Alexander A L Jorge

University of São Paulo | USP · Department of Clinical Medicine (VCM)

Introduction: Mutations in the thyroid hormone receptor alpha (THRA) gene are a rare cause of thyroid hormone resistance, which leads to a pleomorphic phenotypic spectrum. Hormonal profiles are variable and subtle, making laboratory diagnoses challenging. Genetic evaluation can be a helpful tool in diagnosing these cases. Case presentation: Three p...

Genetic analysis of sporadic Medullary Thyroid Carcinoma (MTC) has revealed somatic variants in RET, RAS, and occasionally other genes. However, around 20% of sporadic MTC patients lack a known genetic driver. To uncover potential new somatic or germline drivers we analyze a distinct cohort of patients with sporadic, very early-onset and aggressive...

Syndromic obesity refers to obesity occurring with additional clinical findings, such as intellectual disability/developmental delay, dysmorphic features, and congenital malformations. Purpose of Review To present a narrative review regarding the genetic etiology, clinical description, and molecular diagnosis of syndromic obesity, which is a rare...

Microcephaly is characterized by an occipitofrontal circumference at least two standard deviations below the mean for age and sex. Neurodevelopmental disorders (NDD) are commonly associated with microcephaly, due to perturbations in brain development and functioning. Given the extensive genetic heterogeneity of microcephaly, managing patients is hi...

Disclosure: L.D. Cellin: None. N.L. Menezes De Andrade: None. R.C. Rezende: None. V. Souza: None. N.C. Dantas: None. E. Quedas: None. M.F. Funari: None. G. Vasques: None. R.D. Scalco: None. A.C. Malaquias: None. A. Jorge: Consulting Fee; Self; Novo Nordisk. Grant Recipient; Self; BioMarin. Introduction: Children classified as idiopathic short statu...

Disclosure: N.L. Menezes De Andrade: None. M.F. Funari: None. A. Malaquias: Speaker; Self; Novo Nordisk. N.C. Dantas: None. R. Rezende: None. L.D. Cellin: None. T.K. Homma: None. A.M. Lerario: None. I.J. Arnhold: None. G.A. Vasques: Employee; Self; Eli Lilly & Company. A.A. Jorge: Advisory Board Member; Self; Novo Nordisk. Consulting Fee; Self; Nov...

Disclosure: A.G. de Faria: None. L.R. Montenegro: None. A.A. Jorge: None. R.S. Jallad: None. R.M. Martin: None. M.C. Fragoso: None. A.P. Canton: None. C.E. Seraphim: None. F.R. Tinano: None. N.C. Pinto: None. B.B. Mendonca: None. A. Latronico: None. V.N. Brito: None. Background: McCune-Albright Syndrome (MAS) is a rare congenital disorder caused by...

Disclosure: J.V. Coutinho: None. A.S. Costa: None. M.M. Issa: None. N.P. Paim: None. E.P. Quedas: None. V.S. Nunes: None. A.L. Jorge: None. E.R. Nakandakare: None. A.F. Carrilho: None. Background: Sitosterolemia is a rare autosomal recessive disease caused by inactivating mutations in the ABCG5 or ABCG8 genes. It is characterized by the accumulatio...

Disclosure: L.D. Cellin: None. K.G. Guimaraes: None. N.L. Menezes De Andrade: None. G.A. Vasques: None. E.D. Goiano: None. M. Akkari: None. C. Santili: None. A.A. Jorge: None. A.C. Malaquias: None. Introduction: COL2A1 is the primary collagen synthesized by chondrocytes and plays a critical structural role in regulating cell growth, differentiation...

Disclosure: S.C. Chen: None. E. Charmandari: None. J. Choi: None. X. Dou: None. C. Gong: None. R. Hamza: None. J. Harvey: None. A.R. Hoffman: None. R. Horikawa: None. G. Johannsson: None. A.A. Jorge: None. B.S. Miller: None. S. Roehrich: None. L.S. Savendahl: None. X. Tserotopolou: None. M.P. Wajnrajch: None. S.F. Ahmed: Grant Recipient; Self; Novo...

