Endocrine investigations and laboratory reference ranges

While baseline testing may be appropriate in some endocrine disorders (e.g. hyper/hypothyroidism), many hormones are not secreted in a constant fashion (e.g. pulsatile (growth hormone), diurnal (cortisol)), and are also age (IGF-1) and pubertal stage (Luteinizing hormone/follicle-stimulating hormone/testosterone/oestradiol) dependent. In these circumstances, stimulation (or suppression) testing including using hypothalamic/pituitary hormones may be required. Testing can either be performed to identify occult endocrine dysfunction in high-risk groups, or alternatively to confirm (or exclude) endocrine disorders in conjunction with careful clinical assessment. These tests are, however, often complex and difficult to perform, with both false-positive and false-negative results, so careful and appropriate timing and choice of tests is required to ensure optimal outcomes.

Obesity

• Obesity is defined as: ‘An excess of body fat frequently resulting in a significant impairment of health and longevity’. • In most cases obesity is not due to an underlying endocrine disorder, although it may produce endocrine morbidity such as type 2 diabetes. • Although there are a number of different methods to assess overweight and obesity, the most common is body mass index (BMI): weight (kg)/height (m)2. • Classification is: • primary: exogenous or ‘simple’ obesity • secondary: ■ identified genetic syndromes, e.g. Prader–Willi, Bardet–Biedl, pseudohypoparathyroidism ■ monogenic disorders, e.g. leptin deficiency, leptin/melanocortin receptor defects ■ CNS disease, e.g. hypothalamic obesity ■ endocrine disorders, e.g. hypothyroidism, Cushing syndrome, growth hormone deficiency, precocious puberty ■ immobility, e.g. cerebral palsy ■ iatrogenic. • Generally, children with obesity which is: • primary often have a family history, tall stature, advanced bone age, and no dysmorphic features • secondary often have short stature, delayed bone age, dysmorphic features, and developmental delay. • Complications of obesity are multisystem: metabolic, cardiovascular, respiratory, gastrointestinal/hepatic, orthopaedic, neurological, dermatological, gynaecological, and psychological. • Therapy is aimed at modifiable factors restoring the balance between energy intake (e.g. dietary) and expenditure (e.g. exercise), and preferably a combination of both along with counselling and behaviour modification. There is currently only limited data on the benefits of pharmacotherapy and bariatric surgery.

The pituitary and hypopituitarism

• The pituitary is formed of two anatomically and embryologically distinct lobes: ◦ anterior pituitary: which secretes growth hormone (GH), gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)), adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), and prolactin ◦ posterior pituitary: which secretes vasopressin and oxytocin. • Hypopituitarism is deficiency of one or more pituitary hormones. Some hormones, e.g. GH (LH/FSH), are more likely to present with isolated deficiencies, while others, e.g. TSH, ACTH, are more often found as part of multiple pituitary hormone deficiency (MPHD). • Deficiencies may be congenital (including genetic) or acquired; secondary to tumour, trauma, infiltration, infection, or irradiation. • GH deficiency: ◦ diagnosed using a combination of clinical, radiological, and biochemical assessment (including GH stimulation testing) ◦ treatment is with GH (including if necessary into adulthood). • LH/FSH deficiency: ◦ If acquired, often one of the first anterior pituitary hormones to be lost. ◦ Congenital forms: ■ present with cryptorchidism and/or micropenis in males ■ may occur in isolation, or in association with anosmia (Kallmann and CHARGE syndromes). ◦ Treatment: sex steroid therapy to induce secondary sexual characteristics, and recombinant FSH/LH to induce fertility potential. • ACTH deficiency: ◦ Unlike primary adrenal problems, hyperpigmentation does not occur. ◦ Although mineralocorticoid production is preserved, hyponatraemia may still occur. ◦ Treatment is with hydrocortisone. • TSH deficiency: ◦ TSH may be low, normal, or raised (but inappropriate for free thyroxine level). ◦ Treatment is with thyroxine. • Vasopressin deficiency: ◦ produces cranial diabetes insipidus ◦ treatment is with DDAVP (orally or nasally). • Prolactin and oxytocin deficiency rarely produce clinical problems.

