Charcot arthropathy is a progressive condition of the musculoskeletal system that is characterized by joint dislocations, pathologic fractures, and debilitating deformities. It results in progressive destruction of bone and soft tissues at weight-bearing joints. In its most severe form, it may cause significant disruption of the bony architecture.
Charcot arthropathy can occur at any joint; however, it occurs most commonly in the lower extremity, at the foot and ankle. Diabetes is now considered to be the most common aetiology of Charcot arthropathy.

This patient has hypercalcaemia due to hyperparathyroidism. However, the intestinal absorption of calcium is mainly controlled by 1,25 dihydroxy-vitamin D. Under the influence of calcitriol (active form of vitamin D), intestinal epithelial cells increase their synthesis of calbindin (calcium-binding carrier protein) necessary for active calcium ion absorption.

Free T4 levels or the free T4 index is usually elevated, as is the free T3 level or free T3 index
– Assays for thyrotropin-receptor antibodies (particularly TSIs) almost always are positive.
– Detection of TSIs is diagnostic for Graves disease.
– Other markers of thyroid autoimmunity, such as antithyroglobulin antibodies or antithyroid peroxidase antibodies, are usually present.
– Other autoantibodies that may be present include thyrotropin receptor-blocking antibodies and anti–sodium-iodide symporter antibody.
The presence of these antibodies supports the diagnosis of autoimmune thyroid disease.
– The radioactive iodine uptake is increased and the uptake is diffusely distributed over the entire gland.

Type 1 diabetes is a chronic illness characterized by the body’s inability to produce insulin due to the autoimmune destruction of the beta cells in the pancreas. Approximately 95% of patients with type 1 DM have either HLA-DR3 or HLA-DR4. Although the genetic aspect of type 1 DM is complex, with multiple genes involved, there is a high sibling relative risk. Whereas dizygotic twins have a 5-6% concordance rate for type 1 DM, monozygotic twins will share this diagnosis more than 50% of the time by the age of 40 years.

The patient most likely has Klinefelter’s syndrome.
Klinefelter syndrome (KS) refers to a group of chromosomal disorders in which the normal male karyotype, 46,XY, has at least one extra X chromosome. XXY aneuploidy, the most common human sex chromosome disorder. It is also the most common chromosomal disorder associated with male hypogonadism and infertility.
Klinefelter syndrome is characterized by hypogonadism (micro-orchidism, oligospermia/azoospermia), gynecomastia in late puberty, hyalinization and fibrosis of the seminiferous tubules, elevated urinary gonadotropin levels, and behavioural concerns.

Dapagliflozin works by inhibiting sodium glucose cotransporter 2 (SGLT2) and blocking resorption of glucose in the kidney, leading to an increase in urinary glucose excretion and lowering of both plasma glucose levels and body weight.
All studies with SGLT2 inhibitors have found significant reductions in BP, with greater reductions seen in systolic (1.66 to 6.9mmHg) than diastolic (0.88 to 3.5mmHg) BP.
While some trials have shown no change in lipid parameters, others have shown a modest but statistically significant increase in both HDL and LDL cholesterol with no effect on triglycerides or the LDL/HDL ratio.

The clinical manifestations of Small cell lung cancer (SCLC) can result from local tumour growth, intrathoracic spread, distant spread, and/or paraneoplastic syndromes.
Hypertrophic pulmonary osteoarthropathy (HPO) is a rare paraneoplastic syndrome that is frequently associated with lung cancer; however, the incidence of clinically apparent HPO is not well known.
SIADH is present in 15% of cases and most commonly seen.
Although hypercalcaemia is frequently associated with malignancy, it is very rare in small cell lung cancer despite the high incidence of lytic bone metastases.
Ectopic Cushing’s syndrome in SCLC does not usually exhibit the classic signs of Cushing’s syndrome and Cushing’s syndrome could also appear during effective chemotherapy.
Chemotherapy is the treatment of choice in SCLC.

The patient has hyperprolactinaemia with otherwise normal oestradiol, FSH and LH. This is highly suggestive of Prolactinoma rather than a non functioning tumour.
In polycystic ovaries, there is increase in the level of LH while FSH is normal or low.

European guidelines for the treatment of syndrome of inappropriate antidiuresis include the following recommendations for the management of moderate or profound hyponatremia:
– Restrict fluid intake as first-line treatment.
– Second-line treatments include increasing solute intake with 0.25–0.50 g/kg per day or a combination of low-dose loop diuretics and oral sodium chloride.
– Use of lithium, demeclocycline, or vasopressin receptor antagonists is not recommended.
Recommendations on the treatment of SIADH from an American Expert Panel included the following:
– If chronic, limit the rate of correction.
– Fluid restriction should generally be first-line therapy.
– Consider pharmacologic therapies if serum Na + is not corrected after 24-48 hr of fluid restriction or if the patient has a low urinary electrolyte free water excretion.
– Patients being treated with vaptans should not be on a fluid restriction initially.
– Water, 5% dextrose or desmopressin can be used to slow the rate of correction if the water diuresis is profound.

The use of hormone replacement therapy (HRT) based on unopposed oestrogen increases the risk of endometrial cancer, and uterine hyperplasia or cancer.
Evidence from randomized controlled studies showed a definite association between HRT and uterine hyperplasia and cancer. HRT based on unopposed oestrogen is associated with this observed risk, which is unlike the increased risk of breast cancer linked with combined rather than unopposed HRT.

