Lawson Wilkins Pediatric Endocrine Society Research Articles

Observational study of disorders of sex development in Yaounde, Cameroon.

Introduction According to the current classification of the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Pediatric Endocrinology (ESPE) of Disorders of Sex Development (DSD), etiologies vary around the world. Ethnic or genetic diversity probably explains this variability. We therefore conducted the present study on etiologies of DSDs in a country from central Africa. Methods We carried out an observational retrospective study at the Pediatric Endocrinology Unit of the Mother and Child Centre of the Chantal Biya Foundation in Yaounde, Cameroon from May 2013 to December 2019. All patients diagnosed with a DSD were included, and incomplete files excluded. Results We included 80 patients diagnosed with DSD during the study period. The 46,XX DSD were the most frequent in our study population (n = 41, 51.25%), with congenital adrenal hyperplasia (CAH) as the main diagnosis. The 46,XY DSD accounted for 33.75% and sex chromosome DSD group represented 15% of the study population. Conclusions DSDs are not an exceptional diagnosis in a Sub-Saharan context. 46,XX DSD are the most prevalent diagnosis in our setting. The diagnosis of all these affections is late compared to other centers, justifying advocacy for neonatal screening of DSDs in our context.

What Hospitalists Should Know About Intersex Adults.

An intersex condition is one in which an individual is born with atypical male or female external genitalia, gonads, hormones, or chromosomes. Older terms, such as pseudohermaphroditism and hermaphroditism, are controversial, leading the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Paediatric Endocrinology (ESPE) to propose in 2006 the expression "disorders of sex development" (DSD), a contentious term in its own right, to define congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical. The birth of a child with DSD often prompts a long-term, multidisciplinary strategy, involving an array of health-care professionals. While much has been written about these potentially challenging management decisions, particularly those regarding infant genital surgery, very little has been written on the health management of intersex adults, and no literature exists regarding the role of the hospitalists-specialists in inpatient medicine-in the care of patients with DSD. With more than 50,000 members, Hospital Medicine represents the fast-growing subspecialty in the history of medicine. We believe hospitalists are uniquely positioned to provide high-quality care while educating trainees about issues pertinent to this often marginalized patient population. This essay poses a case study to explore some of the medical issues that intersex patients face as adults and that hospitalists will likely encounter.

A model of delivering multi-disciplinary care to people with 46 XY DSD

In 2006, a consensus statement was jointly produced by the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society of Paediatric Endocrinology (ESPE) concerning the management of disorders of sex development (DSD) [1]. A recommendation provided by this consensus was that evaluation and long-term care for people affected by DSD should be performed at medical centers with multi-disciplinary teams experienced in such conditions. Here we provide our team’s interpretation of the 2006 consensus statement recommendations and its translation into a clinical protocol for individuals affected by 46 XY DSD with either female, or ambiguous, genitalia at birth. Options for medical and surgical management, transitioning of care, and the use of mental health services and peer support groups are discussed. Finally, we provide preliminary data to support the application of our model for delivering multi-disciplinary care and support to patients and their families.

Etiological Classification and Clinical Assessment of Children and Adolescents with Disorders of Sex Development - Original Article

Objective: In 2006, the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Paediatric Endocrinology (ESPE) published a consensus statement on management of intersex disorders. The aim of our study was to determine the etiological distribution of disorders of sex development (DSD) according to the new DSD classification system and to evaluate the clinical features of DSDs in our patient cohort. Methods: We retrospectively reviewed the records of patients followed up during the past three years. The subjects were divided into three etiologic groups according to their karyotypes. The definite diagnosesin each subgroup were established by clinical and laboratory investigations including abdominopelvic imaging as well as basal and stimulated hormone measurements. Molecular genetic testing, except for CYP21A2 gene, could not be performed. Results: Out of a total of 95 patients, 26 had sex chromosome DSD, 45 had 46,XY DSD and 24 had 46,XX DSD. The most common causes of DSDs were Turner’s syndrome (TS), congenital adrenal hyperplasia (CAH) and androgen insensitivity syndrome (AIS). There was a wide variation in age of presentation ranging from 1 day to 17.5 years with a mean of 6.5±6.5 years. The most frequent complaints at presentation were ambiguous genitalia, isolated perineal hypospadias and short stature. Conclusion: The results of our study demonstrate that the new DSD classification system leads to a major change in the distribution of etiological diagnoses of DSDs, which is exemplified by the significant frequencies of TS and vanishing testes syndrome. This alteration expands the clinical spectrum and increases the mean age at diagnosis. However, the most common causes of ambiguous genitalia, such as CAH and AIS, remain unchanged. Further studies using molecular genetic analyses are needed to give a more precise distribution of etiologies of DSDs, especially in 46,XY patients.Conflict of interest:None declared.

