PAE507 — Endocrine and Metabolic Disorders: Lecture Note

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la-NET | ONLINE LEARNING VIDEO PLATFORM FOR POST-SECONDARY & HIGHER INSTITUTION STUDENTS

la-NET | ONLINE LEARNING VIDEO PLATFORM FOR POST-SECONDARY & HIGHER INSTITUTION STUDENTS Course code: PAE 507 Course title: Endocrine and Metabolic Disorders Course credit load: 2 Units Series 1: Disorders of Sexual Development • Part 1.1: Normal Sexual Differentiation and Definition of DSD o Sub Part 1.1.1: Normal sexual differentiation in the fetus o Sub Part 1.1.2: Definition of disorder of sexual development o Sub Part 1.1.3: The significance of ambiguous genitalia at birth • Part 1.2: Classification of Disorders of Sexual Development o Sub Part 1.2.1: Overview of the classification of DSD o Sub Part 1.2.2: 46,XX DSD and 46,XY DSD o Sub Part 1.2.3: Sex chromosome DSD • Part 1.3: Clinical Evaluation of a Child with Ambiguous Genitalia o Sub Part 1.3.1: Relevant clinical history o Sub Part 1.3.2: Physical examination of a child with suspected DSD o Sub Part 1.3.3: The importance of sensitive, structured communication • Part 1.4: Investigation and Management of Disorders of Sexual Development o Sub Part 1.4.1: Investigations used in evaluating DSD o Sub Part 1.4.2: General principles of management o Sub Part 1.4.3: Long-term follow up and psychosocial support Introduction Picture a newborn whose external genitalia do not appear clearly male or female at birth, leaving the delivery room team uncertain what to tell the anxious parents. Moments such as this, though uncommon, require calm, structured, and sensitive clinical evaluation, since the underlying cause can range from a benign variant to a condition with significant, even life-threatening, hormonal implications. This Series opens the PAE 507 course by introducing disorders of sexual development, building the knowledge required to evaluate and appropriately manage a child presenting with ambiguous genitalia or another indication of atypical sexual differentiation.

la-NET | ONLINE LEARNING VIDEO PLATFORM FOR POST-SECONDARY & HIGHER INSTITUTION STUDENTS The aim of this Series is to equip you with the knowledge required to understand normal sexual differentiation, define and classify disorders of sexual development, and evaluate and understand the management of a child presenting with ambiguous genitalia. This Series begins with normal sexual differentiation and the definition of disorder of sexual development, before turning to the classification of DSD into its major categories. Next, we examine the clinical evaluation of a child with ambiguous genitalia, before concluding with the investigation and management of disorders of sexual development. Series Learning Outcomes At the end of this Series, you should be able to: • SLO 1.1: describe the normal process of sexual differentiation in the fetus, • SLO 1.2: define disorder of sexual development and list its major categories, • SLO 1.3: classify disorders of sexual development into 46XX DSD, 46XY DSD, and sex chromosome DSD, • SLO 1.4: give examples of conditions within each category of disorder of sexual development, • SLO 1.5: describe the clinical history relevant to a child presenting with ambiguous genitalia, • SLO 1.6: describe the physical examination of a child with suspected disorder of sexual development, • SLO 1.7: describe the investigations used in evaluating a child with disorder of sexual development, and • SLO 1.8: describe the general principles of management of disorder of sexual development. 1.1 Normal Sexual Differentiation and Definition of DSD 1.1.1 normal sexual differentiation in the fetus Chromosomes set the stage, hormones write the script Normal sexual differentiation begins with chromosomal sex, established at fertilisation as either 46,XX or 46,XY, which determines whether the initially bipotential gonad develops into a testis or an ovary, a process termed gonadal sex. In a 46,XY fetus, the SRY gene on the Y chromosome triggers testicular development, and the resulting testis then produces

