IGF - 1 (protein acted on by GH, used as a screening test for GH deficiency), prolactin, cortisol as pituitary screening.
BOYS - stages of genital development, pubic hair development, axillary hair development and testicular volume.
GIRLS - Breast development:
Girl/boy, androgen/oestrogen (eg virilizing)? Tall (ie advancing bone age)? For a girl, pubertal developmental that follows the normal pattern before the age of 8 is considered abnormal. Differential is:
So do:
Then MRI adrenals, brain, LHRH as appropriate.
The main issue with idiopathic precocious puberty is low final height due to premature fusion of epiphyses. GnRH treatment is then used to suppress.
Virilizing (clitoromegaly) can be due to -
Investigate with LHRH, Adrenal androgens, synacthen, pelvic USS. Androstenedione/DHAS. Adrenal USS.
Bone age is advanced by obesity, CAH.
Boys who are virilized: true precocious (v rarely brain tumour), adrenarche, adrenal/testic tumour.
Functional ovarian hyperandrogenism (FOH), with obesity, hirsutism, acne, LH:FSH >3, irregular menses in perimenarcheal girls. Pelvic ultrasound exams are usually normal.
Common during male puberty, may last for 2 years. Presumably enhanced sensitivity to oestrogens that are byproducts of testosterone. Exclude Klinefelter syndrome - greater than 6 ml testicular volume.
Galactorrhoea with gynaecomastia is suspicious, suggests prolactinoma. Accelerated growth and bone age without virilisation suggests oestrogen secreting gonadal tumour (extremely rare).
No medical treatment - but weight reduction is helpful in the obese boys. Surgical removal may be indicated for psychological reasons.
Pubertal delay is usually associated with apparent poor growth (not necessarily short stature, just failing to hit growth spurt). Beware abnormal development, ie failing to complete puberty at normal rate (arrested puberty) cf late onset of puberty.
Growth/pubertal delay –common, may be primary or else secondary to chronic illness. See Growth above. Usually no underlying pathology (esp boys, but may benefit from treatment anyway). Pubertal delay is defined as reaching an age +2 SDs above the mean, which is 14 years in boys; 13 years in girls.
Pubertal arrest requires investigation. Mean time from puberty onset in boys to adult testicular volume is 3.2±1.8 years (±1SD), and in girls from onset of breast development to menarche is 2.4±1.1 (±1SD) years. Basically 4-5 years for both.
Split into hypogonadotrophic or hypergonadotrophic hypogonadism (depending on whether the defect lies at hypothalamo-pituitary or gonadal level):
Prolactin can be high (2-3x) with tumours compressing pituitary stalk, hence reduced dopaminergic inhibition
= isolated gonadotrophin deficiency. 4x more prevalent in boys than girls, with some recognized X-linked mutations. These patients are of normal stature until they fail to undergo a normal pubertal growth spurt. Associated with:
These features may support the diagnosis until definitive confirmation of a gene defect can be obtained. MRI imaging of the olfactory bulbs may be helpful.
Absence or abnormality of one X chromosome (45XO). Usually diagnosed in early childhood on basis of dysmorphic features (webbed neck, lymphoedema, shield chest), associated cardiac or renal abnormalities. Facial naevi common. Mosaics however have subtle features. With gradually falling height centile, growth failure usually presents at 12-13yrs.
20% have spontaneous onset of puberty, but even those will usually require sex hormone treatment to complete puberty. Typically achieve a final height close to low normal centiles, so growth usually less of an issue than implications for future fertility.
1 in 600 men! Few diagnosed before puberty, probably underrecognized. Pubertal onset may or may not be delayed. Impaired synthesis of testosterone so undervirilized; seminiferous tubule dysgenesis so infertility and characteristic small testes (<6 ml) cf other features of virilisation in later puberty. Features:
Testosterone used to complete pubertal development and epiphyseal fusion, then may be used longterm according to individual need.
Oral or patch oestrogens for hypogonadotrophic hypogonadism. Patch probably more physiological but irritant, variable absorption, and visible so some girls self-conscious. Add progesterone after completion of puberty to induce cycle, either OCP or HRT.
