Endocrinology Flashcards
What is Addison disease
Primary adrenal cortical insufficiency
What are the causes of Addison disease
Autoimmune process
Haemorrhage/infarction
X-linked adrenoleucodystrophy, a neurodegenerative metabolic disorder
TB (now rare)
Which conditions can cause a similar picture to Addison disease?
Hypopituitarism or hypothalamic-pituitary-adrenal suppression from long term steroid therapy.
What are the features of acute presentation of Addison disease?
Hyponatraemia Hyperkalaemia Hypoglycaemia Dehydration Hypotension Circulatory collapse
What are the chronic clinical features of Addison disease?
Vomiting
Lethargy
Brown pigmentation in gums, scars, skin creases
Growth failure
What are the tests to diagnose Addison disease?
Low plasma cortisol
High ACTH
Abnormal short synacthen test
How is an addisonian crisis managed?
IV saline
Glucose
Hydrocortisone
What is the long term management of Addison disease?
Glucocorticoid and mineralocorticoid replacement
Increase glucocorticoid at times of stress
What is the cause of PKU?
Either due to a deficiency of the enzyme phenylalanine hydroxylase (classical PKU) or in the synthesis or recycling of the biopterin cofactor for the enzyme
How does PKU present?
Developmental delay at 6-12 months
Musty odour (due to the metabolite phenylacetic acid)
Some develop eczema and seizures
Many blue eyed and fair haired
How is classical PKU treated
Restrict dietary phenylalanin
How is PKU with cofactor defects treated?
Diet low in phenylalanine and neurotransmitter precursors
Which form of PKU has a worse prognosis?
Cofactor defect
What causes homocystinuria?
cystathionine synthetase deficiency
How does homocystinuria present?
Developmental delay Subluxation of the ocular lens (ectopia lentis) Progressive learning difficulty Psychiatric disorders Convulsions Skeletal issues similar to Marfan Fair complexion with brittle hair Thromboembolic episodes
How is homocystinuria managed?
Almost half respond to large doses of the coenzyme pyridoxine
Those who don’t respond are given a low methionine diet supplemented with cysteine and the re-methylating agent betaine
How is tyrosinaemia inherited?
Autosomal recessive
What causes tyrosinaemia?
deficiency of fumarylacetoacetase
What are the sequelae of tyrosinaemia?
Accumulation of toxic metabolites leads to: Liver failure and Fanconi syndrome
Fatal if untreated
How is tyrosinaemia managed?
NTBC - inhibits an enzyme required in the catabolism of tyrosine
Diet low in tyrosine and phenylalanine
Where is the hypothalamus located?
Between prep-tic area and the mamillary bodies
What are the 3 lobes of the pituitary called and what does each produce?
Anterior:ACTH, GH, LH, FSH, TSH
, Prolactin
Intermediate Posterior: Oxytocin, ADH
What is congenital adrenal hyperplasia?
a number of inherited defects in adrenal steroidogenesis, which cause impaired synthesis of cortisol from cholesterol in the adrenal cortex
What is the most common defect in CAH?
21 hydroxylase deficiency
What are the biochemical consequences of CAH
Lack of cortisol and aldosterone
Increased adrenocortical stimulation by CRH and ACTH, which induces adrenal gland hyperplasia
How is CAH inherited?
Autosomal recessive
How does CAH usually present
Salt losing crisis: hyponatraemia, hyperkalaemia, hypoglycaemia, acidosis and shock
BG of vomiting, weight loss, FTT
Usually at 1-4 weeks
What are the non salt losing crisis features of CAH in females?
Clitoromegaly Early development of pubic hair Hirsutism Acne Increased growth rate Advanced bone age Gynaecological problems e.g. oligomenorrhoea, abnormal menses or infertility
What are the non-crisis features of CAH in boys?
early penile growth, pubic hair, increased growth rate, increased musculature
How is CAH diagnosed?
17-OHP levels
ACTH stimulation test
Urine steroid profile
How is the acute salt losing crisis in CAH managed
Restore volume with normal saline and glucose
Correct hypoglycaemia
Replace fluid and electrolytes over 24-48 hours
Hyperkalaemia may need correction with salbutamol, insulin, glucose and calcium
Bolus hydrocortisone IV
Treat precipitating stress
How is CAH managed?
