MSK - Genetics - Dysmorphology; Skeletal Dysplasia; Newborn Screenings; Inborn Metabolic Errors

Question 1

What are the ‘vital signs’ of dysmorphology?

Answer 1

Height, weight, and head circumference

Question 2

Of newborns with structural defects, about 1/4 have multiple anomalies.

What is the singular leading cause of multiple anomalies in a newborn?

(note: only 50% of cases with multiple anomalies even have a known etiology)

Answer 2

Chromosomal abnormalities

(76% of known etiologies)

Question 3

Do singlular anomalies in newborns typically have an identifiable etiology?

Answer 3

No;

they are typically multi-factorial

Question 4

Define ‘sequence’ in terms of dysmorphology and congenital defects.

Answer 4

One anomaly leads to other developmental anomalies

(e.g. Potter’s syndrome)

Question 5

What is the acronym for the signs of Potter’s syndrome?

Answer 5

POTTER

Pulmonary hypoplasia

Oligohydramnios

Twisted face

Twisted skin

Extremity abnormalities

Renal agenesis

Question 6

Define ‘dysplasia’ in terms of dysmorphology and congenital defects.

Answer 6

Intrinsic developmental abnormality due to defective cellular organization

(e.g. skeletal dysplasia;

effects of fetal alcohol syndrome, thalidomide)

Question 7

Define ‘disruption’ in terms of dysmorphology and congenital defects.

Answer 7

Interruption of normal morphological effects due to an extrinsic force

(e.g. amniotic band syndrome)

Question 8

Define ‘deformation’ in terms of dysmorphology and congenital defects.

Answer 8

A change of normal morphology caused by extrinsic forces

(e.g. clubfoot)

Question 9

Define an ‘association’ disorder in terms of dysmorphology and congenital defects.

Answer 9

An exclusion diagnosis of a nonrandom pattern of effects

(e.g. VACTERL, or CHARGE)

Question 10

Name each type of dysmorphology illustrated by the separate examples below:

Amniotic band syndrome

Potter’s syndrome

Clubfoot

Answer 10

Amniotic band syndrome - disruption

Potter’s syndrome - sequence

Clubfoot - deformation

Question 11

Name each type of dysmorphology illustrated by the separate examples below:

Fetal alcohol syndrome

Skeletal dysplastic syndromes

VACTERL syndrome

Answer 11

Fetal alcohol syndrome - dysplasia

Skeletal dysplastic syndromes - dysplasia

VACTERL syndrome - association

Question 12

True/False.

Facial dysmorphological changes can often predict location changes and problems in the brain.

Answer 12

True

(“the face predicts the brain)

(e.g. a child with a midline cleft lip / palate might also have holoprosencephaly)

Question 13

What are the two steps of clinical research that happen before human test subjects are involved?

Answer 13

Basis - lab work to establish potential therapy basis

Pre-clinical - synthesis, toxicology, formulation, regulatory

Question 14

Phase I studies use a small group of healthy individuals to do what?

Phase II studies do what?

Answer 14

Establish safe dosage and schedule for new therapy;

establish biological effect, establish efficacy

Question 15

Phase III studies do what?

Phase IV studies do what?

Answer 15

Compare new therapy to old therapy;

figure out where the new therapy can fit into the current market

Question 16

In phase I trials, we say: “is it _________?”

In phase II trials, we say: “is it _________?”

In phase III trials, we say: “is it _________?”

In phase IV trials, we say: “is it _________?”

Answer 16

Safe

Efficacious

better than the existing therapy

market-ready

Question 17

What four disorders comprise almost 70% of all skeletal dysplasias?

Answer 17

Achondroplasia,

thanatophoric dysplasia,

osteogenesis imperfecta,

achondrogenesis

Question 18

What is the very severe skeletal dysplasia in which cartilage is not produced?

This condition is often lethal due to a narrow thorax and pulmonary hypoplasia.

Answer 18

Achondrogenesis

Question 19

What disorder is characterized by a ‘clover-leaf’ skull, frontal bossing, midface hypoplasia, micromelia, macrocephaly, brachydactyly, and CNS abnormalities?

What is the inheritance pattern and associated gene?

Answer 19

Thanatophoric dysplasia

Autosomal dominant - FGFR3 gene

Question 20

What is the most common cause of disproportionate short stature?

Answer 20

Achondroplasia

Question 21

In what fairly common skeletal dysplasia is there sometimes craniocervical junction compression, increasing the risk of death in infancy?

Answer 21

Achondroplasia

Question 22

In addition to achondroplasia, what other two disorders are linked to mutations in the FGFR3 gene?

Answer 22

Thanatophoric dysplasia,

hypochondroplasia

Question 23

Name some of the signs associated with thanatophoric dysplasia.

Answer 23

‘Clover-leaf’ skull, frontal bossing, midface hypoplasia, micromelia, macrocephaly, brachydactyly, and CNS abnormalities

Question 24

Which tends to be more severe in its skeletal features, achondroplasia or hypochondroplasia?

