Appetite- and weight-regulating neuroendocrine circuitry in hypothalamic obesity.

Since hypothalamic obesity (HyOb) was first described over 120 years ago by Joseph Babinski and Alfred Fröhlich, advances in molecular genetic laboratory techniques have allowed us to elucidate various components of the intricate neurocircuitry governing appetite and weight regulation connecting the hypothalamus, pituitary gland, brainstem, adipose tissue, pancreas and gastrointestinal tract. On a background of an increasing prevalence of population-level common obesity, the number of survivors of congenital (e.g. septo-optic dysplasia, Prader-Willi syndrome) and acquired (e.g. central nervous system tumours) hypothalamic disorders is increasing, thanks to earlier diagnosis and management as well as better oncological therapies. Although to date the discovery of several appetite-regulating peptides has led to the development of a range of targeted molecular therapies for monogenic obesity syndromes, outside of these disorders these discoveries have not translated into the development of efficacious treatments for other forms of HyOb. This review aims to summarise our current understanding of the neuroendocrine physiology of appetite and weight regulation, and explore our current understanding of the pathophysiology of HyOb.

Quality of Life in Children and Young People With Congenital Adrenal Hyperplasia-UK Nationwide Multicenter Assessment.

CONTEXT: Quality of life (QoL) has been inconsistently reported in children and young people (CYP) with congenital adrenal hyperplasia (CAH). OBJECTIVE: Assess QoL in CYP with CAH in the UK alongside biometric and androgen profiles. DESIGN: To define the evidence base for health care delivery, we conducted a cross-sectional study in CYP with CAH in the UK. Questionnaire results were compared with normative data and between groups, and modelled for association with sex, height, weight, body mass index, or steroid biomarkers of CAH control. SETTING: Tertiary care in 14 UK centers. PATIENTS: Results from 104 patients, 55% female, mean age 12.7 years (SD 3.0), paired responses from parents. INTERVENTIONS: Strengths and Difficulties questionnaire (SDQ) and pediatric QoL questionnaire. MAIN OUTCOME MEASURE: Total QoL scores as assessed by SDQ and a pediatric QoL questionnaire in comparison to normative data. RESULTS: Total scores were worse in parents than normative data, but similar in patients. Patient QoL was rated better in social functioning but worse in emotional, school, and peer domains by patients, and worse in total scores and domains of peer problems, and psychosocial, emotional, and school functioning by parents. Parents consistently scored QoL of their children lower than their child. Larger height-SD score and lower weight-SD score were associated with better QoL. Girls with lower steroid biomarkers had worse SDQ scores. CONCLUSIONS: In CYP with CAH, reduced height, increased weight, and hormonal biomarkers consistent with overtreatment were associated with worse QoL; addressing these problems should be prioritized in clinical management.Clinical Trials Registration Number: SCH/15/088.

Health status of children and young persons with congenital adrenal hyperplasia in the UK (CAH-UK): a cross-sectional multi-centre study.

Objective: There is limited knowledge on the onset of comorbidities in congenital adrenal hyperplasia (CAH) during childhood. We aimed to establish the health status of children with CAH in the UK. Design and methods: This cross-sectional multicentre study involved 14 tertiary endocrine UK units, recruiting 101 patients aged 8-18 years with classic 21-hydroxylase deficiency and 83 controls. We analysed demographic, clinical and metabolic data, as well as psychological questionnaires (Strengths and Difficulties (SDQ), Paediatric Quality of Life (PedsQL)). Results: Patient height SDS in relation to mid-parental height decreased with age, indicating the discrepancy between height achieved and genetic potential height. Bone age was advanced in 40.5% patients, with a mean difference from the chronological age of 1.8 (±2.3) years. Patients were more frequently overweight (27%) or obese (22%) compared to controls (10.8% and 10.8%, respectively, P < 0.001). No consistent relationship between glucocorticoid dose and anthropometric measurements or hormonal biomarkers was detected. A small number of patients had raised total cholesterol (3.0%), low HDL (3.0%), raised LDL (7.0%) and triglycerides (5.0%). SDQ scores were within the 'high' and 'very high' categories of concern for 16.3% of patients. 'School functioning' was the lowest PedsQL scoring dimension with a median (interquartile range) of 70 (55-80), followed by 'emotional functioning' with a median of 75 (65-85). Conclusions: Our results show an increased prevalence of problems with growth and weight gain in CAH children and suggest reduced quality of life. This highlights the urgent need to optimise management and monitoring strategies to improve long-term health outcomes.

Hyperinsulinemic hypoglycemia in children and adolescents: Recent advances in understanding of pathophysiology and management.

