Precocious puberty refers to the appearance of physical and hormonal signs of pubertal development at an earlier age than is considered normal.
Most patients, particularly girls suspected of having central precocious puberty, are otherwise healthy children whose pubertal maturation begins at the early end of the normal distribution curve
In a series of more than 200 patients evaluated at a single medical centre, central precocious puberty occurred 5 times more often in girls than boys.
GnRH-dependent precocious puberty is treated with GnRH agonists or Luteinizing Hormone Releasing Hormone (LHRH).
Follow up every 4-6 months to ensure that progression of puberty has been arrested
Favourable signs include normalization of accelerated growth, reduction (or at least no increase) in size of breasts, and suppression of gonadotropin levels after a challenge of GnRH
The ideal testing frequency has not been established. Monitor bone age yearly to confirm that the rapid advancement seen in the untreated state has slowed, typically to a half year of bone age per year or less

The first sign of pubarche in females is breast-bud development (thelarche).

This begins between the ages of 9 and 12 years and continues to 12-18 years.
Pubic hair growth occurs next (said to occur in stage 3), at ages 9-14 years, and is complete at 12-16 years.
Menarche occurs relatively late in stage 4 (age 11-15 years) and is associated with a deceleration in growth.
The peak height velocity is reached earlier (10-13 years) and growth is completed much earlier than in boys.

This girl most likely has Turner syndrome (TS) also known as 45,X, a condition in which a female is partly or completely missing an X chromosome. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low hairline at the back of the neck, short stature, and swollen hands and feet are seen at birth. Typically, they are without menstrual periods, do not develop breasts, and are unable to have children. Heart defects, diabetes, and low thyroid hormone occur more frequently. Most people with TS have normal intelligence. Many, however, have troubles with spatial visualization such as that needed for mathematics. Vision and hearing problems occur more often. Turner syndrome is not usually inherited from a person’s parents. No environmental risks are known and the mother’s age does not play a role. As a chromosomal condition, there is no cure for Turner syndrome. However, much can be done to minimize the symptoms including prescribing growth hormone, either alone or with a low dose of androgen, and oestrogen replacement therapy which is crucial long term for maintaining good bone integrity, cardiovascular health and tissue health

The thymus is a lymphoid organ located in the anterior mediastinum. In early life, the thymus is responsible for the development and maturation of cell-mediated immunologic functions. The thymus is composed predominantly of epithelial cells and lymphocytes. Precursor cells migrate to the thymus and differentiate into lymphocytes. Most of these lymphocytes are destroyed, with the remainder of these cells migrating to tissues to become T cells.
DiGeorge’s syndrome (DGS) is a developmental abnormality affecting the thymus. The classic triad of features of DGS on presentation is conotruncal cardiac anomalies, hypoplastic thymus, and hypocalcaemia (resulting from parathyroid hypoplasia).

Puberty is the general term for the transition from sexual immaturity to sexual maturity. There are two main physiological events in puberty:
– Gonadarche is the activation of the gonads by the pituitary hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
– Adrenarche is the increase in production of androgens by the adrenal cortex. It is the term for the maturational increase in adrenal androgen production that normally becomes biochemically apparent at approximately six years of age in both girls and boys

A number of other terms describe specific components of puberty:
– Thelarche is the appearance of breast tissue, which is primarily due to the action of oestradiol from the ovaries.
– Menarche is the time of first menstrual bleed.
– Pubarche is the appearance of pubic hair, which is primarily due to the effects of androgens from the adrenal gland. The term is also applied to first appearance of axillary hair, apocrine body odour, and acne.

The earliest detectable secondary sexual characteristic on physical examination in most girls is breast/areolar development (thelarche). Ovarian enlargement and growth acceleration typically precede breast development but are not apparent on a single physical examination. Oestrogen stimulation of the vaginal mucosa causes a physiologic leukorrhea, which is a thin, white, non-foul-smelling vaginal discharge that typically begins 6 to 12 months before menarche. Menarche occurs, on average, 2 to 2.5 years after the onset of puberty

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.

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.

Based on the clinical scenario, the boy is going through normal pubertal changes.

In the 3 years before puberty, low pulsatile LH levels become detectable during sleep. LH and FSH are produced in the anterior pituitary and released due to pulsatile gonadotrophin-releasing hormone (GnRH) secreted by the hypothalamus.
There is an increase in the amplitude and frequency of LH secretion as puberty approaches, which causes enlargement of the gonads. In boys, the testicles produce testosterone, and in girls, the ovaries produce oestradiol and ovarian androgens, which, with the adrenal androgens, produce secondary sexual characteristics.

Note:
The average age at onset of puberty is 11 years in girls. The first sign is breast bud development, followed by the appearance of pubic hair 6-12 months later.
Menarche usually occurs 2-2.5 years after breast bud development. Peak height velocity in girls occurs at breast stage 2-3 and virtually always precedes menarche.
The onset of puberty in boys is at 11.5 years. The first sign is testicular enlargement (>3 ml) and thinning of the scrotum.
This is followed by the pigmentation of the scrotum and growth of the penis, and pubic hair follows.
Peak height velocity (growth spurt) is two years later in boys than in girls and occurs at testicular stage 4-5 (i.e. testicular volume 10-12 ml), which is around 13-14 years of age.
Breast enlargement occurs in 40-60% of boys (rarely, significant enough to cause social embarrassment in 10%) and is a result of oestradiol produced by the metabolism of testosterone.
It usually resolves within three years. During puberty, elongation of the eye often occurs, causing short-sightedness.