Impact of the consensus statement and the new DSD classification system

In 2006, a task force of 50 specialists sponsored by the European Society for Paediatric Endocrinology (ESPE) and the Lawson Wilkins Pediatric Endocrine Society (LWPES) devised a Consensus Statement outlining the recommendations for the management of disorders of sex development (DSDs; then referred to as 'intersex' disorders) as well as proposing a new nomenclature and DSD classification system. In the 2 years subsequent to its publication, the Statement has been widely cited and endorsed in the literature as a model for patient care. In addition, much of the scientific literature incorporates the newly proposed nomenclature and classification system as part of its own discourse. However, without a systematic analysis of the uptake of recommendations of the Statement, it is not possible to make valid conclusions regarding the uptake of the recommendations within clinical practice. Here we discuss the Consensus Statement and its impact with respect to the newly proposed nomenclature and psychosocial management according to a new study following 60 DSD centres throughout Europe. Finally, we discuss future directions for research in the management of DSD, beginning at the moment of disclosure.

63 Years and 715 Days to the “Boxed Warning”: Unmasking of the Propylthiouracil Problem

715 days after potential problems related to PTU use in children were presented in a debate in front of the Lawson Wilkins Pediatric Endocrine Society (LWPES), the US Food and Drug Administration issued a “black-box” warning about the hepatotoxicity risk of the antithyroid drug propylthiouracil (PTU). This safety advisory followed the collective actions of academic societies, medical publishers, the National Institutes of Health, and the FDA. Considering that surgery and radioactive iodine are the legitimate treatment options for Grave Disease (GD), and are now the preferred alternative therapy in individuals who developed toxic reactions to MMI, the use of PTU should now be limited to exceptional circumstances and pregnancy. Long-term PTU therapy, especially in children, is not justifiable. The current advisory comes 63 years after the introduction of PTU for clinical use in 1947.

Obituary of Dr. Angelo Di George

Obituary of Dr. Angelo Di George

Management of children and adolescents with diabetes requiring surgery

Department of Pediatrics, Uddevalla Hospital, Uddevalla,SwedenCorresponding author:Ragnar Hanas, MD, PhDDepartment of Pediatrics,Uddevalla Hospital,S-451 80 Uddevalla,Sweden.Tel: 146 522 92000;fax: 146 522 93149;e-mail: ragnar.hanas@vgregion.seConflicts of interest: SB is the owner of the New EnglandDiabetes and Endocrinology Center (NEDEC) and Presidentof New England Diabetes and Endocrinology ResearchFund, Incorporated (NEDERF, Inc.). He is a member of theadvisory panel, standing committee or board of directors:for American Diabetes Association (ADA), Juvenile DiabetesResearch Foundation (JDRF), International Diabetes Federation(IDF),International SocietyforPediatric andAdolescentDiabetes(ISPAD),AmericanAcademyofPediatrics(AAP),LawsonWilkinsPediatric Endocrine Society (LWPES); has received honorariaor speaker’s fees from Eli Lilly, Novo-Nordisk, Minimed,LifeScan, Genentech, Serono, Teva Pharmaceuticals; and hasreceived grants from Eli Lilly, Novo-Nordisk, NIH, SelfCare,InvernessMedical,MedicalFoods,Abbott-Medisense,LifeScan,Genentech, Pharmacia, Bristol-Squibb Myers, Pfizer, Serono,Johnson and Johnson. The remaining authors have declared noconflicts of interest.Editors of the ISPAD Clinical Practice Consensus Guidelines2009 comperdium: Ragnar Hanas, Kim Donaghue, GeorgeannaKlingensmith, Peter GF Swift.This article is a chapter in the

Primum Non Nocere (First, Not to Harm) and Secundus, Opinio Vulnero (Second, Report the Harm)