Acromesomelic dysplasia, PRKG2 type (AMDP, MIM 619636), is an extremely rare autosomal recessive skeletal dysplasia characterized by severe disproportionate short stature presenting with acromesomelia, mild metaphyseal widening of the long bones and mild spondylar dysplasia. To date, only four variants have been reported; one nonsense, one splice-s...

Introduction Although there are some recommendations in the literature on the assessments that should be performed in children on recombinant human growth hormone (rhGH) therapy, the level of consensus on these measurements is not clear. The objective of the current study was to identify the minimum dataset (MDS) that could be measured in a routine...

Objective Our study aimed to assess the impact of genetic modifiers on the significant variation in phenotype that is observed in individuals with SHOX deficiency, which is the most prevalent monogenic cause of short stature. Design and Methods We performed a genetic analysis in 98 individuals from 48 families with SHOX deficiency with a target pa...

Context: The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than non-carriers. However, the frequency of such variants...

Background Identification of genetic causes of central precocious puberty (CPP) has revealed epigenetic mechanisms as regulators of human pubertal timing. Methyl-CpG-binding protein 2 (MECP2), an X-linked gene, encodes a chromatin-associated protein with a role in gene transcription. MECP2 loss-of-function mutations usually cause Rett syndrome, a s...

Context: Congenital hypopituitarism is a genetically heterogeneous condition. Whole exome sequencing (WES) is a promising approach for molecular diagnosis of patients with this condition. Objectives: To conduct WES in a patient with congenital hypopituitarism born to consanguineous parents, CDH2 screening in a cohort of patients with congenital...

Proliferating Cell Nuclear Antigen (PCNA) is a sliding clamp protein that coordinates DNA replication with various DNA maintenance events that are critical for human health. Recently, a hypomorphic homozygous serine to isoleucine (S228I) substitution in PCNA was described to underlie a rare DNA repair disorder known as PCNA-Associated DNA Repair Di...

Exome sequencing is a powerful tool in prenatal and postnatal genetics and can help identify novel candidate genes critical to human development. We describe seven unpublished probands with rare likely pathogenic variants or variants of uncertain significance that segregate with recessive disease in TBC1D32, including four fetal probands in three u...

Introduction: Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. More than 40 genes have been associated with the pathogenesis of CHH, but most cases still remain without a molecular diagnosis. Mutations involving the same gene (e.g. FGFR1, PROK2/PROKR2, CHD7) were found to cause normosmic CHH and Kallman...

This International Consensus Guideline was developed by experts in the field of SGA of 10 pediatric endocrine societies worldwide. A consensus meeting was held and 1300 articles formed the basis for discussions. All experts voted about the strengths of the recommendations. The guideline gives new and clinically relevant insights into the etiology o...

Short stature is a common concern for physicians caring for children. In traditional investigations, about 70% of children are healthy, without producing clinical and laboratory findings that justify their growth disorder, being classified as having constitutional short stature or idiopathic short stature (ISS). In such scenarios, the genetic appro...

Context Central precocious puberty (CPP) can have a familial form in one quarter of the children. The recognition of this inherited condition increased after the identification of autosomal dominant CPP with paternal transmission caused by mutations in the MKRN3 and DLK1 genes. Objectives To characterize the inheritance and estimate the prevalence...

Microcephaly presents heterogeneous genetic etiology linked to several neurodevelopmental disorders (NDD). Copy number variants (CNVs) are a causal mechanism of microcephaly whose investigation is a crucial step for unraveling its molecular basis. Our purpose was to investigate the burden of rare CNVs in microcephalic individuals and to review gene...

Objective: Most children with short stature remain without an etiologic diagnosis after extensive clinical and laboratory evaluation and are classified as idiopathic short stature (ISS). This study aimed to determine the diagnostic yield of a multigene analysis in children classified as ISS. Design and methods: We selected 102 children with ISS...

