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PAEDS GENETICS & ENDOCRINE Flashcards

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1
Q

GENETICS OVERVIEW
What is the management of Robertsonian translocation?

A
  • Parental chromosomes analysis is needed, one parent may be carrier
  • Translocation carriers have 45 chromosomes on karyotype (one is in wrong place)
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2
Q

GENETICS OVERVIEW
What are the 3 types of Mendelian inheritance?

A
  • Autosomal dominant
  • Autosomal recessive
  • X-linked (recessive)
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3
Q

GENETICS OVERVIEW
In terms of autosomal dominant inheritance…

i) inheritance chance?
ii) general rule?
iii) pattern of inheritance?
iv) examples?

A

i) 50%
ii) AD = structural protein defects
iii) No skipped generations, inherited regardless of sex
iv) Adult PCKD, familial hypercholesterolaemia, Marfan’s, Huntington’s disease, BRCA genes

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4
Q

GENETICS OVERVIEW
What are some reasons for autosomal dominant conditions presenting in families with no family history?

A
  • # 1 = non-paternity
  • New mutation
  • Gonadal mosaicism
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5
Q

GENETICS OVERVIEW
In terms of autosomal recessive inheritance…

i) inheritance chance?
ii) general rule?
iii) requirements to develop disease?
iv) carrier risk in siblings?
v) examples?

A

i) 25% from 2 carrier parents
ii) AR = affects metabolic pathways
iii) Two germline mutations (2 carrier parents)
iv) 2 in 3 (66%) as you take away possibility of them having the disease
v) CF, phenylketonuria, haemochromatosis

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6
Q

GENETICS OVERVIEW
What is a big risk factor for autosomal recessive conditions?
What is the outcome?

A
  • Consanguineous parents, esp. if many generations of it
  • Can give appearance of AD pedigree for a recessive condition
  • Particularly in people with Asian origin
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7
Q

GENETICS OVERVIEW
In terms of X-linked recessive inheritance…

i) who is affected?
ii) who transmits?
iii) what can occur in females?
iv) examples?

A

i) Males more than females
ii) NO male-male transmission but affected males can produce a carrier female
iii) Gonadal mosaicism may occur influenced by X inactivation (lyonisation)
iv) Haemophilia A, Duchenne’s + Becker’s, colour blindness

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8
Q

GENETICS OVERVIEW
What is genomic imprinting + uniparental disomy?
Give an example

A
  • Most genes both copies are expressed, some genes are only maternally or paternally expressed (imprinting)
  • Prader-Willi + Angelman’s syndrome both caused by either cytogenic deletions of the same region of chromosome 15q or by uniparental disomy of chromosome 15
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9
Q

GENETICS OVERVIEW
What do mitochondrial diseases lead to?
What is the inheritance?
Give some examples

A
  • Responsible for ATP production so if abnormal > poor production + hence myopathies
  • Exclusively maternally inherited from circular mitochondrial DNA in cytoplasm of ovum (sperm mitochondria in tail)
  • Myoclonic epilepsy, ragged red fibres (MERRF), mitochondrially inherited DM + deafness (DIDMOAD)
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10
Q

GENETICS OVERVIEW
What is gonadal mosaicism?

A
  • Some cells have mutations in genes giving rise to a particular phenotype e.g. birthmarks
  • Gonadal mosaicism is when germ cells involved
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11
Q

GENETICS OVERVIEW
Explain the process of gonadal mosaicism

A
  • Father = mosaic sperm (some sperm with mutated gene, some sperm normal)
  • Mother = all eggs with normal gene
  • Offspring = fertilised egg > union of male DNA (sperm) with mutated gene + female DNA (egg) with normal gene
  • Every cell of embryo has one copy of mutated + one copy of normal
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12
Q

GENETICS OVERVIEW
What are 3 ways of testing genes?

A
  • DNA analysis via polymerase chain reaction to amplify the DNA + determine the sequence of the relevant gene
  • Karyotyping (look at # of chromosomes, their size + basic structure)
  • Molecular cytogenic analysis = fluorescent in situ hybridisation (FISH) to detect presence, # + chromosomal location of specific sequences
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13
Q

GENETICS OVERVIEW
What is the purpose of DNA analysis?

A
  • Antenatal Dx (amniocentesis or CVS)
  • Confirm clinical Dx
  • Detect female carriers for X-linked disorders
  • Detect carriers of AR disorders
  • Pre-symptomatic diagnosis of AD disorders like Huntington’s disease
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14
Q

GENETICS OVERVIEW
In the case of Huntington’s disease, can healthy children be tested if parents consent for them?

A
  • No, have to be old enough to give informed consent themselves
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15
Q

DOWN’S SYNDROME
What is Down’s syndrome?
What is the life expectancy?

A
  • Trisomy 21 (3x copies of chromosome 21)
  • About 60y
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16
Q

DOWN’S SYNDROME
What are the causes of Down’s syndrome?