Natural pregnancy has occurred in ovarian failure - cryopreservation of ovarian tissue is possible but little experience. If due to radiotherapy, co-existing uterine damage may be more significant.
Free androgen index=(serum total testosterone)/(sex hormone binding protein)*100
Rotterdam PCOS criteria:
Associated with type 2 diabetes, dyslipidaemia, and fatty liver. Absence of ovulation tends to lead to endometrial hyperplasia, besides infertility. Theoretical risk of cancer.
OCP may be needed to regulate cycle. COCP also suppresses androgens. Spironolactone may help hirsutism. Weight loss and Metformin improve insulin sensitivity but also increases fertility!
PMID:14711538
Deficiency or impaired function of one of vitamin D, PTH, and the calcium sensing receptor can lead to hypocalcaemia. The main causes of hypocalcaemia include:
The above can influence calcium concentrations in the newborn period, but babies are also subject to insults that can affect calcium homoeostasis, such as prematurity, asphyxia, and maternal hyperglycaemia.
Clinically, there may be muscle twitching, spasms, tingling and numbness. Chvostek's sign (tapping parotid gland causes facial spasm) is positive in 10% of normal people, and it has a 29% false negative rate. Trousseau's sign (carpopedal spasm induced by BP cuff) is much more specific. Signs are also dependent of rate of fall - longstanding hypocalcaemia can be severe but asymptomatic.
A disorder of growing children in which the newly formed bone matrix is not mineralised appropriately. It reflects a deficiency of the bone constituents, calcium, and/or phosphate. Some children with hypocalcaemia will be found to have rickets, but not all children with rickets will be hypocalcaemic. Rickets can be classified according to the underlying pathology into three main groups: vitamin D deficiency, calcium deficiency, or phosphate deficiency (esp renal tubular losses). Vitamin D deficiency or resistance may be caused by:
Blood:
Second line :
Urine:
In the presence of hypocalcaemia a urine calcium/creatinine ratio greater than 0.3 mmol/mmol (spot sample as good as 24hr collection) suggests inappropriate excretion viz hypocalcaemic hypercalciuria . Sporadic or autosomal dominant, due to activating mutations of the calcium sensing receptor which downshift the set point for calcium responsive PTH release). In contrast, urine calcium excretion is typically low in longstanding hypoparathyroidism.
Other investigations:
NB: beware polyglandular endocrinopathy. See below. Type 1, also known as autoimmune polyglandular endocrinopathy with candidiasis and ectodermal dystrophy (APECED), can present with hypoparathyroidism in the absence of the two other major manifestations, which are candidiasis and adrenal failure. There should be a high index of suspicion in children older than 4 years.
Blounts disease – may look like rickets, in that you get bowed legs. Diagnosed on XR by bridging of physis (?), beaking of proximal medial tibial metaphysis. Physiological genu varum is seen in toddlers, has deformity in both tibia and distal femur, can usually be treated non-operatively.
Treat acutely with IV calcium (NB extravasation esp chloride bad news), change to oral as soon as possible. 1-alphacalcidol or calcitriol are needed if PTH is deficient or non-functional, since it is needed to convert basic Vitamin (ergocalciferol or cholecalciferol). Treat concurrently with calcium. Beware nephrocalcinosis - monitor urinary calcium excretion as well as calcium level.
A group of disorders, classic is Albright hereditary osteodystrophy (AHO):
All manifestations of an abnormal signalling mechanism. PseudopseudohypoPTH, is all the same clinical manifestations but without the calcium problem; bizarrely, the same gene is involved and families can have both types.
Not many causes!
So same bloods as above, pretty much. Urinary calcium/creatinine ratio has age specific norms in young children: anything above 0.5 suggests the kidney is trying to excrete it (so appropriate if plasma level is high).
Get 1 ml lactate & 6 ml lithium heparin plus bloodspots on neonatal screening card during hypo, and first urine (freeze). See below for more details.
