Growth, Endocrine and Metabolism 2 Flashcards
What is precocious puberty?
Early puberty
Girls (breast development) = <8yr
Boys (testicular enlargement) = <9yr
Is precocious puberty concerning?
Usually benign in girls
Concerning in boys, rarely idiopathic/usually has organic cause
What are two types of precocious puberty?
1) Central (true) = gonadotrophin-dependent
2) Peripheral (false) = gonadotrophin-independent
What is central precocious puberty?
Puberty begins as a result of early activation of the hypothalamic pituitary axis
Normal pubertal development follows
What are some causes of central precocious puberty?
Idiopathic - no cause found in 80% girls and 40% boys
CNS abnormalities:
- Tumours eg gliomas, hCG-secreting germ cell tumours
- CNS trauma or injury eg infection, radiation, surgery
- Hamartomas of hypothalamus
- Congenital disorders such as hydrocephalus and arachnoid cysts
What is peripheral precocious puberty?
Puberty begins as a result of excess sex-steroids (androgens, oestrogen, progesterone) which do not involve physiological gonadotrophin secretion from the pituitary = independent of HPG axis
Gonad matures without GnRH stimulation and levels of testosterone and estradiol are elevated whilst LH and FSH are surpassed =abnormal pubertal development follows
What are some causes of peripheral precocious puberty?
Endogenous
- Congenital adrenal hyperplasia
- Gonadal tumours
- Germ cell tumours
- Adrenal tumours
Exogenous
- Environmental exogenous hormones
How may precocious puberty present in females?
- Thelarche (breast development) < 7 years
- Pubarche (pubic hair) < 8 years
- Menarche < 10 years
How may precocious puberty present in males?
- Bilateral enlargement of testes - gonadotrophin release from intracranial lesion
- Small testes - adrenal cause (e.g. adrenal tumour or hyperplasia)
- Unilaterally enlarged testes - gonadal tumour
What are hamartomas?
Mostly benign, focal malformation that resembles a neoplasm of its tissue of origin
What is McCune-Albright syndrome (MAS)?
A genetic condition in which there is increased risk of multiple endocrinopathies:
- Thyrotoxicosis
- Cushing’s syndrome
- Acromegaly
- Hyperparathyroidism etc
What are some signs of MAS?
Café-au-lait spots
Pathological fractures due to fibrous dysplasia of bones
Recurrent ovarian cysts
What investigations are done for precocious puberty?
1) Sex steroids
- Early morning testosterone is higher in boys in early puberty
- Estradiol levels are less reliable marker for puberty in girls as they are very variable (very high = ovarian pathology)
2) Gonadrotrophins LH and FSH
- High in central causes
- Low in peripheral causes
3) TFTs
4) Adrenal steroid precurorors (17-OH) - If CAH suspected
5) HCG
- If hCG secreting tumour suspected
6) Imaging:
- Pelvic US
- MRI of brain
- Hand and wrist x-rays for bone age
7) GnRH stimulation test
- Flat response in gonadotrophin-independent puberty
What is the management of precocious puberty?
Reduce the rate of skeletal maturation - early growth spurt might be associated with early cessation of growth leading to a short stature
Address psychosocial problems associated with early onset puberty
GnRH agonists for all patients
Peripheral PP - sex hormone inhibitors e.g. medroxyprogesterone acetate, cyproterone acetate, testolactone, ketoconazole
How to GnRH agonists help in precocious puberty?
Over-stimulate the pituitary, causing desensitisation and thus less release of LH and FSH
Continued until the time for normal puberty arrives
How does testolactone work?
= aromatase inhibitor thus inhibits steroid biosynthesis
Used most commonly for MAS but also used in testotoxicosis
What is delayed puberty?
Absent or incomplete development of secondary sex characteristics by age of:
- 14 in boys (testicular enlargement)
- 13 in girls (breast development)
What is the most common cause of delayed puberty?
Constitutional delay in growth and puberty (CDGP) = A temporary delay in growth and onset of puberty that is not non-pathological
What are the possible causes of central delayed puberty ?