A
  • Nondisjunction (95%) leaves cell with extra C21 so trisomy on fertilisation
  • Robertsonian translocation (4%) = long arm of C21 translocate to C14 often
  • Mosaicism (1%) = cells have mixed amounts of chromosomes
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17
Q

DOWN’S SYNDROME
What is the classical craniofacial appearance in Down’s syndrome?

A
  • Flat occiput (brachycephaly) + flat bridge of nose
  • Upward sloping palpebral fissures (eyes slant down + inwards)
  • Prominent epicanthic folds (skin overlying medial portion of eye + eyelid)
  • Short neck + stature
  • Small mouth, protruding tongue, small ears
  • Brushfield spots in iris (pigmented spots)
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18
Q

DOWN’S SYNDROME
Other than craniofacial anomalies, what other anomalies can be seen in Down’s syndrome?

A
  • Widely separated first + second toe (sandal gap)
  • Hypotonia
  • Single transverse palmar (simian) crease
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19
Q

DOWN’S SYNDROME
What are some complications of Down’s syndrome?

A
  • LDs + delayed motor milestones
  • Complete AVSD
  • Atlantoaxial instability = risk of neck dislocation during sports
  • Hypothyroidism, duodenal atresia, Hirschsprung’s
  • Hearing + visual impairment, strabismus
  • Increased ALL + early-onset dementia
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20
Q

DOWN’S SYNDROME
How is Down’s syndrome diagnosed?

A
  • Women offered antenatal screening/testing (combined test, CVS, amniocentesis)
  • Clinical suspicion + then FISH for Dx when born
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21
Q

DOWN’S SYNDROME
What regular investigations are required for Down’s syndrome?

A
  • Regular thyroid checks (every 2y)
  • ECHO to Dx any cardiac defects
  • Regular audiometry + eye checks
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22
Q

DOWN’S SYNDROME
What is the management of Down’s syndrome?

A

MDT –

  • Specialist Dr’s (CHD, hypothyroid)
  • Social services (social care + benefits)
  • Optician + audiologist
  • OT/physio/SALT
  • Additional support with educational needs
  • Charities like Down’s syndrome association
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23
Q

PATAU’S SYNDROME
What is Patau’s syndrome?

A
  • Severe physical + mental congenital abnormalities due to trisomy 13
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24
Q

PATAU’S SYNDROME
What are some clinical features of Patau’s syndrome?

