Overgrowth Flashcards
Patterns of overgrowth can fall into what 4 major categories?
- tall stature
- obesity
- macrosomia (all growth parameters elev)
- regional overgrowth
Genetic obesity is most likely found as early onset obesity, at what age and why?
< 5y
> 95% BMI
- this is an age where you are growing a ton and still have restrictions on food access
With low tone, you also have low _____ ?
metabolic rate
When we have adequate amounts of fat stores, then we produce ___? which travels where? to do what?
leptin –> travels to the hypothalamus and stimulates leptin receptor ___> stimualtes POMC neurons to produce hormones to travel through body
ends w dec food intake + inc resting met rate
What is the inheritance pattern for MC4R deficiency?
semi-dominant disorder –> partial phenotype w 1 copy + severe pheno w both
AR form is rare
What are clinical features of MC4R deficiency?
(semi-dom + rare AR)
Dom: hyperphagia, extreme obesity, early onset
AR: hyperphagia, binge
2-5% total early onset obesity = due to?
MC4R deficiency
What is the inheritance pattern for Leptin Def?
AD
AR
What are clinical features of Leptin Def?
AD: hyperphagia + early onset obesity
AR: freq infections, hypogonadotropic hypogonadism, hypothyroidism
What are treatment options for Leptin Def?
leptin replacement
What is more common: Leptin Def OR Leptin receptor def?
Leptin Receptor Def, which is sad bc this one does not have treatment option and accoutns for 3% cases of severe obesity
What does POMC deficiency stand for?
pro-opio-melano-cortin
melano –> melanin that provides dark pigmentation; classic pt = pale ging
cortin –> cortisol bc POMC stsim the ATCH-cortisol pathway
POMC deficiency involves ____ insufficiency and why?
adrenal bc the POMC is supposed to stim the ACTH-cortisol pathway and cannot bc deficiency
What is PSCK1 deficiency?
(AR)
So PSCK1 –> processes propeptide hormones into mature form
so when def, leads to malabsorptive diarrhea, low blood sugar after eating, obesity
(so can think abotu if not abs fatsin the intest, then it is like osmotic pull for water –> diarrhea)
What are the disorders that are assoc w macrosomia?
NOn-Gen:
- infant of diab mom
Gen:
- BWS
- Sotos
- NFIX related disorders
- Weaver
- PTEN-hamartoma syndrome
- Simpson Golabi Behmel
- Gorlin
- Perlman
Why does infant of diabeteic mother have BW > 4kg usually?
they have long exposure to sugar during preg, so then fetus resp by inc insulin levels
they end up storing the extra sugar
What are som symp of infant of diab mom in MILD cases?
- low BS (bc high levels circ insulin)
- prolonged jaundice, high blood counts
- septal hypertrophy of heart
good prognosis, can usu come off IV pretty quick
What are som symp of infant of diab mom in SEVERE cases?
- holoprosencephaly
- caudal regression syndrome –> sacrum + legs def in devel
- proximal femoral deficiency –> hips + femur not dev well
What are the classic findings in BWS?
- fetal overgrowth
- omphalocele
- internal organ overgroth
- hemihyperplasia
- macroglossia
- proptosis
- risk of Wilms tumor + hepatoblastoma
- prolonged hypoglycemia (pancreatic necidioblastosis - so they are not releasing insulin the way they should)
What are outcomes like for BWS?
- usu pretty good as long as there is not severe hypoglycemia)
How often do you screen for cancer risks in BWS?
so Wilms tumor + hepatoblastoma
(think about hwo overgrowth syn have high turnover rate of cells –> inc cancer risk)
every 3 months
hard bc hepatoblastoma NOT have clear treament
What are screening guidelines outside of cancer screens for BWS?
- AFP every 3 months for 1st 4y
- renal US every 3 mo until 8y (then annual until mid-adoles)
What is Sotos syndrome caused by?
90% caused by LOF from NSD1 (gene regulator)
(usu see changes at seq level)
What are classic findings in Sotos syndrome?
(NSD1)
- inc birthweight (and ht cont even if wt does not)
- adv bone age (bones mature faster than they should)
- large, narrow head
- bossing of forehead
- receding hairline
- elongated chin
What are some CNS complications assoc w Sotos?
(NSD1)
- neonatal hypotonia
- 50% w seizures
- 97% w ID (30% mild, 40% mod, 20% severe)
- MRI can detect dilated ventricles, sometimes absent corpus callosum
- dev delay (walk 15mo, talk 2.5y)
What are some birth anomalies assoc w Sotos Syndrome?
(NSD1)
Patent ductus arteriosus (PDA) (=opening between 2 BV leading from heart) and/or ASD
renal anom
scoliosis
What feeding concerns are assoc w Sotos?
(NSD1)
- goes along w the hypotonia
- feeding diffic –> sometimes FTT (even though child is v big)
- when ^ corrected, then rapid progress on growth chart
^ can trick physicians bc they can be conf about growth charts
What cancer risks are assoc w Sotos?
(NSD1)
3% risk for tumors:
- neuroblastoma (any neuroend tumor in adrenal or paraspinal nerves)
- sacrococcygeal teratoma
- presacral ganglioneuroma
- acute lymphocytic leukemia
- small cel lung cancer
What screening guidelines for the cancer risks are rec for Sotos?
tumor screening is actually not effective bc not good management options
What are 2 Sotos-like syndromes?
- Marshall-Smith (NFIX)
- Malan (NFIX)
How did they historically categorize Marshall-Smith?
though it was conn tissue disorder, maybe collagen causing
thought this bc blue sclera + elongated body
now we know it is NFIX
What are some classic findings in Marshall-Smith w regard tot he overgrowth?