Glucose levels are maintained after a meal by release from glycogen stores (glycogenolysis), driven by Glucagon. When glycogen stores are low, then glucose can be produced from fat stores by fatty acid oxidation (via ketones) and from protein by gluconeogenesis. The switching over is moderated by cortisol.
Hypoglycaemia makes you grumpy, sweaty, pale. If severe, it causes seizures. Some cases of sudden unexpected death are thought to be due to inborn errors of metabolism causing hypoglycaemia. Recurrent severe episodes in infancy can lead to permanent neurodisability.
Do Glucagon test - give 1mg glucagon IM, positive if glucose doubles at 15 mins = hyperinsulinism.
Hyperinsulinism can present late, even above 5 yr of age! See Neonates. No ketones, low levels of free fatty acids and amino acids (ie suppressed gluconeogenesis).
HA/HI syndrome can go hypo immediatly post protein rich meal!
Measure GH and Cortisol, do Synacthen - should be stimulated above 20 and 500 respectively. Check pituitary too: FSH/LH should stimulate prepubertally to 2-5. MRI brain.
If you have excluded glycogen storage disorders, can be idiopathic (usually SGA at birth, thin, presents under 4yr, resolves by 7yr). Regular meals + night time complex carbo snack, optimize nutrition, carbs if unwell eg Maxijul + Electroade else Ribena/apple juice.
Various. Not a problem of storing it, a problem of breaking it down! Classic type 1 is G6-phosphatase deficiency. Depending on the type, gluconeogenesis as well as glycogenolysis may be impaired - some of the enzymes are involved in both - so ketones present, lactate and triglycerides high. Liver becomes enlarged with excessive glycogen, Glucagon has no effect. Managed by regular meals and extra complex carbohydrate eg cornstarch, as above.
Glycogen synthase deficiency is sometimes included. If you can't make glycogen then you get an immediate glucose dip post prandially, you don't get a big liver (obviously) but other mechanisms work ok so lactate is normal (cf classic GSD).
Pompe disease is a lysosomal disorder, infantile form affects heart, neurodevelopment (enzyme treatment available). McArdle syndrome is myophosphorylase defect – pain/weakness/cramps on exertion, myoglobinuria, second wind phenomenon.
Various eg CoA disorders eg MCAD, LCAD, VLCAD; Carnitine disorders (transports fatty acids out of mitochondria). There are related lipid storage disorders eg Fabry, Niemann Pick, MCLD where hypoglycaemia is not a feature.
AST/ALT raised, due to protein breakdown for gluconeogenesis. Acylcarnitines, organic acids abnormal.
=Medium Chain Acyl CoA Dehydrogenase deficiency. Can be asymptomatic eg parents of newly diagnosed child, even with same gene defect! Crisis – vomiting, hypoglycaemia, hyperammonaemia, sudden death.
Diagnosis: Octanoyl- acylcarnitine increased. Management is by avoidance of fasting as above, plus carnitine! Newborn screening happens in some parts of the world, as 1 gene responsible for majority of cases.
Cause ketotic hypoglycaemia ie formation of ketones eg beta-hydroxybutyrate is intact, but accompanied by acidosis (unlike GSD) and usually encephalopathy and hyperammonaemia eg methylmalonic acidaemia.
ie Mitochondrial problems. Usually neuromuscular syndromes eg Leighs but now recognised as a cause of hypoglycaemia.
See Neonatal for Congenital hypothyroidism.
TRH test- baseline should be TSH 0-5, rising to 5-30 at 30 min then falling at 60 mins. Primary hypothyroidism has high baseline, peak >100.
You can get funny TFTs in syndromes eg Downs, Albrights.
Isolated TSH elevation >20 is usually treated. May be due to dyshormonogenesis, TSH Receptor defect. Do a Family History.
A suppressed TSH with normal thyroid hormone levels can reflect euthyroid sickness or evolving thyrotoxicosis. Distinguishing between Graves’ disease and Hashimoto’s thyroiditis is important because of the different prognoses - isotope scan will show diffusely increased uptake in Graves’ but decreased uptake in Hashimoto’s. Echogenicity of the thyroid tissue may suggest either Graves’ or Hashimoto’s. A nodule (clinical or isotope) may represent McCune Albright.