A
  • Microcephalic, scalp lesions, small eyes + other eye defects
  • Cleft lip + palate
  • Polydactyly (think 13 fingers)
  • Cardiac + renal malformations
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25
EDWARD'S SYNDROME What is Edward's syndrome?
- Trisomy 18, mostly F - Severe psychomotor + growth retardation if survive 1st year of life
26
EDWARD'S SYNDROME What is the clinical presentation of Edward's syndrome?
- Prominent occiput - Small mouth + chin (micrognathia) - Low set ears - Flexed, overlapping fingers - Rocker-bottom feet (flat) - Cardiac + renal malformations
27
EDWARD'S SYNDROME For both Patau's and Edward's syndrome, what are the investigations?
- Antenatal abnormalities detected on USS (foetal anomaly scan) - Prenatal Dx with amniocentesis or CVS via DNA PCR - Karyotyping genetic analysis confirms at birth
28
FRAGILE X SYNDROME What is fragile X syndrome?
- Inherited condition, 2nd most common cause of LD
29
FRAGILE X SYNDROME What does fragile X result in?
- Mutation in fragile X mental retardation 1 (FMR1) gene on X chromosome - Inadequate FMRP which plays a role in cognitive development
30
FRAGILE X SYNDROME Why do females vary in how much they are affected by fragile X syndrome?
- Spare copy on other X chromosome + reduced penetrance - Even with full mutation usually have fewer problems - Number of CGG repeats often increases as it's inherited so caution in future
31
FRAGILE X SYNDROME What are some cognitive features of fragile X syndrome?
- Intellectual disability - Delay speech + language - Delayed motor development (may be secondary to hypotonia) - Aggressive, hyperactive + poor impulse control - "Cocktail personality" = happy bouncy children
32
FRAGILE X SYNDROME What are some physical features of fragile X syndrome?
- Long narrow face + large ears - Large testicles after puberty - Hypermobile joints (esp. hands) - Hypersensitivity to stimuli
33
FRAGILE X SYNDROME What is associated with fragile X syndrome?
- Autism (up to 30%) - Seizures - ADHD
34
FRAGILE X SYNDROME What issues can fragile X premutation carriers suffer from?
- Men can get Fragile X-associated tremor ataxia syndrome (FXTAS) = intention tremor, ataxia, memory + cognitive issues as adult, white matter changes on MRI - Females can get FMR1-related POI (endocrinologist input)
35
FRAGILE X SYNDROME What are the investigations for fragile X syndrome?
- Carrier testing in pregnancy women, can have CVS or amniocentesis - FISH to look at content of cells, DNA testing once born to count # of CGG repeats
36
FRAGILE X SYNDROME What is the management of fragile X syndrome?
- OT = daily tasks - Social services = social care + benefits - Special education = learning help - Challenging behaviours may benefit from risperidone. - PO lorazepam in acute agitation (after de-escalation strategies)
37
TURNER'S SYNDROME What is Turner's syndrome?
- Lack of a second X chromosome in a female leading to 45, XO
38
TURNER'S SYNDROME What is the clinical presentation of Turner's syndrome?
- Short stature, webbed neck, shield chest + widely spaced nipples (classic) - Delayed puberty, underdeveloped ovaries > primary amenorrhoea + infertility - Cubitus valgus
39
TURNER'S SYNDROME What are some complications of Turner's syndrome?
- Coarctation or bicuspid aortic valve - Increased risk of CHD > HTN, obesity - DM, osteoporosis, hypothyroidism - Recurrent otitis media + UTIs - Horseshoe kidney, susceptible to x-linked recessive conditions
40
TURNER'S SYNDROME What is the investigation of choice for Turner's syndrome?
- Karyotyping after clinical suspicion = 45XO
41
TURNER'S SYNDROME What is the management of Turner's syndrome?
- GH therapy to prevent short stature - Oestrogen + progesterone replacement to establish 2ary sex characteristics, regulate menstrual cycle + prevent osteoporosis - Fertility treatment like IVF
42
DUCHENNE'S What is Duchenne's muscular dystrophy?
- X-linked recessive chromosome 21 = gene deletion for dystrophin (connects muscle fibres to ECM)
43
DUCHENNE'S What is the clinical presentation of Duchenne's muscular dystrophy?
- Proximal muscle weakness from 5y - Delayed milestones - Waddling gait - Gower sign +ve - Calf pseudohypertrophy (replaced by fat + fibrous tissue)
44
DUCHENNE'S What is Gower's sign?
- Patient uses hands + arms to "walk" themselves upright from a squatting position due to lack of hip + thigh muscle strength
45
DUCHENNE'S What are some complications of Duchenne's muscular dystrophy?
- Wheelchair by 13y - Cardiac involvement (dilated cardiomyopathy) in teenagers - Resp involvement - Survival >30y unusual
46
DUCHENNE'S What are some investigations for Duchenne's muscular dystrophy?
- Clinical exam = Gower's sign - Creatinine kinase markedly raised - Genetic testing to confirm
47
DUCHENNE'S What is the medical management of Duchenne's muscular dystrophy?
- Steroids (prednisolone) appear best treatment as improves QOL, longer life expectancy + decreased progression of heart problems - Manage congestive HF + arrhythmias with beta blocker, ACEi.
48
DUCHENNE'S What is the supportive therapy for Duchenne's muscular dystrophy?
- OT = aids + adaptations to help live with condition - Physio = prevent contractures, scoliosis correction - NIV for resp failure, gene therapy
49
DUCHENNE'S What is another type of muscular dystrophy very similar to Duchenne's? How does it differ?
- Becker's = some functional dystrophin produced - Features similar but clinically progresses slower, average age of onset 11y with inability to walk from 20s
50
KLINEFELTER SYNDROME What is Klinefelter syndrome?
- When a male has an additional X chromosome, making 47XXY - Rarely even more X chromosomes like 48XXXY (more severe) - Chief genetic cause of hypergonadotropic hypogonadism
