Syndromes Flashcards
Turner syndrome - what is the cause of the short stature
SHOX haploinsufficiency
Features of Turner syndrome
Cubitus valgus,
shortened 4th metacarpals,
webbed neck,
high arched palate,
scoliosis,
Madelung deformity,
neurosensory hearing loss,
horseshoe kidney,
left sided heart defects (coarctation of aorta and/or bicuspid aortic value),
difficulty in visual-spatial tasks, math;
excel in reading
Short stature
what is the usual final height of someone w Turners syndrome
8-10 cm below MPH
What is the ovarian function in turner
varying degrees
labs: primary hypogonadism
Malignant transformation in gonads of persons with Y chromosome material
Those w Turner sydrome have higher risk fo?
Higher risk for autoimmune thyroiditis, celiac disease, T1DM
Turner syndrome: treatment w GH
- when to start
- what is the expected benefit
Recommendation to start at 4-6 years of age
Gain of 5-8 cm over 5.5-7.5 years of treatment.
0.3-0.35 mg/kg/week
can add oxandrolone 0.03-0.5mg/kg/day from age 10 years if dx is delayed or if adult height outcome is likely to be unsatisfactory
- works by increasing IGF-1
Turner syndrome: treatment w estrogen
- when to start
- what to use
- how to progress
Ideally start between 11-12 yo.
Systemic estradiol (transdermal»oral). Start low, go slow (reaching adult dose 2-3 years later).
No Equine Estrogens! (Premarin)
Add progesterone once vaginal bleeding commences or after 2 years
what other specialities should follow turner syndrome
cardiology, audiology, developmental pediatrician
what is the incidence of Turner syndrome
1 in 2000
Klinefelter syndrome - what is height due to
Tall stature due to higher SHOX gene dosage
features of klinefelter
Cryptorchidism,
micropenis,
learning disability,
behavior difficulties/impulse control,
speech delay,
varying degrees of testicular function gynoid body habitus,
gynecomastia,
pubertal development may be stalled
Small, firm testes
Hormone pattern is primary hypogonadism
Klinefelter: what are they at higher risk of
breast cancer,
T2DM,
metabolic syndrome
germ cell (HCG secreting) tumors
osteoporosis
Klinefelter - when to start Testo
what to target
Controversial on how early to start
when LH/FSH high? vs ?when testosterone levels low for age/puberty stage
*Intratesticular testosterone necessary for spermatogenesis -> postpone T treatment until after sperm collection
Once treatment decided, agreed to target testosterone levels in mid-normal range for age.
Normalization of LH may or may not be achieved
McCune Albright Syndrome
- main features
1) Gonadotropin Independent (peripheral ) precocious puberty
2) Café-Au-Lait: large, “Coast of Maine”
3) Fibrous Dysplasia of Bone
4) Endocrine dysfunction in other Hormone Receptors that use G protein Gsα signaling cascade
- TSH receptor – hyperthyroidism
- ACTH receptor – Cushing syndrome
- GHRH receptor – GH excess
- PTH receptor – hyperparathyroidism
PRL excess
McCune Albright Syndrome - gene and what it does
GNAS gene is imprinted – mutation variably present in tissues; may not be present in blood sample
activating mutation of the alpha subunit of the G protein receptor
constitutive activation of adenylyl cyclase and up regulation of cAMP in absence of ligand interaction with the receptor
McCune Albright Syndrome
- how to treat precocious puberty
Ketoconazole – Increases sex steroid metabolism via liver induction of P450 enzymes
Tamoxifen - Estrogen receptor modulator
boys: androgen receptor blocker and aromatase inhibitor
McCune Albright Syndrome
- how to treat the fibrous dysplasia
supportive
?denausomab
Bardet-Biedl Syndrome- features
obesity,
short stature,
mental retardation,
kidney dysfunction,
polydactyly,
retinitis pigmentosa
**progressive vision loss due to retinal deterioration, multicystic kidney dysplasia, polydactyly, gait and coordination impairment, intellectual disability
Hypogonadotropic hypogonadism and primary hypogonadism have been reported
Smith-Lemli-Opitz Syndrome
- what is It
an autosomal recessive defect in cholesterol biosynthesis resulting from abnormalities in the sterol Δ-7-reductase gene, DHCR7
Smith-Lemli-Opitz Syndrome
features
microcephaly,
developmental delay,
typical facial appearance (short nose with broad nasal bridge and anteverted nares, long philtrum, microretrognathia, blepharoptosis, low- set, posterior-rotated ears, cleft and/or high-arched palate),
proximal thumbs,
syndactyly of the second and third toes
Cardiac, renal, lung, and gastrointestinal abnormalities
Genital anomalies include hypospadias, cryptorchidism, and even ambiguous genitalia in males.
