Edition 73 - May 2019 / Bibliographic Reviews

Bibliographic Reviews – Ed. 73

Marco A. Rivarola y Alicia Belgorosky. Hospital de Pediatria Garrahan, Buenos Aires, Argentina.

For this issue of Endocrinología Pediátrica On Line, we have selected to comment on the following publications:

358

J Pediatr Urol. 2018 Nov 17.
Variations of sex development: The first German interdisciplinary consensus paper. Krege S1, Eckoldt F2, Richter-Unruh A3, Köhler B4, Leuschner I5, Menzel HJ6, Moss A7, Schweizer K8, Stein R9, Werner-Rosen K10, Wieacker P11, Wiesemann C12, Wünsch L13, Richter-Appelt H8.
1 Dept. of Urology, Kliniken Essen-Mitte, Germany. 2 Dept. of Pediatric Surgery, University of Jena, Germany. 3 Dept. of Pediatric Endocrinology, University of Münster, Germany. 4 Dept. of Pediatric Endocrinology and Diabetology, Charite – University of Berlin, Germany. 5 Dept. of Pathology, University of Kiel, Germany. 6 Section of Pediatric Radiology, University of Jena, Germany. 7 Division of Pediatric Endocrinology and Diabetes, Dept. of Pediatrics and Adolescent Medicine, University of Ulm, Germany. 8 Institute for Sex Research and Forensic Psychiatry, University Medical Center, Hamburg-Eppendorf, Germany. 9 Department of Pediatric, Adolescent and reconstructive Urology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 10 Psychotherapist, Berlin, Germany. 11 Institute of Human Genetics, University of Münster, Germany. 12 Institute of Medical Ethics and History of Medicine, University of Göttingen, Germany. 13 Dept. of Pediatric Surgery, University of Lübeck, Germany.

Abstract
INTRODUCTION: The term variations of sex development subsumes a large number of congenital conditions including chromosomal mosaics and variations of chromosomal, gonadal, and phenotypic sex. A situation of this nature may cause severe distress to both, parents and affected persons. One of the reasons for this is the binary form of gender classification in the society. In the past, because of a fear of possible stigmatization and an inability to cope with complex situations, it has been medical policy and practice for newborns to undergo early, mostly ‘feminizing’ elective surgery with the aim of achieving an outer genital appearance that is unambiguously male or female. Protests by advocacy groups for the most part as well as the results of outcome studies have shown that the development of affected persons may be very different to what has been expected and often does not result in the intended clear female or male gender identity as had been intended. It, therefore, seemed a matter of urgency to implement this new awareness as well as the ethical and personal human rights perspectives in the recommendations for the medical and psychosocial management of diverse sex development (DSD) in the future. STUDY DESIGN: In 2012, an interdisciplinary group of German academics engaged in the field of DSD decided to work on a consensus paper for this topic. It involved the participation of all faculties and non-scientific groups dealing with DSD, in particular advocacy and service-user groups. In a structured consensus, process recommendations were developed based on scientific literature as well as personal experiences of clinicians and affected individuals. RESULTS: Finally, 37 recommendations were agreed on. The strength of consensus is reflected in the degree of agreement as expressed in percentages. CONCLUSION: The introduction of the consensus paper reflects on the emerging paradigm shift and the necessity for a more open view of gender within society. The paper is intended to aid the performance of appropriate diagnostics in DSD-affected newborns and especially to help parents and affected persons cope with the biological and social consequences of DSD. With regard to medical or surgical therapy, it gives information about the most recent treatment trends.

359

Horm Res Paediatr. 2018;90(1):8-18.
Adrenocortical Carcinoma in Children: A Clinico-pathological Analysis of 41 Patients at the Mayo Clinic from 1950 to 2017. Gupta N1, Rivera M2, Novotny P3, Rodriguez V4, Bancos I5, Lteif A1.
1 Division of Pediatric Endocrinology and Metabolism, Mayo Clinic, Rochester, Minnesota, USA. 2 Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA. 3 Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA. 4 Division of Pediatric Hematology-Oncology, Mayo Clinic, Rochester, Minnesota, USA. 5 Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA.