Antibodies to one of TSH receptor, thyroid peroxidase, and thyroglobulin can be detected in more than 90% of patients with autoimmune thyroid disease. Thyroid binding inhibiting immunoglobulin (TBII; autoantibodies to the TSH receptor) are highly specific and present in approximately 75–90% of patients with Graves’ disease, while thyroid peroxisomal antibodies or thyroglobulin antibodies are less sensitive as well as less specific (present in approximately 68% of patients). Hashimoto’s does not target the TSH receptor but is destructive to thyroid tissue hence can become euthyroid and then hypothyroid. Graves can also become hypothyroid, presumably because of other antibodies. The TBII titre in pregnant patients with Graves’ can be used to predict the risk of hyperthyroidism in the fetus.
Use beta blockers intially to get symptom control, then wean. Carbimazole and Propylthiouracil do not affect the release of preformed thyroid hormone so take weeks to act. The obvious advantage of carbimazole over PTU is that it can be administered once daily (although many doctors choose to administer the drug twice daily initially); also, the incidence of major side effects may be lower. Potential advantages of the "block and replace" regimen include:
Potential advantages of the dose titration approach include:
The initial dose of carbimazole used to block thyroid hormone production is around 0.75–1 mg/kg/day and for propylthiouracil, 5–10 mg/kg/day. These doses are then reduced by up to 50% if dose titration is used.
Thyroid storm or crisis is precipitated by surgery, infections, withdrawal, or non-compliance with antithyroid treatment. Presents with fever, tachycardia, sweating, widened pulse pressure, hypertension, also seizures, low platelets. Can lead to high output cardiac failure. Correcting hyperthyroidism. Give:
The severity of CAH depends on the degree of 21 hydroxylase deficiency caused by CYP21A2 mutations. The classic forms present in childhood and are characterised by striking overproduction of cortisol precursors and adrenal androgens. In the most severe form, concomitant aldosterone deficiency leads to loss of salt. In the mildest form, there is sufficient cortisol production, but at the expense of excess androgens.
Female infants with classic CAH typically have ambiguous genitalia at birth because of exposure to high concentrations of androgens in utero, and CAH due to 21-hydroxylase deficiency is the most common cause of ambiguous genitalia in 46XX infants. The internal female organs, the uterus, fallopian tubes, and ovaries, are normal; wolffian duct structures are not present. Boys with classic CAH have no signs of CAH at birth, except subtle hyperpigmentation and possible penile enlargement. Thus, the age at diagnosis in boys varies according to the severity of aldosterone deficiency. Boys with the salt-losing form typically present at 7–14 days of life with vomiting, weight loss, lethargy, dehydration, hyponatraemia, and hyperkalaemia, and can present in shock. Boys with the non-salt-losing form present with early virilisation at age 2–4 years.
Patients with non-classic CAH do not have cortisol deficiency, but instead have manifestations of hyperandrogenism, generally later in childhood or in early adulthood eg early pubarche, or as young women with hirsutism (60%), oligomenorrhoea or amenorrhoea (54%) with polycystic ovaries, and acne (33%). 5–10% of children with precocious pubarche have been found to have non-classic CAH. Conversely, some women with non-classic CAH have no apparent clinical symptoms, and many men with non-classic CAH remain free of symptoms!
A very high concentration of 17-hydroxyprogesterone (more than 242 nmol/L; normal less than 3 nmol/L at 3 days in full-term infant) in a randomly timed blood sample is diagnostic of classic 21-hydroxylase deficiency. Typically, salt-losers have higher 17-hydroxyprogesterone concentrations than non-salt-losers. False-positive results from neonatal screening are common with premature infants. A corticotropin stimulation test (250 µg cosyntropin) can be used to assess borderline cases. Genetic analysis can be helpful to confirm the diagnosis.