Which tends to show intellectual disability and/or epilepsy more often?

Answer 24

Achondroplasia;

hypochondroplasia

Question 25

What type of osteogenesis imperfecta is a ‘progressively deforming’ type?

Answer 25

Type III

Question 26

What type of osteogenesis imperfecta is characterized by blue sclerae, fragile bones, triangular face, and (sometimes) deformed teeth?

Answer 26

Type I

(Note: multiple fractures in various stages of healing)

Question 27

What type of osteogenesis imperfecta is similar to type I but is not characterized by blue sclerae?

Answer 27

Type IV

Question 28

What type of osteogenesis imperfecta is often lethal at or near birth?

Answer 28

Type II

Question 29

The ratio of upper to lower body segment is a way of confirming proper limb length.

What ratio is normal at birth?

What ratio is normal ≤ 10 years of age?

What ratio is normal after > 10 years of age?

Answer 29

1.7

1

< 1

(a higher number may indicate short extremities)

Question 30

What should arm span typically be approximately equal to?

Answer 30

Height

Question 31

What are some types of skeletal dysplasia that are often lethal in the fetal or perinatal stage?

Answer 31

Achondrogenesis

Thanatophoric dysplasia

Asphyxiating thoracic dysplasia

Osteogenesis imperfecta type II

Question 32

What shape is the skull in thanotophoric dysplasia?

What shape is the thorax?

Answer 32

Clover-leaf shaped;

bell-shaped

Question 33

Why is achondrogenesis a lethal disorder?

Answer 33

Failure of cartilage growth = no endochondral ossification = no long bones

Question 34

The achondroplastic mutation in FGFR3 is a _____________ mutation.

Answer 34

gain-of-function

(FGF receptor 3 supresses bone growth)

Question 35

FGF receptor 3 has what effect on bone growth?

How does this play into achondroplasia?

Answer 35

It suppresses bone growth;

the FGFR3 mutation seen in achondroplasia is a gain-of-function mutation

Question 36

What disorder presents very similarly to achondroplasia but is a result of mutation in the cartilage oligometric protein gene (COMP)?

Answer 36

Pseudoachondroplasia

Question 37

The clinical heterogeneity of osteogenesis imperfecta is explained by which, allelic or locus heterogeneity?

Answer 37

Both

Question 38

In type I osteogenesis imperfecta, is the problem of type I collagen quality or quantity?

Answer 38

Quantity

Question 39

What are the general requirements for sensitivity and specificity of a screening test?

Answer 39

Sensitivity as high as possible (~0 false negatives);

acceptably high specificty

Question 40

Phenylketones are produced in high number when what substance is found in high concentrations in the body?

What enzyme is likely absent?

Answer 40

Phenylalanine;

phenylalanine hydroxylase

Question 41

Phenylalanine hydroxylase turns phenylalanine into:

Answer 41

Tyrosine

Question 42

Individuals with phenylketonuria have excessively high levels of _________ and low levels of _________.

Answer 42

Phenylalanine;

tyrosine

Question 43

What are the three components of PKU treatment?

Answer 43

Phenylalanine restriction (but not complete removal!);

tyrosine supplementation;

tetrahydrobiopterin (BH4) supplementation

Question 44

Why do individuals with PKU often have a ‘musty’ smell?

Why do individuals with PKU often have lightly colored skin and hair?

Answer 44

Phenylketone abundance;

tyrosine deficiency (a precursor to melanin)

Question 45

How is PKU screening done today?

Answer 45

Mass spectrometry

(extremely accurate)

Question 46

Why is it important that metabolic disorders be screened for in newborns?

Answer 46

Proper nutrition + medication of these infants can often save their lives / neurological capacity

Question 47

What cofactor is necessary for proper phenylalanine hydroxylase function?

Answer 47

Tetrahydrobiopterin

(BH4)

Question 48

What is a confounding factor that makes the diagnosis of acute metabolic diseases of infancy difficult to diagnose?

Answer 48

They are clinically indistinguishable from sepsis

Question 49

What are the signs and symptoms associated with the VACTERL diagnosis?

Answer 49

Vertebral anomalies;

anal atresia;

cardiac anomalies;

tracheo-esophageal fistulas;

renal anomalies;

limb deformities

Question 50

What are the signs and symptoms associated with the CHARGE diagnosis?

Answer 50

Coloboma,

heart anomalies,

atresia choanae,

growth retardation, genital abnormalities,

ear abnormalities.

Question 51

In diagnosing a child with disproportional short stature, which of the following

tests is most useful?

A. chromosomal analysis

B. urine organic acid analysis

C. complete skeletal series

D. bone marrow biopsy

Answer 51

C. complete skeletal series

Question 52

A newborn baby is very ill and has a distinctive ‘sweaty socks’ smell.

Assuming this comes from an inborn error of metabolism, what disorder is responsible for the smell and illness?

Answer 52

Isovaleric acidemia