Abstract
BACKGROUND/AIMS: Adrenocortical carcinoma (ACC) is an aggressive childhood cancer. Limited evidence exists on a definite histopathological criterion to differentiate ACC from adrenocortical adenoma. The aim of this study was to investigate the clinic-pathological data of children with ACC, identify prognostic factors, and validate a histopathological criterion to differentiate ACC from adrenocortical adenoma. METHODS: This retrospective cohort included 41 children, followed at the Mayo Clinic from 1950 to 2017 (onset of symptoms ≤21 years). Outcomes of interest were: alive with no evidence of disease, alive with evidence of disease, and dead of disease. RESULTS: Median age at onset of symptoms was 15.7 years (n = 41; range, 0.2-21 years). Female:male ratio was 3.6: 1. Mixed symptomatology (> 1 hormone abnormality) was the most common presentation (54%, n = 22). Sixty-six percent of patients (n = 27 out of 41) underwent total adrenalectomy. Metastatic disease was more common in children aged > 12 years (p = 0.002 compared to < 4 years). The most common sites of metastases were the liver and lungs. Overall 2-year and 5-year survival rates were 61% (95% CI 45-77) and 46% (95% CI 30-62), respectively. Metastasis at the time of diagnosis was independently associated with poor prognosis (risk ratio 13.7%; 95% CI 3.9-87.7). Weiss criteria (29%) and modified Weiss criteria (33%) were less accurate in younger patients (< 12 years), compared to the Wieneke index (100%). CONCLUSION: The presence of metastases was an independent prognostic factor. The Wieneke index was the most accurate in predicting clinical outcomes in younger children.

Selected Authors’ Comments:
ACC commonly presents with virilization and Cushing syndrome and rarely with feminization and hyperaldosteronism. ACC can also be nonfunctional and diagnosed incidentally during the evaluation of abdominal pain, fatigue or other nonspecific symptoms. The majority of ACC are sporadic, but some are associated with a genetic defect. Individuals with the Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, multiple endocrine neoplasia type 1, and familial adenomatous polyposis have an increased risk of ACC.
Surgery is the mainstay of treatment. Even after complete resection, a high risk of recurrence of ACC remains. Age < 4 years, tumor size 3, tumor weight and stage, metastatic disease, and quality of surgery have been suggested as important prognostic markers. Despite multimodality approaches including mitotane [an adrenolytic drug, chemotherapy with cisplatin, etoposide and doxorubicin (CED), and radiotherapy, prognosis of pediatric ACC remains poor with an estimated 5-year survival rate ranging from 30 to 90%. There is considerable overlap in clinical, radiological and histological features of ACC and adrenocortical adenoma, which makes decision-making challenging. Due to the rarity and heterogeneity of pediatric ACC, limited evidence exists on a definite histopathological criterion to differentiate ACC from adrenocortical adenomas.
Forty-one patients met the pre-specified inclusion criteria. Median age of all patients at onset of symptoms was 15.7 years (range, 0.2–21 years). High female preponderance was noted in all age categories with an overall female:male ratio of 3.6:1. Mixed symptomatology representing more than one hormonal abnormality was the most common presentation (54%, n = 22) followed by virilization alone (17%, n = 7). Evidence of isolated feminization in males or premature thelarche in females was not noted. None of the 41 patients had a known family history of ACC.
The findings from this study provide strong evidence that the natural course of ACC is significantly different and favorable in children younger than 4 years of age compared to those older than 12 years of age. Presence of metastases at the time of diagnosis of ACC is an independent prognostic factor for survival. Histopathological classification of ACC in pediatrics remains controversial. The Wieneke index was the most accurate in predicting clinical outcomes in younger children in this study.
These patients were treated with adjuvant therapy in settings of metastatic, recurrent, inoperable or stage IV disease. For localized disease, surgery alone was recommended. In a cohort of 111 children with ACC from the National Cancer Database (NCDB), adjuvant systemic therapy was utilized in 30% of children who underwent surgical resection. Mitotane (frequently selected) has been associated with significant gastrointestinal, neuropsychiatric and hepatic toxicity.
At a median follow-up of 2 years and 5 months, 61.8% patients remained alive. The 5-year overall survival estimate was 54.7% (95% CI 48.7–60.7). The age at which survival declines remains unclear. Results from the Surveillance, Epidemiology, and End Results (SEER) database indicated that overall 5-year survival for patients younger than 4 years was 91.1% (95% CI 74.8–97.1) and that it reduced significantly for patients aged 5–19 years to 29.8% (95% CI 16.8–44.1). Age less than 4 years was an important predictor of survival in these patients as well as in several other cohorts. This was likely related to a smaller tumor size, disease localized to adrenal gland, less advanced disease, and lower incidence of metastatic disease in younger children compared to older ones.