Hyperinsulinemic hypoglycemia (HH) is characterized by unregulated insulin release, leading to persistently low blood glucose concentrations with lack of alternative fuels, which increases the risk of neurological damage in these patients. It is the most common cause of persistent and recurrent hypoglycemia in the neonatal period. HH may be primary, Congenital HH (CHH), when it is associated with variants in a number of genes implicated in pancreatic development and function. Alterations in fifteen genes have been recognized to date, being some of the most recently identified mutations in genes HK1, PGM1, PMM2, CACNA1D, FOXA2 and EIF2S3. Alternatively, HH can be secondary when associated with syndromes, intra-uterine growth restriction, maternal diabetes, birth asphyxia, following gastrointestinal surgery, amongst other causes. CHH can be histologically characterized into three groups: diffuse, focal or atypical. Diffuse and focal forms can be determined by scanning using fluorine-18 dihydroxyphenylalanine-positron emission tomography. Newer and improved isotopes are currently in development to provide increased diagnostic accuracy in identifying lesions and performing successful surgical resection with the ultimate aim of curing the condition. Rapid diagnostics and innovative methods of management, including a wider range of treatment options, have resulted in a reduction in co-morbidities associated with HH with improved quality of life and long-term outcomes. Potential future developments in the management of this condition as well as pathways to transition of the care of these highly vulnerable children into adulthood will also be discussed.

The Molecular Basis of Congenital Hypopituitarism and Related Disorders.

CONTEXT: Congenital hypopituitarism (CH) is characterized by the presence of deficiencies in one or more of the 6 anterior pituitary (AP) hormones secreted from the 5 different specialized cell types of the AP. During human embryogenesis, hypothalamo-pituitary (HP) development is controlled by a complex spatio-temporal genetic cascade of transcription factors and signaling molecules within the hypothalamus and Rathke's pouch, the primordium of the AP. EVIDENCE ACQUISITION: This mini-review discusses the genes and pathways involved in HP development and how mutations of these give rise to CH. This may present in the neonatal period or later on in childhood and may be associated with craniofacial midline structural abnormalities such as cleft lip/palate, visual impairment due to eye abnormalities such as optic nerve hypoplasia (ONH) and microphthalmia or anophthalmia, or midline forebrain neuroradiological defects including agenesis of the septum pellucidum or corpus callosum or the more severe holoprosencephaly. EVIDENCE SYNTHESIS: Mutations give rise to an array of highly variable disorders ranging in severity. There are many known causative genes in HP developmental pathways that are routinely screened in CH patients; however, over the last 5 years this list has rapidly increased due to the identification of variants in new genes and pathways of interest by next-generation sequencing. CONCLUSION: The majority of patients with these disorders do not have an identified molecular basis, often making management challenging. This mini-review aims to guide clinicians in making a genetic diagnosis based on patient phenotype, which in turn may impact on clinical management.

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 ± 0.7 cm (-8.3 ± 0.1 SDS; females). DESIGN: We hypothesized that a consanguineous Pakistani family with IGHD in three siblings (two males, one female) would have mutations in GH1 or GHRHR. RESULTS: Two novel homozygous missense variants [c.11G>A (p.R4Q), c.236C>T (p.P79L)] at conserved residues were identified in all three siblings. Both were absent from control databases, aside from pR4Q appearing once in heterozygous form in the Exome Aggregation Consortium Browser. The brothers were diagnosed with GH deficiency at 9.8 and 6.0 years (height SDS: -2.24 and -1.23, respectively), with a peak GH of 2.9 µg/liter with low IGF-1/IGF binding protein 3. Their sister presented at 16 years with classic GH deficiency (peak GH <0.1 µg/liter, IGF-1 <3.3 mmol/liter) and attained an untreated near-adult height of 144 cm (-3.0 SDS); the tallest untreated patient with GHRHR mutations reported. An unrelated Pakistani female IGHD patient was also compound homozygous. All patients had a small anterior pituitary on magnetic resonance imaging. Functional analysis revealed a 50% reduction in maximal cAMP response to stimulation with GHRH by the p.R4Q/p.P79L double mutant receptor, with a 100-fold increase in EC50. CONCLUSION: We report the first coexistence of two novel compound homozygous GHRHR variants in two unrelated pedigrees associated with a partial loss of function. Surprisingly, the patients have a relatively mild IGHD phenotype. Analysis revealed that the pP79L mutation is associated with the compromise in function, with the residual partial activity explaining the mild phenotype.

Sox2(+) stem/progenitor cells in the adult mouse pituitary support organ homeostasis and have tumor-inducing potential.