Objectives: To analyze the efficiency of a multigenic targeted massively parallel sequencing panel related to endocrine disorders for molecular diagnosis of patients assisted in a tertiary hospital involved in the training of medical faculty. Material and methods: Retrospective analysis of the clinical diagnosis and genotype obtained from 272 pa...

Proliferating Cell Nuclear Antigen (PCNA) is a sliding clamp protein that coordinates DNA replication with various DNA maintenance events that are critical for human health. Recently, a hypomorphic homozygous serine to isoleucine (S228I) substitution in PCNA was described to underlie a DNA repair disorder known as PCNA-Associated DNA Repair Disorde...

Background: Syndromic obesity (SO) refers to obesity with additional phenotypes, including intellectual disability (ID)/developmental delay (DD), dysmorphic features, or organ-specific abnormalities. SO is rare, has high phenotypic variability, and frequently follows a monogenic pattern of inheritance. However, the genetic etiology of most cases o...

Purpose Polycystic ovary syndrome (PCOS) etiology remains to be elucidated but familial clustering and twin studies have shown a strong heritable component. The purpose of this study was to identify rare genetic variants that are associated with the etiology of PCOS in a preselected cohort. Methods This prospective study was conducted among a sele...

Back Cover: The cover image is based on the Research Article Phenotypic and mutational spectrum of ROR2-related Robinow syndrome by Juliana Forte Mazzeu de Araujo et al., https://doi.org/10.1002/humu.24375.

Most infants born with very low birth weight (VLBW, birth weight < 1500 g) show spontaneous catch‐up growth in postnatal life. The reasons for the absence of catch‐up growth are not entirely understood. We performed a comprehensive investigation of 52 children born with VLBW. Ten children had a history of an external cause that explained the VLBW a...

Introduction: Isolated SHOX haploinsufficiency is a common monogenic cause of short stature. Few studies compare untreated and rhGH-treated patients up to adult height(AH). Our study highlights a growth pattern from childhood to AH in patients with SHOX haploinsufficiency and analyzes the real-world effectiveness of rhGH alone or plus GnRHa or aro...

Aims To describe the clinical and genetic characteristics and long-term follow-up of a cohort with maturity-onset diabetes of the young (MODY), and to evaluate how molecular diagnosis impacted on treatment. Methods A large observational, retrospective, cohort study included individuals referred to the University of São Paulo’s Monogenic Diabetes U...

Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb short stature and genital hypoplasia. A significant degree of phenotypic variability seems to correlate with different genes/loci. Disturbances of the non-canonical WNT-pathway have been identified as the main cause of the syndrome. Biallelic variants i...

Genes associated with isolated short stature (bold) and candidated genes included in the targeted panel sequencing applied for genetic investigation of children with idiopathic short stature

The lines of computational evidence applied in our genetic study to support a deleterious effect on the gene or gene product (supporting pathogenic criterion - PP3 in ACMG/AMP, ≥4/7 in silico tools).

Our clinical case for discussion is about a short statured boy who was 14.6 years old at his first evaluation. He was born after a 39-week gestation as the third child of a non-consanguineous marriage. His birth weight was 3.250 g (−0.3 SDS), and his birth length was not available. His neuropsychomotor development was normal, his school performance...

Introduction: Mutations in PTPN11 are associated with Noonan syndrome (NS). Although the effectiveness of growth hormone therapy (GHT) in treating short stature due to NS has been previously demonstrated, the effect of PTPN11 mutation status on the long-term outcomes of GHT remains to be elucidated. Methods: This analysis included pooled data fr...

Objectives The normal development of the pituitary gland requires multiple induction signals and transcription factors encoded by more than 30 genes, including OTX2 . OTX2 mutations have been described with eye abnormalities and variable congenital hypopituitarism, but rarely with hypopituitarism without ocular manifestations. Case presentation We...

