Genetic Disorders You Don’t Want To Miss Flashcards
Case 1)
- 2 month old male presents to the ER with swelling of his left arm
- He refuses to move the arm and cries with palpation
- Parents report no history of trauma
- Child protection team meets and they feel that this injury is consistent with child abuse but request genetics consultation to rule out disorders that can mimic child abuse
- What next?
Genetic consult
- Further history reveals that mother occasionally pulls the infant to sitting position by his hands
- Family history: Mother is 32 years old and is healthy. Father is 30 years old and has a history of 12 fractures in his lifetime, several of which occurred with minimal trauma. Father’s ethnic background is German/Irish. Mother’s ethnic background is Mexican.
- No history of other family members with multiple fractures.
- There is no known consanguinity.
Suspect Osteogenesis Imperfecta
Key physical exam findings of Osteogenesis Imperfecta?
- Grayish tint to sclera
Which OI type is the classic?
OI type I: classic non-deforming OI with blue/grey sclera
What are the other OI types/main phenotypes?
- OI type I: classic non-deforming OI with blue/grey sclera
- OI type II: perinatally lethal OI
- OI type III: progressively deforming OI
- OI type IV: common variable OI with normal sclerae
Describe OI type I
- Protein involved
- Symptoms
- Associations
- Type I collagen
- QUANTITATIVE defect in Type I Collagen
- Multiple recurrent fractures
- Normal stature
- Little or no bone deformity
- Blue sclera
- Hearing loss in 50%
What are genetic testing recommendations for OI?
COL1A1 and COL1A2 genes
Case 2)
- 7 mo old girl
- Presents to PCP for routine well-child care (a month late)
- Normal newborn screen.
- No hospitalizations or surgeries
- Mild developmental delay (she is not yet sitting independently)
- Physical examination
- Alert and playful.
- Macrocephaly. (FOC was normal at birth, it has been steadily increasing over time.) Soft anterior fontanelle.
- Mild generalized hypotonia, normal reflexes and normal CNs.
- What is seen in the CT
- What test would evaluate macrocephaly?
- What do you suspect?
- CT of brain shows large bilateral subdural hematomas
- Glutaric aciduria type 1
What is seen here?
MRI imaging with opercular cisterns (bat sign)
- Increased signal in globus pallidus
What should a non-accidental trauma investigation involve?
- Retinal exam (look for hemorrhages/shaken baby)
- Skeletal survey (fractures)
- MRI imaging
What metabolic results do you expect to see in Glutaric Aciduria Type I?
Urine Organic Acids
- ↑glutaric acid
- ↑ 3OH-glutaric acid
Plasma Acylcarnitines
- ↓ plasma carnitine
- ↑ glutaryl carnitine
Describe the pathogenesis Glutaric Aciduria Type I (don’t memorize)
- Deficiency in glutaryl-CoA dehydrogenase in mitochondria which mediates the decarboxylation of glutaryl-CoA to crotonyl-CoA in the degradation pathway of lysine, hydroxylysine and tryptophan.
- Accumulation of glutaric acids can result in acute striatal necrosis resulting in metabolic stroke.
- Resulting damage to the globus pallidus can result in resting tremor, rigidity, dyskinesia, and hypotonia
What factors can lead to what serious complication in Glutaric Aciduria type I?
Stress, concurrent illnesses, and surgery can precipitate metabolic stroke
What is treatment for Glutaric Aciduria type I?
- Low-protein diet
- Supplemental carnitine
- Medical management: emphasizing importance of emergent medical attention and caloric support in times of illness, decreased caloric intake, stress, and surgery.
Describe the genetic component of Glutaric Aciduria type I?
- What testing should be done
This is an autosomal recessive disorder with RR of 25% for parents
- Prenatal testing via DNA analysis
Describe Glutaric Aciduria Type I
- Genetic inheritance
- Prevalence - More in what populations
- Testing when
- Presentation when
- Prognosis
- Autosomal recessive
- 1/30,000
- 1/300 Amish and Ojibway-Cree
- On NBS panel, but may be negative
- Typically presents 6-18 months
- Macrocephaly; poor feeding; irritable; mild hypotonia; dystonia; dyskenesia
- Mild manifestations may be overlooked
- Prognosis variable
Case 3)
- 4 year old male presents to his PCP with parental concerns about “spots” that have appeared over the past year
- PMH: Previously healthy, no hospitalizations or surgeries. Full term, NSVD.
- Development: Patient is showing some delay in learning his colors, but his motor development has been normal
- PE: relative macrocephaly (95th %ile), multiple hyperpigmented macules scattered over chest, back, and extremities (>10 in total). Freckling in the axilla and inguinal regions
- Diagnosis?
Neurofibromatosis Type I
What are the clinical criteria for NF type I?
