MSK - Genetics - Dysmorphology; Skeletal Dysplasia; Newborn Screenings; Inborn Metabolic Errors Flashcards
What are the ‘vital signs’ of dysmorphology?
Height, weight, and head circumference
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)
Chromosomal abnormalities
(76% of known etiologies)
Do singlular anomalies in newborns typically have an identifiable etiology?
No;
they are typically multi-factorial
Define ‘sequence’ in terms of dysmorphology and congenital defects.
One anomaly leads to other developmental anomalies
(e.g. Potter’s syndrome)
What is the acronym for the signs of Potter’s syndrome?
POTTER
Pulmonary hypoplasia
Oligohydramnios
Twisted face
Twisted skin
Extremity abnormalities
Renal agenesis
Define ‘dysplasia’ in terms of dysmorphology and congenital defects.
Intrinsic developmental abnormality due to defective cellular organization
(e.g. skeletal dysplasia;
effects of fetal alcohol syndrome, thalidomide)
Define ‘disruption’ in terms of dysmorphology and congenital defects.
Interruption of normal morphological effects due to an extrinsic force
(e.g. amniotic band syndrome)
Define ‘deformation’ in terms of dysmorphology and congenital defects.
A change of normal morphology caused by extrinsic forces
(e.g. clubfoot)
Define an ‘association’ disorder in terms of dysmorphology and congenital defects.
An exclusion diagnosis of a nonrandom pattern of effects
(e.g. VACTERL, or CHARGE)
Name each type of dysmorphology illustrated by the separate examples below:
Amniotic band syndrome
Potter’s syndrome
Clubfoot
Amniotic band syndrome - disruption
Potter’s syndrome - sequence
Clubfoot - deformation
Name each type of dysmorphology illustrated by the separate examples below:
Fetal alcohol syndrome
Skeletal dysplastic syndromes
VACTERL syndrome
Fetal alcohol syndrome - dysplasia
Skeletal dysplastic syndromes - dysplasia
VACTERL syndrome - association
True/False.
Facial dysmorphological changes can often predict location changes and problems in the brain.
True
(“the face predicts the brain)
(e.g. a child with a midline cleft lip / palate might also have holoprosencephaly)
What are the two steps of clinical research that happen before human test subjects are involved?
Basis - lab work to establish potential therapy basis
Pre-clinical - synthesis, toxicology, formulation, regulatory
Phase I studies use a small group of healthy individuals to do what?
Phase II studies do what?
Establish safe dosage and schedule for new therapy;
establish biological effect, establish efficacy
Phase III studies do what?
Phase IV studies do what?
Compare new therapy to old therapy;
figure out where the new therapy can fit into the current market
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 _________?”
Safe
Efficacious
better than the existing therapy
market-ready
What four disorders comprise almost 70% of all skeletal dysplasias?
Achondroplasia,
thanatophoric dysplasia,
osteogenesis imperfecta,
achondrogenesis
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.
Achondrogenesis
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?
Thanatophoric dysplasia
Autosomal dominant - FGFR3 gene
What is the most common cause of disproportionate short stature?
Achondroplasia
In what fairly common skeletal dysplasia is there sometimes craniocervical junction compression, increasing the risk of death in infancy?
Achondroplasia
In addition to achondroplasia, what other two disorders are linked to mutations in the FGFR3 gene?
Thanatophoric dysplasia,
hypochondroplasia
Name some of the signs associated with thanatophoric dysplasia.
‘Clover-leaf’ skull, frontal bossing, midface hypoplasia, micromelia, macrocephaly, brachydactyly, and CNS abnormalities
Which tends to be more severe in its skeletal features, achondroplasia or hypochondroplasia?
Which tends to show intellectual disability and/or epilepsy more often?
Achondroplasia;
hypochondroplasia
What type of osteogenesis imperfecta is a ‘progressively deforming’ type?
Type III
What type of osteogenesis imperfecta is characterized by blue sclerae, fragile bones, triangular face, and (sometimes) deformed teeth?
Type I
(Note: multiple fractures in various stages of healing)
What type of osteogenesis imperfecta is similar to type I but is not characterized by blue sclerae?
Type IV
What type of osteogenesis imperfecta is often lethal at or near birth?
Type II
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?
1.7
1
< 1
(a higher number may indicate short extremities)
What should arm span typically be approximately equal to?
Height
What are some types of skeletal dysplasia that are often lethal in the fetal or perinatal stage?
Achondrogenesis
Thanatophoric dysplasia
Asphyxiating thoracic dysplasia
Osteogenesis imperfecta type II
What shape is the skull in thanotophoric dysplasia?
What shape is the thorax?
Clover-leaf shaped;
bell-shaped
Why is achondrogenesis a lethal disorder?
Failure of cartilage growth = no endochondral ossification = no long bones
The achondroplastic mutation in FGFR3 is a _____________ mutation.
gain-of-function
(FGF receptor 3 supresses bone growth)
FGF receptor 3 has what effect on bone growth?
How does this play into achondroplasia?
It suppresses bone growth;
the FGFR3 mutation seen in achondroplasia is a gain-of-function mutation
What disorder presents very similarly to achondroplasia but is a result of mutation in the cartilage oligometric protein gene (COMP)?
Pseudoachondroplasia
The clinical heterogeneity of osteogenesis imperfecta is explained by which, allelic or locus heterogeneity?
Both
In type I osteogenesis imperfecta, is the problem of type I collagen quality or quantity?
Quantity
What are the general requirements for sensitivity and specificity of a screening test?
Sensitivity as high as possible (~0 false negatives);
acceptably high specificty
Phenylketones are produced in high number when what substance is found in high concentrations in the body?
What enzyme is likely absent?
Phenylalanine;
phenylalanine hydroxylase
Phenylalanine hydroxylase turns phenylalanine into:
Tyrosine
Individuals with phenylketonuria have excessively high levels of _________ and low levels of _________.
Phenylalanine;
tyrosine
What are the three components of PKU treatment?
Phenylalanine restriction (but not complete removal!);
tyrosine supplementation;
tetrahydrobiopterin (BH4) supplementation
Why do individuals with PKU often have a ‘musty’ smell?
Why do individuals with PKU often have lightly colored skin and hair?
Phenylketone abundance;
tyrosine deficiency (a precursor to melanin)
How is PKU screening done today?
Mass spectrometry
(extremely accurate)
Why is it important that metabolic disorders be screened for in newborns?
Proper nutrition + medication of these infants can often save their lives / neurological capacity
What cofactor is necessary for proper phenylalanine hydroxylase function?
Tetrahydrobiopterin
(BH4)
What is a confounding factor that makes the diagnosis of acute metabolic diseases of infancy difficult to diagnose?
They are clinically indistinguishable from sepsis
What are the signs and symptoms associated with the VACTERL diagnosis?
Vertebral anomalies;
anal atresia;
cardiac anomalies;
tracheo-esophageal fistulas;
renal anomalies;
limb deformities
What are the signs and symptoms associated with the CHARGE diagnosis?
Coloboma,
heart anomalies,
atresia choanae,
growth retardation, genital abnormalities,
ear abnormalities.
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
C. complete skeletal series
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?
Isovaleric acidemia