Introduction: Pubertal delay is described as one of the clinical features in Noonan Syndrome (NS) and it may be one of the factors causing short adult height in those patients. The present study aims at characterizing pubertal development in NS and identifying pubertal delay predictors. Methods: We analyzed 133 individuals with a molecular diagn...

Context Massively parallel sequencing (MPS) technologies have emerged as a first-tier approach for diagnosing several pediatric genetic syndromes. However, MPS has not been systematically integrated into the diagnostic workflow along with clinical/biochemical data for diagnosing 46,XY DSD. Objective to analyze the contribution of phenotypic classi...

We present the unique case of an adult Brazilian woman with severe short stature due to growth hormone deficiency with a heterozygous G to T substitution in the donor splice site of intron 3 of the growth hormone 1 (GH1) gene (c.291+1G>T). In this autosomal dominant form of growth hormone deficiency (type II), exon 3 skipping results in expression...

Hypospadias is a common congenital disorder of male genital formation. Children born small for gestational age (SGA) present a high frequency of hypospadias of undetermined etiology. No previous study investigated the molecular etiology of hypospadias in boys born SGA using massively parallel sequencing. Our objective is to report the genetic findi...

The third edition of the Oxford Textbook of Endocrinology and Diabetes is an up-to-date, objective and comprehensive text that covers the full scope of endocrinology and diabetes. It contains wide ranging and pragmatic advice on diagnosis and clear guidelines for recommended management, while also covering the scientific principles that underlie th...

We report four allelic variants (three novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p.Phe 57Leufs*43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A hemizygou...

Pituitary hormone deficiency occurs in ∼1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated individuals with hypopituitarism that were predicted to affect a minor isoform, POU1F1 beta...

Hormone resistances have been described in association with growth disorders, the majority involving the growth hormone (GH)/insulin-like growth factor 1(IGF-1) axis or hormones with specific paracrine-autocrine actions in the growth plate. Defects in hormone receptors or in proteins involved in intracellular signal transduction (post-receptor defe...

Disorders of the GH-IGF axis include a large heterogeneous group of conditions with distinct phenotypes. Each of the defects identified in this axis is responsible for a rare and specific condition that endocrinologists need to be familiar with. Traditionally, clinical and hormonal evaluations are the cornerstones of their diagnosis but in recent y...

Context: Treatment with growth hormone (GH) is considered effective in improving adult height (AH) in Turner syndrome (TS). However, there are few studies comparing AH between treated patients and a concurrent untreated group. Objective: To assess the efficacy of GH treatment in improving AH in TS and to review previous published studies with tr...

We report four allelic variants (3 novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p. Phe 57Leufs * 43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A SOX3 allel...

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 in the human brain, with a view to investigating the m...

Chromosomal microarray analyses (CMA) have greatly increased both the yield and diagnostic accuracy of postnatal analysis; it has been used as a first‐tier cytogenetic test in patients with intellectual disability, autism spectrum disorder, and multiple congenital abnormalities. During the last 15 years, we performed CMA in approximately 8,000 pati...

Objective: To increase molecular diagnostic yield by reanalyzing genetic data from targeted next generation sequencing (tNGS) panel.

Purpose Non-syndromic pituitary gigantism (PG) is a very rare disease. Aryl hydrocarbon receptor-interacting protein (AIP) and G protein-coupled receptor 101 (GPR101) genetic abnormalities represent important etiologic causes of PG and may account for up to 40% of these cases. Here, we aimed to characterize the clinical and molecular findings and l...

Background: Even students with previous academic success may face challenges that affect their academic performance. Many medical schools offer programs to students at the risk of academic failure, to ensure that they succeed in the course. Objective and methods: In this report we describe a pioneering academic tutoring program developed at a Br...

Pituitary hormone deficiency occurs in ~1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated hypopituitarism patients that were predicted to affect a minor isoform, POU1F1 beta, which...