Growth (including short stature and tall stature)

• Growth occurs in three separate phases, all of which are under different nutritional and/or hormonal controls: ◦ infantile (mainly nutritional) ◦ childhood (hormonal, mainly growth hormone (GH)) ◦ pubertal (hormonal; GH and sex steroids acting synergistically). • Height: ◦ should be measured supine up until 2 years of age, and standing after that, and plotted on appropriate charts ◦ is a normally distributed variable, with extremes (0.4th/2nd centiles and 99.6th/98th centiles) arbitrarily defined as short and tall stature respectively. • Two major sets of genes determine height and rate of development; the first is assessed using mid-parental and target height, and the second using bone age. • Short stature: ◦ Failure to achieve an acceptable height can be due to a primary growth problem, or secondary to an underlying disorder. ◦ Causes include familial, genetic disorders (syndromic), small birth size, chronic illness, psychological, environmental, and endocrine. ◦ Generally, short stature due to a hormonal issue is associated with (relative) overweight, and that due to an underlying chronic disorder with (relative) underweight. ◦ GH therapy is licensed for short stature in children in the following situations: GH deficiency, Turner syndrome, chronic renal insufficiency, children born small for gestational age, Prader–Willi syndrome, and SHOX deficiency. • Tall stature: ◦ Although in theory this should present as frequently as short stature, in practice this is not the case. ◦ The commonest cause of tall stature is constitutional, although other forms include: ■ syndromic: e.g. Klinefelter, Marfan, and Sotos syndromes ■ hormonal: GH, sex steroid excess. ◦ Therapy (sex steroids, GH blockade, epiphyseal stapling) is less effective than in short stature.

Gender incongruence

• Gender dysphoria is a disassociation with birth gender and identification with the opposite gender. • The diagnosis needs to be made by an experienced mental health practitioner in accord with the Endocrine Society and World Professional Association for Transgender Health guidelines. • Most presenting in childhood are less likely to go onto physical treatment, whereas the majority of adolescents may wish to socially and physically transition. • Appropriate help and support should only be provided by an integrated medical and psychological/mental health team working in collaboration, with a psychosocial assessment preceding the medical review. • Initial medical assessment should be supportive only. A physical diagnostic approach is not required, and it is not considered similar to a disorder of sex development. • Counselling about fertility loss is required. • Endocrine supportive treatment is with gonadotropin-releasing hormone analogues initially. • Cross-sex hormone/gender-affirming hormone therapy may be considered after further counselling. • Surgical gender reassignment is carried out in adulthood only after additional detailed counselling.

Differences of sex development (DSD)

• Embryology: the gonad is initially bipotential. • The testes develop under active control of SRY and other genes. Disorders of sex development (DSDs) are classified according to the karyotype: • 46,XY DSD (incomplete masculinization of a male fetus): ◦ The commonest cause is androgen insensitivity syndrome (AIS): ■ mutations in androgen receptor (AR) gene on X chromosome in complete forms ■ alterations in androgen binding in partial forms. ◦ Abnormalities of testosterone synthesis and conversion, may be: ■ isolated, e.g. 17β‎HSD, 5α‎RD ■ occur in association with defects in steroid biosynthesis, e.g. StAR, 3β‎HSD. • Pure 46,XY gonadal dysgenesis (Swyer syndrome): ◦ phenotype unambiguously female; may present with delayed puberty ◦ Müllerian structures are present but only streak gonads are seen. • Mixed gonadal dysgenesis: ◦ usually asymmetrical, e.g. ovary/streak gonad or ovotestis ◦ karyotype is 45,X/46,XY or 46,XX/46,XY. • Pure 46,XX gonadal dysgenesis: ◦ absent puberty in a phenotypically normal female ◦ intact Müllerian structures but streak ovaries; normal genitalia. • 46,XX DSD (masculinization of a female fetus): ◦ the commonest cause is congenital adrenal hyperplasia, with the vast majority (>90%) due to 21-hydroxylase deficiency (21OHD). • Ovotesticular DSD is rare: ◦ aetiology is unknown, and karyotype usually 46,XX ◦ asymmetrical gonad development; ovary and testis or ovotestis. • DSD may also be part of other genetic syndromes, e.g. Antley–Bixler, Smith–Lemli–Opitz, trisomy 13. • Management requires careful evaluation and counselling, working as part of a multidisciplinary team.

Calcium, vitamin D, and bone disorders

• Calcium metabolism is complex and dependent upon parathyroid hormone (PTH), calcitonin, and vitamin D3. • Bone mineralization is dependent on normal health, diet growth, and puberty. • Osteoporosis or osteopenia is a loss of total bone content, due to: ◦ decreased bone formation ◦ increased bone resorption. • Osteomalacia is a defect in bone mineralization. • Osteogenesis imperfecta is the most common cause of primary osteoporosis (although rare). • Bisphosphonates can be used to reduce symptoms. • Hypocalcaemia (<2.2 mmol/L) can be caused by: ◦ primary hypoparathyroidism ◦ PTH resistance syndromes ◦ hypomagnesaemia ◦ vitamin D deficiency ◦ activating mutations of calcium-sensing receptor gene (CASR) ◦ autoimmune (may occur as part of polyglandular syndrome) ◦ metabolic disease. • Albright’s hereditary osteodystrophy (AHO): ◦ is a family of PTH resistance syndromes caused by abnormalities in function of the GS-α‎ part of the G protein-coupled PTH receptor (GNAS1 gene). ◦ Treatment is with 1α‎-hydroxyvitamin D3 (alfacalcidol). Oral calcium supplements may be needed. • Hypercalcaemia is rare in infancy and childhood; calcium >2.65 mmol/L usually detected by chance. Caused by: ◦ neonatal primary hyperparathyroidism: homozygous inactivating mutations of the CASR gene ◦ Williams syndrome, with mild hypercalcaemia is a feature in 20% ◦ vitamin D excess. • Rickets can present with: ◦ symptoms and signs of hypocalcaemia ◦ muscle weakness ◦ metaphyseal flaring ◦ bowed legs ◦ rickety rosary. • Treatment is with vitamin D3 or D2. • Other genetic forms of rickets are rare.