Conclusions, ACC in younger children has a distinct natural history compared to older children. Though age 4 years was an important predictor of survival in this study, metastatic disease at the time of diagnosis of ACC was an independent prognostic factor. Based on these findings, authors advocate utilization of the Wieneke index (in conjunction with clinical features) in predicting outcomes at least in younger children, though validation studies with a larger sample size are required. Efficacy of adjuvant systemic therapy remains unclear. Authors recommend observation after complete surgical resection in patients with localized disease and a low Wieneke index score.

360

REVIEW
Partially extracted from the following publication:
Expert Rev Endocrinol Metab. 2019 Mar;14(2):123-130
Update on Central Precocious Puberty (CPP): from Etiologies to Outcomes. Sena Cantas-Orsdemira and Erica A. Eugsterb
aDepartment of Pediatrics/Division of Pediatric Endocrinology, University of California School of Medicine, Orange, CA, USA; bDepartment of Pediatrics/Division of Pediatric Endocrinology and Diabetology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA.

Treatment of Precocious Puberty
GnRH analogs (GnRHas) are standardly utilized for the treatment of CPP. These agents stimulate the pituitary gonadotrophs in a continuous fashion as opposed to the physiologic pulsatile secretion of hypothalamic GnRH. This continuous stimulation leads to suppression of gonadotropins, resulting in decreased sex steroid production.
GnRHas are derived from native GnRH but contain modifications that result in increased potency and a longer half-life. They were initially approved for the treatment of prostate cancer. After a study showing that treatment with a GnRHa slowed growth velocity and bone age advancement and increased predicted final height in children with CPP [53], the monthly version Lupron Depot was approved by the FDA in 1993. This long-acting GnRHa in the form of monthly intramuscular leuprolide acetate was prescribed almost exclusively for the treatment of CPP in the U.S. for many years. Three-monthly depot preparations, also administered via intramuscular injection, have also been used to treat CPP, particularly in Europe [54]. Several studies as well as a meta-analysis have suggested that the degree of biochemical suppression achieved with 3-monthly dosing is consistently less than that seen with monthly GnRHa administration [54–57]. However, the clinical response to treatment appears to be similar based on limited data. Several other GnRHas have been developed through the years and used for the treatment of CPP including a subcutaneous implant containing histrelin and a six-monthly formulation of triptorelin (Triptodur) that was approved by the FDA for the treatment of CPP in 2017. Similar to other long-acting intramuscular GnRHa preparations, Triptodur has been shown to be effective and safe in children with CPP [58]. Additional 6-monthly forms of GnRHas are being investigated with promising initial results. The initial histrelin implant (Vantus) was first developed for the treatment of metastatic prostate cancer. A similar device (Supprelin) was approved by the FDA in 2007 after it was shown that it suppressed LH and sex steroid concentrations for at least 1 year. The subcutaneous implant allows for sustained release of the potent GnRHa histrelin, and requires a minor outpatient surgical procedure for implantation and removal, which are usually performed under local anesthesia [59]. The device is usually placed in the inner aspect of the upper arm. An initial pilot study in 11 girls previously treated with depot triptorelin revealed satisfactory maintenance of LH and FSH suppression following placement of a histrelin implant. Clinical evidence was also promising and included regression of breast development, decreased growth velocity, and attenuation in the rate of skeletal maturation during 15 months of treatment. Less discomfort and lifestyle interference as compared to monthly injections was another plus from this study [60]. This was followed by a phase III study in 36 patients with CPP (20 naïve) that demonstrated profound suppression of the HPG axis within 1 month of placement of the histrelin implant [61]. The extension phase of this study revealed a significant improvement in predicted adult height after up to 6 years of sequential annual histrelin implants [62]. However, an important advancement has been the establishment that a single histrelin implant lasts at least 2 years. This was demonstrated in a study involving 33 children with CPP in whom a single implant was left in place for 2 years [63]. Peak stimulated LH levels at 12 and 24 months were equivalent, and clinical parameters of CPP improved progressively. Use of a single implant for 2 years decreases the cost and numbers of surgical procedures in children treated with this modality. Other formulations include a daily subcutaneous injection and an intranasal spray with a multiple daily dosing schedule. The biggest concern with these formulations is compliance and subsequent failure of HPG axis suppression. Thus, they are rarely used in the clinical arena. Several adjunctive treatments above and beyond GnRHas have been proposed for the treatment of CPP including aromatase inhibitors and growth hormone. However, there is no clear evidence at present to support these in routine CPP treatment.