Objectives: Single nucleotide variants (SNVs) are the most common type of genetic variation among humans. High-throughput sequencing methods have recently characterized millions of SNVs in several thousand individuals from various populations, most of which are benign polymorphisms. Identifying rare disease-causing SNVs remains challenging, and of...

Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized...

RASopathies are a heterogeneous group of syndromes caused by germline mutations in genes encoding components of the RAS/MAPK pathway. Postnatal short stature is a cardinal feature of the RASopathies. Although the pathophysiology of these conditions is not fully understood to date, growth hormone insensitivity is one possibility, based on the observ...

Children often present to the pediatric endocrinologist because their height or growth pattern raises concerns about a possible underlying health problem, about their psychosocial function and adjustment, and/or about the height they are headed to become as an adult. Many children are short or tall because they inherited a set of polymorphisms that...

Noonan syndrome (NS) and NS related disorders (NRD) are frequent monogenic diseases. Pathogenic variants in PTPN11 are observed in approximately 50% of these NS patients. Several pleiotropic phenotypes have previously been described in this condition. This study aimed at characterizing glucose and lipid profiles in patients with NS/NRD. We assessed...

Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized...

STUDY QUESTION: Is there an (epi)genetic basis in patients with central precocious puberty (CPP) associated with multiple anomalies that unmasks underlying mechanisms or reveals novel genetic findings related to human pubertal control? SUMMARY ANSWER: In a group of 36 patients with CPP associated with multiple phenotypes, pathogenic or likely path...

We report the clinical and molecular data of a large cohort comprising 242 individuals with RASopathies, from a single Tertiary Center in Brazil, the largest study from Latin America. Noonan syndrome represented 76% of the subjects, with heterozygous variants in nine different genes, mainly PTPN11, SOS1, RAF1, LZTR1, and RIT1, detected by Sanger an...

Background: The utility of insulin-like growth factor type 1 (IGF-1) is well established in the diagnosis of growth hormone deficiency (GHD), whereas IGF-binding protein type 3 (IGFBP-3) has a more controversial role. Most studies evaluated the value of these peptides by assessing their sensitivity and specificity but not considering the low preva...

Objectives: High-throughput sequencing of genomes, exomes, and disease-focused gene panels is becoming increasingly common for molecular diagnostics. However, identifying a single clinically relevant pathogenic variant among thousands of genetic polymorphisms is a challenging task. Publicly available genomic databases are useful resources to filte...

Context Individual patients vary in their response to growth hormone (GH). No large scale genomewide studies have looked for genetic predictors of GH responsiveness. Objective To identify genetic variants associated with GH responsiveness. Design Genomewide association study Setting Cohorts from multiple academic centers and a clinical trial Pa...

Background: Short stature is the most frequent clinical manifestation in Turner syndrome (TS), occurring in 98% of these patients. Growth hormone was shown to improve adult height in TS patients from diverse genetic backgrounds. However, there are few studies on adult height in TS patients from developing countries, where the diagnosis is frequentl...

Background: Loss of imprinting has been implicated in the pathogenesis of several human diseases. Monogenic causes of central precocious puberty (CPP) were identified in families with loss-of-function mutations affecting mainly the coding region of two paternally expressed imprinted genes: Makorin ring finger 3 (MKRN3) and Delta-like 1 homolog (DLK...

Background: Growth hormone deficiency (GHD) occurs in ~ 1/8000 individuals, and 14% of the patients have mutations in five major candidate genes. However, over 30 genes have been implicated in hypopituitarism. WES (Whole Exome Sequencing) is a promising approach for molecular diagnosis of patients with GHD because it offers the opportunity to scree...

BACKGROUND CSHS refers to the association of epidermal nevus syndrome (ENS), skeletal dysplasia, and hypophosphatemic osteomalacia (OM) mediated by FGF23 resulting from post zygotic mutations in RAS signaling pathway, with known by relationship with human cancers. CLINICAL CASE Patient 1 presented ENS since birth at right hemibody. At 1.6-yr-old, s...

