The boy had a renal transplant, for which he needs immune suppression. For the exogenous immune suppression an exogenous steroid is needed, which in this case is responsible for the primary Cushing syndrome manifesting with short stature. The administration of steroids before the physiological fusion of the growth plate can lead to premature fusion with permanent cessation of bone growth.

A low serum free T4 level with a low, or normal serum TSH level would indicate secondary hypothyroidism. A normal TSH response to TRH is a rise at 20 minutes post-dose and then a fall by 60 minutes, while a normal prolactin response would be a rise at 20 minutes and then a fall by 60 minutes. A continued rise of TSH at 60 minutes implies hypothalamic damage. Secondary hypothyroidism is indicated by a low baseline TSH level, while primary hypothyroidism is demonstrated by a raised TSH.

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.

The most probable diagnosis for this boy is primary hypothyroidism.Rationale:The development of secondary sexual characteristics in a boy aged less than 9 years of age is highly suggestive of precocious puberty.Around 80% of boys with precocious puberty have pathological causes and require detailed investigation. In this case, the child has long-standing short stature but coupled with the early puberty and delay in bone age, the diagnosis is primary hypothyroidism, which is the only cause of this clinical picture.

The child’s problem should be assessed properly to find the reason for unhappiness at the school. There can be many reasons such as bullying at school, abuse etc. A clinical psychologist should assess this child to take the necessary details and plan the further management.

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.

The most overt phenotypic features of Klinefelter syndrome are caused by testosterone deficiency and, directly or indirectly, by unsuppressed follicle-stimulating and luteinizing hormones. Affected men typically have (in decreasing order of frequency): infertility, small testes, decreased facial hair, gynecomastia, decreased pubic hair, and a small penis. Because of their long legs, men with Klinefelter syndrome often are taller than predicted based on parental height. Body habitus may be feminized. In childhood, when there is a relative quiescence in the hormonal milieu, ascertainment of the syndrome may be difficult because the effects of hypogonadism (i.e., small external genitalia and firm testes) may be subtle or not present at all.

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.

Insertion sites and sensor sites should be rotated each time the infusion set or glucose sensor is changed. This keeps the tissue healthy and allows previous sites to completely heal before reusing them. Change infusion set every 2 to 3 days to help prevent infection.

Precocious puberty is the attainment of normal pubertal biochemical and physical features at an abnormally early age. The age cut-offs commonly used to define precocious puberty are 8 years for females and 9 years for males. Precocious puberty may be central (true) or peripheral (false) based on the aetiology. Central precocious puberty is due to the premature activation of the hypothalamic-pituitary-gonadal axis, which in turn leads to the development of secondary sexual characteristics at an earlier than usual age. The best laboratory investigation to diagnose central precocious puberty is a gonadotropin-releasing hormone stimulation test, which is regarded as the gold standard. It requires the collection of multiple blood samples at different time points to measure FSH and LH levels. If the LH levels increase to >8IU/L after stimulation with GnRH, then the diagnosis of central precocious puberty is confirmed.

Tanner stage two presents with the following: Downy hair, Breast bud palpable under areola (1st pubertal sign in females).Stage 1 (prepubertal) – elevation of papilla only – no pubic hairStage 2 – breast bud forms – sparse, slightly pigmented hair on labia majoraStage 3 – Breast begins to become elevated, extends beyond areola borders – hair becomes more coarse and curlyStage 4 – increased size and elevation. Areola and papilla form secondary mound – adult like, but sparing medial thighsStage 5 – final size, areola returns but papilla remains projected – hair extends to medial thighs

Findings described are suggestive of Waterhouse-Friderichsen syndrome which develops secondary to meningococcaemia. The reported incidence of Addison’s disease is 4 in 100,000. It affects both sexes equally and is seen in all age groups. It tends to show clinical symptoms at the time of metabolic stress or trauma. The symptoms are precipitated by acute infections, trauma, surgery or sodium loss due to excessive perspiration.

Deficiency of 21-hydroxylase, resulting from mutations or deletions of CYP21A, is the most common form of Congenital Adrenal Hyperplasia, accounting for more than 90% of cases.Females with mild 21-hydroxylase deficiency are identified later in childhood because of precocious pubic hair, clitoromegaly, or both, often accompanied by accelerated growth and skeletal maturation (simple virilizing adrenal hyperplasia)Diagnosis of 21-hydroxylase deficiency: High serum concentration of 17-hydroxyprogesterone (usually >1000 ng/dL) and urinary pregnanetriol (metabolite of 17-hydroxyprogesterone) in the presence of clinical features suggestive of the disease| 24-hour urinary 17-ketosteroid levels are elevated