Randomly measured 17-hydroxyprogesterone concentrations can be normal in patients with non-classic CAH. Thus, the gold standard for diagnosis of the non-classic form is a corticotropin stimulation test, with measurement of 17-hydroxyprogesterone at 60 min. This test can be done at any time of day and at any time during the menstrual cycle. A stimulated concentration of 17 hydroxyprogesterone higher than 45 nmol/L is diagnostic of 21-hydroxylase deficiency. Many carriers have slightly raised concentrations of 17 hydroxyprogesterone (less than 30 nmol/L) after a corticotropin stimulation test. An early-morning (before 0800 h) measurement can be used for screening, but it is not as sensitive or specific as a corticotropin stimulation test. Early-morning 17 hydroxyprogesterone concentrations of less than 2·5 nmol/L in children rule out the diagnosis of non-classic CAH in most cases.
In classic CAH, glucocorticoids are given to suppress adrenal androgen secretion, without total suppression of the HPA axis; mineralocorticoids are given to return electrolyte concentrations and plasma renin activity to normal. For most that means a hydrocortisone dose of 12–18 mg/m2 daily divided into two or three doses. The target 17-hydroxyprogesterone range is 12–36 nmol/L (early morning) before medication. Adrenal androgen concentrations later in the day and after medication has been taken will be lower, but they should not be suppressed below the normal range because of risk of iatrogenic Cushing's syndrome.
Hydrocortisone is the glucocorticoid of choice during childhood. Longer-acting glucocorticoids are generally avoided in children because of concerns about growth suppression. A lower dose is given in the evening to mimic circadian rhythm. Mineralocorticoid replacement is achieved with fludrocortisone. The dose should be adjusted to maintain plasma renin activity in the mid-normal range. A typical daily dose of fludrocortisone ranges from 100 µg to 200 µg - the dose is independent of body size from childhood to adulthood, although higher doses are commonly needed in early infancy. The use of fludrocortisone therapy in patients with non-salt-losing classic CAH is recommended and allows management with lower doses of glucocorticoid.
Infants with salt-losing CAH commonly need supplementation of sodium chloride (1–2 g daily) until 6–12 months of life. However, patients should be encouraged to use salt freely to satisfy salt cravings. Additional salt intake may be needed with exposure to hot weather or with intense exercise.
Many patients with non-classic CAH do not need treatment. Treatment is recommended only for those with symptoms and aims to reduce hyperandrogenism. Glucocorticoid treatment is indicated in children with androgen excess.
Drugs that induce hepatic microsomal enzymes (CYP450), such as antiepileptic drugs, affect the metabolism of glucocorticoids and can greatly alter the appropriate glucocorticoid dose.
Patients with classic CAH cannot mount a sufficient cortisol response to physical stress and need pharmacological doses of hydrocortisone in situations such as febrile illness, surgery, and trauma. Give double the usual morning dose three times daily, else give 10x the morning dose IM especially if vomiting or unwell. For inpatient maintenance, give hydrocortison as an infusion 50mg in 50ml saline @ 2ml/hr for 6hrs then 1ml/hr thereafter. This Yorkhill policy is aggressive but usually means a shortened inpatient stay. The combination of cortisol deficiency and epinephrine deficiency puts patients at risk of hypoglycaemia with illness or fasting - during illness, encourage intake of carbohydrates and glucose-containing fluids should be encouraged and glucose monitoring should be considered, especially in children. Patients and parents should receive instructions for these types of emergencies. All patients should wear or carry medical alert identification specifying adrenal insufficiency.
There is no evidence that higher doses of glucocorticoid are needed in times of mental or emotional stress, and higher doses of glucocorticoid should be given only for physical stressors. Exercise, although a physical stressor, does not require increased dosing. However, the normal exercise-induced rise in blood glucose concentrations is blunted in patients with CAH, and extra intake of carbohydrates might be useful with exercise.
Patients with non-classic CAH do not need stress doses of hydrocortisone unless they have iatrogenic suppression of their adrenal glands by glucocorticoid treatment, in which case treat them as above.