Authors´ References transcribed from their publications:

  1. Comte F, Cassorla F, Barnes KM, et al. Luteinizing hormone releasing hormone analogue therapy for central precocious puberty. Long-term effect on somatic growth, bone maturation, and predicted height. JAMA. 1986;255:2613–2616.
  1. Carel JC, Blumberg  J,  Seymour  C,  et  al.  Three-month sustained-release triptorelin (11.25 mg) in the treatment of central precocious puberty. Eur J Endocrinol. 2006;154:119e24.
  2. Lee PA, Klein K, Mauras N, et al. Efficacy and safety of leuprolide acetate 3-month depot 11.25 milligrams or 30 milligrams for the treatment of central precocious puberty. J Clin Endocrinol Metab. 2012 ;97:1572e80.
  3. Fuld K, Chi C, Neely EK. A randomized trial of 1- and 3-month depot leuprolide doses in the treatment of central precocious puberty. J Pediatr. 2011;159(6):982–987.
  1. Duarnd A, Tauber M, Patel B, et al. Meta-analysis of paediatric patients with central precocious puberty treated with intramuscular triptorelin 11.25 mg 3-month prolonged-release formulation. Horm Res Paediatr. 2017 ;87:224e32.•• Meta-analysis of 3-monthly triptorelin.
  2. Klein K, Yang J, Aisenberg J, et al. Efficacy and safety of triptorelin 6-month formulation in patients with central precocious puberty. J Pediatr Endocrinol Metab. 2016;29:1241e8. •• First report of a 6-monthly depot GnRHa.
  1. Lewis KA, Eugster EA. Experience with the once-yearly histrelin (GnRHa) subcutaneous implant in the treatment of central precocious puberty. Drug Des Dev Ther. 2009 ;3:1e5.
  2. Hirsch HJ, Gillis D, Strich D, et al. The histrelin implant: a novel treatment for central precocious puberty. Pediatrics. 2005;116:e798–80 2. •• First report of the use of the histrelin implant to treat CPP.
  1. Silverman LA, Neely EK, Kletter GB, et al. Long-term continuous suppression with once-yearly histrelin subcutaneous implants for the treatment of central precocious puberty: a final report of a phase 3  multicenter  trial.  J  Clin  Endocrinol  Metab. 2015 ;100:2354 2363.
  2. Eugster EA, Clarke W, Kletter GB, et al. Efficacy and safety of histrelin subdermal implant in children with central precocious puberty: a multicenter  trial.  J  Clin  Endocrinol  Metab. 2007;92:1697–1704.
  3. Lewis KA, Goldyn AK, West KW, et al. A single histrelin implant is effective for 2 years for treatment of central precocious puberty. J Pediatr. 2013 ;163:1214 –

361.