- large body size
- accelerated bone age
- macrocephaly + high forehead
(NFIX)
What are some classic findings in Marshall-Smith when thinking of Resp?
- was consid lethal before bc of resp insuff
- resp problems/laryngomalacia
(NFIX)
What are some classic findings in Marshall-Smith w regard to dysmorphic features?
- large body
- connective tissue like, hypermobility + blue sclera
- macrocephaly + high forehead
- proptosis/prom eyes
- short nose
- long, narrow face
- micrognathia
(NFIX)
Is there risk of ID w Marshall-Smith?
(NFIX)
yes, they can have corpus callosum abnorm
What is the cause of Weaver syndrome?
EZH2 (methyl transferase)
AD
How is Weaver sim to Sotos?
(EZH2)
Both inv overgrowth + adv bone age
How does Weaver differ from Sotos in CNS?
- milder ID than Sotos
(20% normal v 2% in Sotos)
What are some classic dysmorphic features in Weaver?
(EZH2)
- Overgrowth
- camptodactyly
- fleshy ears
- micrgnathia, “stuck-on” chin
What is the tumor freq in Weaver? What tumors?
~4%
- neuroblastoma
- acute lymphoblastic leukemia
- ovarian sinus tumor
- sacrococcygeal teratoma
- lymphoma
What tumor screening is rec for Weaver syn?
(EZH2)
None, similar to Sotos
What are the main findings in PTEN hamartoma syndrome?
- macrosomia (but w norm of ht)
- macrocephaly
- skin papules + lipomata
- autism
can be V variable w/in fams
What are the 3 major criteria with a star for PTEN ham syn?
- GI hamartomas (inc ganglioneuromas but NOT hyperpalstic polyps; >/= 3)
- Lhermitte-Duclos disease (adult) –> dysplastic gangliocytoma of cerebellum (sudden inab to walk normal gait)
- macrocephaly (>/= 97th% - 58cm fe and 60cm ma)
What cancers are assoc w PTEN ham syn?
- breast cancer
- endometrial cancer (epithelial)
- thyroid cancer (follicular)
also (less common)
- colon
- RCC
- thyroid (pap OR fol variant of pap)
*review screeninG for PTEN
*OK
What is the cause of Simpson Golabi Behmel?
x-linked loss of function in GPC3
What symp of overgrowth do we see in Simpson Golabi Behmel during preg?
(GPC3)
Pre and posnatal overgrowth, and we can see w polyhydramnios in preg
What are classic facial features assoc w Simpson Golabi Behmel?
(GPC3)
- macrocephaly
- coarse feat
- hypertelorism
- epicanthal folds
- midline groove in lower lip
What are classic NON-facial dysmorph features assoc w Simpson Golabi Behmel?
(GPC3)
- postaxial polydactyly, syndactyly, broad hands, nail, hypoplasia
- organomegaly, supernumerary nipples
What are other classic clincal findings (so other than physical) assoc w Simpson Golabi Behmel?
(GPC3)
- CHD, cardiac conduction defects
- cryptorchidism, hernia
- diaphragmatic hernia (~30%)
- cleft lip or palate (~25%)
- ID mild to severe
What are 4 things to do to manage symp (non-cancerous) for Simpson Golabi Behmel?
(GPC3)
1. EKG
2. Renal US
3. Neuro eval if seizures
4. dev therapies
What cancer risks are assoc w Simpson Golabi Behmel?
(GPC3)
- Wilms
- Hepatoblastoma
(same as BWS)
What is the cause of Gorlin syndrome?
PTCH1 or SUFU
What overgrowth symp dow e see in Gorlin?
- macrocephaly
- tall stature
- tons of BCC
What type of therapy should we avoid for Gorlin syn?
X-ray therapy
(hard bc need x-rays for ribverteb anom, falx calcification, jaw kerat)
What is the cause of Perlman syndrome?
DIS3L2
exoribonuclease
What are classic findings in Perlman syndrome? (non-cancer)
- polyhydramnios
- neonatal macrosomia
- visceromegaly
- crytochordism
- ID
high neonatal mortality
(DIS3L2)
What are classic cancerous findings in Perlman syndrome?
DIS3L2
nephroblastomatosis
64% Wilms
also cystic renal dysplasia
What main organs suffer from overgrowth in Proteus Syndrome?
spleen, liver, thymus, GI tract
(think of disfigured overgrowth)
(som mos AKT1)
What is cause of Proteus syndrome?
somatic mosaic variant in AKT1
What are some char physical findings in Proteus syndrome?
(som mos AKT1)
- disfiguring
- limbs, skull, spin are asym
- cerebriform overgrowth of palms/soles (“moccasin soles”)
What are 3 major criteria that must be present for a dx of Proteus syndrome?
(som mos AKT1)
- mosaic distribtion of lesions
- sporadic occurence
- progressive course
(usu
What can Proteus syndrome look like for a newborn?
(som mos AKT1)
can present normally as newborn
once we see symp though, goes fast downhill –> could lead to amputations, for ex
CLOVES is what type of overgrowth syndrome category?
PIK3CA-Related Overgrowth Spectrum
caused by mosaic mut
What does CLOVES stand for?
Congenital Lipomatous (fatty) Overgrowth, Vascular malformations, epidermal nevi and Scoliosis/Skeletal/Spinal anomalies
(PIK3CA-related overgrowth spec; mosaic)
What is the inheritance pattern of CLOVES?
it is somatic mosaicism, so none
PIK3CA