Glucocorticoids and mineralocorticoids, extra steroids in periods of stress
What are the causes of congenital hypothyroidism
Most common: maldescent of thyroid and athyrosis
Dyshormonogenesis
Iodine deficiency
TSH deficiency
How does congenital hypothyroidism present?
Usually asymptomatic and picked up on screening Failure to thrive Feeding problems Prolonged jaundice Constipation Pale, cold, mottled dry skin Coarse facies Large tongue Hoarse cry Goitre (occasionally) Umbilical hernia Delayed development
What’s the difference between Cushing syndrome and Cushing disease?
○ Syndrome = cortisol excess
Disease = due to a pituitary ACTH producing tumour (adenoma)
What are the clinical features of Cushing syndrome?
Central obesity Buffalo hump Purple striae Hypertension Osteoporosis Hypogonadism Growth failure Muscle wasting/hypotonia
What investigations should be done for Cushing syndrome
24h urine cortisol
Dexamethasone suppression test
MRI of brain
CT of adrenals
How much do you adjust a parent’s height for to calculate mid parental height?
13cm
What are the three main groups of causes of delayed puberty?
Constitutional delay
Gonadotrophin deficiency
Primary gonadal failure
What are the causes of gonadotrophin deficiency?
Severe and chronic undernutrition
Chronic illness
Endocrine conditions e.g. hypothyroidism
In boys particularly: Isolated gonadotrophin deficiency, Kallman syndrome
What are the causes of primary gonadal failure in boys?
Klinefelter
Cryptorchidism
Previous testicular torsion
Post radiation
What are the causes of primary gonadal failure in girls?
Turner’s
Autoimmune damage to ovaries
Total body irradiation or chemo
How is galactosaemia inherited?
Recessive
What is the cause of galactosaemia?
deficiency of the enzyme galactose-1-phosphate uridyltransferase, which is needed for galactose metabolism
How does galactosaemia present?
When lactose-containing milk feeds are introduced, they cause poor feeding, vomiting, jaundice and hepatomegaly and hepatic failure
What are the consequences of untreated galactosaemia?
Chronic liver disease
Cataracts
Developmental delay
How is galactosaemia managed?
Lactose and galactose free diet for life
How are glycogen storage disorders inherited?
Recessive
What are the causes of glycogen storage disorders
9 main enzyme defects, all of which prevent mobilisation of glucose from glycogen, resulting in an abnormal storage of glycogen in liver and/or muscle
Which organs are most affected by glycogen storage disorders?
Muscle
Cardiac muscle
Liver
How are glycogen storage disorders managed?
Maintain blood glucose by frequent feeds or by carbohydrate infusion via a gastrostomy or nasogastric tube
In older children, glucose levels can be maintained with slow release oligosaccharides
In type II, enzyme replacement is available
In type III, a high protein diet is needed to prevent growth retardation and myopathy
What are the 5 broad groups of disorders of sexual development?
46XX DSD: genetic females with ambiguous or male phenotype
46XY DSD: genetic males with ambiguous or female phenotype
Ovotesticular DSD: usually 46XX, genitalia usually ambiguous, gonads contain both ovarian and testicular components
Sex chromosome and aneuploidy DSD: e.g. 45X/46XY mosaicism with one streak gonad and one dysgenetic testis
Other: Dysmorphic syndromes, Cloacal anomalies, Bladder exstrophy
What is the most common disorder of sexual development?
CAH female
Where does a craniopharyngioma come from?
Arises from the craniopharyngeal cleft, which develops from the fusion of Rathke’s pouch and the infundibulum
What are the usual histological features of a craniopharyngioma?
Calcified Cystic Slow growing Squamous epithelial Extra axial
How big is a craniopharyngioma before symptoms appear?
3cm
When do craniopharyngiomas usually present?
5-14 years
What are the symptoms of craniopharyngioma?
Headache, mainly in the morning, accompanied by projectile vomiting
Endocrine hypofunctions e.g. growth disturbance
○ Visual symptoms e.g. bitemporal hemianopia, unilateral temporal hemianopia, loss of acuity, diplopia or blurring of vision
Diabetes insipidus
Trouble waking
Loss of balance
Difficulty walking
Change in energy level
Sleepiness
Hearing loss
Change in personality
How are craniopharyngiomas managed
Surgery
Radiation
Chemo
Hormone replacement
How is CHARGE syndrome inherited?
AD
What makes up CHARGE syndrome?
