Syndromes + Tumour Syndromes Flashcards
Carney Complex
- gene
- features
- protein kinase A type I-alpha regulatory subunit gene (PRKAR1A)
- AD inheritance
1) Lentiginous (Distinctive pigmented lesions of the skin and mucosal surfaces)
2) Cardiac and non-cardiac myxomatous tumors
- Cutaneous myxomas (benign dermal tumors): eyelids, external ear canal, areolae
- Cardiac myxoma
- Benign breast tumors: Myxomas, myoxoid fibroadenomas, ductal adenomas with tubular
3) Multiple endocrine tumors
- Primary pigmented nodular adrenocortical disease (ACTH-independent CS)
- Asymptomatic GH hypersecretion
- Large cell calcifying Sertoli cell tumor
- Thyroid nodules: Usually euthyroid; thyroid ca (papillary and follicular) <10%
- Ovarian cysts, serous cystadenoma, teratomas, endometrioid carcinoma
syndromes associated with adrenal corticocarcinoma
- Hemihypertrophy syndromes like Beckwith-Wiedemann Syndrome
- Germline mutations or loss of heterozygosity of p53 tumour suppressor gene ie Li-Fraumeni Syndrome
- MEN1
- FAP (Familial adenomatous polyposis)
- Carney Complex
MAS features
- CAL
- Pre Puberty
- Polyostotic fibrous dysplasia
- Functioning thyroid adenoma (accept hyperthyroidism)
- Cushing Syndrome (in neonates)
- Pituitary adenoma
- Sudden death from cardiac arrhythmia
- Hypophosphatemic rickets/osteomalacia (accept hypophosphatemia)
- Hepatobiliary disease
- Intestinal polyps
- Scoliosis
- Growth hormone excess
Turner syndrome
- how to dx
- most common karyotype
Phenotypic females with a karyotype containing one x chromosome and complete or partial absence of the second sex chromosome associated with >/= 1 typical clinical manifestation of Turner Syndrome
45XO = 40-50%
45X/46XX (mosaicism) = 15-25%
Turner syndrome - increased AI d/o
T1DM
Autoimmune thyroid disease
Celiac disease
Inflammatory bowel disease
Turner syndrome - increased met conditions
Obesity
T2DM
Dyslipidemia
gene for PPGL syndromes
- SDH
ROHHAD = stands for
Rapid onset obesity with hypoventilation, hypothalamic dysfunction, autonomic dysfunction
ROHHAD hypothalamic problems
GH deficiency
Central precocious puberty
Hypogonadotropic hypogonadism
DI
Hypothyroidism
Hyperprolactinemia
ACTH deficiency
Hypoventilation
when does ROHHAD start to gain weight
2-4 yrs of age there is hyperphagia and rapid weight gain
ROHHAD Autonomic dysfunction
Blurred vision
Altered pupillary response to light
Strabismus
Ptosis
GI dysmotility with chronic constipation or diarrhea
Bradycardia
Excessive sweating
Thermal dysregulation
Urinary incontinence
Syncope
how to dx ROHHAD
no genetic testing
rapid-onset obesity starting in early childhood & alveolar hypoventilation during sleep
signs and symptoms of hypothalamic dysfunction and autonomic disturbances
exclusion of other condition causing similar features, such as congenital central hypoventilation syndrome
features of klinefelter
o Growth
○ Tall stature
· extra SHOX
○ Decreased upper segment-lower segment ratios
o Puberty
○ Cryptorchidism
○ Micropenis
○ Small, firm testes
○ Hypergonadotropic hypogonadism
○ Infertility
○ Gynecomastia
o Congenital malformations
○ Inguinal hernia
○ Cleft palate
o Behaviour/Learning
○ Learning difficulties
○ Speech Delay
○ Behaviour difficulties/impulse control
○ Psychiatric disturbances
○ Increased rate of criminal behaviours
o Increased risk
○ Breast cancer
○ T2DM
○ Metabolic syndrome
○ Abdominal adiposity
○ Osteopenia, fracture
○ Extragonadal Germ cell (HCG secreting) tumors -> can cause precocious puberty
○ Epilepsy
○ Cerebrovascular disease
○ Intestinal vascular insufficiency
○ Non-Hodgkin lymphoma
○ Lung ca
puberty / fertility in Klinfelter
start puberty on time
initially FSH, LH, and testosterone normal
mid puberty Testes become firm and are rarely larger than 3.5 cm in diameter
seminiferous tubules undergo hyalinization and fibrosis,
adenomatous changes of the Leydig cells
impaired spermatogenesis
Kline felter labs in adult
Decreased: Testosterone, inhibin B, AMH
Increased: LH, FSH, estradiol, SHBG
47XYY -
features
puberty and fertility
macroorchidism
macrocephaly
learning disabilities such as speech delay and dyslexia
ASD
ADHD
not usually aggressive behaviour
genitals normal usually
but can have micropenis, cryptorchidism, and hypospadias
puberty usually normal
but inhibit doesn’t rise
increased of infertility
Congenital anomalies Klinefelter vs Turner
KS:
Cleft palate
Inguinal hernia
TS:
High arch palate
Renal anomalies
Klinefelter puberty
Small firm testes
Hypergonadotropic hypogonadism
Delayed puberty
Gynecomastia
Infertility
Cryptorchidism
Turner syndrome puberty
Streak ovaries
Hypergonadotropic hypogonadism
Delayed puberty
Widely spaced nipples, shield chest (80%)
Infertility
Turner syndrome MSK features
Short stature
Osteopenia, fractures, vitD deficiency
Scoliosis, kyphosis
Short, webbed, neck
Cubitus valgus (80%)
Genu valgum (60-80%)
Hyperextension of great toe (80%)
how to dx Turner syndrome
standard 20-cell karyotype
- repeat post natally if dx prenatally
high risk aortic dissection
Child birth
Bicuspid aortic valve
Coarctation
Hypertension
Elongation of the transverse aorta
how much will GH increase Turner syndrome final height
about 5-8cm
when to stop GH in TS
wbone age ≥14y.o and GV <2cm/yr
when to start E in TS
age 11-12
increase over 2-3y
increased chance of spontaneous puberty in TS?
