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

1
Q

What are the ‘vital signs’ of dysmorphology?

A

Height, weight, and head circumference

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2
Q

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)

A

Chromosomal abnormalities

(76% of known etiologies)

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3
Q

Do singlular anomalies in newborns typically have an identifiable etiology?

A

No;

they are typically multi-factorial

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4
Q

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

A

One anomaly leads to other developmental anomalies

(e.g. Potter’s syndrome)

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5
Q

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

A

POTTER

Pulmonary hypoplasia

Oligohydramnios

Twisted face

Twisted skin

Extremity abnormalities

Renal agenesis

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6
Q

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

A

Intrinsic developmental abnormality due to defective cellular organization

(e.g. skeletal dysplasia;

effects of fetal alcohol syndrome, thalidomide)

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7
Q

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

A

Interruption of normal morphological effects due to an extrinsic force

(e.g. amniotic band syndrome)

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8
Q

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

A

A change of normal morphology caused by extrinsic forces

(e.g. clubfoot)

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9
Q

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

A

An exclusion diagnosis of a nonrandom pattern of effects

(e.g. VACTERL, or CHARGE)

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10
Q

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

Amniotic band syndrome

Potter’s syndrome

Clubfoot

A

Amniotic band syndrome - disruption

Potter’s syndrome - sequence

Clubfoot - deformation

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11
Q

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

Fetal alcohol syndrome

Skeletal dysplastic syndromes

VACTERL syndrome

A

Fetal alcohol syndrome - dysplasia

Skeletal dysplastic syndromes - dysplasia

VACTERL syndrome - association

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12
Q

True/False.

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

A

True

(“the face predicts the brain)

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

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13
Q

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

A

Basis - lab work to establish potential therapy basis

Pre-clinical - synthesis, toxicology, formulation, regulatory

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14
Q

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

Phase II studies do what?

A

Establish safe dosage and schedule for new therapy;

establish biological effect, establish efficacy

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15
Q

Phase III studies do what?

Phase IV studies do what?

A

Compare new therapy to old therapy;

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

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16
Q

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 _________?”

A

Safe

Efficacious

better than the existing therapy

market-ready

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17
Q

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

A

Achondroplasia,

thanatophoric dysplasia,

osteogenesis imperfecta,

achondrogenesis

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18
Q

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.

A

Achondrogenesis

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19
Q

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?

A

Thanatophoric dysplasia

Autosomal dominant - FGFR3 gene

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20
Q

What is the most common cause of disproportionate short stature?

A

Achondroplasia

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21
Q

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

A

Achondroplasia

22
Q

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

A

Thanatophoric dysplasia,

hypochondroplasia

23
Q

Name some of the signs associated with thanatophoric dysplasia.

A

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

24
Q

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

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

A

Achondroplasia;

hypochondroplasia

25
Q

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

A

Type III

26
Q

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

A

Type I

(Note: multiple fractures in various stages of healing)

27
Q

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

A

Type IV

28
Q

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

A

Type II

29
Q

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?

A

1.7

1

< 1

(a higher number may indicate short extremities)

30
Q

What should arm span typically be approximately equal to?

A

Height

31
Q

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

A

Achondrogenesis

Thanatophoric dysplasia

Asphyxiating thoracic dysplasia

Osteogenesis imperfecta type II

32
Q

What shape is the skull in thanotophoric dysplasia?

What shape is the thorax?

A

Clover-leaf shaped;

bell-shaped

33
Q

Why is achondrogenesis a lethal disorder?

A

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

34
Q

The achondroplastic mutation in FGFR3 is a _____________ mutation.

A

gain-of-function

(FGF receptor 3 supresses bone growth)

35
Q

FGF receptor 3 has what effect on bone growth?

How does this play into achondroplasia?

A

It suppresses bone growth;

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

36
Q

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

A

Pseudoachondroplasia

37
Q

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

A

Both

38
Q

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

A

Quantity

39
Q

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

A

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

acceptably high specificty

40
Q

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

What enzyme is likely absent?

A

Phenylalanine;

phenylalanine hydroxylase

41
Q

Phenylalanine hydroxylase turns phenylalanine into:

A

Tyrosine

42
Q

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

A

Phenylalanine;

tyrosine

43
Q

What are the three components of PKU treatment?

A

Phenylalanine restriction (but not complete removal!);

tyrosine supplementation;

tetrahydrobiopterin (BH4) supplementation

44
Q

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

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

A

Phenylketone abundance;

tyrosine deficiency (a precursor to melanin)

45
Q

How is PKU screening done today?

A

Mass spectrometry

(extremely accurate)

46
Q

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

A

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

47
Q

What cofactor is necessary for proper phenylalanine hydroxylase function?

A

Tetrahydrobiopterin

(BH4)

48
Q

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

A

They are clinically indistinguishable from sepsis

49
Q

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

A

Vertebral anomalies;

anal atresia;

cardiac anomalies;

tracheo-esophageal fistulas;

renal anomalies;

limb deformities

50
Q

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

A

Coloboma,

heart anomalies,

atresia choanae,

growth retardation, genital abnormalities,

ear abnormalities.

51
Q

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

A

C. complete skeletal series

52
Q

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?

A

Isovaleric acidemia