○ Colobomatous malformation of the eye (retinal coloboma most common)
Heart anomalies e.g. ToF
Atresiae of the choanae
Retardation: cognitive and somatic growth
Genital anomalies and/or hypoplasia
Ear anomalies and/or deafness
and often hypopituitarism
Which gene is responsible for CHARGE syndrome?
2/3 have mutation of CHD7
What is the most common mutation in combined pituitary hormone deficiency?
PROP1
How is septo-optic dysplasia defined?
Heterogeneous disorder with two or more of a classical triad of:
- Hypoplasia of the optic nerves
- Hypoplasia of the pituitary gland with variable levels of hypopituitarism
- Absence of septum pellucidum and/or agenesis of corpus callosum
What are the clinical features of septo-optic dysplasia?
Neurological abnormalities
Wandering nystagmus
Endocrine deficiencies
How are the endocrine deficiencies in septo-optic dysplasia managed?
Hydrocortisone replaced before others to avoid precipitating an adrenal crisis
What is the defect in holoprosencephaly?
failure of the prosencephalon to divide adequately into 2 halves, which usually happens at 3-4 weeks’ gestation
What are the three subtypes of holoprosencephaly?
Alobal: thalami are fused with one ventricle, and facial anomalies such as cyclopia
Semilobar: more separation than alobar, but still fusion anteriorly including fused thalami, and absence of olfactory tracts and corpus callosum
Lobar: fusion of the cingulate gyrus and thalami, with absent or hypoplastic olfactory tracts and absent/hypoplastic corpus callosum
What are the clinical features of holoprosencephaly
Hypotonia Hypothalamic dysfunction Microcephaly Pituitary deficiency including diabetes insipidus Epilepsy Feeding difficulties Spina bifida Sleep disturbance Developmental delay
What’s the prognosis in holoprosencephaly?
• Half of children with semilobar or lobar forms live beyond 12 months
How is type 1 MEN/ Werner syndrome inherited?
AD
What are the associations with Werner syndrome?
○ Pancreatic: gastrinoma, insulinoma
Pituitary
Parathyroid
What causes Werner syndrome?
mutations in MEN1 gene which codes for menin, a tumour suppressor
What are the associations with type 2 MEN (Sipple syndrome)
Medullary thyroid cancer
Parathyroid
Phaeochromocytoma
What causes Sipple syndrome?
Mutations in RET gene
What are the phenotypic features of MEN2b?
Marfanoid habitus
Skeletal abnormalities
Abnormal dental enamel
Multiple mucosal neuromas
What does PTH do normally?
Promotes bone formation via osteoblasts
What does PTH do when calcium is low?
Promotes bone resorption via osteoclasts
Increases renal uptake of calcium
Activates metabolism of vitamin D
What does vitamin D do to raise calcium?
Promotes gut absorption of calcium
Increases osteoclastic bone resorption
Inhibits PTH secretion and hence increases 1 alpha hydroxylation
What are the biochemical features in hypoparathyroidism?
Low serum calcium
Raised serum phosphate
Normal ALP
PTH is very low
What are the clinical features of severe hypocalcaemia?
Muscle spasm
fits
Stridor
Diarrhoea
What are the causes of hypoparathyroidism?
In infants, usually due to a congenital deficiency e.g. DiGeorge syndrome
In older children, usually autoimmune and associated with Addison disease
What is the defect in pseudohypoparathyroidism
End organ resistance to PTH caused by a mutation in a signalling molecule
What are the biochemical features of pseudohypoparathyroidism?
Serum calcium and phosphate are low, but PTH levels are normal or high
What are the clinical features of pseudohypoparathyroidism
Short stature Obesity Subcutaneous nodules Short fourth metacarpals Learning difficulties Teeth enamel hypoplasia Calcification of the basal ganglia
What are the features of pseudopseudohypoparathyroidism?
Physical characteristics of pseudohypoparathyroidism but serum calcium, phosphate and PTH are all normal
How is hypoparathyroidism treated?
Calcium and vit D
What are the features of hyperparathyroidism?
Causes high calcium, which in turn causes: Constipation Anorexia Lethargy Behavioural disturbance Polyuria Polydipsia Bony erosions of phalanges can be seen on XR
What are the causes of hyperparathyroidism?
In neonates and young children, associated with some rare genetic diseases e.g. William syndrome
In older children, can be related to MEN or adenomas
How is severe hypercalcaemia treated?