Puberty and its disorders

• Puberty is defined as the acquisition of secondary sexual characteristics, with a view to reproductive capability. • Assessment of puberty can be done by Tanner stages or the puberty phases. • Timing of pubertal onset and sequence of changes is carefully controlled. • Premature sexual maturation: ◦ <8 years in girls; menarche <11 years ◦ <9 years in boys. • Central precocious puberty or gonadotropin-dependent precocious puberty: ◦ hormone secretion is similar to normal puberty ◦ may be idiopathic, genetic, or secondary to central nervous system/pituitary tumour or insult ◦ treatment is with gonadotropin-releasing hormone analogues. • Gonadotropin-independent precocious puberty (independent source of sex steroid, e.g. gonadal tumour): ◦ treatment should address the primary cause. • Late puberty: ◦ pubertal events within the later normal range. • Delayed onset of puberty: ◦ absence of secondary sexual characteristics: ■ >13 years in a girl ■ >14 years in a boy • Central causes (low follicle-stimulating hormone (FSH)/luteinizing hormone (LH)): ◦ chronic illness ◦ eating disorders ◦ physiological ◦ hypogonadotropic hypogonadism. • Peripheral causes (high FSH/LH): ◦ gonadal dysgenesis including chromosomal syndromes, e.g. Turner, Klinefelter ◦ gonadal damage including cancer treatments. • Treatment: ◦ low-dose sex hormone to induce growth and secondary sexual characteristics ◦ recombinant FSH/LH to induce fertility potential.

Thyroid gland disorders

• The thyroid gland produces all of the T4 and 20% of T3. • Congenital hypothyroidism is caused by: ◦ anatomical defects: agenesis/dysgenesis, ectopic, sublingual ◦ inborn errors of thyroid hormone metabolism ◦ secondary (pituitary thyroid-stimulating hormone (TSH)) or tertiary (hypothalamic thyrotropin-releasing hormone) deficiency ◦ iodine deficiency (commonest cause worldwide of hypothyroidism, patients are usually euthyroid). • Genetic causes are rare. • In most countries worldwide, newborn TSH screening is performed at 0–5 days of age. Treatment with l-thyroxine is (usually) lifelong. • Neonatal thyrotoxicosis due to transplacental passage of thyroid-stimulating immunoglobulins (TSIs) from mothers with thyrotoxicosis/Graves’ disease and may require antithyroid drugs (ATDs). • Acquired autoimmune hypothyroidism in children and adolescents: ◦ is caused by lymphocytic infiltration of the thyroid gland (Hashimoto’s disease/thyroiditis) • raised thyroid peroxidase antibodies are diagnostic • treatment is with l-thyroxine. • Hyperthyroidism (Graves’ disease, Hashimoto’s stimulatory phase (Hashitoxicosis)): ◦ is caused by autoantibodies to the TSH receptor (TSI, or TRAbthyrotropin receptor antibody) ◦ the first-line drug of choice is the ATD carbimazole ◦ thyroidectomy or radioiodine treatment can be considered for drug-resistant cases or after relapse. • Thyroid cancer is rare in childhood and adolescence, usually presenting with a nodule, but can be part of the multiple endocrine neoplasia syndromes.

Endocrine emergencies

• This chapter is intended to be brief, providing readily accessible information required in an endocrine emergency in an infant, child, or adolescent. • Endocrine emergencies are rare but because of this they are usually unexpected. • Always take a few moments to assess the situation. • Getting the clinical signs and obtaining the right biochemical samples at the time is often the key to getting the correct diagnosis and management. • The theory and background about each problem are dealt with in the relevant chapter. • The key endocrine emergencies are: • diabetic ketoacidosis • hypoglycaemia • adrenal insufficiency • hypocalcaemia • hypercalcaemia • acute diabetes insipidus • syndrome of inappropriate antidiuretic hormone secretion • hyperthyroid crisis • hypothyroid coma • unclear sex (ambiguous genitalia—disorders of sex development).