Undescended testis (UDT) is a common abnormality, affecting about 1/20 males at birth. Half of these have delayed testicular descent, with the testis in the scrotum by 10-12 weeks after term. Beyond this spontaneous descent is rare. Current treatment recommendations are that UDT beyond 3 months need surgery between 6-12 months of age. Some children have scrotal testes in infancy but develop UDT later in childhood because the spermatic cord does not elongate with age, leaving the testis behind as the scrotum moves further from the groin. The maldescended testis suffers heat stress when not at the lower scrotal temperature (33 degrees Celsius), interfering with testicular physiology and development of germ cells into spermatogonia. Recent evidence suggests orchidopexy between 6-12 months improves germ cell development, with early reports of improved fertility, but no evidence yet for changes in malignancy prognosis.Hypospadias is also a common abnormality in new-born males, affecting about 1/150 boys. Androgens control masculinization of the genital tubercle into penis between 8-12 weeks’ gestation, with tabularization of the urethra from the perineum to the tip of the glans. If this process is disrupted hypospadias occurs, with a variable proximal urethral meatus, failed ventral preputial development producing a dorsal hood, and discrepancy in the ventral versus dorsal penile length, causing a ventral bend in the penis, known as chordee. Surgery to correct hypospadias is recommended between 6-18 months.

Puberty is a period of transitioning into adulthood by developing full reproductive potential by undergoing drastic physiological and psychological changes. For boys, it occurs around 9-16 years of age typically. The process of pubertal changes is usually divided into stages called tanner’s stages. The physiologic changes of puberty are initiated by the release of gonadotropin-releasing hormones from the hypothalamus, which then interact with numerous endogenous and environmental stimuli to bring about the physical pubertal features. Tanner stage 2 in boys is characterized by the thinning and reddening of the scrotal skin.The growth spurt of around 9cm per year is expected in boys, at the peak velocity.Testicular enlargement of >3cm commences puberty.Pubarche, in the absence of other secondary sexual characteristics, is pathological.Adrenarche is the increase in the secretion of adrenal androgens, occurring prior to increased gonadotropin release.

Turners syndrome is a chromosomal syndrome affecting the development of females. In this condition, all or part of the X chromosome gets deleted, producing the Karyotype 45 XO or 45XO/46XX. Spontaneous foetal loss is common in the first trimester, but foetuses which survive are born small for date, and may have lymphedema, and poor feeding in the neonatal period. These patients face numerous medical and developmental problems throughout their lifetimes including growth and puberty failure due to premature ovarian failure/ hypergonadotropic hypogonadism. However spontaneous puberty can be seen in up to 20% of females with Turner’s syndrome.

Fragile X syndrome is a genetic condition that causes a range of developmental problems including learning disabilities and cognitive impairment. Usually, males are more severely affected by this disorder than females.Affected individuals usually have delayed development of speech and language by age 2. Most males with fragile X syndrome have mild to moderate intellectual disability, while about one-third of affected females are intellectually disabled. Children with fragile X syndrome may also have anxiety and hyperactive behaviour such as fidgeting or impulsive actions. They may have attention deficit disorder (ADD), which includes an impaired ability to maintain attention and difficulty focusing on specific tasks. About one-third of individuals with fragile X syndrome have features of autism spectrum disorder that affect communication and social interaction. Seizures occur in about 15 percent of males and about 5 percent of females with fragile X syndrome.Most males and about half of females with fragile X syndrome have characteristic physical features that become more apparent with age. These features include a long and narrow face, large ears, a prominent jaw and forehead, unusually flexible fingers, flat feet, and in males, enlarged testicles (macroorchidism) after puberty.

Klinefelter’s syndrome: The low follicle-stimulating hormone (FSH) and luteinising hormone (LH), together with the low testosterone, suggests a hypogonadotropic hypogonadism. We know that there is no mental retardation, and we are told that physical examination is normal and sense of smell would usually not be tested. Consequently a diagnosis of Kallman’s is suggested. We are not told of a family history of growth delay, thus this is unlikely to be constitutional delay. The thyroid-stimulating hormone (TSH) is normal, making hypothyroidism unlikely and this together with the normal prolactin make hypopituitarism most unlikely.

Cortisol is secreted in a circadian pattern.The secretion of cortisol is regulated by the suprachiasmatic nucleus located in the hypothalamus.Other options:- FSH, LH, GH and prolactin are secreted in a pulsatile pattern, i.e. these hormones are secreted in an episodic manner rather than continuously.- Thyroxine is secreted in a continuous pattern, not pulsatile.- The secretion of ACTH is in response to stress.Secondary to stress, the hypothalamus secretes corticotrophin releasing hormones, which are transported to the pituitary gland via the hypophyseal–portal system. ACTH is then released by the pituitary gland and binds to its receptor on the adrenal gland, which releases cortisol.