Bone age is a valuable tool for determining the skeletal maturation in children. An X-ray of the left hand and wrist or knee is used to calculate bone age, which is then compared with the chronological age of the subject to know if the bone age is advanced or delayed. Certain standardized methods are used to score skeletal maturity; most common methods are the Tanner-Whitehouse (TW) and Greulich-Pyle (GP) methods. The growth plate comprises a resting zone, a proliferative zone, hypertrophic cartilage zone, calcified cartilage zone, and then the ossification zone. This is the zonal distribution from the epiphysis to the diaphysis. After the closure of growth plates, spinal growth still occurs to some extent, adding up to the final height. The growth plates in boys close at around 17 to 19 years of age, while in girls, they close at around 13 to 15 years.

The patient’s sugar levels typically show the Dawn phenomenon.

Dawn phenomenon:
This is an early morning rise in blood glucose levels secondary to a rise in hormones that increase blood glucose levels. The question suggests that he is undergoing a pubertal growth spurt, suggesting that an increase in these hormones is what has led to the higher morning glucose levels.

Other options:
– Inactivity at night-time: It is expected, and insulin dose should be adequate despite inactivity during the night.
– Inadequate bedtime insulin: It is possible that this is a contributing factor. However, inadequate background insulin is also likely to result in high blood glucose in the day, which the question does not suggest.
– Somogyi effect: There are no features suggestive of nocturnal hypoglycaemia that can cause the Somogyi effect.
– Nocturnal glycogenesis: Glycogenesis would result in hypoglycaemia, not hyperglycaemia.

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.

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.

Among the statements provided, boluses of insulin are given to treat diabetic ketoacidosis (DKA).
The following methods are adopted for the treatment of DKA:
– Fluids: Boluses of 10 ml/kg of normal saline. Stop at three boluses to avoid precipitating cerebral oedema. The remaining deficit has to be corrected over 48 hours.
Strict input/output, U&E, and pH monitoring is necessary in such patients.
– Insulin: Insulin infusion can be initiated at 0.05-0.1 unit/kg/hour. It is essential to monitor blood glucose closely, and the aim is to decrease by 2 mmol/hour.
– Potassium: Initially, it will be high, but following insulin administration, the levels drop quickly as K+ enters cells with glucose, and thus, replacement is almost always necessary.
– Acidosis: Bicarbonate is avoided unless pH is less than 7. Acidosis will get corrected with the correction of fluid and insulin deficits. The definitive treatment is directed towards correcting the underlying precipitants of DKA, e.g. sepsis, infections.

Lypohypertrophy is the most common skin-related complication of insulin injection.

Most healthy infants and children grow predictably, following a typical pattern of progression in weight, length, and head circumference. Normal human growth is pulsatile; periods of rapid growth (growth spurts) are separated by periods of no measurable growth
Growth hormone levels and responsiveness’ develop in late infancy, increase during childhood and peak during puberty.
Typical milestones – General guidelines regarding length or height gain during infancy and childhood include the following:
– The average length at birth for a term infant is 20 inches (50 cm)
– Infants grow 10 inches (25 cm) during the first year of life
– Toddlers grow 4 inches (10 cm) between 12 and 24 months, 3 inches (7.5 cm) between 24 and 36 months, and 3 inches (7.5 cm) between 36 and 48 months
– Children reach one-half of their adult height by 24 to 30 months
– Children grow 2 inches per year (5 cm per year) between age four years and puberty
– There is a normal deceleration of height velocity before the pubertal growth spurt.
Growth continues past pubertal growth spurt as there is increase in spinal length.

Precocious puberty is the development of secondary sexual characteristics before the age of 8 in females, and 9 in males. The first sign of early puberty in females is breast enlargement, followed by the appearance of pubic and axillary hair, and finally menarche, 2-3 years after the onset of thelarche. Precocious puberty is caused by the premature activation of the hypothalamic-pituitary-gonadal axis where FSH and LH levels are raised. Less common is the gonadotrophin independent form, which is due to excess sex hormones, but low FSH and LH levels.

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.

Among the given options, Di-George syndrome is not associated with adrenal gland disorders.

Di-George syndrome is characterised by distinct facial features (micrognathia, cleft palate, short philtrum, and low-set ears), hypocalcaemia, mental retardation, cardiac defects (especially tetralogy of Fallot), and immune deficiencies.