Adrenal insufficiency is present in some cases, especially during times of stress or when LDL-derived cholesterol sources are inadequate (e.g., dietary insufficiency/bile salt depletion)
what are the genital anomalies in SLO
Genital anomalies include hypospadias, cryptorchidism, and even ambiguous genitalia in males.
what to do if a pt with Turners wants to get pregnant
First two are the main ones:
i) Imaging of the thoracic aorta and heart with a transthoracic echocardiography (TTE) and CT/cardiac magnetic resonance scan (CMR) within 2 years before planned pregnancy to look for aortic dilatation. TEE should be done again at 20 weeks gestation to look for aortic dilatation
ii) Blood pressure monitoring for hypertension. Conservative goal of BP under 135/85. Recommended exercise testing prior to pregnancy to reveal exercise induced hypertension.
iii) Thyroid function to look for hypothyroidism
iv) A1C or fasting glucose to screen for diabetes
v) Liver enzymes to look for transaminitis
v) Uterus ultrasound: they are often not fully mature and can lead to fertility complications and inability
vi) LH/FSH and estrogen to look for primary ovarian failure
vii) AMH and Inhibin B to look for ovarian reserve
Kallman syndrome gene
inactivating (prokinectin receptor 2)
● Mutation in a receptor involved in the signalling pathway of anosmin (which guides axonal development of the GnRH and olfactory neurons)
comorbidities in turner syndrome
- hypertension
- hypothyroidism
- T1DM/T2DM
- Dyslipidemia
- Celiac disease
- Vit D def
- renal anomalies
- nevi
- low BMD
- Coarctation and aortic root dilation
- SNHL and CHL
- scoliosis
- Psych – poor visuospatial and arithmetic
what labs do you need to do to screen for comorbidities in turner syndrome
Hypothyroidism: TSH, fT4
Annual from Diagnosis
Dyslipidemia: Lipid panel
Annual from 18 years (measure once between 9-11yrs)
Diabetes (T1D/T2D): HbA1c ± fasting BG
Annual from 10 years
Liver dysfunction: AST, ALT, GGT, ALP
Annual from 10 years
Celiac disease: Anti-TTG, IgA
Every 2 years from 2 years
Vitamin D deficiency: 25OHD
Every 2-3 years from 9-11 yrs
what screening do you do for Turner’s syndrome on physical exam and on imaging
Renal abnormalities: Renal US
Once At diagnosis
Nevi: Physical exam
Annual at Diagnosis
Low BMD: BMD
Every 5 years starting at 18 years
Coarctation and aortic root dilation: Echo
Every 5 years (if no AoD, CoArc, HTN) starting at Diagnosis
Scoliosis Exam:
Every 6months (on GH)
Annual (not GH)
from Diagnosis
what is the screening for hearing loss in Turner syndrome
SNHL and CHL: audiology
Every 3-5 years from Diagnosis
RISK FACTORS FOR AORTIC DISSECTION in Turner syndrome
-Bicuspid aortic valve
-Elongation of the transverse aorta
-Coarctation of the aorta
-Hypertension
What does the SHOX gene do
what happens If it’s missing
● The SHOX gene is expressed in fetal skeleton fibroblasts and in chondrocytes and if not present leads to disorganization of the chondrocytes at the growth plate
Syndromes assoc w SHOX
i) Turner Syndrome (due to loss of the entire X chromosome)
ii) Leri-Weill dyschondrosteosis (haploinsufficiency)
1) Classic triad: Madelung deformity, short stature, mesomelic limb shortening (these are normally only seen after puberty, except for short stature)
iii) Langer mesomelic dysplasia (homozygous deficiency)
1) Severe mesomelic dwarfism and limb deformities
features in SHOX mutations
short stature
short limbs
i) Madelung deformity
ii) Cubitus valgus
iii) Muscular hypertrophy
iv) Ulna dislocation
v) Micrognathia
vi) High arched palate
vii) Genu valgum
viii) Short 4th and 5th metacarpals
ix) Scoliosis
Criteria for Russell Silver syndrome
· SGA (weight or length) - ≤-2SD for gestational age
· Postnatal growth failure – height at 24±1 mo ≤-2 SDS or height ≤-2SD below MPH
· Relative macrocephaly at birth – HC ≥1.5SD above birth weight and/or length SD
· Protruding forehead
· Body asymmetry – LLD or other asymmetry
· Feeding difficulties and/or low BMI – BMI ≤2 SD at 24mo, or using feeding tube or cyproheptadine for appetite stimulation
Other features
● Low muscle mass
● Crowded or irregular teeth
● micrognathia
● Down-turned mouth
● Clinodactyly
● Excessive sweating
● Triangular facies
what is the major long term complication of Turners Syndrome
aortic dissection
orthopedic manifestations of Turner syndrome