Addison disease is adrenocortical insufficiency due to the destruction or dysfunction of the entire adrenal cortex. It affects glucocorticoid and mineralocorticoid function. The onset of disease usually occurs when 90% or more of both adrenal cortices are dysfunctional. The most common symptoms are fatigue, muscle weakness, loss of appetite, weight loss, and abdominal pain. Adrenal insufficiency can be caused by autoimmune disease or suddenly stopping steroid medicines used to treat other conditions, among other causes.

Hypogonadism is found to be a feature in gigantism also known as acromegaly, a condition caused by growth hormone abnormalities. The most common cause of gigantism is a pituitary adenoma. Hypogonadism exists among other endocrinopathies found in gigantism. Other causes of hypogonadism include Kleinfelter’s syndrome, which is characterized by premature testicular failure. The other options listed, primary hypothyroidism, teratoma, tuberous sclerosis and hepatoblastoma are all associated with precocious puberty.

Among the given options, pituitary adenoma is an acquired anterior pituitary disorder which represent between 10 and 25% of all intracranial neoplasms.Other options:- Agenesis of the corpus callosum is characterised by the partial or complete absence of the corpus callosum. This condition is associated with pituitary hormone deficiencies.- Congenital disorders such as hydrocephalus or arachnoid cysts may be a cause of precocious puberty.- Pituitary hypoplasia and septo-optic dysplasia are congenital disorders of the pituitary gland.

Metformin works by improving the sensitivity of peripheral tissues to insulin, which results in a reduction of circulating insulin levels. Metformin inhibits hepatic gluconeogenesis and it also increases the glucose uptake by peripheral tissues and reduces fatty acid oxidation. Metformin has a positive effect on the endothelium and adipose tissue independent of its action on insulin and glucose levels.Metformin was the first insulin sensitising drug (ISD) to be used in PCOS to investigate the role of insulin resistance in the pathogenesis of the syndrome Several effects have been reported as related to metformin in PCOS patients including restoring ovulation, reducing weight, reducing circulating androgen levels, reducing the risk of miscarriage and reducing the risk of gestational diabetes mellitus (GDM). Other studies have reported that the addition of metformin to the ovarian stimulation regime in invitro fertilization (IVF) improves the pregnancy outcome. These effects will be addressed individually.

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.

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.

Congenital hypothyroidism is one of the most important diseases of the new-born, which may lead to mental and physical retardation when treatment is delayed or an appropriate dosage of thyroxine is not administered. The most alarming and earliest sign is jaundice, especially when it is prolonged, during the neonatal period.

Cases of neonatal infant ambiguous genitalia can be a great source of psychological stress for families. One of the most important next steps in managing the case is reassuring the parents that the best care will be given to the baby and then informing them about the investigations that will need to be performed before a sex can be assigned. The sex should not be guessed just by examination nor assigned by karyotyping. Thorough investigations must be completed with the help of endocrinologists for the best outcome.

Craniopharyngiomas (also known as Rathke pouch tumours, adamantinomas or hypophyseal duct tumours) affect children mainly between the age of 5 and 10 years. It constitutes 9% of brain tumours affecting the paediatric population. These are slow-growing tumours which can also be cystic, and arise from the pituitary stalk, specifically the nests of epithelium derived from Rathke’s pouch. Histologically, this tumour shows nests of squamous epithelium which is lined on the outside by radially arranged cells. Calcium deposition is often seen with a papillary type of architecture.
ACTH-secreting pituitary adenomas are rare and mostly microadenomas. Paediatric astrocytoma’s usually occur in the posterior fossa. Although null cell adenomas can cause mass effect and give rise to the described symptoms, they are not suprasellar. Prolactinomas can also show symptoms of headache and disturbances in the visual field, however they are known to be small and slow-growing.

Based on the clinical scenario, the most probable diagnosis in this patient is Kallmann’s syndrome.Kallmann’s syndrome is due to isolated gonadotrophin-releasing hormone (GnRH) deficiency. It is often inherited in an X-linked recessive manner. Other options:- While Klinefelter’s syndrome is also associated with hypogonadism, the other clinical features of Klinefelter’s are not seen. – Cryptorchidism is ruled out by the presence of testes in the scrotum. – The presentation of the child is not suggestive of mumps orchitis or hyperprolactinaemia.

Intensive physical training and participation in competitive sports during childhood and early adolescence may affect athletes’ pubertal development.Female athletes who do not begin secondary sexual development by the age of 14 or menstruation by the age of 16 warrant a comprehensive evaluation and treatment.Since she is still 14, adequate diet and observation are enough.