The water deprivation test (i.e., the Miller-Moses test), is a semiquantitative test to ensure adequate dehydration and maximal stimulation of ADH for diagnosis. It is typically performed in patients with more chronic forms of Diabetes Insipidus (DI). The extent of deprivation is usually limited by the patient’s thirst or by any significant drop in blood pressure or related clinical manifestation of dehydration.

In healthy individuals, water deprivation leads to a urinary osmolality that is 2-4 times greater than plasma osmolality. Additionally, in normal, healthy subjects, administration of ADH produces an increase of less than 9% in urinary osmolality. The time required to achieve maximal urinary concentration ranges from 4-18 hours.

In central and nephrogenic DI, urinary osmolality will be less than 300 mOsm/kg after water deprivation. After the administration of ADH, the osmolality will rise to more than 750 mOsm/kg in central DI but will not rise at all in nephrogenic DI. In primary polydipsia, urinary osmolality will be above 750 mOsm/kg after water deprivation.
A urinary osmolality that is 300-750 mOsm/kg after water deprivation and remains below 750 mOsm/kg after administration of ADH may be seen in partial central DI, partial nephrogenic DI, and primary polydipsia.

The patients high morning blood sugar levels are suggestive to Somogyi Phenomenon which suggests that hypoglycaemia during the late evening induced by insulin could cause a counter regulatory hormone response that produces hyperglycaemia in the early morning.
Substitution of regular insulin with an immediate-acting insulin analogue, such as Humulin lispro, may be of some help.

Pregnancies affected by T1DM are at increased risk for preterm delivery, preeclampsia, macrosomia, shoulder dystocia, intrauterine fetal demise, fetal growth restriction, cardiac and renal malformations, in addition to rare neural conditions such as sacral agenesis.
Successful management of pregnancy in a T1DM patient begins before conception. Research indicates that the implementation of preconception counselling, emphasizing strict glycaemic control before and throughout pregnancy, reduces the rate of perinatal mortality and malformations.
The 2008 bulletin from the National Institute for Health and Clinical Excellence recommends that preconception counselling be offered to all patients with diabetes. Physicians are advised to guide patients on achieving personalized glycaemic control goals, increasing the frequency of glucose monitoring, reducing their HbA1C levels, and recommend avoiding pregnancy if the said level is > 10%.
Other sources suggest deferring pregnancy until HbA1C levels are > 8%, as this margin is associated with better outcomes.

Diabetes insipidus (DI) is defined as the passage of large volumes (>3 L/24 hr) of dilute urine (< 300 mOsm/kg). It has the following 2 major forms:
Central (neurogenic, pituitary, or neurohypophyseal) DI, characterized by decreased secretion of antidiuretic hormone (ADH; also referred to as arginine vasopressin [AVP])
Nephrogenic DI, characterized by decreased ability to concentrate urine because of resistance to ADH action in the kidney.
The boy most probably has nephrogenic diabetes insidious (DI) not central DI so he is not responding to the ADH treatment.

During pregnancy, profound changes in thyroid physiology occur to provide sufficient thyroid hormone (TH) to both the mother and foetus. This is particularly important during early pregnancy because the fetal thyroid starts to produce considerable amounts of TH only from approximately 20 weeks of gestation, until which time the foetus heavily depends on the maternal supply of TH. This supply of TH to the foetus, as well as increased concentrations of TH binding proteins (thyroxine-binding globulin) and degradation of TH by placental type 3 iodothyronine deiodinase, necessitate an increased production of maternal TH. This requires an intact thyroid gland and adequate availability of dietary iodine and is in part mediated by the pregnancy hormone human chorionic gonadotropin, which is a weak agonist of the thyroid-stimulating hormone (TSH) receptor. As a consequence, serum-free thyroxine (FT4) concentrations increase and TSH concentrations decrease from approximately the eighth week throughout the first half of pregnancy, resulting in different reference intervals for TSH and FT4 compared to the non-pregnant state.

The main cause of growth hormone (GH) deficiency is a pituitary tumour or the consequences of treatment of the tumour including surgery and/or radiation therapy.
Sheehan’s syndrome (SS) is postpartum hypopituitarism caused by necrosis of the pituitary gland. It is usually the result of severe hypotension or shock caused by massive haemorrhage during or after delivery. Patients with SS have varying degrees of anterior pituitary hormone deficiency.

Laron syndrome is Insulin-like growth factor I (IGF-I) deficiency due to GH resistance or insensitivity due to genetic disorders of the GH receptor causing GH receptor deficiency.

Graves’ disease is the most common cause of thyrotoxicosis in pregnancy.

– Poor control of thyrotoxicosis is associated with pregnancy loss, pregnancy-induced hypertension, prematurity, low birth weight, intrauterine growth restriction, stillbirth, thyroid storm, and maternal congestive heart failure.