Maternal dexamethasone treatment has successfully suppressed the fetal HPA axis and reduced the genital ambiguity of affected female infants. Masculinisation of the external genitalia begins by 8 weeks of gestation. Therefore, if treatment is desired, it should be started as soon as the pregnancy is confirmed. Prenatal treatment is controversial, since the risk of having an affected female fetus is only one in eight when both parents are known carriers. Therefore, seven of eight fetuses will receive dexamethasone treatment unnecessarily. The efficacy and safety of prenatal dexamethasone treatment remains to be fully defined.
Management of patients with classic CAH during the neonatal period is challenging. Two-thirds of these patients are salt-losers. Neonates are particularly vulnerable to hypovolaemia and electrolyte disturbances, as well as hypoglycaemia. Increased mortality has been reported in patients with CAH. Despite hormone replacement and parental education, about 8% of patients have been reported to experience hypoglycaemia during the first few years of life. These risks have led some practitioners to treat neonates with higher doses of hydrocortisone; however, there is no evidence that higher doses of glucocorticoid protect against hypoglycaemia or life-threatening complications, and epinephrine deficiency probably has a role. Moreover, many studies have found that excessive glucocorticoid use during the first 2 years of life is a risk factor for short stature in adulthood. The hydrocortisone dose in neonates should not exceed 25 mg/m2 daily, and monitoring of weight and length supplemented by serial measurement of adrenal steroid concentrations, plasma renin activity, and electrolyte concentrations should guide management. As in older children, the therapeutic goal in the neonatal period should be to find the lowest glucocorticoid dose that achieves acceptable concentrations of adrenal cortical hormones and an acceptable rate of linear growth.
Less than optimum. High concentrations of sex steroids induce premature epiphyseal closure, and excess glucocorticoids suppress growth. Another complication is central precocious puberty, which is most likely to develop when the diagnosis of CAH is delayed or with poor control of adrenal androgen secretion.
Obesity is common in patients with CAH, and the body-mass index of normally growing children with CAH increases throughout childhood more than the expected age-related increase. The cause of the obesity is unknown, and several factors are probably involved.
Reduced fertility has been reported in patients with classic and non-classic CAH, especially in women. An increased incidence of polycystic ovaries is a common finding in mild, but also in classic CAH, and this disorder could contribute to infertility. In men with classic and non-classic CAH, ectopic adrenal tissue located in the testes (adrenal rest) can result in oligoazoospermia or Leydig-cell failure.
Studies of female patients with classic CAH suggest that exposure to excess androgens during prenatal development influences brain development. Indeed, female patients with classic CAH have been found to have more male-typical childhood play than unaffected girls, are more likely to use physical aggression in conflict situations, have less interest in infants and nurturing activities etc. Nevertheless, girls with CAH have been found to identify as female and do not have gender-identity confusion or dysphoria.
Lancet Volume 365, Issue 9477 2125-2136
Centile charts available for BMI through childhood. Obesity cut off starts high in babies, drops to 20 in early childhood then rises progressively to 25 in later childhood and 30 in teenagers (as per adults).
There are some rare monogenic causes eg MC4R defects. Otherwise, probably polygenic, with environmental factors including diet, exercise.
Other causes to consider are:
Autoimmune Polyendocrinopathy Syndrome type I particularly affects PTH, adrenals, gonads. Also known as APECED - associated with Candida + Ectodermal Dystrophy. caused by AIRE (AutoImmune REgulator) deficiency. Can have alopecia, vitiligo, chronic active hepatitis, but it is unclear why other forms of autoimmunity not seen. BMT does not work. NB may be FH of premature menopause, male infertility.
Type 2 is more variable (polygenic rather than recessive) - affects adrenals, thyroid, IDDM predominantly. Hypogonadism may be seen.
IPEX is the most severe - Immunodysregulation Polyendocrinopathy Enteropathy X linked esp IDDM + eczema, variable immunodeficiency as well as cytopenias etc. FOXP3 defect. Neonatal onset, infection is not usually the presenting problem. Rarely bloody diarrhoea (villous atrophy), erthyroderma or psoriaform rash. Raised IgE, eosinophilia.
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