Rehydration, diuretics and bisphosphonates
What are the features of hypercalcaemia?
Anorexia Constipation Polyuria Nausea Vomiting Failure to thrive
What are the causes of hypercalcaemia
Low PTH: Vitamin D intoxication Infantile hypercalcaemia Transient Williams syndrome Associated with tumours
High PTH:
Primary hyperparathyroidism
Familial hypocalciuric hypercalcaemia
What are the causes of rickets?
Hypocalcaemia
Phosphopenia
Abnormal bones
Renal osteodystrophy
How is precocious puberty defined?
<8 years in girls
<9 years in boys
What is true precocious puberty?
when the hypothalamic control mechanism for puberty (the GnRH pulse generator) is prematurely turned on, leading to early gonadal maturation
What is pseudoprecocious puberty?
Gonadotrophin independent precocious puberty
In which gender is true precocious puberty more common?
Girls
What is the cause of achondroplasia?
Caused by mutations in the FGFR3 gene, which provides the instructions for making a protein involved in the maintenance and development of brain and bone tissue
How is achondroplasia inherited?
AD, but new mutations in 80%
What are the features of achondroplasia
Megalocephaly Short limbs Prominent forehead Thoracolumbar kyphosis Midfacial hypoplasia Disproportionate short stature Diminishing interpeduncular distances between L1 and L5
What are the complications of achondroplasia?
Short stature
Dental malocclusion
Hydrocephalus
Repeated otitis media
What is hypochondroplasia?
Rhizomelic short stature, distinct from achondroplasia
What is the cause of hypochondroplasia?
70% affected have mutations in FGFR3
What are the clinical features of hypochondroplasia?
Stocky or muscular appearance
Usually recognised at age 2-3
Wide variability in severity
No change in interpeduncular distances between L1 and L5
How are the mucopolysaccharidoses inherited?
AR or X linked recessive
What is the cause of the mucopolysaccharidoses?
Result from enzyme deficiences that break down the complex carbohydrates called glycosaminoglycans
What are the clinical features of mucopolysaccharidoses
Depend on the type:
Short spine and limbs
Coarse facial features
Reduced intelligence and abnormal behaviour in some forms
Hurler - shortened lifespan
Marked skeletal abnormalities and severe short stature in Morquio syndrome
How is Russell-Silver syndrome inherited?
Sporadic, may relate to chr7 or 11, or parental specific expression
What is the main feature of Russell-Silver syndrome?
Prenatal onset short stature
What are the clinical features of Russell-Silver syndrome?
Limb asymmetry Short incurved 5th finger Small triangular face Café au lait spots Normal intelligence Bluish sclerae in early infancy
What is Turner syndrome?
45XO (or XO/XX or XO/XY) karyotype associated with short stature, ovarian dysgenesis and dysmorphic features
How is Turner syndrome inherited?
Sporadically
What are the features of Turner syndrome?
Neonatal lymphedema of hands and feet Skeletal anomalies Facial anomalies Specific space-form perception defect Endocrine defects
What are the skeletal anomalies associated with Turner syndrome?
Short stature Widely spaced nipples Shield-shaped chest Wide carrying angle Short 4th metacarpal Hyperconvex nails
What are the facial features of Turner syndrome?
Prominent, backward rotated ears Squint Ptosis High arched palate Low posterior hairline Webbed neck
What are the endocrine defects seen in Turner syndrome?
Autoimmune diseases
T2DM
Infertility and pubertal failure
What are the associated conditions with Turner syndrome?
Horseshoe kidneys
Coarctation of the aorta
Excessive pigmented nave
What causes short stature with delayed bone age?
Constitutional delay
What causes short stature with advanced bone age?
Precocious puberty
Androgen excess e.g. CAH
GH excess
What causes Prader Willi?
Deletion from paternally derived long arm of chromosome 15q
What are the clinical features of Prader willi?
Neonatal hypotonia Feeding difficulties in newborn period Obesity (food seeking behaviour) Hypogonadism Tendency to diabetes mellitus Strabismus Characteristic facies Orthopaedic abnormalities Reduced IQ, usually 40-70 Behavioural difficulties Insulin resistance
What are the facial features of Prader Willi?
§ Narrow forehead Olive-shaped eyes Anti-mongoloid slant Carp mouth Abnormal ear lobes
What are the orthopaedic features of Prader Willi?
