitary development is a complex process that depends on the co-ordinated spatial and temporal expression of transcription factors and signalling molecules that culminates in the formation of a complex organ that secretes six hormones from five different cell types. Given the fact that all distinct hormone producing cells arise from a common ectodermal primordium, the patterning, architecture and plasticity of the gland is impressive. Among the transcription factors involved in the early steps of pituitary organogenesis are SOX2 and SOX3, members of the SOX family that are emerging as key players in many developmental processes.

Renal pseudotumor simulating malignancy in a patient with Adamantiades-Behçet's disease: case report and review of the literature.

Adamantiades-Behçet's disease is a multisystem recurrent syndrome with vasculitis being the underlying histopathological lesion. We report on a patient with Behçet's disease who developed a renal mass raising the suspicion of a malignant neoplasm. The pathologic examination revealed an inflammatory pseudotumor.