Intact axis:
- CDPG = most common but must rule out other causes
- Chronic illness eg Crohn’s
- Malnutrition eg CF
- Excessive physical exercise
- Psychological deprivation
- Steroid therapy
- Hypothyroidism
Hypogonadism (impaired axis):
Low gonatrophin secretion (hypogonadotrophic hypogonadism)
- Hypopituitarism
- Idiopathic hypogonadotrophic hypogonadism
- Hypothalamic-pituitary disorders - Prader-Willi, Kallmann syndrome
High gonadtrophin secretion (hypergonatrophic hypogonadism)
- Chromosomal abnormalities - Klinefelters, Turners
- Steroid hormone deficiencies
- Acquired gonadal damage
What is Idiopathic hypogonadotrophic hypogonadism ?
Low gonadotrophin and sex steroid levels in the absence of abnormalities in hypothalamic-pituitary-gonadal system
What features may be seen in IHH?
Cryptotorchordism Micropenis Synkinesia (mirror movements) Cleft lip and palate Dental agenesis Skeletal anomalies Hearing loss \+/- Loss of smell (Kallman's syndrome)
What are some causes of peripheral delayed puberty in boys?
Bilateral testicular damage eg torsion / mumps
Syndromes causing cryptorchidism or gonadal dysgensis eg Prader-Wili, Kallmann’s
Irradiation
Drugs eg cyclophosphamide
What are some causes of peripheral delayed puberty in girls?
Gonadal dysgenesis e.g. Turner’s syndrome
Irradiation
Drugs eg cyclophosphamide or busulfan (ovarian failure)
DSD eg CAH
PCOS
Toxic damage eg iron overload (thalassaemia) or galactosaemia
What investigations should be done for delayed puberty?
Usually not required as most are CDGP
Investigations for chronic disease: FBC Ferritin Renal function tests U&Es Coeliac screen Urinalysis
Investigations for disorders of gonadal axis: Basal FSH/LH and estradiol/testosterone TFTs GNRH and GH Pelvic USS Bone age - wrist x ray MRI/CT of pituitary Chromosome analysis
What may LH and FSH be in CDGP and IHH? And gonadal failure?
Low in constitutional delay in growth and puberty and idiopathic hypogonadotrophic hypogonadism
Elevated in gonadal failure
What is the management of CDGP?
Not often necessary but short courses of sex steroid can help individuals catch up with peers
Boys: testosterone PO or depot injection for 3-6 months then reassess
- Usually rapid and effective
girls: gradually increasing oestrogen treatment, with cyclical progesterone once adequate oestrogen levels
What is given in primary testicular / ovarian failure?
Pubertal induction followed by ongoing hormone replacement
What is congenital hypothyroidism?
Lack of thyroid hormones present from birth, if not detected early = irreversible neuroligcal problems and poor growth
- some develop after birth = primary hypothyroidism rather than CH
Is CH more common in boys or girls? And in which areas of the world?
2x more common in girls
Areas with iodine deficiency eg Bangladesh / China / Peru
What are some causes of CH?
1) Thyroid gland defects = 75%
- Not inherited so low chance of sibling affected
2) Disorders of thyroid metabolism = 10%
- Eg TSH unresponsiveness / defects in thyroglobulin structure
- Usually inherited
3) Hypothalamic or pituitary dysfunction = 5%
- Pituitary hypothyroidism usually occurs with other disorders of pituitary function if GH deficiency
- Hypothalamic causes include tumours, ischaemic damage etc
4) Transient hypothyroidism = 10%
What is transient hypothyroidism usually related to?
Maternal medications eg carbimazole or maternal antibodies
In maternal thyroid disease, IgG auto-antibodies can cross the placenta and block thyroid function in utero - this improves after delivery
What genetic defects have been associated with CH?
PAX8 - related to formation of kidney and thyroid gland
DUOX2 - related to production of thyroid hormones
Why are infants with CH usually clinically normal at birth?
Presence of maternal thyroid hormones
What symptoms may an infant with CH present with? (4)
1) Feeding difficulties
2) Somnolence (sleepiness)
3) Low freq of crying
4) Constipation
What signs may an infant with CH present with? (15)
1) Large fontanelles
2) Myxoedema
3) Nasal obstruction
4) Macroglossia
5) Low temp (<35) with cold and mottled skin on extremities
6) Jaundice = prolongation of physiological jaundice
7) Umbilical hernia
8) Hypotonia
9) Hoarse voice
10) Cardiomegaly
11) Bradycardia
12) Pericardial effusion - usually asymptomatic
13) Failure of fusion of distal femoral epiphyses
14) Refractory anaemia
15) Goitre = more common with thyroid hormone resistance and transient hypothyroidism
What is the appearance of a child with hypothyroidism?
