Pediatric Syndromes Flashcards
What are the hallmark features of Osteogenesis Imperfecta?
- Multiple Fractures with little/no trauma
- Dentogenesis imperfect
- Hearing Loss
- Skeletal deformities
- Short stature
How many types of OI are there? How many have an identified gene?
There are 7 types. A gene COL1A1 and COL1A2 have been implicated in the first 4 types
What features should you ask about on family history when evaluating for OI
- Fractures
- Blue sclerae
- Dental problems
- Hearing loss
- Short stature
- Age at walking
What are the key history questions to ask for OI?
- Fractures at birth?
- Number fractures, bones involved, cause
- Limb deformities
- Joint dislocation
- Hearing Loss
What are the features on xray for OI?
1, Wormian bones (esp skull) for type 1.
- Bone density normal or reduced
- Progressive boney deformities type III
- Occiptial overhand and platyblasia in type IV
What are some disorders on the differential for OI
- NAT
- Juvenile osteoporosis
- Premature osteopoposis
- Hypophosphatasia (low or absent alk phos)
- Skeletal dysplasias with wormian bones
- Arthrogryposis
How is OI inherited?
Autosomal dominant Type II (perinatal lethal) usually de novo mutation
What is the genetic defect in OI?
OI I-IV due to mutations in either alpha1 or alpha2 chains of collagen 1
Mutations in COL1A1 or COL1A2 lead to either a premature stop codon -> 50% reduction in type 1 collagen
or glycine substitution -> disturb helical structure and stability of the collagen
How is lethality defined in perinatally detected skeletal dysplasias?
- Molecular diagnosis of a known lethal disorder
- U/S measurements associated with lethality (GA age dependent)
- chest-to-abdomen ratio 50%
- abdomen-to-femur ratio
Which of the following malformation syndromes is not associated with maternal diabetes?
A. Caudal dysgenesis B. Femoral hypoplasia-unusual face syndrome C. Amyoplasia congenita D. Oculoauriculovertebral spectrum E. Holoprosencephaly
c-thought to be secondary to in utero vascular event
What percentage of 22q11.2 deletions are de novo vs inherited?
- de novo ~ 90-93%
2. familial ~7-10%
What gene is responsible for the phenotype of 22q11.2 deletion?
TBX1
Bile duct paucity on liver biopsy + any 3 of:
- cardiac defects
- choleastasis
- skeletal abnormalities (butterfly vertebrae)
- eye (posterior embryotoxin)
- characteristic facial features
-other features including developmental delay, growth failure
Alagille syndrome
What percentage of Alagille syndrome mutations in JAG1 or NOTCH2 are de novo?
50-70%
Manifests primarily in adulthood Syncope or nocturnal agonal respiration ST segment abnormalities High risk ventricular arrhythmias Sudden death or SIDS Family history of sudden death
Brugada syndrome
Name the disorder.
Slowly progressive weakness and atrophy of distal muscles in the feet and/or hands Onset in the 1st-3rd decades Hearing loss Pes cavus deformity Hip dysplasia
Charcot-Marie Tooth (hereditary motor and sensory neuropathy)
- many subtypes classified by inheritance and primary abnormality (abnormal myelin, axonopathy, or both)
- usually AD or AR but CMTX is X-linked
Name the disorder.
Progressive symmetric muscle weakness, proximal>distal
Calf hypertrophy
Onset before 5 years
Cardiomyopathy
Duchenne and Becker Muscular Dystrophy
X-linked recessive, mutations in DMD -> decreased or absent dystrophin production or abnormal dystrophin produced
CK 10x normal in DMD, CK 5x normal in BMD
Name the disorder and mechanism
Progressive limb and gait ataxia, absent DTRs in LE Onset before 25 yrs glucose intolerance/diabetes Hypertrophic Cardiomyopathy Scoliosis, optic nerve atrophy
Fredereich’s ataxia
Autosomal recessive, triplet repeat disorder (GAA expansion in intron 1) -> loss of transcription of FRDA gene and decreased frataxin
66-1700 repeats disease causing.
Name the disorder and gene.
Recurrent focal pressure palsies Mild polyneuropathy Absent ankle reflexes, reduced DTRs, Pes cavus foot deformity Adult onset
Hereditary neuropathy with liability to pressure palsies
PMP22 (deletion in 80%, mutation in 20%)
Autosomal dominant
Name the disorder and gene.
Multi-systemic disorder of:
- skeletal and smooth muscle (myotonia, distal muscle weakness and atrophy)
- Eye (early cataracts)
- Heart (arrhythmias)
- Impaired glucose tolerance
Anticipation with successive generations
Myotonic dystrophy
Autosomal dominant triplet repeat disease (CTG repeat expansion in 3’ UTR) in DMPK
Thought to cause disease through RNA gain of function mechanism: the transcribed CUG repeats interfere with alternative splicing of multiple genes including a chloride channel
disease with >50 repeats
Name the disorder and pattern of inheritance.
Newborn male infant with macrosomia (BW > 5 kg), coarse facies, post-axial polydactyly.
=Simpson-Golabi-Behmel syndrome
- X-linked recessive disorder due to mutations in GPC3
- prenatal onset of overgrowth
- macrocephaly often present at birth
- cardiac conduction defects are common
Name the disorder and pattern of inheritance.
relative macrocephaly, broad forehead, delayed closure of cranial sutures/fontalelle, clavicle defects, dental anomalies.
=cleidocranial dysplasia
-autosomal dominant disorder due to defects in RUNX2
- wormian bones and delayed mineralization of pubic bone can be seen
- short stature
- narrow pelvis may necessitate c=section for pregnant women
Name the disorder and gene.
Onset in infancy with muscle weakness, tongue fasciculations, absent DTRs.
Spinal muscular atrophy
95-98% have deletions of exon 7 of SMN1, 2-5% have a SNV
of copies of SMN 2 modifies the severity of the disease (more copies of SMN2, more mild phenotype and later onset of disease)
Which molecular type of Tuberous Sclerosis is more likely to be associated with renal cyts: TSC1 or TSC2
=TSC2
-occurs if contiguous gene deletion with PKD1
What is meant by SMA due to a gene conversion event
SMN1 and SMN2 genes differ in a key amino acid at the beginning of exon 7.
In SMN1 it is a T (or SMN1=SMNT), in SMN2 it is a C (or SMN2=SMNC). The presence of SMNC causes exclusion of exon 7 of SMN during RNA splicing and leads to an unstable mRNA that creates a non-functional protein.
While most SMA is due to a SMN1 deletion, a SNV at that key residue in exon 7 will convert SMN1 to the SMN2 form and result in a deficiency of SMN1 functional protein
Most cases of SMA or caused by a SMN1 deletion or a point mutation?
=deletion of SMN1
Which of the following genes causes X-linked hypohidrotic ectodermal dysplasia?
a. EDA
b. WNT10A
c. GJB6
d. MSX1
=EDA
AD form caused by mutations in EDAR
What is the inheritance pattern, gene, and what is the most common molecular defect for incontinentia pigmenti?
X-linked dominant (lethal in males)
due to mutations in the IKBKG genes
2/3 due to multi-exon deletion (exons 4-10)
State where the defect occurs in the epidermis and/or dermis with each of the following types of epidermolysis bullosa:
a. EB simplex
b. junctional EB
c. dystrophic EB
EB simplex- splitting in or above the basal layer
Junctional EB-defect within the basement membrane
Dystrophic EB-scarring below the basement membrane