51
KLINEFELTER SYNDROME What is the clinical presentation of Klinefelter syndrome?
- Often appear normal until puberty - Taller height + wider hips - Delayed puberty (lack of pubic hair, poor beard growth) - Gynaecomastia, small testicles/penis, infertility - Weaker muscles, shyness, subtle learning difficulties (esp. speech + language)
52
KLINEFELTER SYNDROME What are some complications of Klinefelter syndrome?
- Increased risk of breast cancer compared to other males - Osteoporosis - Diabetes - Anxiety + depression
53
KLINEFELTER SYNDROME What is the medical management of Klinefelter syndrome?
- Monthly testosterone injections to promote sexual characteristics - Advanced IVF techniques for infertility - Breast reduction surgery for cosmesis
54
KLINEFELTER SYNDROME What is the MDT management for Klinefelter syndrome?
- SALT - OT for day-day tasks - Physio to strengthen muscles + joints - Educational support if learning difficulties
55
PRADER-WILLI SYNDROME What is the clinical presentation of Prader-Willi syndrome?
- Constant, insatiable hunger > hyperphagia + obesity - Initially failure to thrive due to hypotonia - Small genitalia, hypogonadism + infertility - Narrow forehead, almond eyes, strabismus - LDs, MH issues
56
PRADER-WILLI SYNDROME What causes the constant, insatiable hunger in Prader-Willi? How can this be managed?
- Marked elevated levels of ghrelin (hormone associated with hunger) - Dietician = careful limitation of access to food to control weight (may have to lock food cupboards or fridge)
57
PRADER-WILLI SYNDROME What is the management of Prader-Willi syndrome?
- GH to improve muscle development + body composition | - MDT = education support, social workers, psychologists/CAMHS, physio + OT
58
ANGELMAN'S SYNDROME What is Angelman's syndrome? What is it caused by?
- Genetic imprinting disorder due to deletion of maternal chromosome 15 or paternal uniparental disomy - Loss of function of maternal UBE3A gene
59
ANGELMAN'S SYNDROME What is the clinical presentation of Angelman's syndrome?
- "Happy puppet" = unprovoked laughing, clapping, hand flapping, ADHD - Fascination with water - Epilepsy, ataxia, broad based gait - Severe LD, delayed development - Widely spaced teeth, microcephaly
60
ANGELMAN'S SYNDROME What is the management of Angelman's syndrome?
- Chromosomal analysis with FISH to detect deletions - MDT approach = parental education, CAMHS, psychology, physio, SALT, OT
61
NOONAN'S SYNDROME What is Noonan's syndrome?
- Autosomal dominant condition with defect on chromosome 12, normal karyotype
62
NOONAN'S SYNDROME What is the clinical presentation of Noonan's syndrome?
- Short stature, webbed neck, widely spaced nipples (Male Turner's) - Pectus excavatum, low set ears - Hypertelorism (wide space between eyes) - Downward sloping eyes with ptosis - Curly/woolly hair
63
NOONAN'S SYNDROME What are some complications of Noonan's syndrome?
- CHD = pulmonary valve stenosis - Cryptorchidism which can lead to infertility (fertility in women normal) - LDs, bleeding disorders (XI deficient)
64
NOONAN'S SYNDROME What is the management of Noonan's syndrome?
- MDT support - Main complication CHD so may need surgical correction
65
WILLIAM'S SYNDROME What is William's syndrome?
- Random deletion of genetic material on one copy of chromosome 7 resulting in only single copy of genes from other chromosome 7
66
WILLIAM'S SYNDROME What is the clinical presentation of William's syndrome?
- Very friendly + sociable - Starburst eyes (star-pattern on iris) - Wide mouth, big smile + widely spaced teeth - Broad forehead, short nose + small chin - Mild LD, short stature
67
WILLIAM'S SYNDROME What are some complications of William's syndrome?
- Supravalvular aortic stenosis - ADHD - HTN + hypercalcaemia
68
WILLIAM'S SYNDROME What is the management of William's syndrome?
- MDT approach - ECHO + BP monitoring for complications - Low Ca2+ diet - FISH to confirm Dx
69
GENETICS OVERVIEW What is non-disjunction? What is the outcome? Management? Karyotype?
- Error in meiosis where pair of chromosomes fail to separate so one gamete has 2 chromosome copies and one has none - Fertilisation of the gamete with 2 chromosomes gives rise to a trisomy - Parental chromosomes do not need to be examined, related to maternal age - 47 chromosomes
70
GENETICS OVERVIEW What is Robertsonian translocation? Karyotype?
- Extra copy of one chromosome is joined onto another chromosome - 46 chromosomes but 3 copies of one chromosomes material
71
PRADER-WILLI SYNDROME What is Prader-Willi syndrome?
- Genetic imprinting disorder due to deletion of paternal chromosome 15 or maternal uniparental disomy
72
PUBERTY In terms of female puberty... i) age? ii) first sign? iii) other signs?
i) 8.5–12.5 ii) Thelarche (breast development) iii) Pubarche (growth of pubic hair) + rapid height spurt occur rapidly after thelarche, menarche occurs roughly 2.5y after start of puberty (signals growth coming to an end)
73
PUBERTY In terms of male puberty... i) age? ii) first sign? iii) other signs?
i) 10–14 ii) Testicular enlargement >4ml (Prader orchidometer) iii) Pubarche follows testicular enlargement, height spurt about 18m after puberty but greater magnitude than in females
74
PUBERTY What features of puberty are consistent with both sexes?
- Adrenarche = maturation of adrenal gland leading to androgen production causing body odour + mild acne - Development of acne, axillary hair, body odour + mood changes
75
PUBERTY What can be used to measure puberty? What are the components?
- Tanner staging - B (breasts) - PH (pubic hair) - G (male genitals)
76
PUBERTY Explain the tanner stages for... i) breast? ii) pubic hair? iii) genitalia?
