Overgrowth

Question 1

What is hyperphagia

Answer 1

Excessive hunger/overeating

Question 2

What are causes of obesity?

Answer 2

Hyperphagia
Short Stature
Low tone
Food quality

Question 3

MC4R deficiency

Answer 3

“Semidominant”–partial phenotype with one copy, severe phenotype with both
Recessive form: hyperphagia, extreme obesity, early onset
2-5% of total early onset obesity
Dominant: Hyperphagia, binge eating

Question 4

Which disorder has hyperphagia and early onset obesity, frequent infections, hypogonadotropic hypogonadism, and hypothyroidism?

Answer 4

Leptin Deficiency
Dominant form: Hyperphagia and early onset obesity
AR: also has frequent infections, hypogonadotropic hypogonadism, and hypothyroidism
Treatable with leptin replacement

Question 5

Which disorder accounts for 3% of cases with severe obesity?

Answer 5

Leptin Receptor Deficiency

Question 6

In which disorder are patients usually pale and red-headed, present with adrenal insufficiency (low BP, salt wasting) and prolonged jaundice

Answer 6

POMC deficiency (AR)
Pro-opio-melano-cortin
Melano-patient usually pale and red-headed
Cortin-corisol; presents with adrenal insufficiency (low BP, salt wasting) and prolonged jaundice

Question 7

Which disorder has malabsorptive diarrhea, low blood sugar after eating, obesity

Answer 7

PSCK1 Deficiency (AR)
PSCK1 processes propeptide hormones into their mature form

Question 8

What are some causes of macrosomia?

Answer 8

Infant of Diabetic Mother
Beckwith Wiedemann
Sotos syndrome
NFIX related disorders
Weaver syndrome
PTEN-hamartoma syndrome
Simpsom Golabi Behmel
Gorlin
Perlman

Question 9

What is macrosomia?

Answer 9

Increased height, weight, and head size (>97th %tile)

Question 10

What are the results of diabetes in a pregnant person (mild cases)?

Answer 10

Birthweight >4kg

Low blood sugar due to high levels of circulating insulin
Prolonged jaundice, high blood counts
Septal hypertrophy of the heart
Long term outcome is good

Question 11

What are the results of diabetes in a pregnant person (severe cases)?

Answer 11

Birthweight > 4kg

Holoprosencephaly
Caudal regression syndrome
Proximal femoral deficiency

Question 12

What are the main characteristics of Beckwith Wiedemann syndrome?

Answer 12

Fetal overgrowth
Omphalocele
Internal organ overgrowth
Hemihyperplasia
Macroglossia
Proptosis
Prolonged hypoglycemia
Risk of Wilms tumor and hepatoblastoma (screen every 3 mos)

Question 13

What are the screening guidelines for BWS?

Answer 13

AFP every 3 months for first 4 years of life (have to BWS-based values–AFP is much higher at baseline)

Renal ultrasound every 3 months for first 8 years (then annually till mid-adolescence)

Question 14

What percentage of Sotos syndrome is caused by LoF mutations?

Answer 14

90%

In Japan whole gene deletions more likely

Question 15

What is the phenotype of Sotos syndrome?

Answer 15

Increased birthweight
Continued increased height
Advanced bone age
Large, narrow head
Bossing of forehead, bitemporal narrowing
Receding hairline
In time, elongated chil

Question 16

What is the phenotype of Sotos?

Answer 16

Neonatal hypotonia

Birth anomalies (PDA, ASD, renal, scoliosis)

50% seizures

Feeding difficulties –> sometimes present as FTT

DD (clumsy with poor coordination)

97% with ID (30% mild, 40% mod, 20% severe)

Question 17

What is the tumor risk for Sotos syndrome?

Answer 17

3% risk for tumors
- Neuroblastoma
- Sacrococcygeal teratoma
- Presacral ganglioneuroma
- Acute lymphocytic leukemia
- Small cell lung cancer

Tumor screening not effective for early detection or intervention

Question 18

What is the genetic cause of Marshall-Smith?

Answer 18

NFIX (AD)
De novo

Question 19

What is the phenotype of Marshall-Smith syndrome?