Short stature Hypertelorism Depressed bridge of nose Narrow palpebral fissures Swollen eyes
What causes myxoedema in hypothyroidism?
Connective tissue reacts to increased TSH levels
How is CH diagnosed?
All babies are screened at birth via heel pinprick and analysed for TSH and T4 (Guthrie)
- High TSH and low T4 confirm diagnosis
Thyroglobulin levels
Thyroid USS or radionuclide scanning
What is included in the UK Newborn Screening Programme?
TSH and T4
Phenylketonuria
CF
Sickle cell disease
What is the management of CH?
Aim = early detection and early thyroid hormone replacement to avoid irreversible neurological disability
Lifelong thyroxine replacement with L-thyroxine given once daily and titrated to TFTs
- Levothyroxine 10-15mcg/kg/day
Regular monitoring
Transient hypothyroidism does not need to be treated unless low T4 and raised TSH last >2 weeks
- Treatment for this is usually terminated after 3-5 months
What monitoring is required in CH?
TFTs
Growth charts
Achievement of childhood milestones
Mental development in all 4 areas = fine motor, gross motor, speech and language, social
What is the most common form of acquired childhood hypothyroidism?
Lymphocytic thyroiditis = Hashimoto’s autoimmune thyroiditis
When does Hashimoto’s autoimmune thyroiditis usually present?
Adolescence
In what condition are there a high incidence of Hashimoto’s autoimmune thyroiditis?
Turner syndrome
Down’s syndrome
What are the signs of Hashimoto’s autoimmune thyroiditis?
Slowing of growth
+ other hypothyroid symptoms eg skin changes, cold intolerance
Delayed puberty (younger children may have galactorrhea or precocious puberty)
What is a particular issue with adolescents with Hashimoto’s autoimmune thyroiditis?
Poor compliance in medication
What are some causes of Hashimoto’s autoimmune thyroiditis?
Iatrogenic eg treatment of hyperthyroidism
Suppurative thyroiditis
Subacute non-supperative thyroiditis = de Quervain’s disease
What are causes of painless and painful thyroiditis?
Painful = caused by radiation/infection/trauma
- Suppurative thyroiditis
- De Quervain’s disease
Painless = AI or medication
- Hashimotos
How common is childhood obesity?
1/10 children aged 4-5yr
1/5 children aged 10-11yr
What are some contributory factors for childhood obesity? (8)
1) Poor dietary habits
2) Lack of exercise
3) Sleep deprivation
4) Genetics
5) Lower socio-economic status
6) Medication
Also:
7) High birth weight or low birth weight associated with catch-up growth
8) Intrauterine exposure to maternal gestational DM or obesity
What endocrine disorders may cause obesity? (8)
1) Hypothyroidism
2) Cushing’s syndrome
3) GH deficiency
4) Muscular dystrophy and other causes of immobility
5) OCIS
6) Hypothalamic damage
7) Spina bifida
8) Genetic conditions eg Prader-Willi
What medications may aggravate weight gain?
Antidepressants - mirtazapine, paroxetine, imipramine
Anticonvulsants - sodium valporate, gabapentin, vigabatrin and carbamazepine
Antipsychotics - clozapine, olanzapine, pimozide
Lithium
Corticosteroids
What are good measures of obesity in children?
BMI not as useful as does not consider age, gender, puberty, race/ethnicity
Gold standard = densitometry or dual-energy X-ray absorptiometry (DEXA) scanning
What BMI centiles are:
1) Overweight
2) Obese
3) Severely obese
1) Overweight = >91st
2) Obese = >98th
3) Severely obese = >99.6th
What are some complications of obesity in children?
1) T2DM
2) Breathing problems eg sleep apnoea
3) Orthopaedic conditions
4) Non-alcoholic fatty liver disease
5) Psychosocial morbidity
6) PCOS
7) Metabloc syndrome
8) Vit D and iron deficiency
What is phenylketonuria (PKU)?
Most common inborn error of amino acid metabolism
Absent / virtually absent phenylalanine hydroxylase (PAH) enzyme activity
This enzyme converts dietary phenylalanine to tyrosine
Products of this pathway are important in formation of catecholamines, neurotransmitters and melanin
What does high plasma concentrations of phenylalanine in PKU cause?
Formation of byproducts phenylpyruvic acid and phenylethylamine
Neurotoxic above a certain threshold
How may PKU present?