The practice of medicine involves definite and random risks. These risks relate to the unpredictable biology that we deal with; genetic and nongenetic individual variabilities; age and gender; compliance and environmental factors. Uniformly applied, standard approaches to care that have been shaped by clinical trials and modified by empiricism typically result in desired favorable outcomes. In the best of circumstances, though, adverse outcomes occur that need to be collectively harnessed. As new drugs enter our pharmacopoeia, some which are approved based on modest size clinical trials and others being used “off-label,” our obligation for vigilance and reporting adverse events (AEs) increases. Let us consider recombinant IGF-1 therapy. The number of individuals with bonafide growth hormone resistance, the United States Food and Drug Administration (FDA) approved indication [1], is very small [2, 3]. FDA approval of recombinant IGF-1 was based on an experience of about 100 patients [1]. If one looks to situations where other drugs have been recalled from the market place, safety signals were not apparent in preapproval studies involving thousands of individuals [4] (http://www.fda.gov/opacom/7alerts.HTML; http://www.consumerjusticegroup.com/drugrecall/drugrecalls.html). Only when the drugs hit the market place and use was expanded by thousands more, problems leading to withdrawal of the compounds took place. Not long ago, a patient of ours had a life-threatening anaphylactic reaction to recombinant IGF-1 and was subsequently shown to have allergy to the preparation by a formal testing [5]. This adverse event was reported to the manufacturer who reported it to the FDA. Last month, I received a call from an endocrinologist in another part of the US describing a possible similar occurrence for this compound, illustrating the need for further collection of clinical experience data for new medications. Aromatase inhibitors are used “off-label” at many pediatric endocrine centers as a therapeutic for potential height augmentation. Investigational studies of such compounds have revealed modest, but tantalizing increases in long-term growth [6, 7]. But with the promise comes the poise. Vertebral abnormalities have been found in children treated with one such compound [8]. Although further studies are needed to assess if there are indeed adverse effects of specific aromatase inhibitors or the class of compounds in general on the growing spine [8], it is very likely that many “off-label” prescribers of aromatase inhibitors are not aware of this potential problem. Problems also rest with drugs that have been around for so long that they may escape rereview of their safety. Recently, a potential safety concern related to the use of propylthiouracil was brought to the attention of Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and a special workshop was convened by the Obstetric and Pediatric Pharmacology Branch (OPPB) of NICHD to look at the issue of PTU safety. As detailed in the minutes of the meeting, a serious hepatotoxicity safety concern related to PTU use in children was recognized (http://bpca.nichd.nih.gov/outreach/index.cfm) [9]. Thus, it took 60 years since PTU was introduced before safety concerns related to the use of this compound in children were formally addressed, highlighting the special challenges involved in monitoring drugs that have been in the market for decades. It is clear that as a discipline, we need to become proactively engaged in drug safety and monitoring issues and assist pharmaceutical companies and regulatory agencies in this area. It is a disservice for AEs to be hidden in clinic files. We all need to spare a few minutes and report AEs to the FDA, which is easily accomplished via the MedWatch Program (http://www.medwatch.com/). In pediatrics in the United States, we have a special opportunity afforded by the Best Pharmaceuticals for Children Act (BPCA) Program to address such issues. The BPCA was signed into law on January 4, 2002, to establish a process for studying on-patent and off-patent drugs used in children. The Obstetric and Pediatric Pharmacology Branch (OPPB) of NICHD leads BPCA efforts on behalf of the NIH (http://bpca.nichd.nih.gov/index.cfm). As highlighted by the recent workshop on PTU safety, it is hoped that the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the American Academy of Pediatrics (AAP) will partner with OPPB and NICHD and establish new ways to identify drug and therapeutic safety concerns in our field. In using “on-label” or “off-label” therapies, we need to remember a tenet of medicine “Primum non nocere” (First, not to harm). To this credo, we must add “Secundus, opinio vulnero” (Second, report the harm).