● Short stature
● cubitus valgus
● short 4th metacarpal/tarsal
● Madelung deformity
● Scoliosis
● Decreased BMD
● Genu valgum
● Congenital hip subluxation
orthopedic manifestations of Turner syndrome
● Short stature
● cubitus valgus
● short 4th metacarpal/tarsal
● Madelung deformity
● Scoliosis
● Decreased BMD
● Genu valgum
● Congenital hip subluxation
what does SHOX stand for
short stature homeobox containing gene of chromosome X
what gene is affected in Prader Willi Syndrome
Defect in paternal allele of chromosome 15q11-13 (deletion, mutation, defective imprinting or uniparental disomy of paternal chromosome 15)
features of Prader Willi Syndrome
-hypotonia
-failure to thrive (neonatal)
-hypogonadism
-short stature
-intellectual disability
-severe obesity
-hyperphagia
-resting energy expenditure is about 60% normal, promoting adiposity
-elevated ghrelin levels also contribute to hyperphagia
-could also be due to GHD +/- defective lipolysis
Endocrine features of Prader Willi Syndrome
i) Growth hormone deficiency
ii) Obesity
iii) Hypogonadism
iv) Osteoporosis
v) Premature adrenarche
vi) Hypothyroidism
vii) Central adrenal insufficiency
Noonan syndrome
can be 46XX or 46XY
Infancy
■ Pulmonary stenosis or other CHD
■ Cryptorchidism
Childhood
■ Short stature (may have GH deficiency)
■ Delayed speech or motor milestones
■ Easy bruising or bleeding
■ Strabismus
■ Deafness (SNHL, CHL, or mixed)
■ Lymphedema
■ Craniosynostosis
■ Facial features: high forehead, hypertelorism, downslanting palpebral fissures with high arched eyebrows, epicanthic folds, a full upper lip with a depressed nasal bridge, and low-set ears.
● Strikingly blue irides, ptosis, and a degree of neck webbing may be observed
other congenital features that may be associated:
○ Cystic hygroma
○ Pulmonary stenosis
what is the recommended management of puberty in Russell silver syndrome?
recommended that GnRH agonist implant be used at the start of puberty, even if it is normal timing to try and preserve time to adult growth.
They typically have premature adrenarche and advanced bone ages and then go through puberty on average 1 year early and progress very rapidly.
DICER1 Syndrome
-Inactivating pathogenic variants in DICER1 involved in microRNA regulation of multiple pathways
tumours of the thyroid, lung and female reproductive tract, kidney, brain + others.
-Lung tumours = early and from simple cysts to malignant pleuropulmonary blastomas
-Thyroid nodules develop in up to 30% by age 20 y/o and thyroid CA as early as 8 y/o
-Ovarian Sertoli-Leydig cell tumours or embryonal rhabdomyosarcomas of cervix may arise in adolescence or early adulthood
-This patient has relative macrocephaly, lung cyst, functional ovarian tumour and thyroid nodules so fits the most with this
-Recommend: thyroid u/s beginning age 8 and q2-3 years; if treated with chemo for other tumours, u/s yearly x 5 years and then q2-3 years
Prader Willi Syndrome - what to expect with weight /feeding
infant - poor feeding, FTT
~2yo - increase in weight %ile without increase in appetite or calories consumed
~4.5yo - increase in weight % with increase interest in food
~8yo - hyperphagia with food seeking behaviour and lack of satiety
adulthood - better control over appetite
risk of gonadoblastoma in Turner Syndrome
●~10% of girls with TS have Y-chromosomal sequences
● Risk of gonadoblastoma is 10-15%
●If Y material present, then gonadectomy is recommended
so should do Assessment for Y-chromosome-specific markers
How to assess fertility in males with Klinefelter
**LH and testosterone levels – markers of Leydig-cell function –> correlate best with presence of spermatozoa in patients who undergo testicular microdissection
● FSH, testicular volume, AMH – associated with Sertoli-cell function
● In 46XY – FSH, inhibin B and testosterone are predictors of fertility
○ Doesn’t hold true for 47XXY
○ progressive hyalinization of the Sertoli cells seen in Klinefelter syndrome suggests that Leydig-cell function best predicts the possibility of fertility.
what kind of learning issue do Turner Syndrome have
visuospatial skills
how does estrogen affect growth in Turner syndrome
oral conjugated estrogen exposes the liver to high concentrations of estrogen and thereby, decreases IGF-1 production by the liver! (that’s why we prefer transdermal)