– Antithyroid drugs are the treatment of choice of hyperthyroidism during pregnancy. The lowest dose of ATD needed to maintain TT4 1.5× the upper limit of the non-pregnant reference range or FT4 at the upper limit of the reference range should be used.
Two different antithyroid drug (ATD) regimens are in common use for Grave’s disease: i) Titration method and ii) Block-and-replace method.
In the titration method, the usual starting dose is 15–30 mg/day methimazole (or equivalent doses of other thionamides); further to periodic thyroid status assessment, daily dose is tapered down to the lowest effective dose (avoiding both hyper- and hypothyroidism).
The block-and-replace method uses persistently high ATD doses in association with L-thyroxine replacement to avoid hypothyroidism; treatment lasts 6 months. This method has advantages and disadvantages over the titration method. Higher doses of ATDs may have a greater immunosuppressive action useful for a permanent remission of hyperthyroidism, but this effect remains to be demonstrated.
Avoidance of hypothyroidism or ‘escape’ of hyperthyroidism seems easier than with the titration method; treatment is shorter, and the number of visits lower. On the other hand, the much higher number of tablets taken every day may create problems of poor compliance. The block-and-replace method should not be used during pregnancy.

– Breastfeeding has been shown to be safe in mothers taking ATDs in appropriate doses.

A muscarinic receptor antagonist (MRA) is a type of anticholinergic agent that blocks the activity of the muscarinic acetylcholine receptor. There are six antimuscarinic drugs currently marketed for the treatment of urge incontinence: oxybutynin, tolterodine, propiverine, trospium, darifenacin, and solifenacin.

Euthyroid sick syndrome (also known as nonthyroidal illness syndrome) can be described as abnormal findings on thyroid function tests that occurs in the setting of a nonthyroidal illness (NTI), without pre-existing hypothalamic-pituitary and thyroid gland dysfunction. After recovery from an NTI, these thyroid function test result abnormalities should be completely reversible.
Multiple alterations in serum thyroid function test findings have been recognized in patients with a wide variety of NTIs without evidence of pre-existing thyroid or hypothalamic-pituitary disease. The most prominent alterations are low serum triiodothyronine (T3) and elevated reverse T3 (rT3), leading to the general term low T3 syndrome. Thyroid-stimulating hormone (TSH), thyroxine (T4), free T4 (FT4), and free T4 index (FTI) also are affected in variable degrees based on the severity and duration of the NTI. As the severity of the NTI increases, both serum T3 and T4 levels drop, but they gradually normalize as the patient recovers.
Reverse T3 is used to differentiate between this condition and secondary thyroid failure.

Once thyrotoxicosis has been identified by laboratory values, the thyroid radio-iodine uptake and scan may be used to help distinguish the underlying aetiology. Thyroid radioiodine uptake is raised in Graves’ disease. It may be normal or raised in patients with a toxic multinodular goitre. It is very low or undetectable in thyrotoxicosis resulting from exogenous administration of thyroid hormone or the thyrotoxic phase of thyroiditis.

For medical management of carcinoid syndrome, there are two somatostatin analogues available, Octreotide and Lanreotide. Somatostatin is an amino acid peptide which is an inhibitory hormone, which is synthesized by paracrine cells located ubiquitously throughout the gastrointestinal tract. Both somatostatin analogues provide symptom relief in 50% to 70% of patients and biochemical response in 40% to 60% patients. Many studies have shown that Octreotide and Lanreotide also inhibit the proliferation of tumour cells.

This child has pseudo hypoparathyroidism. It is a heterogeneous group of rare endocrine disorders characterized by normal renal function and resistance to the action of parathyroid hormone (PTH), manifesting with hypocalcaemia, hyperphosphatemia, and increased serum concentration of PTH.
Patients with pseudo hypoparathyroidism type 1a present with a characteristic phenotype collectively called Albright hereditary osteodystrophy (AHO). The constellation of findings includes the following:
Short stature
Stocky habitus
Obesity
Developmental delay
Round face
Dental hypoplasia
Brachymetacarpals
Brachymetatarsals
Soft tissue calcification/ossification
The goals of therapy are to maintain serum total and ionized calcium levels within the reference range to avoid hypercalcaemia and to suppress PTH levels to normal. This is important because elevated PTH levels in patients with PHP can cause increased bone remodelling and lead to hyper-parathyroid bone disease.
The goals of pharmacotherapy are to correct calcium deficiency, to prevent complications, and to reduce morbidity. Intravenous calcium is the initial treatment for all patients with severe symptomatic hypocalcaemia. Administration of oral calcium and 1alpha-hydroxylated vitamin D metabolites, such as calcitriol, remains the mainstay of treatment and should be initiated in every patient with a diagnosis of pseudo hypoparathyroidism.

Diabetes insipidus (DI) is defined as the passage of large volumes (>3 L/24 hr) of dilute urine (< 300 mOsm/kg). It has the following 2 major forms:
– Central (neurogenic, pituitary, or neurohypophyseal) DI, characterized by decreased secretion of antidiuretic hormone (ADH; also referred to as arginine vasopressin [AVP])
– Nephrogenic DI, characterized by decreased ability to concentrate urine because of resistance to ADH action in the kidney
This patient has the central type from metastases.
In patients with central DI, desmopressin is the drug of choice. It is a synthetic analogue of antidiuretic hormone (ADH). It is available in subcutaneous, IV, intranasal, and oral preparations. Generally, it can be administered 2-3 times per day. Patients may require hospitalization to establish fluid needs. Frequent electrolyte monitoring is recommended during the initial phase of treatment.