Answer 19

Large body size
Accelerated bone age
Dysmorphic findings
-Connective tissue-like
-Hypermobility
-Blue Sclerae

FTT
Macrocephaly, high forehead
Proptosis/prominent eyes
Short nose, underdeveloped midface, long narrow face
Micrognathia
Resp problmes/laryngomalacia
Decreased muscle mass
CC abnormality
ID

Question 20

What is the genetic cause of Weaver syndrome?

Answer 20

EZH2 (AD)

Question 21

What is the phenotype of Weaver syndrome?

Answer 21

Similar to Sotos (typically milder ID)

20% with normal intelligence
Overgrowth, advanced bone age
Camptodactyly
Fleshy ears, micrognathia, “stuck-on” chin

Tumor frequency ~4%
- neuroblastoma, acute lymphoblastic leukemia, ovarian endodermal sinus tumor, sacrococcygeal teratoma, and lymphoma
- no tumor screening

Question 22

What is the phenotype of PTEN Harmartoma syndrome?

Answer 22

Macrosomia, but with normalized height
Head remains large (+5SD)
Skin

Question 22

What is the phenotype of PTEN Harmartoma syndrome?

Answer 22

Macrosomia, but with normalized height
Head remains large (+5SD)
Skin papules and lipomata
Autism + macrocephaly (+3 SD)
Widely variable presentation within families

Question 23

What is the screening in patients with PTEN for children <18years?

Answer 23

Yearly thyroid US (from time of dx)
Skin check w/physical exam

Question 24

What is recommended screening for women with PTEN

Answer 24

30 years:
Monthly breast self-examination
Annual breast screening (MRI or mammogram)

35 years:
Transvaginal US or endometrial biopsy
Colonoscopy (male as well)

40 years:
Renal imaging (q2y)(males as well)

Family hx:
Screening 5-10 years prior to youngest age of dx

Question 25

What is the genetic change in Simpson Golabi Behmel syndrome?

Answer 25

GPC3 (X-linked LoF); Dup of GPC4 (2 cases)

Question 26

What is the phenotype of Simpson Golabi Behmel syndrome?

Answer 26

Pre- and postnatal overgrowth (often with polyhydramnios)

Macrocephaly

Coarse facial features: hypertelorism, epicanthal folds, midline groove in lower lip

Postaxial polydactyly, syndactyly, broad hands, nail hypoplasia

Organomegaly, supernumerary nipples

CHD, Cardiac conduction defects

Cryptorchidism, hernia

Diaphragmatic hernia (~30%)

Cleft lip or palate (~25%)

ID from mild to severe

Question 27

What tumor screening do you perform in Simpson Golabi Behmel syndrome?

Answer 27

Wilms
Hepatoblastoma
Same strategy as Beckwith Wiedemann syndrome

Question 28

What are the genetic changes in Gorlin syndrome?

Answer 28

LoF in PTCH1 or SUFU

Question 29

What is the minor criteria for Gorlin syndrome?

Answer 29

Macrocephaly
Childhood meduloblastoma (5%)
Lympho-mesenteric or pleural cysts
Cleft lip/palate
Vertebral/rib anomalies
Preaxial or postaxial polydactyly
Ovarian/cardiac fibromas
Ocular anomalies

Question 30

What is the major criteria for Gorlin syndrome?

Answer 30

Calcification of the falx cerebi
Jaw keratocyst
Palmar/plantar pits (>=2)
Multiple basal cell carcinomas (>5 lifetime) or a BCC before age 30 years
First degree relative with NBCCS

Question 31

What are the features of Perlman syndrome?

Answer 31

Polyhydramnios
Neonatal macrosomia
Visceromegaly
Renal dysplasia (cystic)
Nephroblastomatosis
Predisposition to Wilms tumor (64%)
Cryptorchidism

High neonatal mortality
ID

Question 32

What is the genetic cause of Perlman syndrome?

Answer 32

DIS3L2 (AR)

Question 33

What is the genetic cause of Proteus syndrome?

Answer 33

Somatic mosaic variant in AKT1

Question 34

What is the phenotype of Proteus syndrome?

Answer 34

Disfiguring overgrowth
Cerebriform overgrowth of palms/soles (Moccasin soles)