spontaneous puberty
mosacism
normal FSH
normal AMH
normal astral follicle count
screening for cardiac before pregnancy in TS
*Structural abnormality: Aortic dilatation, bicuspid aortic valve, elongation of the transverse aorta, coarctation of the aorta
§ Imaging of the thoracic aorta and heart with a transthoracic echocardiography (TTE) and CT/cardiac magnetic resonance scan (CMR)
○ *Hypertension
§ Conservative goal of BP under 135/85.
*Exercise induced hypertension
Noonan syndrome gene
PTPN11
KRAS, RAF1
cardiac prob in noonan
generally right sided heart lesions - pulmonary stenosis/dysplastic pulmonary valve
Also mitral valve stenosis
karyotype in noonan
normal
Features of noonan
○ Skin
§ Multiple pigmented nevi (+TS)
§ Cafe-au-lait spots
○ Ortho
§ Scoliosis (+TS)
§ Pectus excavatum (+TS)
§ Short, webbed neck (+TS)
○ Ophtho
§ Strabismus, amblyopia (+TS)
§ Refractive errors (+TS)
§ Nystagmus
○ ENT
§ Otitis media (+TS)
§ Hearing loss (+TS)
§ Feeding problems
§ Articulation defects
○ Neuro
§ Psychological and behavioral challenges (+TS)
§ ASD, impaired social skills
§ Language delays
○ Hematology
§ Bleeding disorders
○ Endo
§ Short stature +/- GH deficiency (+TS)
○ Cardiac (+TS)
§ Mitral valve dysplasia
§ Pulmonary stenosis
§ Biventricular hypertrophy
○ Renal (+TS)
§ Hydronephrosis
§ Rarely horseshoe kidney
§ Variable, milder than in TS
Endocrinopathies in MAS
1) Precocious puberty
2) Fetal/Neonatal Cushing
3) Thyroid nodule/hyperthyroidism
4) HyperPRL
5) GH excess
6) Hyperpara
7) FGF23 excess - renal phosphate wasting
-> rickets
MAS - most common site of fibrous dysplasia
Proximal femurs & base of skull
MAS - common deformity
“Shepherd’s Crook”
first presentation of MAS
CAL
CAL in MAS
“Coast of Maine” (jagged) border
Some association with the midline (i.e. “respect” the midline)
thyroid in MAS
Hyperplasia and hyperfunction
Increased T4 to T3 conversion (T3-dominant biochemical phenotype)
adenoma
thyroid cancer is rare
GH excess in MAS - what do you see
concerning association
always have skull base FD
Increased growth velocity
Coarsening of the facial features
Majority of patients also have hyperprolactinemia
Association with aortic root dilatation
cancers in MAS
bone
breast
testicular
thyroidg
genetics of PWS
Lack of expression of the paternally-inherited genes on chromosome 15q11.2-q13
(maternally imprinted)
typically sporadic mutation
causes:
○ paternal deletion, inherited from an unaffected father (75%)
○ maternal uniparental disomy (both copies from mom - 20%)
○ imprinting defect of this region (5%)
Endo features in PWS
○ GH deficiency
○ Hypogonadism (hypothalamic but also testicular dysfunction - Lange)
○ Obesity (hypothalamic)
○ Diabetes
○ Central AI
○ Central hypothyroidism
○ Poor BMD
○ low E expenditure
GH tx in PWS
- get baseline sleep study, then 3-6m after starting and then annually
- IGF1 after 3-6m then q6-12m
- A1C annually
what kind of hypogonadism in PWS?
both hypogonadotropic hypogonadism and primary gonadal failurep
puberty in PWS males?
- usually starts normally
- arrest of pubertal progression typically occurs at Tanner stage 3, coinciding with testicular failure.