i) BI = pre-pubertal, BII = breast bud, BIII = juvenile smooth contour, BIV = areola + papilla project above breast, BV = adult ii) PHI = none, PHII = sparse, PHIII = dark, coarser, curlier, PHIV = filling out, PHV = adult iii) GI = pre-adolescent, GII = lengthens, GIII = growth in length + circumference, GIV = glans penis develops, GV = adult
77
PRECOCIOUS PUBERTY What are the 2 main types of precocious puberty?
- Gonadotropin-dependent (central/true) = premature activation of hypothalamic-pituitary-gonadal axis - Gonadotropin-independent (pseudo/false) = excess sex steroids
78
PRECOCIOUS PUBERTY What is the pathophysiology and potential causes of central precocious puberty?
Pathophysiology: LH++, FSH+ > oestrogen from ovary ++ or testosterone from testis ++ & adrenal + Causes: - Familial, - hypothyroidism, - CNS (neurofibroma, tuberous sclerosis)
79
PRECOCIOUS PUBERTY What is precocious puberty in females?
- Development of secondary sexual characteristics (thelarche) <8y
80
PRECOCIOUS PUBERTY What is the management of precocious puberty in females?
- Full Hx, ages parents went into puberty, USS of uterus + ovaries - If ok = reassure - GnRH analogues stop puberty progressing further by suppressing pulsatile GnRH secretion until she is ready
81
PRECOCIOUS PUBERTY What is precocious puberty in males?
- Development of secondary sexual characteristics <9y - Less common, more worrying
82
PRECOCIOUS PUBERTY What is the management of precocious puberty in males?
- Full Hx including ages parents went into puberty - MRI head for ?tumour - Treat underlying cause
83
PRECOCIOUS PUBERTY What is premature thelarche? Who does it normally affect?
- Breast enlargement (may be asymmetrical) rarely beyond stage 3 but absence of axillary/pubic hair or growth spurt (differentiating from precocious puberty) - Females 6m–2y, non-progressive + self-limiting
84
PRECOCIOUS PUBERTY What is premature pubarche (adrenarche)?
- Pubic hair development <8y (F), <9y (M) but no other signs of sexual development
85
PRECOCIOUS PUBERTY What causes premature pubarche (adrenarche)? How can you tell?
- Accentuation of normal maturation of androgen production by adrenal gland (adrenarche), can be late-onset CAH or adrenal tumour - Urinary steroid profile to help differentiate
86
PRECOCIOUS PUBERTY What are the risk factors with premature pubarche (adrenarche)?
- More common in Asian + Afro-Caribbean, increased risk of PCOS later in life
87
CAH What is congenital adrenal hyperplasia (CAH)?
- Autosomal recessive condition with deficiency of 21-hydroxylase enzyme - Small minority = 11-beta-hydroxylase
88
CAH What is the normal physiology of the adrenal gland?
- Glucocorticoids (cortisol) deal with stress > raise glucose, reduce inflammation, suppresses immune system - Mineralocorticoids (aldosterone) act on kidneys to control balance of salt (mineral) + Water in blood > increases Na+ reabsorption + K+ excretion
89
CAH What is the pathophysiology of CAH?
- 21-hydroxylase responsible for converting progesterone into cortisol + aldosterone - Progesterone also used to create testosterone, but not with 21-hydroxylase - Excess progesterone (as not converted to aldosterone or cortisol) gets converted into testosterone instead (high)
90
CAH What is the clinical presentation of CAH in females?
MILD - ambiguous genitalia - abnormal/absent periods - deeper voice, early puberty + facial hair - taller for age during childhood but become short as an adult if untreated - skin hyperpigmentation SEVERE - virilised (male-appearing) genitalia from birth - may exhibit features of mineralocorticoid and glucocorticoid deficiency from birth (hyponatraemia, hypoglycaemia + dehydration)
91
CAH what is the clinical presentation in males?
MILD - may be asymptomatic - enlarged penis - small testicles - early puberty - deep voice - taller for their age during childhood bit become short as adults if untreated - skin hyperpigmentation SEVERE - exhibit mineralocorticoid and glucocorticoid deficiency soon after birth (hypoglycaemia, hyponatraemia, dehydration) - large penis size
92
CAH What is a critical complication of CAH?
- Male salt-losers present in salt-losing crisis shortly after birth
93
CAH What are some investigations for CAH?
- serum 17-hydroxyprogesterone levels - serum electrolytes = hyponatraemia, hyperkalaemia, acidosis - serum hormone levels = raised ACTH and renin, low cortisol + aldosterone to consider - genetic testing - pelvic USS (to visualise internal genitalia if ambiguous)
94
CAH What management is needed for females with CAH?
- Corrective surgery to external genitalia within 1st year - Definitive surgical reconstruction usually delayed until puberty
95
CAH What is the general management of CAH?
- Lifelong glucocorticoids (HYDROCORTISONE) to suppress ACTH > normal growth - Lifelong mineralocorticoids (FLUDROCORTISONE) if there's salt loss, - infants may need NaCl replacement - Additional hydrocortisone to cover illness/surgery - Antenatal dexamethasone controversial treatment, risks>benefits currently
96
SEXUAL DIFFERENTIATION In embryology, when does sexual differentiation occur? How does a male foetus not produce female sexual characteristics?
- Foetal gonad bipotential until 6w - Sex-determining region on Y chromosome (SRY) gene present - Production of anti-mullerian hormone inhibits Mullerian (paramesonephric) duct from persisting which > uterus + fallopian tubes
97
SEXUAL DIFFERENTIATION How does a male foetus produce male sexual characteristics?
- Leydig cells produce testosterone causing Wolffian duct differentiation > vas, epididymis, seminal vesicles - Later, dihydrotestosterone leads to virilised external genitalia
98
SEXUAL DIFFERENTIATION What is the process of female sexual differentiation?