Carcinoid tumours are of neuroendocrine origin and derived from primitive stem cells in the gut wall, especially the appendix. They can be seen in other organs, including the lungs, mediastinum, thymus, liver, bile ducts, pancreas, bronchus, ovaries, prostate, and kidneys. While carcinoid tumours tend to grow slowly, they have the potential to metastasise.
Signs and symptoms seen in larger tumours may include the following:
– Periodic abdominal pain: Most common presentation for a small intestinal carcinoid; often associated with malignant carcinoid syndrome.
– Cutaneous flushing: Early and frequent (94%) symptom; typically affects head and neck.
– Diarrhoea and malabsorption (84%): Watery, frothy, or bulky stools, gastrointestinal (GI) bleed or steatorrhea; may or may not be associated with abdominal pain, flushing, and cramps.
– Cardiac manifestations (60%): Valvular heart lesions, fibrosis of the endocardium; may lead to heart failure with tachycardia and hypertension.
– Wheezing or asthma-like syndrome (25%): Due to bronchial constriction; some tremors are relatively indolent and result in chronic symptoms such as cough and dyspnoea.
– Pellagra with scale-like skin lesions, diarrhoea and mental disturbances.
– Carcinoid crisis can be the most serious symptom of the carcinoid tumours and life-threatening. It can occur suddenly or after stress, including chemotherapy and anaesthesia.

Lactic acidosis is occasionally responsible for metabolic acidosis in diabetics. It may occur in the presence of normal blood levels of the ketone bodies, and such cases are often described as having “non-ketotic diabetic acidosis.
It is most commonly associated with tissue hypoperfusion and states of acute circulatory failure.
Appropriate measures include treatment of shock, restoration of circulating fluid volume, improved cardiac function, identification of sepsis source, early antimicrobial intervention, and resection of any potential ischemic regions. Reassessment of lactate levels for clearance assists ongoing medical management.

Oestrogen therapy reduces plasma levels of LDL cholesterol and increases levels of HDL cholesterol. It can improve endothelial vascular function, however, it also has adverse physiological effects, including increasing the plasma levels of triglycerides (small dense LDL particles). Therefore, although HRT may have direct beneficial effects on cardiovascular outcomes, these effects may be reduced or balanced by the adverse physiological effects.

Mild deficiencies of 21-hydroxylase or 3-beta-hydroxysteroid dehydrogenase activity may present in adolescence or adulthood with oligomenorrhea, hirsutism, and/or infertility. This is termed nonclassical adrenal hyperplasia.
Late-onset or nonclassical congenital adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency is one of the most common autosomal recessive disorders. Reported prevalence ranges from 1 in 30 to 1 in 1000. Affected individuals typically present due to signs and symptoms of androgen excess.
Treatment needs to be directed toward the symptoms. Goals of treatment include normal linear growth velocity, a normal rate of skeletal maturation, ‘on-time’ puberty, regular menstrual cycles, prevention of or limited progression of hirsutism and acne, and fertility. Treatment needs to be individualized and should not be initiated merely to decrease abnormally elevated hormone concentrations.
Normal Ultrasound rules out Turner’s syndrome.

11-beta hydroxylase is stimulated by ACTH and responsible for conversion of 11-deoxycortisol to cortisol and deoxycorticosterone to corticosterone.

In 11-beta hydroxylase deficiency, the previously mentioned conversions are partially blocked, leading to:
– Increased levels of ACTH
– Accumulation of 11-deoxycortisol (which has limited biological activity) and deoxycorticosterone (which has mineralocorticoid activity)
– Overproduction of adrenal androgens (DHEA, androstenedione, and testosterone)

This patient has polycystic ovarian syndrome (PCOS). Medical management of PCOS is aimed at the treatment of metabolic derangements, anovulation, hirsutism, and menstrual irregularity.
First-line medical therapy usually consists of an oral contraceptive to induce regular menses. The contraceptive not only inhibits ovarian androgen production but also increases sex hormone-binding globulin (SHBG) production. The American College of Obstetricians and Gynaecologists (ACOG) recommends the use of combination low-dose hormonal contraceptive agents for long-term management of menstrual dysfunction.
If symptoms such as hirsutism are not sufficiently alleviated, an androgen-blocking agent may be added. Pregnancy should be excluded before therapy with oral contraceptives or androgen-blocking agents are started.
First-line treatment for ovulation induction when fertility is desired is clomiphene citrate. Second-line strategies may be equally effective in infertile women with clomiphene citrate–resistant PCOS.

Biguanides (Metformin):
People who take metformin alone should be able to fast safely given that the possibility of hypoglycaemia is minimal. However, patients should modify its dose and administration timing to provide two-thirds of the total daily dose, which should be taken immediately with the sunset meal, while the other third is taken before the predawn meal.

Thiazolidinediones: No change needed.

Sulfonylurea:
Once-daily sulfonylurea (such as glimepiride or gliclazide MR): the total daily dose should be taken with the sunset meal.
Shorter-acting sulfonylurea (such as gliclazide twice daily): the same daily dose remains unchanged, and one dose should be taken at the sunset meal and the other at the predawn meal.
Long-acting sulfonylurea (such as glibenclamide): these agents should be avoided.