- generally thought to be infertile
- Inhibin B, a marker of spermatogenesis and Sertoli cell function, is low or undetectable in most adolescents and adults, which is when testicular failure is most evident
- testosterone replacement in delayed or incomplete puberty, usually by age 15–16 years
puberty in PWS females
hypogonadotropic hypogonadism and primary gonadal failure
- born with hypoplasia of external genital with labia minora and clitoral hypoplasia
- Onset of puberty with breast development typically occurs a a normal age, but progression of breast tissue to Tanner 3 and 4 is usually significantly delayed (very few reach tanner 5)
- Most do not progress to menarche, or if they do, will have oligomenorrhea
Labs
○ Estrogen low normal
○ LH low normal
○ FSH variable = indicative of mixed central and primary effects
○ Inhibin B, a measure of gonadal function, is reported to be low in most adult females with PWS
§ Subset of PWS females may have preservation of fertility
how to deal wi th hypoBG in RSS
not glucagon - poor stores of glycogen
ketone meter at home to detect when to come in
ER for IV dextrose
GH can help
GH in RSS
don’t do GH stim!
start GH around age 2-4y for:
○ improve body composition (especially lean body mass),
○ Improve psychomotor development
○ Improve appetite
○ reduce the risk of hypoglycaemia
○ optimise linear growth
measure IGF1 and IGFBP3 at least yearly
BWS syndrome
feature
- Hyperinsulinism
- Hemihypertrophy
- Abdo wall defects
- Macroglossia
- Macrosomia
- Abnormal ear creases - transverse
- Tall stature
- Kidney abnormalities
Homocysteinuria
features
○ Marfanoid habitus characterized by arachnodactyly, pectus excavatum, and scoliosis
○ Eye disease
§ nearsightedness and inferior lens dislocation
○ Intellectual delay
○ Osteoporosis
○ Increased risks of thromboses
○ No cardiac problems (like in marfan)
○ FHx thromboembolic events
○ FHx calcium oxalate stones is more consistent
how to dx homocysteinuria
serum homocysteine and methionine levels, which would be elevated in an amino acid profile
endo abnormality in Williams and why
hyperCa
increased absorption
Peutz-Jeghers syndrome
features
GI tract polyps
freckling on the lips, eyes, nostrils, fingers, and in and around the mouth
girls: increased risk of developing benign ovarian tumors that can cause peripheral precocious puberty
genetics DMD
Dystrophin gene
features MEN1
1) Hyperparathyroid/Parathyroid Hyperplasia/Adenoma
2) Enteropancreatic tumours
*PRLoma > GHsecreting
3) Pituitary Adenoma
*Gastrinoma > insulinoma
Other: DERM, 2ADR, NET
Adrenocortical tumour
Pheo ++ rare
Lipoma, Collagenoma, Angiofibroma, Meningioma
NETs: bronchopulmonay, thyme, gastric
Screening in MEN1
at age 5(-8)
- PRL/GHoma - PRL and IGF1 + MRI
- Insulinoma: FBG + Insulin
- Parathyroid: PTH, Ca
<10yo
- Adrenal:
Genetics of MEN1
MEN1 gene
MENIN protein
AD
loss of function of tumour suppressor
no hot spot
Endocrine specific tumours in MEN1
Pituitary adenoma
Enteropancreatic tumour can be:
- Insulinoma
- Gastronome
- GHRH secreting
- Glucagon- or VIP-producing tumors,
- somatostatinomas
PTHoma
ACC
most common and earliest manifestation of MEN1
parathyroid
Gastrinoma assoc w what syndrome
Zollinger Ellison
PIt adenoma in MEN1 - what H
PRL>PRL+GH»ACTH>GH
Adrenal tumour in MEN1
what kind
what do they secrete
<10% have hormonal hypersecretion
· Primary hyperaldo
· ACTH independent Cushings
–Adrenal adenomas
· Cortisol-producing (however, most hypercortisolemia in MEN1 is due to pituitary disease)
–Adrenocortical Tumors (benign & malignant)
- Cortisol, Androgens
Pheo rare
when to start screening for PHEo in MENS
MEN2A: 5yo
MEN2B: 3yo
not in MEN1
when to start screening for parathyroid in MENs
1: 8 yo
2A: 10yo
2B: n/a
how to prep for adrenalectomy for pheo
· Alpha adrenergic blockade first, then beta adrenergic blockade
· Restore normal intravascular volume
Then unilateral adrenalectomy and monitor the other side (rather than bilateral adrenalectomy at the get go)
TTx in MEN2 - important points
by age 6m-1y in 2B
by age 5y in 2A
remove pheo first if present!!
PPLG
- what kind of mutation usually
- who should get genetic testing
An underlying somatic mutation can be detected in 65-80% of all PPGL
Somatic = not heredity
Genetic testing is recommended for all patients with a pheo or PGL
features NF1
- Café-au-lait spots
- Subcutaneous neurofibromas
- Axillary and inguinal freckles
- Neural gliomas (optic nerve)
- Harmartomas of the iris (Lisch nodules)
- Endocrine neoplasias
○ Pheochromocytoma
○ HyperPTH
○ MCT
Somatostatin-producing carcinoid tumors of the duodenal wall
Macrocephaly, ASD and thyroid nodule
-> think PTEN
most common tumours in PTEN
breast
thyroid
Cancer in Lifraumeni
ACC -> ACTH indep Cushing
Breast Ca
Sarcoma
CNS tumour
GI tumour
Leukemia
Melanoma