Sox2(+) adult mouse pituitary cells can self-renew and terminally differentiate in vitro, but their physiological role in vivo and possible contribution to oncogenesis remain largely unknown. Using genetic lineage tracing, we show here that the Sox2(+) cell compartment of both the embryonic and adult pituitary contains stem/progenitor cells that are able to differentiate into all hormone-producing lineages and contribute to organ homeostasis during postnatal life. In addition, we show that targeted expression of oncogenic ß-catenin in Sox2(+) cells gives rise to pituitary tumors, but, unexpectedly, the tumor mass is not derived from the Sox2(+) mutation-sustaining cells, suggesting a paracrine role of Sox2(+) cells in pituitary oncogenesis. Our data therefore provide in vivo evidence of a role for Sox2(+) stem/progenitor cells in long-term physiological maintenance of the adult pituitary, and highlight an unexpected non-cell-autonomous role for these cells in the induction of pituitary tumors.

Role of transcription factors in midline central nervous system and pituitary defects.

The anterior pituitary gland is a central regulator of growth, reproduction and homeostasis, and is the end-product of a carefully orchestrated pattern of expression of signalling molecules and transcription factors leading to the development of this complex organ secreting six hormones from five different cell types. Naturally-occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of combined pituitary hormone deficiency (CPHD). These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, SOX2 and SOX3. The expression pattern of these transcription factors dictates the phenotype that results when the gene encod-ing the relevant transcription factor is mutated. The highly variable phenotype may consist of isolated hypopituitarism, or more complex disorders such as septo-optic dysplasia. Since mutations in any one transcription factor are uncommon, and since the overall incidence of mutations in known transcription factors is low in patients with CPHD, it is clear that many genes remain to be identified, and characterization of these will further elucidate the pathogenesis of these complex conditions, and also shed light on normal pituitary development.

Septo-optic dysplasia - novel insights into the aetiology.

Septo-optic dysplasia (SOD) is a highly heterogeneous condition comprising a variable phenotype of optic nerve hypoplasia, midline brain abnormalities and pituitary hypoplasia with consequent endocrine deficits. The majority of cases are sporadic and several aetiologies have been suggested to account for the pathogenesis of the condition. However, a number of familial cases have been described and the identification of mutations in key developmental genes including HESX1, SOX2 and SOX3 in patients with SOD and associated phenotypes suggests that a genetic causation is likely in the more common sporadic cases of the condition. The precise aetiology of SOD is most likely multifactorial involving contributions from environmental factors in addition to an important role for crucial developmental genes. The variability of the penetrance and phenotypes within a single SOD pedigree may also suggest a complex interaction between genetics and the environment, and at present, the understanding of these interactions is rudimentary. Further study of these critical factors may shed light on the aetiology of this complex disorder. We have reviewed recent literature selecting relevant references based on the keywords HESX1, SOX2, SOX3, Septo-optic dysplasia, genetics and pituitary development.

Hypothalamic and pituitary development: novel insights into the aetiology.

The anterior pituitary gland is a central regulator of growth, reproduction and homeostasis, and is the end-product of a carefully orchestrated pattern of expression of signalling molecules and transcription factors leading to the development of this complex organ secreting six hormones from five different cell types. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of combined pituitary hormone deficiency (CPHD). These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, TBX19, SOX2 and SOX3. The expression pattern of these transcription factors dictates the phenotype that results when the gene encoding the relevant transcription factor is mutated. The highly variable phenotype may consist of isolated hypopituitarism, or more complex disorders such as septo-optic dysplasia and holoprosencephaly. Since mutations in any one transcription factor are uncommon, and since the overall incidence of mutations in known transcription factors is low in patients with CPHD, it is clear that many genes remain to be identified, and the characterization of these will further elucidate the pathogenesis of these complex conditions and also shed light on normal pituitary development.

Genetics of septo-optic dysplasia.

Septo-optic dysplasia (SOD) is a highly heterogeneous condition comprising a variable phenotype of optic nerve hypoplasia, midline forebrain abnormalities and pituitary hypoplasia with consequent endocrine deficits. The majority of cases 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 and the identification of mutations in the key developmental gene HESX1 in patients with SOD and associated phenotypes suggests that a genetic causation is likely in the more common sporadic cases of the condition. More recently, we have implicated duplications of SOX3 and mutations of both SOX2 and SOX3 in the aetiology of variants of SOD. As with other developmental disorders such as holoprosencephaly, the precise aetiology is most likely multifactorial involving contributions from environmental factors in addition to an important role for crucial developmental genes. This potentially complex interaction between genetics and the environment is borne out by the variability of the penetrance and phenotypes in patients with genetic SOD, but at present, the understanding of these interactions is rudimentary. Further study of these critical factors may shed light on the aetiology of this complex disorder.