- No SRY gene present so no AMH | - Mullerian duct persists which develops into ovaries + female genitalia
99
SEXUAL DIFFERENTIATION What are some causes of sexual differentiation disorders?
- CAH (#1) - Congenital hypopituitarism (Prader-Willi) - Ovotesticular disorder of sex development (true hermaphroditism) leading to both testicular + ovarian tissues as XX + XY containing cells present
100
SEXUAL DIFFERENTIATION What is the management of sexual differentiation disorders?
- Do not guess sex - Karyotyping, adrenal + sex hormone levels measured - USS of internal structures + gonads - Surgical reconstruction may be delayed so individual can make choice
101
DELAYED PUBERTY What are the two categories for delayed puberty?
- Hypogonadotropic hypogonadism = deficiency of LH + FSH leading to deficiency of sex hormones - Hypergonadotropic hypogonadism = gonads fail to respond to stimulation from gonadotrophins (LH + FSH), no -ve feedback from sex hormones so increased LH + FSH
102
DELAYED PUBERTY What are some causes of hypogonadotropic hypogonadism?
- Constitutional delay in growth + puberty (FHx) - Chronic diseases (IBD, CF, coeliac) - Excess stress (anorexia, intense exercise, low weight) - Hypothalamo-pituitary disorders (panhypopituitarism, Kallman's + anosmia, GH deficiency)
103
DELAYED PUBERTY What are some causes of hypergonadotropic hypogonadism?
- Chromosomal abnormalities (Turner's XO, Klinefelter's 47XXY) - Acquired gonadal damage (post-surgery, chemo/radio, torsion) - Congenital absence of the testes or ovaries
104
DELAYED PUBERTY In delayed puberty, what are some causes of... i) short stature (delayed + short)? ii) normal stature (delayed + normal)?
i) Turner's, Prader-Willi + Noonan's ii) PCOS, androgen insensitivity, Kallmann's + Klinefelter's
105
DELAYED PUBERTY What is delayed puberty in... i) females? ii) males?
i) Absence of pubertal development by 14y ii) Absence of pubertal development by 15y (more common in males)
106
DELAYED PUBERTY What are some investigations for delayed puberty?
- FBC + ferritin (anaemia), U+E (CKD), coeliac antibodies - Hormonal testing - Genetic testing/karyotyping - XR wrist to assess bone age (low in constitutional delay) - Pelvic USS to assess ovaries + other pelvic organs - MRI head if ?pituitary pathology + assess olfactory bulbs (Kallmann)
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DELAYED PUBERTY What are the hormonal tests you would do in delayed puberty?
- Early morning serum gonadotropins (FSH/LH) - TFTs - GH provocation testing (insulin, glucagon) - IGF-1 levels - Serum prolactin
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DELAYED PUBERTY What is the management of delayed puberty?
- Constitutional = reassure, can Tx if severe distress - F = oestradiol - Young M = PO oxandrolone (weak androgenic steroid will induce some catch-up growth but not 2ary sexual characteristics) - Older M = low dose IM testosterone for growth + sexual characteristics
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PICA what is it?
an eating disorders in which a person eats things that are not usually considered food
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PICA what is the clinical presentation?
craving/eating non-food items: - dirt - clay - rocks - paper - ice - crayons - hair - paint chips - chalk - faeces
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PICA what health problems can be caused?
- iron deficiency anaemia - lead poisoning - constipation or diarrhoea - infections - intestinal obstruction - mouth or teeth injuries
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PICA what are the causes?
- developmental problems e.g. autism - mental health problems e.g. OCD, schizophrenia - malnutrition or hunger - stress
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PICA how is it diagnosed?
eating non-food items and: - doing so for 1 month - behaviour is not normal for child's age - has risk factors for pica
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PICA what are the investigations?
- blood tests - anaemia, lead levels - stool tests - parasites - x-rays
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PICA what is the management?
- prevent child from getting to non-food items - psychological support
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CRYPTORCHIDISM What are the 3 types of cryptorchidism?
- Retractile (normal variant in prepubescent boys) - Palpable - Impalpable
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CRYPTORCHIDISM What is retractile cryptorchidism?
- Testis can be manipulated into bottom of scrotum without tension but subsequently retracts into inguinal region (pulled by cremaster muscle) - Usually present later as hard to notice on NIPE, eventually testes should permanently reside in scrotum (follow-up to check)
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CRYPTORCHIDISM What is palpable cryptorchidism?
- Testis palpated in groin but cannot be manipulated into scrotum - Sometimes ectopic so lie outside the normal line of descent + may be found in perineum or femoral triangle
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CRYPTORCHIDISM What is impalpable cryptorchidism?
- No testis felt on detailed examination | - May be in the inguinal canal, intra-abdominal or absent
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CRYPTORCHIDISM What are some investigations for cryptorchidism?
- Genital exam = warm room + hands, relaxed child, try "milk" testes into scrotum - USS in bilateral impalpable testes to verify internal pelvic organs - Hormonal for bilateral impalpable testes to confirm presence of testicular tissue (record rise in serum testosterone in response to IM hCG) - Laparoscopy = Ix of choice for impalpable