A useful memory aid is CATCH-22:

– Cardiac defects
– Abnormal facial features
– Thymic aplasia/hypoplasia
– Cleft palate
– Hypocalcaemia/Hypoparathyroidism
– 22 – Due to 22q11 deletion

Other options:
– Addison’s disease is a result of adrenal hypofunction and may present with collapse secondary to a salt-losing crisis.
– Congenital adrenal hyperplasia: CAH is caused by the deficiency of an enzyme (classically 21-hydroxylase deficiency) in the biosynthetic pathway in the adrenal cortex, leading to insufficient production of cortisol and aldosterone, and a build-up of 17-hydroxyprogesterone.
– Cushing’s syndrome is a syndrome of cortisol excess. An adrenal tumour is a primary cause.
– Pheochromocytoma is a catecholamine releasing tumour of the adrenal gland/s.

Adrenal insufficiency is a serious medical condition that leads to inadequate secretion of corticosteroids. There are three main types of adrenal insufficiency: primary, secondary, and tertiary, based on the location of the abnormality.
Primary adrenal insufficiency is caused by any pathology located inside the adrenal glands. The most common cause of primary adrenal insufficiency is Addison’s disease, which is an autoimmune condition. Adrenoleukodystrophy is an X-linked neurodegenerative disease that also causes primary adrenal insufficiency.
Secondary adrenal insufficiency is caused by any pathological impairment of the pituitary gland or the hypothalamus. The important causes of secondary adrenal insufficiency include iatrogenic (steroid use), pituitary tumours like craniopharyngioma, and conditions leading to panhypopituitarism like Sheehan’s syndrome.
Tertiary adrenal insufficiency is caused by the deficiency of the corticotropin-releasing hormone.
Hypoparathyroidism does not cause adrenal insufficiency.

A bone age study helps doctors estimate the maturity of a child’s skeletal system. It’s usually done by taking a single X-ray of the left wrist, hand, and fingers. It is a safe and painless procedure that uses a small amount of radiation. The bones on the X-ray image are compared with X-rays images in a standard atlas of bone development, which is based on data from large numbers of other kids of the same gender and age. The bone age is measured in years.

HLA-DR (3 and 4) have been associated with an increased risk for idiopathic diabetes mellitus.
Type 1 diabetes has a high heritability compared to type 2
Identical twins have a 30-50% risk if their twin has type 1 diabetes

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.

Somogyi effect presents with night-time hypoglycaemia followed by early-morning hyperglycaemia, hence the glycosuria.

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.

Zona fasciculata of the adrenal produces the maximum levels of cortisol in the body.

Functions of cortisol:
– Increases blood pressure: permits normal response to angiotensin II and catecholamines by up-regulating alpha-1 receptors on arterioles.
– Inhibits bone formation: decreases osteoblasts, type 1 collagen and absorption of calcium from the gut, and increases osteoclastic activity.
– Increases insulin resistance.
– Increases gluconeogenesis, lipolysis and proteolysis.
– Inhibits inflammatory and immune responses.
– Maintains function of skeletal and cardiac muscle.

An excess of corticosteroids in the body causes various symptoms that are a part of Cushing’s syndrome.

Precocious puberty is the attainment of normal pubertal biochemical and physical features at an abnormally earlier age. The age cut-offs commonly used to define precocious puberty are 8 years for females and 9 years for males.
The onset of normal puberty is triggered by gonadotropic-releasing hormones from the hypothalamus.
In most of the familial cases, the condition is transmitted by affected father. In boys, this makes up about 5% of the cases.
Full adult height potential is not achieved in patients of precious puberty, although there is an advanced bone maturation.

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.

The adult height potential may be calculated for a male child by (father’s height in cm + mother’s height in cm) / 2 then add 7 cm.

In the scenario provided: (170 + 150)/2 + 7 = 167 cm = 1.67 m.

For a female child by (father’s height in cm + mother’s height in cm) / 2 then minus 7 cm.

This can then be plotted on a height centile chart to find the mid-parental centile.

Causes of short stature include:
– Normal variant (often familial)
– Constitutional delay of growth and puberty
– Chronic illness, e.g. cystic fibrosis, inflammatory bowel disease
– Endocrine: growth hormone deficiency, hypothyroidism, steroid excess syndromes: Turner’s, Down’s, Prader-Willi
– Skeletal dysplasias, e.g. achondroplasia

Graves disease is an autoimmune disorder in which patients present with thyrotoxicosis and related ophthalmopathy, and dermopathy. Many affected patients experience hyperthyroidism. Peak incidence of graves disease is after the 3rd decade of life and is more common in women than in men. Graves susceptibility is association with HLA-DR3. Clinical features of Graves disease include an increased metabolic rate, heat intolerance, irritability, weight loss despite increasing appetite, diarrhoea palpitations, chemosis, acropachy and onycholysis.

In this case scenario, the pH is too low to be fully explained by a respiratory acidosis.
Usually, if there is a metabolic acidosis, the respiratory system will try to compensate by hyperventilation and reduced pCO2. In this case, however, the pCO2 is raised suggesting the presence of a respiratory component.
Therefore, this boy has mixed metabolic and respiratory acidosis, most probably due to severe exacerbation of this asthma, which led to diabetic ketoacidosis.

Note:
Normal values:
pH: 7.35 – 7.45
pO2: 10 – 14 kPa
pCO2: 4.5 – 6 kPa
Base excess (BE): -2 – 2 mmol/L
HCO3: 22 – 26 mmol/L