Use of Insulin Pump Therapy in the Pediatric Age-Group

Young patients with diabetes, their families, and their diabetes care providers continue to be faced with the challenge of striving to maintain blood glucose levels in the near-normal range. High blood glucose levels with elevated A1C levels are associated with long-term microvascular and macrovascular complications. Recurrent episodes of hypoglycemia, especially at young ages, may cause short- and long-term adverse effects on cognitive function and lead to hypoglycemia unawareness and may be associated with significant emotional morbidity for the child and parents. Fear of hypoglycemia, especially during the night, may compromise quality of life (QOL) for the family and jeopardize efforts to achieve optimal metabolic control. Over the past decade, continuous subcutaneous insulin infusion (CSII) has gained increasing popularity among patients with diabetes. CSII is the most physiologic method of insulin delivery currently available. It is able to closely simulate the normal pattern of insulin secretion, namely continuous 24-h adjustable “basal” delivery of insulin upon which are superimposed prandial “boluses.” In addition, CSII offers the possibility of more flexibility and more precise insulin delivery than multiple daily injection (MDI). However, there is still debate among diabetes care practitioners around the world as to whether CSII has advantages over MDI in terms of reduction in A1C levels, occurrence of severe hypoglycemic events, episodes of diabetic ketoacidosis (DKA), and frequency of hospitalizations in young patients. Furthermore, no clear criteria have been established to help the physician choose the “appropriate” patient for CSII therapy. To address these issues, the European Society for Pediatric Endocrinology (ESPE), the Lawson Wilkins Pediatric Endocrine Society (LWPES), and the International Society for Pediatric and Adolescent Diabetes (ISPAD) convened a panel of expert physicians for a consensus conference endorsed by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). For each major topic area, …

Current prescribing practices and opinions about growth hormone therapy: results of a nationwide survey of paediatric endocrinologists

With the advent of several new treatment indications for recombinant hGH, endocrinologists are being asked to make some difficult decisions regarding eligibility for treatment. The purpose of this study was to summarize prevailing attitudes about GH diagnosis and treatment among paediatric endocrinologists. We sent surveys to all active US members of the Lawson Wilkins Pediatric Endocrine Society (LWPES) listed in the 2004-05 directory (excluding our own group of physicians). Thirty-eight per cent of the surveys were returned and 182 met eligibility for analysis. Surveys were divided into four parts: demographic data, answers reflecting current diagnosis practices for GH deficiency and treatment with GH, attitudes and clinical practice for the idiopathic short stature (ISS) diagnosis, and four case studies. Through a series of questions, we elicited the influence towards prescribing GH of current height, growth velocity, predicted height, pubertal progression and other variables. Results were entered into a Microsoft Access database and statistical evaluation was conducted. Eighty-eight per cent of respondents answered 'no' to the statement that there is good consensus on who should be treated with GH and over 90% answered 'no' to the statement that secretagogue testing was the best way to determine if a child would benefit from GH. Factors listed by respondents as important for prescribing GH include: growth velocity less than the 25th percentile, target height less than the 5th percentile and pubertal stage greater than Tanner 2. Current height was also important; however, answers varied as to what height percentile indicated the need for treatment. When queried about prescribing practices for nonstraightforward cases, 62% of respondents answered that the cost of GH influenced their decision to treat, 55% responded that concerns of future unknown side-effects affected their decision and 37% noted family persistence influenced their decision. In response to queries about ISS, 82% answered that they were currently using the new indication and 69% answered that there was a need for the indication. The statement that short stature could be a disability received a 'yes' response from 78%. Answers to the four cases reflected lack of consensus, with one-third of all respondents answering that they would treat each case, one-third choosing to treat more than two of the cases and one-third treating less than two of the cases. Endocrinologists differed in their answers about cause for treatment with GH but in general favoured use of poor growth velocity, poor target height and low IGF-1 levels as indications to treat a paediatric patient with GH.

Approach to Adolescent Polycystic Ovary Syndrome (PCOS) in the Pediatric Endocrine Community in the USA

