Syndromes

Question 1

Turner syndrome - what is the cause of the short stature

Answer 1

SHOX haploinsufficiency

Question 2

Features of Turner syndrome

Answer 2

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

Question 3

what is the usual final height of someone w Turners syndrome

Answer 3

8-10 cm below MPH

Question 4

What is the ovarian function in turner

Answer 4

varying degrees

labs: primary hypogonadism

Malignant transformation in gonads of persons with Y chromosome material

Question 5

Those w Turner sydrome have higher risk fo?

Answer 5

Higher risk for autoimmune thyroiditis, celiac disease, T1DM

Question 6

Turner syndrome: treatment w GH
- when to start
- what is the expected benefit

Answer 6

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

Question 7

Turner syndrome: treatment w estrogen
- when to start
- what to use
- how to progress

Answer 7

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

Question 8

what other specialities should follow turner syndrome

Answer 8

cardiology, audiology, developmental pediatrician

Question 9

what is the incidence of Turner syndrome

Answer 9

1 in 2000

Question 10

Klinefelter syndrome - what is height due to

Answer 10

Tall stature due to higher SHOX gene dosage

Question 11

features of klinefelter

Answer 11

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

Question 12

Klinefelter: what are they at higher risk of

Answer 12

breast cancer,
T2DM,
metabolic syndrome
germ cell (HCG secreting) tumors
osteoporosis

Question 13

Klinefelter - when to start Testo
what to target

Answer 13

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

Question 14

McCune Albright Syndrome
- main features

Answer 14

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

Question 15

McCune Albright Syndrome - gene and what it does

Answer 15

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

Question 16

McCune Albright Syndrome
- how to treat precocious puberty

Answer 16

Ketoconazole – Increases sex steroid metabolism via liver induction of P450 enzymes

Tamoxifen - Estrogen receptor modulator

boys: androgen receptor blocker and aromatase inhibitor

Question 17

McCune Albright Syndrome
- how to treat the fibrous dysplasia

Answer 17

supportive
?denausomab

Question 18

Bardet-Biedl Syndrome- features

Answer 18

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

Question 19

Smith-Lemli-Opitz Syndrome
- what is It

Answer 19

an autosomal recessive defect in cholesterol biosynthesis resulting from abnormalities in the sterol Δ-7-reductase gene, DHCR7

Question 20

Smith-Lemli-Opitz Syndrome
features

Answer 20

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)

Question 21

what are the genital anomalies in SLO

Answer 21

Genital anomalies include hypospadias, cryptorchidism, and even ambiguous genitalia in males.

Question 22

what to do if a pt with Turners wants to get pregnant

Answer 22

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

Question 23

Kallman syndrome gene

Answer 23

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)

Question 24

comorbidities in turner syndrome

Answer 24

1. hypertension
2. hypothyroidism
3. T1DM/T2DM
4. Dyslipidemia
5. Celiac disease
6. Vit D def
7. renal anomalies
8. nevi
9. low BMD
10. Coarctation and aortic root dilation
11. SNHL and CHL
12. scoliosis
13. Psych – poor visuospatial and arithmetic

Question 25

what labs do you need to do to screen for comorbidities in turner syndrome

Answer 25

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

Question 26

what screening do you do for Turner’s syndrome on physical exam and on imaging

Answer 26

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

Question 27

what is the screening for hearing loss in Turner syndrome

Answer 27

SNHL and CHL: audiology
Every 3-5 years from Diagnosis

Question 28

RISK FACTORS FOR AORTIC DISSECTION in Turner syndrome

Answer 28

-Bicuspid aortic valve
-Elongation of the transverse aorta
-Coarctation of the aorta
-Hypertension

Question 29

What does the SHOX gene do
what happens If it’s missing

Answer 29

● 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

Question 30

Syndromes assoc w SHOX

Answer 30

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

Question 31

features in SHOX mutations

Answer 31

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

Question 32

Criteria for Russell Silver syndrome

Answer 32

· 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

Question 33

what is the major long term complication of Turners Syndrome

Answer 33

aortic dissection

Question 34

orthopedic manifestations of Turner syndrome

Answer 34

● Short stature
● cubitus valgus
● short 4th metacarpal/tarsal
● Madelung deformity
● Scoliosis
● Decreased BMD
● Genu valgum
● Congenital hip subluxation

Question 34

orthopedic manifestations of Turner syndrome

Answer 34

● Short stature
● cubitus valgus
● short 4th metacarpal/tarsal
● Madelung deformity
● Scoliosis
● Decreased BMD
● Genu valgum
● Congenital hip subluxation

Question 35

what does SHOX stand for

Answer 35

short stature homeobox containing gene of chromosome X

Question 36

what gene is affected in Prader Willi Syndrome

Answer 36

Defect in paternal allele of chromosome 15q11-13 (deletion, mutation, defective imprinting or uniparental disomy of paternal chromosome 15)

Question 37

features of Prader Willi Syndrome

Answer 37

-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

Question 38

Endocrine features of Prader Willi Syndrome

Answer 38

i) Growth hormone deficiency
ii) Obesity
iii) Hypogonadism
iv) Osteoporosis
v) Premature adrenarche
vi) Hypothyroidism
vii) Central adrenal insufficiency

Question 39

Noonan syndrome

Answer 39

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

Question 40

what is the recommended management of puberty in Russell silver syndrome?

Answer 40

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.

Question 41

DICER1 Syndrome

Answer 41

-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

Question 42

Prader Willi Syndrome - what to expect with weight /feeding

Answer 42

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

Question 43

risk of gonadoblastoma in Turner Syndrome

Answer 43

●~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

Question 44

How to assess fertility in males with Klinefelter

Answer 44

**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.

Question 45

what kind of learning issue do Turner Syndrome have

Answer 45

visuospatial skills

Question 46

how does estrogen affect growth in Turner syndrome

Answer 46

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)