J Clin Endocrinol Metab. 2019 Apr 1; 104(4):1160-1170.
Psychosexual Aspects, Effects of Prenatal Androgen Exposure, and Gender Change in 46,XY Disorders of Sex Development. Loch Batista R1, Inácio M2, Prado Arnhold IJ1, Gomes NL1, Diniz Faria JA1, Rodrigues de Moraes D1, Frade Costa EM1, Domenice S1, Bilharinho Mendonça B1. 1Developmental Endocrinology Unit, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. 2 Psychology Department, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.

Abstract
CONTEXT: In 46,XY disorders of sexual development (DSD) patients, several factors may affect psychosexual development, leading to gender identity discrepancy and gender change later in life. Prenatal sexual steroid exposure and external genital virilization are considered to influence human psychosexual development, but their roles not completely understood yet. DESIGN: A total of 144 individuals (18 to 60 years of age) with a clinical/molecular diagnosis of 46,XY DSD from a single tertiary center were enrolled. Psychosexual outcomes (gender role, gender identity, and sexual orientation) were assessed using questionnaires and psychological test. The Sinnecker score was used for genital virilization measurement. Prenatal androgen exposure was estimated according to 46,XY DSD etiology. RESULTS: We found a positive association between prenatal androgen exposure and male psychosexual outcomes. Alternatively, prenatal estrogen exposure, age of gonadectomy, and the degree of external genital virilization did not influence any psychosexual outcome. There were 19% (n = 27) with gender change, which was associated with prenatal androgen exposure (P < 0.001) but not with the external genital virilization. The median age of gender change was 15 years, but most of the patients reported the desire for gender change earlier. Prenatal androgen exposure influenced psychosexual development in 46,XY DSD favoring male psychosexuality in all psychosexual outcomes, whereas the degree of external genital virilization did not influence these outcomes. The organizational effect of sexual steroids on psychosexuality at puberty appears to be weak in comparison with the prenatal effects. Prenatal androgen exposure also influenced female-to-male gender change frequency. All 46,XY DSD conditions with prenatal androgen exposure must be followed for gender issues in their management.

Extracted Authors´Comments
During certain critical prenatal periods, androgens act directly on neural regions, containing the corresponding steroid receptors and providing organizational changes in the brain in areas related to sexual behavior. The first and strongest period of brain sensitivity to sexual steroids is the prenatal time. The second one occurs at puberty, and the psychosexual development will be done at late puberty. It has been largely demonstrated that prenatal androgen exposure favors a male gender role.
In conclusion, authors demonstrated that prenatal androgen exposure influenced human psychosexual development, favoring male gender role, gender identity, and sexual orientation in 46,XY DSD patients. Despite the evidence on estrogens favoring the development of male brain structures and inducing male behaviors in exposed female mice, there was no evidence that estrogens influence a human male psychosexuality. The degree of external genital virilization did not influence the psychosexual development. The pubertal organizational effects of sex steroids were not enough to change psychosexual outcomes, suggesting that these effects are weaker than prenatal androgen exposure in human psychosexuality. Gender change was common in this 46,XY DSD cohort, particularly from female to male, especially in 5a-RD2 and 17b-HSD3 deficiencies. However, the gender change occurs also in other 46,XY DSD diagnoses, showing that all 46,XY DSD etiologies deserve attention about gender issues. Among patients who changed their gender, the desire for gender change usually occurred since childhood. Extensive care about gender issues should be instituted very early in the management of 46,XY DSD patients with 46,XY DSD to avoid this suffering. They think that these findings might help guide the sex assignment of male newborns with atypical genitalia and to expand the knowledge on the influence of prenatal sexual steroids in the human psychosexuality.