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CRYPTORCHIDISM What is the first line management of cryptorchidism?
- If unilateral monitor as most newborns descend - Wait 3m then refer to paeds urologist so they're seen by 6m - If bilateral needs urgent senior review within 24h
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CRYPTORCHIDISM What is the management of cryptorchidism that has not resolved?
- Surgical placement of testis in scrotum (orchidopexy = before or around 1y) - May need testosterone at age 10 to start puberty if absent altogether, ?prosthesis
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CRYPTORCHIDISM What are the reasons for performing orchidopexy around 1y?
- Fertility = optimises spermatogenesis as testis need to be below body temp - Malignancy = massive risk of seminoma in undescended testes - Cosmesis, psychological + avoid torsion
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KALLMAN SYNDROME what is it?
genetic disorder that can be inherited via autosomal dominant, autosomal recessive and x-linked
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KALLMAN SYNDROME what are the clinical features?
- hypogonadotropic hypogonadism - anosmia - synkinesia (mirror-image movements) - renal agenesis - visual problems - craniofacial anomalies
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KALLMAN SYNDROME why do you get anosmia in this condition?
due to a defect in the co-migration of GnRH releasing neurons and olfactory neurons that occurs during early foetal development
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ANDROGEN INSENSITIVITY SYNDROME what is it?
a genetic condition in which there are defects in the androgen receptor - is x-linked recessive - patients are genetically male (46XY)but develop female phenotype
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ANDROGEN INSENSITIVITY SYNDROME what are the different types?
- complete AIS - partial AIS - true hermaphroditism
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ANDROGEN INSENSITIVITY SYNDROME what is complete AIS?
- karyotype = 46XY - results in a completely female phenotype - external genitalia are female (clitoris, hypoplastic labia majora + blind-ending vagina) - testes may be present in abdomen - absence of pubic + axillary hair - normal breast development
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ANDROGEN INSENSITIVITY SYNDROME what is partial AIS?
- presents with a wide range of phenotypes - can present as normal male with fertility issues - sex assignment depends on the degree of genital ambiguity
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ANDROGEN INSENSITIVITY SYNDROME what is true hermaphroditism?
- have both ovarian tissue with follicles and testicular tissue with seminiferous tubules, either in the same organ or one on either side - external genitalia are often ambiguous
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ANDROGEN INSENSITIVITY SYNDROME what is the inheritance pattern?
x-linked recessive
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ANDROGEN INSENSITIVITY SYNDROME what are the results of hormone tests?
- raised LH - normal/raised FSH - normal/raised testosterone - raised oestrogen
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ANDROGEN INSENSITIVITY SYNDROME how does it typically present?
- present in infancy with an inguinal hernia - present at puberty with primary amenorrhoea
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ANDROGEN INSENSITIVITY SYNDROME what is the management?
- bilateral orchidectomy to avoid testicular tumours - oestrogen therapy - vaginal dilators or vaginal surgery - generally patients are raised as female - offered support and counselling
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DOWN'S SYNDROME What are some risk factors?
- Increasing maternal age #1 (1 in 100 by 40y, increased nondisjunction), - FHx - mother has Down's (rare)
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FRAGILE X SYNDROME What causes it?
Trinucleotide expansion repeat of CGG caused by slipped mispairing = ≤44 normal, 60–200 = premutation carriers, >200 = fragile X
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FRAGILE X SYNDROME What sex is affected by fragile X syndrome?
Always males but females vary
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PRECOCIOUS PUBERTY What is the pathophysiology of pseudo precocious puberty?
Low LH + FSH as gonadal or extra-gonadal source leads to increased testosterone or oestrogen
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PRECOCIOUS PUBERTY What are the causes in females?
More common in girls, usually idiopathic or familial, occasionally late presenting CAH
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PRECOCIOUS PUBERTY What are the causes in males?
Less common, more worrying – Pituitary adenoma (bilateral testicular enlargement suggests gonadotropin release) – CAH or adrenal tumour (small testes) – Gonadal tumour (unilateral testicular enlargement)
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PRECOCIOUS PUBERTY What is a genetic cause of precocious puberty?
McCune Albright syndrome (café-au-lait, short stature)
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CAH What is a major risk factor?
Consanguineous parents
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HYPOGONADISM Name the 3 types of hypogonadism?
Primary = hypergonadotropic hypogonadism Secondary = hypogonadotropic hypogonadism Tertiary = hypogonadotropic hypogonadism
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GONADOTROPIN DEFICIENCY What is Hypergonadotropic hypogonadism?
Primary gonadal failure - Testes or ovarian failure