It is important that diabetic patients to eat a healthy balanced diet and choose foods with a low glycaemic index (such as complex carbohydrates), which can help to maintain blood glucose levels during fasting. Moreover, it is crucial to consume adequate fluids to prevent dehydration. Physical activity is encouraged, especially during non-fasting periods.

Classically, pheochromocytoma manifests with the following 4 characteristics:
– Headaches
– Palpitations
– Sweating
– Severe hypertension

The Endocrine Society, the American Association for Clinical Chemistry, and the European Society of Endocrinology have released clinical practice guidelines for the diagnosis and management of pheochromocytoma.
Biochemical testing via measurement of plasma free metanephrines or urinary fractionated metanephrines should be performed in patients suspected of having pheochromocytoma.

Catecholamines produced by pheochromocytomas are metabolized within chromaffin cells. Norepinephrine is metabolized to normetanephrine and epinephrine is metabolized to metanephrine. Because this process occurs within the tumour, independently of catecholamine release, pheochromocytomas are best diagnosed by measurement of these metabolites rather than by measurement of the parent catecholamines.

The patient has primary Hypogonadism.
Since he already had two children, Klinefelter syndrome is excluded and the patient does not need karyotyping.
His lab results are normal indicating normal pituitary gland functions.
So the next step is testicular ultrasound as testicular tumour, infiltration or idiopathic failure is suspected.

The patient has small cell lung cancer presented by paraneoplastic syndrome; Ectopic ACTH secretion.

Small cell lung cancer (SCLC), previously known as oat cell carcinoma is a neuroendocrine carcinoma that exhibits aggressive behaviour, rapid growth, early spread to distant sites, exquisite sensitivity to chemotherapy and radiation, and a frequent association with distinct paraneoplastic syndromes.
Common presenting signs and symptoms of the disease, which very often occur in advanced-stage disease, include the following:
– Shortness of breath
– Cough
– Bone pain
– Weight loss
– Fatigue
– Neurologic dysfunction
Most patients with this disease present with a short duration of symptoms, usually only 8-12 weeks before presentation. The clinical manifestations of SCLC can result from local tumour growth, intrathoracic spread, distant spread, and/or paraneoplastic syndromes.
SIADH is present in 15% of the patients and Ectopic secretion of ACTH is present in 2-5% of the patients leading to ectopic Cushing’s syndrome.

Thyroid malignancies are divided into papillary carcinomas (80%), follicular carcinomas (10%), medullary thyroid carcinomas (5-10%), anaplastic carcinomas (1-2%), primary thyroid lymphomas (rare), and primary thyroid sarcomas (rare).
Hürthle cell carcinoma is a rare thyroid malignancy that is often considered a variant of follicular carcinoma.
– Papillary and Follicular carcinoma are slow-growing tumours
– Sporadic cases of Medullary thyroid carcinoma also typically manifest with painless solitary thyroid nodules in the early stages.
– Anaplastic thyroid carcinoma has the most aggressive biologic behaviour of all thyroid malignancies and has one of the worst survival rates of all malignancies in general. It manifests as a rapidly growing thyroid mass in contrast to a well-differentiated carcinoma, which are comparatively slow-growing. Patients commonly present with associated symptoms due to local invasion. Hoarseness and dyspnoea resulting from the involvement of the recurrent laryngeal nerve and airway occur in as many as 50% of patients.
– Almost all patients with primary thyroid lymphoma have either a clinical history or histological evidence of chronic lymphocytic thyroiditis. The risk of primary thyroid lymphoma increases 70-fold in patients with chronic lymphocytic thyroiditis compared with the general population. Regional and distant lymphadenopathy is common.

Classic Kallmann syndrome (KS) is due to isolated hypogonadotropic hypogonadism. Most patients have gonadotropin-releasing hormone (GnRH) deficiency, as suggested by their response to pulsatile GnRH therapy. The hypothalamic-pituitary function is otherwise normal in most patients, and hypothalamic-pituitary imaging reveals no space-occupying lesions. By definition, either anosmia or severe hyposmia is present in patients with Kallmann syndrome.

Osteopenia is an early sign of bone weakening that is less severe than osteoporosis.
The numerical result of the bone density test is quantified as a T score. The lower the T score, the lower the bone density. T scores greater than -1.0 are considered normal and indicate healthy bone. T scores between -1.0 and -2.5 indicate osteopenia. T scores lower than -2.5 indicate osteoporosis.
DEXA also provides the patient’s Z-score, which reflects a value compared with that of person matched for age and sex.
Z-score values of –2.0 SD or lower are defined as below the expected range for age and those above –2.0 SD as within the expected range for age.

Raloxifene is a selective oestrogen-receptor modulator (SERM) that has been approved for use in the prevention and treatment of osteoporosis in postmenopausal women.
A SERM interacts with oestrogen receptors, functioning as an agonist in some tissues and an antagonist in other tissues. Because of their unique pharmacologic properties, these agents can achieve the desired effects of oestrogen without the possible stimulatory effects on the breasts or uterus.

This girl most probably has Turner’s syndrome, which is caused by the absence of one set of genes from the short arm of one X chromosome.
Turner syndrome is a lifelong condition and needs lifelong oestrogen replacement therapy. Oestrogen is usually started at age 12-15 years. Treatment can be started with continuous low-dose oestrogens. These can be cycled in a 3-weeks on, 1-week off regimen after 6-18 months; progestin can be added later.