la-NET | ONLINE LEARNING VIDEO PLATFORM FOR POST-SECONDARY & HIGHER INSTITUTION STUDENTS testosterone and anti-Mullerian hormone, which together drive the development of male internal and external genitalia. In the absence of a Y chromosome and SRY gene expression, the bipotential gonad develops as an ovary, and, in the absence of testosterone and anti-Mullerian hormone, the internal and external genitalia develop along the default female pathway. This orderly sequence, from chromosomal sex through gonadal sex to the development of internal and external genitalia, is termed phenotypic sex, and a disruption at any point in this sequence can result in a disorder of sexual development. Fill in the blank: In a 46,XY fetus, the ________ gene on the Y chromosome triggers testicular development. 1.1.2 definition of disorder of sexual development A disorder of sexual development, abbreviated DSD, is defined as a congenital condition in which the development of chromosomal, gonadal, or anatomical sex is atypical, meaning there is a mismatch or ambiguity somewhere along the normal sequence of chromosomal, gonadal, and phenotypic sex described in the previous sub-Part. DSD encompasses a wide spectrum, from externally ambiguous genitalia noted at birth to more subtle presentations identified later in childhood or even adolescence. The term DSD has largely replaced older, less precise or potentially stigmatising terminology, and its use reflects a broader shift towards a more structured, biologically grounded classification system, which in turn supports a more systematic and less anxiety-provoking approach to evaluation and communication with affected families, a theme that will be developed further later in this Series. Fill in the blank: DSD is defined as a congenital condition in which chromosomal, gonadal, or ________ sex is atypical. 1.1.3 the significance of ambiguous genitalia at birth Ambiguous genitalia at birth is one of the more striking presentations of DSD, and represents both a diagnostic and a significant communication challenge, since parents naturally expect to be told clearly whether their baby is a boy or a girl, and a delay or uncertainty in this assignment can be understandably distressing without careful, empathetic explanation. Beyond the diagnostic and psychosocial dimensions, ambiguous genitalia in a newborn can, in certain underlying conditions, signal a medical emergency, particularly where salt-wasting congenital adrenal hyperplasia is the underlying cause, since affected infants are at risk of a

la-NET | ONLINE LEARNING VIDEO PLATFORM FOR POST-SECONDARY & HIGHER INSTITUTION STUDENTS life-threatening adrenal crisis within the first weeks of life if the diagnosis is missed, making prompt, structured evaluation genuinely urgent rather than purely of academic interest. Fill in the blank: Ambiguous genitalia can signal a medical emergency, particularly where salt-wasting congenital adrenal ________ is the underlying cause. Figure 1.1: The normal sequence from chromosomal sex to phenotypic sex. Pilot questions 1.1 1. Describe the normal sequence from chromosomal sex to phenotypic sex. (Linked to SLO 1.1) 2. Explain the role of the SRY gene in normal sexual differentiation. (Linked to SLO 1.1) 3. Define disorder of sexual development. (Linked to SLO 1.2) 4. Explain why the term DSD is now preferred to older terminology. (Linked to SLO 1.2) 5. Explain why ambiguous genitalia in a newborn can represent a medical emergency. (Linked to SLO 1.2)

la-NET | ONLINE LEARNING VIDEO PLATFORM FOR POST-SECONDARY & HIGHER INSTITUTION STUDENTS 1.2 Classification of Disorders of Sexual Development 1.2.1 overview of the classification of DSD Classification follows the karyotype Disorders of sexual development are classified into three major categories based on karyotype: sex chromosome DSD, in which the sex chromosome complement itself is atypical, 46,XY DSD, in which the karyotype is male but the gonadal or phenotypic development is atypical, and 46,XX DSD, in which the karyotype is female but the gonadal or phenotypic development is atypical. This classification system provides a structured starting point for both diagnosis and discussion with families. Within each of these three broad categories, conditions can be further subdivided according to whether the primary abnormality lies at the level of gonadal development itself or at the level of hormone production or action further along the differentiation pathway, a distinction that becomes particularly important when selecting appropriate investigations, discussed later in this Series. Fill in the blank: DSD is classified into three major categories based on ________. 1.2.2 46,XX DSD and 46,XY DSD 46,XX DSD most commonly results from congenital adrenal hyperplasia, particularly due to 21-hydroxylase deficiency, in which excess adrenal androgen production causes virilisation of an otherwise chromosomally and gonadally female fetus, producing a spectrum of external genital ambiguity while internal female reproductive structures remain present. This is the single most common identifiable cause of ambiguous genitalia overall and is of particular importance because of its potential to cause salt-wasting adrenal crisis, as discussed earlier. 46,XY DSD encompasses a broader range of underlying mechanisms, including disorders of testicular development, such as complete or partial gonadal dysgenesis, and disorders of androgen synthesis or action, such as 5-alpha reductase deficiency, which impairs conversion of testosterone to its more potent form, or androgen insensitivity syndrome, in which tissues fail to respond normally to circulating androgens despite normal or even elevated levels. Fill in the blank: The single most common identifiable cause of ambiguous genitalia overall is congenital adrenal ________.

la-NET | ONLINE LEARNING VIDEO PLATFORM FOR POST-SECONDARY & HIGHER INSTITUTION STUDENTS 1.2.3 sex chromosome DSD Sex chromosome DSD includes conditions in which the sex chromosome complement itself deviates from the typical 46,XX or 46,XY pattern, such as

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