Small, tapering fingers
Congenital dislocation of the hips
Retarded bone age
What is the cause of Bardet-Biedl?
At least 14 different gene mutations
Often referred to as BBS genes - involved in structure and function of cilia
What are the clinical features of Bardet-Biedl?
Learning disability Obesity - marked by 4 years of age Retinitis pigmentosa/strabismus Polydactyly/clinodactyly Moderate short stature Hypogonadism
What problems are associated with Bardet-Biedl?
Renal anomalies
Diabetes insipidus
What is the cause of Beckwith-Wiedemann syndrome?
Usually occurs with abnormal regulation of genes on chromosome 11
Up to 20% of case are due to paternal uniparental disomy
What are the clinical features of Beckwith-Wiedemann?
Large birthweight Transient hyperinsulinism Macrosomia Linear fissures on ear lobes Umbilical hernia/exomphalos Hemihypertrophy
What problem is Beckwith-Wiedemann associated with?
Wilms tumour
What are 3 syndromes causing tall stature?
Marfan
Klinefelter
Sotos
What causes Marfan and how is it inherited?
Autosomal dominant
Mutations in the FBN1 gene which codes for fibrillin 11
25% those affected have a new mutation
What are the skeletal features of Marfan?
Arachnodactyly Tall stature Scoliosis High arched palate Pectus excavatum/carinatum Joint hypermobility
What are the non-skeletal features of Marfan?
Learning disability Lens dislocation Aortic dissection Mitral valve prolapse Pneumothorax
What is the karyotype in Klinefelter
47XXY
What are the clinical features of Klinefelter?
Tall and slim Cryptoorchidism Gynaecomastia Learning disability Azoospermia and infertility Immature behaviour
How is Sotos syndrome inherited?
Inheritance is sporadic, caused by mutations in the NSD1 gene
What are the clinical features of Sotos syndrome?
Birthweight and length >90th centile
Excessive linear growth during the first few years, which characteristically falls back
Head circumference proportional to length
Large hands and feet
Large ears and nose
Intellectual retardation
Clumsiness
What are the three parts of the adrenal gland and what do they produce?
Zona glomerulosa: aldosterone
Zona fasciculata: cortisol/androstenedione
Zona reticularis: DHEAS
What is a phaeochromocytoma?
Catecholamine secreting tumour
Is a phaeochromocytoma malignant?
Not usually
What is the main clinical feature of pheochromocytoma?
Sustained hypertension
Which conditions is pheochromocytoma associated with?
Von Recklinghausen disease
Von Hippel-Landau
MEN syndromes
What investigations should be done in phaeochromocytoma?
MIBG isotope scan
Plasma and urine catecholamine measurement
What is the management for phaeochromocytoma?
○ Surgical excision
Need pre op alpha and beta adrenoceptor blockade to prevent acute hypertensive crisis or cardiac dysrhythmias
What causes neonatal thyrotoxicosis?
Caused by transplacental passage of thyroid stimulating antibodies from mothers with Graves disease or Hashimoto thyroiditis
What are the clinical features of neonatal thyrotoxicosis?
○ Tachycardia Dysrhythmia Hypertension Weight loss Goitre Jaundice Thrombocytopenia
How is neonatal thyrotoxicosis treated?
self limiting but requires treatment with propranolol, carbamazepine and Lugol’s iodine if severe
How common is T1DM?
1:1000 children, 1.5:1 males:females
Which HLA haplotypes is T1DM associated with?
DR3 and DR4
What is the pathophysiology of T1DM?
T cell mediated: Islet tissue from patients with recent-onset T1DM shows insulitis, with an infiltrate made up of CD4 and CD8 T-lymphocytes and macrophages
What are the diagnostic criteria for T1DM?
Fasting BSL>7
Post prandial 2hr BM >11.1
HbA1c >6.5%
How is DKA defined
Glucose >11
pH <7.3
Bicarbonate <15
How is DKA managed?
Fluid resuscitation: 10ml/kg 0.9% saline unless shocked, in which case 20ml/kg
After initial bolus, give 0.9% saline with potassium after calculating deficit
Confirm the diagnosis with bloods and further assessment
Add glucose to fluid later, once glucose is 14mmol/l or lower: 5% glucose, Change to 10% if glucose <6mmol/l
Don’t start insulin until intravenous fluids have been running for at least an hour, use sliding scale