Polycystic ovarian syndrome (PCOS) is the most common endocrinopathy in adult women, and is emerging as a common cause of menstrual disturbances in the adolescent population. Insulin resistance, which is considered one of its underlying causes, has increased substantially in the past decade, putting more adolescent girls at risk for PCOS and its complications. Our objective was to survey pediatric endocrinologists' approach to diagnosis and treatment of PCOS in the adolescent population, as there is presently no structured recommended approach to this emerging problem. A questionnaire survey was sent to 839 members of the Lawson Wilkins Pediatric Endocrine Society (LWPES). A total of 176 (21%) responses was received and analyzed. REDULTS: The majority of the participants would consider initiating work-up in an adolescent with oligomenorrhea or secondary amenorrhea 12-24 months after menarche. The following work-up was selected as a baseline for a teenager with oligomenorrhea or secondary amenorrhea by more than 50% of participants: LH and FSH, total and free testosterone, prolactin, 17-OH-progesterone, DHEAS and glucose/insulin measurements. For treatment of PCOS, the majority of surveyed endocrinologists suggested estrogen/progesterone combination. Metformin was considered appropriate treatment in the general adolescent population with PCOS by 30% and in obese teenagers with PCOS by 68% of surveyed endocrinologists. Our findings indicate the trend among pediatric endocrinologists towards earlier work-up of menstrual irregularities in adolescents--unlike the traditional practice of waiting for 2 years after menarche. Most pediatric endocrinologists would consider evaluation for insulin resistance using glucose/insulin measurement, but only a small percentage considers performing OGTT in these patients. Even though using estrogen/progesterone combination is the preferred therapeutic approach, 30% of surveyed endocrinologists consider metformin therapy for the general adolescent population with PCOS, and 68% would consider using it in obese adolescents with PCOS.

Growth Hormone Effects on Adult Height in Idiopathic Short Stature

Growth Hormone Effects on Adult Height in Idiopathic Short Stature

Identification and treatment of cystic fibrosis-related diabetes. A survey of current medical practice in the U.S.

To describe physicians' attitudes and practices in screening for and treating abnormalities in glucose homeostasis in cystic fibrosis (CF) patients and to test the hypotheses that guidelines for screening for CF-related diabetes (CFRD) are not followed at most centers and that screening and treatment vary by the care provider's background. This cross-sectional survey included three groups of physicians: 1) 593 members of the Lawson Wilkins Pediatric Endocrine Society (LWPES), 2) 462 members of the pediatric assembly of the American Thoracic Society (ATS), and 3) 194 directors of cystic fibrosis centers (CFD). A mailed questionnaire was used for the survey. The overall response rate was 67%. Of these, 224 LWPES, 143 ATS, and 135 CFD physicians reported actively seeing CF patients. About two-thirds of CF physicians (ATS and CFD) reported routine screening for impaired glucose tolerance (IGT) in asymptomatic CF patients; a random glucose is most often used (60%), followed by HbA1c (50%), urine glucose (44%), fasting glucose (21%), and oral glucose tolerance test (2%). Only 40% of LWPES physicians reported intervening for stress-induced hyperglycemia, but 61% reported use of insulin for persistent IGT. Management of CFRD was similar for all groups; most physicians used insulin (91%). LWPES recommended more intensive glucose testing and nutritional guidelines than did ATS/CFD (P < 0.0001). LWPES reported less concern about risks of diabetes complications (P < 0.0001) and the importance of minimizing burdensome interventions (P < 0.01). All groups considered weight management a top priority. Screening for IGT is not routinely done in CF patients and screening tests vary. Greater agreement exists on methods of treating patients with persistent IGT or CFRD, although goals and aggressiveness of treatment vary with the provider's background. A consensus conference is recommended.

Estrogen Use in Children and Adolescents: A Survey

Members of the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society of Pediatric Endocrinology (ESPE) were mailed a questionnaire to survey their views and practices with respect to the use of estrogens in children and adolescents. The purpose of this survey was to ascertain the prevalence of estrogen therapy in children and adolescents, as well as the estrogen preparation used, dose, benefits, and observed complications. Seventy-four of 213 LWPES members or groups and 29 of 106 ESPE members or groups returned the survey. The lack of rapid retrieval systems in many clinics and the necessity for return of the survey data within a ten-week period precluded many respondents from the exhaustive, careful chart reviews necessary to answer many of the questions posed. Accordingly, data generated in this survey must be interpreted in this light. Estrogens are used primarily in children and adolescents for (1) the treatment of tall stature, (2) replacement therapy in hypogonadal adolescents, and (3) as a component of contraceptive pills given to sexually active teenagers. ESTROGEN TREATMENT OF TALL GIRLS The treatment of "excessively" tall adolescent girls with pharmacologic doses of estrogen, in an attempt to decrease mature height, has been a subject of controversy since its inception by Goldzieher1 in 1956; 50% of the LWPES and 17% of the ESPE respondents indicated that they never treat "tall" girls with pharmacologic doses of estrogen, basing their decision primarily on the fact that the long-term side effects of such doses of estrogens are unknown. In addition, the risk-benefit ratio and the fact that tall stature is not a disease were other important reasons for not treating these girls.