 

362

Clin Endocrinol (Oxf). 2019 Apr;90(4):506-516
Management of hypothalamic disease in patients with craniopharyngioma. Christopher J. Thompson1,2 | Richard W. Costello2,3, Rachel K. Crowley4,5
1Academic Department of Endocrinology, Beaumont Hospital, Dublin, Ireland 2Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland 3Department of Respiratory Medicine, Beaumont Hospital, Dublin, Ireland 4Department of Endocrinology, St Vincent’s University Hospital, Dublin, Ireland 5University College, Dublin, Ireland

Abstract
Patients with craniopharyngioma experience excess morbidity and mortality when compared with the background population and with other hypopituitary patients.
Large, suprasellar tumours which form micropapillae into surrounding structures can cause hypothalamic damage before any therapeutic intervention; attempted gross total resection can lead to hypothalamic obesity, sleep disorders, thirst disorders and dysregulation of temperature as well as panhypopituitarism. The management of tumour bulk and the pathophysiology of hypothalamic complications have been reviewed extensively. They present a practical, clinical approach to management of hypothalamic disease in a patient with craniopharyngioma and highlight potential targets for future pharmacological or surgical intervention.

Comments
In this clinical review, authors describe a clinical approach to assessment of the pediatric or adult patient with CP, with particular focus on the post‐operative long‐term management of hypothalamic disease, and review the evidence for interventions to improve survival, health and quality of life for such a patient. A literature search was conducted using PubMed including the terms CP, hypothalamus, and specifically CP AND hypopituitarism, CP AND obesity, CP AND sleep, CP AND fertility, CP AND thirst. The diagnosis of a patient with CP challenges the endocrinologist to broaden his or her traditional clinical role. The endocrinologist should be involved at the beginning of a CP patient’s clinical treatment in designing a treatment plan to minimize hypothalamic damage by surgery or radiotherapy, should diagnose any hormone deficiency and address it with appropriate replacement within the disease‐specific considerations for CP and should have a plan for prevention or treatment of HO.
After surgery or radiotherapy re‐assessment of endocrine axes may be indicated, weight gain should be addressed promptly and any symptom of thirst, sleep or thermoregulatory disorder should be investigated. The endocrinologist may co‐ordinate input from the sleep service, dietetics, metabolic surgery and psychology as well as the more traditional pituitary multidisciplinary team. Hypothalamic complications such as adipsic DI should prompt surveillance for associated disorders such as poikilothermia or disordered sleep; patients with such conditions benefit from increased community support.
Treatment of one complication may have an impact on another—for example, treatment of somnolence may aid weight loss efforts. There is no evidence that treatment of hypothalamic conditions would impact on the increased mortality observed in CP patients but it seems reasonable that treatment of OSA might improve respiratory mortality or cardiovascular mortality, and that use of thromboprophylaxis in hypernatraemia would prevent fatal venous thromboembolism. Their experience with these patients is that an individualized approach is key and that a proactive attitude within the team can lead to clinical benefit for patients.

 

363

Steroid Biochem Mol Biol. 2019 Feb 25;189:73-80.
Isolated glucocorticoid deficiency: Genetic causes and animal models. Maharaj A1, Maudhoo A1, Chan LF1, Novoselova T1, Prasad R1, Metherell LA1, Guasti L2.
1 Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, Charterhouse Square, London, United Kingdom. 2 Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, Charterhouse Square, London, United Kingdom.

Abstract
Hereditary adrenocorticotropin (ACTH) resistance syndromes encompass the genetically heterogeneous isolated or Familial Glucocorticoid Deficiency (FGD) and the distinct clinical entity known as Triple A syndrome. The molecular basis of adrenal resistance to ACTH includes defects in ligand binding, MC2R/MRAP receptor trafficking, cellular redox balance, cholesterol synthesis and sphingolipid metabolism. Biochemically, this manifests as ACTH excess in the setting of hypocortisolaemia. Triple A syndrome is an inherited condition involving a tetrad of adrenal insufficiency, achalasia, alacrima and neuropathy. FGD is an autosomal recessive condition characterized by the presence of isolated glucocorticoid deficiency, classically in the setting of preserved mineralocorticoid secretion. Primarily there are three established subtypes of the disease: FGD 1, FGD2 and FGD3 corresponding to mutations in the Melanocortin 2 receptor MC2R (25%), Melanocortin 2 receptor accessory protein MRAP (20%), and Steroidogenic acute regulatory protein STAR (5-10%) respectively. Together, mutations in these 3 genes account for approximately half of cases. Whole exome sequencing in patients negative for MC2R, MRAP and STAR mutations, identified mutations in minichromosome maintenance 4 MCM4, nicotinamide nucleotide transhydrogenase NNT, thioredoxin reductase 2 TXNRD2, cytochrome p450scc CYP11A1, and sphingosine 1-phosphate lyase SGPL1 accounting for a further 10% of FGD. These novel genes have linked replicative and oxidative stress and altered redox potential as a mechanism of adrenocortical damage. However, a genetic diagnosis is still unclear in about 40% of cases. Authors describe here an updated list of FGD genes and provide a description of relevant mouse models that, despite some being flawed, have been precious allies in the understanding of FGD pathobiology.