Introduction: Hypopituitarism is defined as a deficiency of one or more pituitary hormones. Pathogenic allelic variants in genes implicated in pituitary development were associated in 15% of the patients with congenital hypopituitarism (CH). To improve the molecular diagnosis we performed whole exome sequencing of ten patients born from consanguine...

Background: Central precocious puberty (CPP) is mostly described as an isolated entity. Few studies have shown an association of CPP with complex cases or genetic syndromes, but without making inferences on molecular causalities. Objective: To genetically investigate a cohort of patients with CPP associated with complex phenotypes using high throug...

Introduction: Children with isolated (former known as idiopathic) short stature (ISS) have been treated with rhGH with a variable response. Objectives: To evaluate the short-term response to rhGH therapy in children with ISS with or without a genetic diagnosis. Methods: We analyzed retrospectively the growth rate and height SDS change in the first...

Next-generation sequencing (NGS) has been transforming the endocrine diagnostic methodology allowing the genetic testing to assume an exploratory role rather than only a confirmatory one. This is possible due to lower costs and increased yield of information. A way to further increase efficiency and sensitivity for variant detection is the use of a...

Background: It is recommended a multidisciplinary approach consisted of clinical, hormonal and genetic workups for diagnosing 46,XY DSD. However, no previous study has quantified how useful is this combined approach. Objectives: To retrospectively review the clinical and genetic findings for diagnosing a large cohort of patients with 46,XY DSD from...

Context Heterozygous variants in IHH have been reported to cause brachydactyly type A1 and mild hand and feet skeletal anomalies with short stature. Genetic screening in individuals with short stature and mild skeletal anomalies has been increasing over recent years, allowing us to broaden the clinical spectrum of skeletal dysplasias. Objective To...

The somatotropic axis is the main hormonal regulator of growth. Growth hormone (GH), also known as somatotropin, and insulin-like growth factor 1 (IGF-1) are the key components of the somatotropic axis. This axis has been studied for a long time and the knowledge of how some molecules could promote or impair hormones production and action has been...

Introduction: Constitutional delay of growth and puberty (CDGP) is the most prevalent cause of delayed puberty in both sexes. Family history of delayed puberty (two or more affected members in a family) has been evidenced in 50 to 75% of patients with CDGP and the inheritance often is consistent with autosomal dominant pattern, with or without com...

Background: Floating-Harbor syndrome (FHS) is a rare condition characterized by dysmorphic facial features, short stature, and expressive language delay. Objective: The aim of this study was to describe a cohort of patients with FHS and review the literature about the response to recombinant human growth hormone (rhGH) therapy. Methods: Anthro...

Context: Patients with tall stature often remain undiagnosed after clinical investigation and few studies have genetically assessed this group, most of them without a systematic approach. Objective: To assess prospectively a group of individuals with tall stature, with and without syndromic features, and to establish a molecular diagnosis for th...

Background: Maturity‐onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. To date, mutations in 11 genes have been frequently associated with this phenotype. In Brazil, few cohorts have been screened for MODY, all using a candidate gene approach, with a high prevalence of undiagnosed cases (MODY‐X)...

Objective: To perform a prospective genetic investigation using whole exome sequencing of a group of patients with syndromic short stature born small for gestational age of unknown cause. Study design: For whole exome sequencing analysis, we selected 44 children born small for gestational age with persistent short stature, and additional feature...

Most patients with Turner Syndrome (TS) need hormone replacement therapy because of hypergonadotropic hypogonadism; individual outcomes, however, are highly variable. Our objective was to assess the influence of five estrogen receptor 1 gene ( ESR1 ) polymorphisms (rs543650, rs1038304, rs2046210, rs2234693 and rs9340799) on adult height, breast dev...

The Growth Hormone Research Society (GRS) convened a Workshop in March 2019 to evaluate the diagnosis and therapy of short stature in children. Forty-six international experts participated at the invitation of GRS including clinicians, basic scientists, and representatives from regulatory agencies and the pharmaceutical industry. Following plenary...