Usually normal at birth but picked up on newborn baby heel-prick screen
1) Very fair with blue eyes (compared to family)
2) Musty / ‘mousey’ odour
3) Developmental delay and general learning disability
4) Recurrent vomitting
5) Eczematous skin eruptions and scleroderma-like skin lesions
6) Seizures
What are the types of PKU?
Type I
Type II
Malignant
How is type I PKU inherited? Which chromosome?
Autosomal recessive
Chr 12
What is type II PKU?
5% enzyme activity retained - less serious
What is malignant PKU?
Deficiency in enzymes co-factor THB
= more severe
What investigations are done for PKU?
Heel-prick blood assayed for phenylalanine >12hrs after birth
Blood levels of phenylalanine
Phenylketones detected in urine
How is PKU managed?
Diet:
- Low penylalanine
- High tyrosine
Avoid milk, dairy, fish, chicken, beans, eggs, nuts
Regular monitoring of blood phenylalanine and its metabolites
What are some complications of PKU? (4)
1) Developmental delay / intellectual disability if non-adherence to diet
2) Epilepsy
3) Severe behavioural disturbance
4) Congenital anomaly and intellectual disability in offspring of PKU mothers
What are the 3 main groups of short stature?
1) Primary growth disorders - condition intrinsic to growth plate
2) Secondary growth disorders - growth plate changes as a consequence of the condition
3) Idiopathic
What is the causes the majority of short statures?
CDGP
Familial growth stature
Idiopathic
What are some primary growth disorders? (3)
1) Genetic syndromes:
- Down’s syndrome
- Prader-Willi etc
2) IUGR with failure to catch up:
- Prematurity
- Placental dysfunction
3) Congenital bone disorders:
- Achondroplasia
- Hydrochondroplasia
- Osteogenesis imperfecta
What are some secondary growth disorders? (7)
1) Endocrine:
- Hypothyroidism
- Cushings
- GH deficiency
- Precocious puberty
2) Metabolic
- Glycogen storage disease
3) DM poorly controlled
4) Chronic disease:
- CV
- Resp eg CF
- Haemoglobinopathies
- JA
5) Malnutrition:
- IBD
- Coeliac
- Rickets
6) Psychosocial deprivation
- Hyperphagic short stature syndrome
7) Medication
- Steroid therapy
What is important to determine regarding height in a child with a short stature?
Determine if there is steady growth behind centiles (more likely to be constitutional or maturational delay)
or if there is a fall-off in growth across centiles (more likely to be chronic illness or acquired hypothyroidism)
What is important to include on examination of a child with a short stature?
Height and weight
- inc sitting and standing height to consider skeletal disproportion eg achondroplasia
GH deficiency
- Look for other features of pituitary deficiency eg hypogonadism
- Or features of pituitary tumour eg bitemporal hemaniopia
Features of Cushing’s, CKD, hypothyroidism, fetal alcohol syndrome, Turner syndrome
Skeletal causes
- Eg rickets = craniotabes, bulbous wrists and bowing of extremeties
Skin lesions
- Café-au-lait (McCune-Albright syndrome)
- Large hemaniomas
How is expected final height calculated?
Mid-parental height
How is mid-parental height used to calculate expected height in boys?
Mid parental height =
(fathers height + (mothers height + 13)) /2
How is mid-parental height used to calculate expected height in girls?
Mid parental height =
((fathers height - 13) + mothers height) /2
What investigations should be done for short stature?
Bloods - FBC, renal function, LFTs, TFTs, ESR, CRP, urinalysis
Karyotyping
Specific tests eg CF
Bone age
Dental age
What is bone age?
Predicts final adult height by estimating skeletal maturation from an assessment of the ossification of the epiphyseal centres
How is bone age measured?
Radiograph L hand and wrist using standards from standards from Greulich-Pule atlas
When is bone age considered delayed?
Two standard deviations below chronological age
What is the management of short stature?
Depends on cause
Growth hormone = somatropin
Can be used in:
- GH deficiency
- Prader-Wili
- CKD
- SGA with subsequent growth failure at 4yrs or later
What should be considered in hx of short stature?
FH
- Parental growth rate, early/late puberty/menarche
SH
- neglect
DH
- Steroids
+ BIND !!!!!
Birth history
- Antenatal illness/drugs
- Gestational age
Immunisations
Neonatal
- Birthweight
- Illnesses
Developmental
- Goals met/ delayed
What should be plotted in short stature?
Height
Weight
Head circumference
= plot growth chart