Highlights.

  • The molecular basis of adrenal resistance to ACTH is heterogeneous.
  • Clinically, ACTH resistance manifests as ACTH excess in the setting of hypo-cortisolemia.
  • Genes whose mutations cause Familial GlucocorticoidDeficiency include MC2RMRAP, and STAR.
  • Genes involved in cellular redox balance, cholesterol synthesisand sphingolipid metabolism, have also been involved.
  • Mouse modelsof FDG have been developed and they mimic, completely or only partially, the human phenotype.

 

364

Nature. 2018 April ; 556(7700): 249–254.
Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer. Dasgupta S1,2, Rajapakshe K3, Zhu B3, Nikolai BC3, Yi P3, Putluri N3, Choi JM3, Jung SY4, Coarfa C3, Westbrook TF4, Zhang XH3, Foulds CE3,5, Tsai SY3, Tsai MJ3, O’Malley BW6.
1 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. 2Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. 3 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. 4 Verna & Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA. 5 Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA 6 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.

Abstract
Alterations in both cell metabolism and transcriptional programs are hallmarks of cancer that sustain rapid proliferation and metastasis1 However, the mechanisms that control the interaction between metabolic reprogramming and transcriptional regulation remain unclear. Here we show that the metabolic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) regulates transcriptional reprogramming by activating the oncogenic steroid receptor coactivator-3 (SRC-3). We used a kinome-wide RNA interference-based screening method to identify potential kinases that modulate the intrinsic SRC-3 transcriptional response. PFKFB4, a regulatory enzyme that synthesizes a potent stimulator of glycolysis2, is found to be a robust stimulator of SRC-3 that co-regulates estrogen receptor. PFKFB4 phosphorylates SRC-3 at serine 857 and enhances its transcriptional activity, whereas either suppression of PFKFB4 or ectopic expression of a phosphorylation-deficient Ser857Ala mutant SRC-3 abolishes the SRC-3-mediated transcriptional output. Functionally, PFKFB4-driven SRC-3 activation drives glucose flux towards the pentose phosphate pathway and enables purine synthesis by transcriptionally upregulating the expression of the enzyme transketolase. In addition, the two enzymes adenosine monophosphate deaminase-1 (AMPD1) and xanthine dehydrogenase (XDH), which are involved in purine metabolism, were identified as SRC-3 targets that may or may not be directly involved in purine synthesis. Mechanistically, phosphorylation of SRC-3 at Ser857 increases its interaction with the transcription factor ATF4 by stabilizing the recruitment of SRC-3 and ATF4 to target gene promoters. Ablation of SRC-3 or PFKFB4 suppresses breast tumour growth in mice and prevents metastasis to the lung from an orthotopic setting, as does Ser857Ala-mutant SRC-3. PFKFB4 and phosphorylated SRC-3 levels are increased and correlate in estrogen receptor-positive tumors, whereas, in patients with the basal subtype, PFKFB4 and SRC-3 drive a common protein signature that correlates with the poor survival of patients with breast cancer. These findings suggest that the Warburg pathway enzyme (aerobic glycolysis) PFKFB4 acts as a molecular fulcrum that couples sugar metabolism to transcriptional activation by stimulating SRC-3 to promote aggressive metastatic tumors.

Comments
Even though the present subject is outside the pediatric field, it seems to be an impressive step forward for a better management of breast cancer.


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