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GONADOTROPIN DEFICIENCY Briefly describe the mechanism of Hypergonadotropic hypogonadism
Gonads not working properly so less oestrogen/testosterone Increase in GnRH as less negative feedback Increase in LH and FSH Hypogonadism occurs
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GONADOTROPIN DEFICIENCY Give 2 causes of primary hypogonadism
Hypergonadotropic hypogonadism Klinefelter’s Syndrome (47XXY) Tuner’s Syndrome (45X)
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GONADOTROPIN DEFICIENCY What is the effect of Hypergonadotropic hypogonadism on FSH/LH and oestrogen/testosterone levels?
FSH/LH = high Oestrogen/testosterone = low
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GONADOTROPIN DEFICIENCY What is Hypogonadotropic hypogonadism?
Secondary gonadal failure = problem with pituitary OR Tertiary gonadal failure = Problem with hypothalamus
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GONADOTROPIN DEFICIENCY Briefly describe the mechanism of secondary hypogonadism
Less FSH and LH So less activation at gonads Girls = no response to feedback so oestrogen decreases Boys = no response to feedback so testosterone decreases
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GONADOTROPIN DEFICIENCY Briefly describe the mechanism of tertiary hypogonadism
Less GnRH produced So less FSH and LH So less activation at gonads Girls = no response to feedback so oestrogen decreases Boys = no response to feedback so testosterone decreases
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GONADOTROPIN DEFICIENCY Give 2 causes of Hypogonadotropic hypogonadism
1. Kallmann’s Syndrome 2. Tumours - craniopharyngiomas, germinomas
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GONADOTROPIN DEFICIENCY What is the effect of hypogonadotropic hypogonadism on FSH/LH and oestrogen/testosterone levels?
FSH/LH = low Oestrogen/testosterone = low
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GONADOTROPIN DEFICIENCY What is the treatment for hypogonadism?
Hormone replacement therapy Males = testosterone gel/injections Females = Ethinyl oestradiol or oestrogen (tablet or transdermal), progesterone added once full oestrogen dose reached
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HYPOTHALAMIC TUMOUR what is it?
A hypothalamic tumour is an abnormal growth in the hypothalamus gland, which is located in the brain.
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HYPOTHALAMIC TUMOUR what are the causes?
The exact cause of hypothalamic tumours is not known. It is likely that they result from a combination of genetic and environmental factors.
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HYPOTHALAMIC TUMOURS what are the risk factors for developing hypothalamic tumours?
neurofibromatosis undergone radiation therapy
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HYPOTHALAMIC TUMOURS what is the most common type of tumour to cause a hypothalamic tumour in children?
glioma
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HYPOTHALAMIC TUMOUR what is the clinical presentation?
- euphoric 'high' sensations - failure to thrive - headache - hyperactivity - loss of body fat and appetite - vision loss - precocious puberty
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HYPOTHALAMIC TUMOUR what are the investigations?
- full neurological examination - blood tests for CRH, GH, GnRH, TRH, dopamine and somatostatin - CT/MRI scan - visual field testing
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HYPOTHALAMIC TUMOURS what is the management?
- surgery - radiation - chemotherapy - steroids to treat brain swelling - hormone replacement/imbalance corrected
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PRECOCIOUS PUBERTY What are the causes of pseudo precocious puberty?
Causes: – Adrenal (tumours, CAH) – Granulosa cell tumour (ovary) – Leydig cell tumour (testicular)
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PRECOCIOUS PUBERTY What is the management for premature pubarche (adrenarche)?
USS of ovaries + uterus with bone age to exclude central precocious puberty
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CAH How does salt-losing crisis present?
– Vomiting, weight loss, floppiness + circulatory collapse – Hyponatraemic, hyperkalaemic, metabolic acidosis, hypoglycaemic
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CAH What is the management of salt-losing crisis?
IV 0.9% NaCl + dextrose, IV hydrocortisone
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OBESITY when does NICE recommend intervention?
tailored intervention if >91st centile assess for comorbidities if >98th centile
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OBESITY what is the most common cause?
lifestyle factors
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OBESITY what factors are associated with a higher rate of obesity?
- asian children - female - tall
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OBESITY what are the causes of obesity in children other than lifestyle factors?
- growth hormone deficiency - hypothyroidism - Down's syndrome - Cushing's syndrome - Prader-Willi syndrome
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OBESITY what are the consequences of obesity in children?
- orthopaedic problems: slipped upper femoral epiphyses, Blount's disease (a development abnormality of the tibia resulting in bowing of the legs), musculoskeletal pains - psychological consequences: poor self-esteem, bullying sleep apnoea benign intracranial hypertension - long-term consequences: increased incidence of type 2 diabetes mellitus, hypertension and ischaemic heart disease

MY REVISION - ALL PHASES (36 decks)

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