- Café au lait macules (6+)
- Neurofibromas or one plexiform neurofibroma (2+)
- Frecking in the axillary or inguinal regions
- Optic glioma
- Lisch nodules (2+)
- Sphenoid dysplasia or tibial pseudoarthrosis
- Affected first degree relative
What is seen here? Seen in what condition?
Lisch nodules
- Benign iris hamartomas
- Seen in NF type I
What is seen here? Seen in what condition?
Tibial psueodarthrosis
- One of the bone abnormalities you may see in NF type I
What is seen here? Seen in what condition?
Optic pathway glioma
- NF type I
What is seen here? Seen in what condition?
Neurofibromas
- NF type I
What is seen here? Seen in what condition?
Plexiform Neurofibromas
- NF type I
How is NF type I diagnosed? Caveats?
Based on clinical criteria
- Early in course patient may not meet the clinical criteria soGenetic Testing (NF1 gene sequencing) can be done to rule in the diagnosis.
Describe genetics of NF type I
- Gene involved
- Inheritance pattern
- Penetrance
- Expressivity
- Recurrence risk
- Heterozygous loss-of-function mutations of NF1
- Pathogenic variants are very heterogeneous
- Autosomal dominant
- Typically penetrant
- Extremely variable expressivity even within family
- Recurrence risk: 50%
What is management/treatment for NF type I?
Management involves close follow up and therapy for various organ system involvement.
- Routine examinations should focus on the potential complications.
- Annual examinations permit early detection of problems, decreasing morbidity and improving quality of life.
- Annual eye examinations are important in early detection of optic nerve lesions. mTOR (rapamycin complex 1) inhibitors shown to slow tumor growth
- Others in investigation.
Case 4)
- 14yo male presents to dermatology clinic for evaluation for acne refractory to OTC meds.
- PMH: Seizures controlled on Keppra, ADHD on Ritalin.
- PE: Ash leaf spot, Shagreen patch, Perinungual fibroma
- What are you thinking for Dx?
Tuberous sclerosis
What are physical exam findings of tuberous sclerosis?
- Ash leaf spot
- Shagreen patch
- Periungual fibroma
What are major features of Tuberous Sclerosis?
- Facial angiofibromas
- Hypomelanotic macules (three or more)
- Shagreen patch (connective tissue nevus)
- Cortical tuber
- Subependymal nodule (SEN)
- Cardiac rhabdomyoma, single or multiple
- Lymphangiomyomatosis
- Renal angiomyolipoma
Describe the genetics of Tuberous Sclerosis
- Genes
- Inheritance pattern
- Penetrance
- Expressivity
- Mutation rate
- Caused by mutation in one of two genes:
- TSC1 and TSC2
- Autosomal dominant inheritance
- Complete penetrance
- Variable expressivity
- High new-mutation rate (~70% de novo mutations)
What is management/treatment for Tuberous Sclerosis?
Multidisciplinary followup and management of various organ system involvement.
Case 5)
- 24 yo female who presents with auditory hallucinations and paranoid delusions
- She is diagnosed with schizophrenia
- PMH: History of ADHD and learning disability in childhood
- History of heart murmur as a child that resolved without intervention
- What genetic test should be ordered?
Test for 22a11.2 Deletion Syndrome (DiGeorge Syndrome/Velocardiofacial syndrome)
What are clinical features of 22q11.2 (DiGeorge/Velocardiofacial syndrome)?
CATCH 22 (chrom 22)
- Cardiac abnormality
- Abnormal facies
- Thymic hypoplasia/aplasia
- Cleft palate
- Hypocalcemia / Hypoparathyroidism
- Other features: learning difficulties in 70-90%
Describe the timing and clinical features of DiGeorge
- Very mild to very severe
- Varies based on age (prenatal, neonatal, infancy, childhood, adolescent, adult)
What are features of intrauterine fetal devo at 24 wks with DiGeorge?
Intrauterine fetal disease (complication of DiGeorge that may be missed)
- Absent thymus
- Conotruncal heart defect
- Absent parathyroid glands
How to diagnose del(22q11.2)?
- When is it diagnosed
- Incidence
1/2-4,000
Timing:
- Birth (3050
- By 5 yrs (70%)
- By 18 yrs (95%)
Sx: psychotic symptoms are seen in 14-28% of children
Dx: aCGH
Describe the DiGeorge presentation for each age group:
- Neonatal
- Infancy
- Early childhood
- Late childhood
- Adolescence
- Adulthood
- Neonatal: major CHD, Hypocalcemic seizures, Immunodeficiency
- Infancy: feeding difficulty
- Early Childhood: developmental delay
- Later Childhood: learning disabilities
- Adolescence: behavioural psychiatric problems
- Adulthood: parent who has a child with deletion 22q11.2 syndrome
What is the recurrence risk for DiGeorge?
50% for those with deletion