In childhood, growth hormone therapy is standard to prevent short stature as an adult.

Fetal ovarian development seems to be normal in Turner syndrome, with degeneration occurring in most cases around the time of birth so pulsatile GnRH and luteinising hormone would be of no use.

The somatotroph cells of the anterior pituitary gland produce growth hormone (GH).
GH deficiency in adults usually manifests as reduced physical performance and impaired psychological well-being. It results in alterations in the physiology of different systems of the body, manifesting as altered lipid metabolism, increased subcutaneous and visceral fat, decreased muscle mass, decreased bone density, low exercise performance, and reduced quality of life.

Three classes of medications are appropriate for the management of major triglyceride elevations: fibric acid derivatives, niacin, and omega-3 fatty acids.

Fibrate is used as a first-line agent for reduction of triglycerides in patients at risk for triglyceride-induced pancreatitis.

High-dose niacin (vitamin B-3) (1500 or more mg/d) decreases triglyceride levels by at least 40% and can raise HDL cholesterol levels by 40% or more. Niacin also reliably and significantly lowers LDL cholesterol levels, which the other major triglyceride-lowering medications do not.

Omega-3 fatty acids are attractive because of their low risk of major adverse effects or interaction with other medications. At high doses (>4 g/d), triglycerides are reduced.

In boys, the first manifestation of puberty is testicular enlargement; the normal age for initial signs of puberty is 9 to 14 years in males. Pubic hair in boys generally appears 18 to 24 months after the onset of testicular growth and is often conceived as the initial marker of sexual maturation by male adolescents.

Primary hyperparathyroidism (PHPT) is diagnosed based upon levels of blood calcium and parathyroid hormone (PTH). In most people with PHPT, both levels are higher than normal. Occasionally, a person may have an elevated calcium level and a normal or minimally elevated PTH level. Since PTH should normally be low when calcium is elevated, a minimally elevated PTH is considered abnormal and indicates PHPT.

RET (rearranged during transfection) is a receptor tyrosine kinase involved in the development of neural crest derived cell lineages, kidney, and male germ cells. Different human cancers, including papillary and medullary thyroid carcinomas, lung adenocarcinomas, and myeloproliferative disorders display gain-of-function mutations in RET.
In over 90% of cases, MEN2 syndromes are due to germline missense mutations of the RET gene.
Multiple endocrine neoplasias type 2 (MEN2) is an inherited disorder characterized by the development of medullary thyroid cancer (MTC), parathyroid tumours, and pheochromocytoma.

Insulin is produced by the beta-cells in the islets of Langerhans in the pancreas while Glucagon is secreted from the alpha cells of the pancreatic islets of Langerhans.
Type 1 diabetes mellitus is the culmination of lymphocytic infiltration and destruction of the beta cells of the islets of Langerhans in the pancreas. As beta-cell mass declines, insulin secretion decreases until the available insulin is no longer adequate to maintain normal blood glucose levels. After 80-90% of the beta cells are destroyed, hyperglycaemia develops and diabetes may be diagnosed.

The patient has hyperinsulinemia and hypoglycaemia, but her C-peptide levels are normal. This is strongly suggestive of the fact that she is self-administering insulin.
In Insulinoma, common diagnostic criteria include:
– blood glucose level < 50 mg/dl with hypoglycaemic symptoms,
– relief of symptoms after eating
– absence of sulfonylurea on plasma assays.
The classic diagnostic criteria include the demonstration of the following during a supervised fast:
Increased plasma insulin level
Increased C peptide level
Increased proinsulin level
However, the patient has normal C-peptide levels.
In type-1 diabetes mellitus, insulin and C-peptide levels are low.

A fasting blood glucose level from 110 to 126 mg/dL (5.5 to 6.9 mmol/L) is considered prediabetes. This result is sometimes called impaired fasting glucose.
Diabetes mellitus (type 2): diagnosis

The diagnosis of type 2 diabetes mellitus can be made by plasma glucose. If the patient is symptomatic:
fasting glucose greater than or equal to 7.0 mmol/l
random glucose greater than or equal to 11.1 mmol/l (or after 75g oral glucose tolerance test)
If the patient is asymptomatic the above criteria apply but must be demonstrated on two separate occasions.

Androgen insensitivity syndrome (AIS), previously referred to as testicular feminization, is an X-linked disorder in which the patients are genotypically male (possessing and X and Y chromosome) and phenotypically female. This disorder is rare, with reported incidences from 1 in 20,000 to 1 in 60,000 live male births, and is the result of a missing gene on the X chromosome that is responsible for the cytoplasmic or nuclear testosterone receptor. In its absence, the gonad, which is a testis, produces normal amounts of testosterone; however, the end tissues are unable to respond due to the deficient receptors leading to the external genitalia developing in a female fashion. Anti-mullerian hormone, which is produced by the testis, is normal in these patients, leading to regression of the Mullerian duct. Wolffian duct development, which depends on testosterone, does not occur as the ducts lack the receptors.
The cumulative effect is a genotypic male with normal external female genitalia (without pubic or axillary hair), no menses, normal breast development, short or absent vagina, no internal sex organs, and the presence of testis. Frequently, these patients have bilateral inguinal hernias in childhood, and their presence should arouse suspicion of the diagnosis.

Bicarbonate therapy is not indicated in mild and moderate forms of DKA because metabolic acidosis will correct with insulin therapy. The use of bicarbonate in severe DKA is controversial due to a lack of prospective randomized studies. It is thought that the administration of bicarbonate may actually result in peripheral hypoxemia, worsening of hypokalaemia, paradoxical central nervous system acidosis, cerebral oedema in children and young adults, and an increase in intracellular acidosis. Because severe acidosis is associated with worse clinical outcomes and can lead to impairment in sensorium and deterioration of myocardial contractility, bicarbonate therapy may be indicated if the pH is 6.9 or less.

The patient is most likely to have Bulimia nervosa. A young girl with a low body mass contributes to the low urea. Hypokalaemia and hyponatraemia are due to vomiting. Her urine sodium is also low.
– In Addison’s diseases, there are low levels of sodium and high levels of potassium in the blood. In acute adrenal crisis: The most consistent finding is elevated blood urea nitrogen (BUN) and creatinine. Urinary and sweat sodium also may be elevated.
– In Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) there is hyponatremia with corresponding hypo-osmolality, continued renal excretion of sodium, urine less than maximally dilute and absence of clinical evidence of volume depletion.

The combination of Insulinoma and Parathyroid diseases is suggestive of MEN 1 syndrome.
Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary tumour syndrome inherited in an autosomal dominant manner and characterized by a predisposition to a multitude of endocrine neoplasms primarily of parathyroid, entero-pancreatic, and anterior pituitary origin, as well as non-endocrine neoplasms.
Other endocrine tumours in MEN1 include foregut carcinoid tumours, adrenocortical tumours, and rarely pheochromocytoma. Nonendocrine manifestations include meningiomas and ependymomas, lipomas, angiofibromas, collagenomas, and leiomyomas.

Primary hyperparathyroidism (PHPT), due to parathyroid hyperplasia is the most frequent and usually the earliest expression of MEN-1, with a typical age of onset at 20–25 years.

It has been determined that HPV infection is the most powerful epidemic factor. This virus is needed, but not sufficient for the development of cervical cancer.
The WHO’s International Agency for Research on Cancer (IARC) classified HPV infection as carcinogenic to humans (HPV types 16 and 18), probably carcinogenic (HPV types 31 and 33) and possibly carcinogenic (other HPV types except 6 and 11).
Tobacco smoking, the use of contraceptives, and the number of births are factors that showed no statistically significant deviations in the studied population compared to other countries in the region, as well as European countries. They have an equal statistical significance in all age groups.

Klinefelter syndrome (KS), the most common human sex chromosome disorder 47,XXY. It is characterized by hypogonadism (micro-orchidism, oligospermia/azoospermia) and gynecomastia in late puberty. If Klinefelter syndrome is not diagnosed prenatally, a patient with 47,XXY karyotype may demonstrate various subtle, age-related clinical signs that would prompt diagnostic testing. These include the following:
Infants: Hypospadias, small phallus, cryptorchidism.
Toddlers: Developmental delay (especially expressive language skills), hypotonia.
Older boys and adolescent males: Tall stature; delayed or incomplete pubertal development with eunuchoid body habitus; gynecomastia; small, firm testes; sparse body hair.

From childhood with progression to early puberty, the pituitary-gonadal function observed is within normal limits for 47,XXY males.
At mid puberty and later, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) concentrations rise to hyper-gonadotropic levels, inhibin B levels fall until they are undetectable, and testosterone levels are at low or low-normal levels after an initial increase.

Fragile X syndrome, also termed Martin-Bell syndrome or marker X syndrome, is the most common cause of inherited mental retardation, intellectual disability, and autism.
However, the patient here does not have any mental disabilities as he already works as a clerk, and that too would make Down’s Syndrome less likely.

Classic Kallmann syndrome (KS) and idiopathic hypogonadotropic hypogonadism (IHH) are rare genetic conditions that encompass the spectrum of isolated hypogonadotropic hypogonadism. Most patients have gonadotropin-releasing hormone (GnRH) deficiency, as suggested by their response to pulsatile GnRH therapy. Hypothalamic-pituitary function is otherwise normal in most patients, and hypothalamic-pituitary imaging reveals no space-occupying lesions. By definition, either anosmia or severe hyposmia is present in patients with Kallmann syndrome, in contrast to patients with idiopathic hypogonadotropic hypogonadism, whose sense of smell is normal.

Synacthen test interpretation:
– Basal Cortisol level should be greater than 180nmol/L
– 30min or 60min Cortisol should be greater than 420nmol/L (whatever the basal level)
– The increment should be at least 170nmol/L, apart from in severely ill patients where adrenal output is already maximal.
The patient’s results show that she has Acute Adrenal Insufficiency
The guidelines include the following recommendations for emergency treatment:
Administer hydrocortisone: Immediate bolus injection of 100 mg hydrocortisone intravenously or intramuscularly followed by continuous intravenous infusion of 200 mg hydrocortisone per 24 hours (alternatively, 50 mg hydrocortisone per intravenous or intramuscular injection every 6 h)
Rehydrate with rapid intravenous infusion of 1000 mL of isotonic saline infusion within the first hour, followed by further intravenous rehydration as required (usually 4-6 L in 24 h; monitor for fluid overload in case of renal impairment and elderly patients)
Contact an endocrinologist for urgent review of the patient, advice on further tapering of hydrocortisone, and investigation of the underlying cause of the disease, including the diagnosis of primary versus secondary adrenal insufficiency
Tapering of hydrocortisone can be started after clinical recovery guided by an endocrinologist; in patients with primary adrenal insufficiency, mineralocorticoid replacement must be initiated (starting dose 100 μg fludrocortisone once daily) as soon as the daily glucocorticoid dose is below 50 mg of hydrocortisone every 24 hours

Selective sodium-glucose transporter-2 (SGLT2) is expressed in the proximal renal tubules and is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen.
Empagliflozin; SGLT2 inhibitors reduce glucose reabsorption and lower the renal threshold for glucose, thereby increasing urinary glucose excretion, thus increasing the risk of urinary tract infections.

Exposure to excessive androgens is usually accompanied by premature epiphyseal maturation and closure, resulting in a final adult height that is typically significantly below that expected from parental heights.

congenital adrenal hyperplasia (CAH) is associated with precocious puberty caused by long term exposure to androgens, which activate the hypothalamic-pituitary-gonadal axis. Similarly, CAH is associated with hyperpigmentation and hyperreninemia due to sodium loss and hypovolaemia.

Prolactinomas, benign lesions that produce the hormone prolactin, are the most common hormone-secreting pituitary tumours.
Based on its size, a prolactinoma can be classified as a microprolactinoma (< 10 mm diameter) or a macroprolactinoma (>10 mm diameter). If the prolactinoma is large enough to compress the surrounding normal hormone-secreting pituitary cells, it may result in deficiencies of one or more hormones (e.g., thyroid-stimulating hormone [TSH], growth hormone [GH], adrenocorticotropic hormone). However, the patient has microadenoma so it is unlikely to cause compression manifestations.
Hyperprolactinemia inhibits GnRH secretion from the medial basal hypothalamus and LH release from the pituitary.

Exogenous thyroid hormone use has been associated with episodes of thyroid storm as well as thyrotoxic periodic paralysis.
It presents with marked proximal muscle weakness in both upper and lower limbs, hypokalaemia and signs of hyperthyroidism.
Hyperthyroidism generally presents with tachycardia, hypertension, hyperthermia, and cardiac arrhythmias

Laxatives and diuretics can result in electrolyte abnormalities.
Medical complications associated with laxatives include chronic diarrhoea which disrupts the normal stool electrolyte concentrations that then leads to serum electrolyte shifts; acutely, hypokalaemia is most typically seen. The large intestine suffers nerve damage from the chronic laxative use that renders it unable to function properly. The normal peristalsis and conduction are affected; the disorder is thought to be secondary to a degeneration of Auerbach’s Plexi. However, it does not cause muscle weakness.

Insulin tends to cause weight gain, not weight loss.
Metformin does not cause muscle weakness but can cause headaches.

Cabergoline, an ergot derivative, is a long-acting dopamine agonist. It is usually better tolerated than Bromocriptine (BEC), and its efficacy profiles are somewhat superior to those of BEC. It offers the convenience of twice-a-week administration, with a usual starting dose of 0.25 mg biweekly to a maximum dose of 1 mg biweekly. Some studies have shown efficacy even with once-a-week dosing. Cabergoline appears to be more effective in lowering prolactin levels and restoring ovulation. Up to 70% of patients who do not respond to BEC respond to cabergoline.

The patient is most likely to have Medullary Thyroid Carcinoma (MTC).
Sporadic, or isolated MTC accounts for 75% of cases and inherited MTC constitutes the rest.
Inherited MTC occurs in association with multiple endocrine neoplasia (MEN) type 2A and 2B syndromes, but non-MEN familial MTC also occurs.
A 24-hour urinalysis for catecholamine metabolites (e.g., vanillylmandelic acid [VMA], metanephrine) has to be done to rule out concomitant pheochromocytoma in patients with MEN type 2A or 2B, as Pheochromocytoma must be treated before MTC.

In patients with polycystic ovarian syndrome (PCOS), FSH levels are within the reference range or low. Luteinizing hormone (LH) levels are elevated for Tanner stage, sex, and age. The LH-to-FSH ratio is usually greater than 3.

Women with PCOS have abnormalities in the metabolism of androgens and oestrogen and in the control of androgen production. PCOS can result from abnormal function of the hypothalamic-pituitary-ovarian (HPO) axis.
The major features of PCOS include menstrual dysfunction, anovulation, and signs of hyperandrogenism. Other signs and symptoms of PCOS may include the following:
– Hirsutism
– Infertility
– Obesity and metabolic syndrome
– Diabetes
– Obstructive sleep apnoea

Androgen excess can be tested by measuring total and free testosterone levels or a free androgen index. An elevated free testosterone level is a sensitive indicator of androgen excess. Other androgens, such as dehydroepiandrosterone sulphate (DHEA-S), may be normal or slightly above the normal range in patients with polycystic ovarian syndrome (PCOS). Levels of sex hormone-binding globulin (SHBG) are usually low in patients with PCOS.

Some women with PCOS have insulin resistance and an abnormal lipid profile (cholesterol >200 mg/dL; LDL >160 mg/dL). Approximately one-third of women with PCOS who are overweight have impaired glucose tolerance or type 2 diabetes mellitus by 30 years of age.