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Survey of Human Genetic Disorders Second Half > Short Stature > Flashcards

Short Stature Flashcards

1
Q

How do we define short stature?

A

Growing 2 SD below the mean (<2.3 %ile)
* Extrapolation to adults: 4’11” for women, 5’3” for men
* Varies by sex and ethnicity

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2
Q

What are factors that influence height?

A
  • Social: Poor nutrition (weight percentile lower than height)
  • Vitamin D deficiency: Sunlight and supplements
  • Endocrine: Growth hormone deficiency, hypothyroidism
  • Chronic disorders:
    -Anemia, renal disease, inflammatory bowl disease (Crohns), juvenile
    idiopathic arthritis, heart disease, chronic diarrhea
  • Genetic disorders
    -Chromosomal (trisomy 21), cystic fibrosis, developmental disorders (Kabuki,
    Cornelia de Lange, and a very long list of others)
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3
Q

What does growth arrest imply?

A

New onset hormone deficiency or medical disorder

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4
Q

How do you access bone age?

A
  • Hand films most common
  • Or, X-ray films to count growth centers from half the body—more accurate, but less used
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5
Q

What is the definition of a skeletal dysplasia?

A
  • Disproportionate bones
  • Short segments of limbs
  • Abnormal upper:lower segment ratio
    -Lower segment = long bones, upper = spine and head
    -Sitting Height
  • Disproportionate head size in some
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6
Q

You have a patient with the following:
* Short stature with rhizomelia
* Macrocephaly
* Facial changes: Bossing, midface retrusion
* Exaggerated lordosis, gibbus
* Limited Extension of the arms
* Brachydactyly / trident hands

What do you suspect?

A

Achondroplasia

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7
Q

What does rhizomelia mean?

A

“Rhizo”= root
Shortening of the bones in the upper arms and thighs

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8
Q

What does “Acro” mean?

A

“Acro” = tip

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9
Q

What are complications of Achondroplasia?

A
  • Narrow craniocervical junction can compress the spinal cord
    -Hydrocephalus
    -Spasticity
    -Bladder/bowel disorders
    -Apnea –> Death in 7.5%, untreated
  • Low tone and motor delay, especially with head control
  • Restrictive lung disease
  • Sleep apnea
  • Ear infections
  • Spinal complications: Kyphosis, lordosis, spinal stenosis
  • Intelligence: normal, if no CNS complication
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10
Q

What are the Screening/interventions for Achondroplasia?

A
  • MRI of the brain at diagnosis
  • CT of the spine at diagnosis
  • Sleep study at diagnosis
    -May need tonsils out or CPAP
  • If the above abnormal, may need decompression surgery
  • Orthopedic evaluation for bowing of legs
  • Prevention of kyphosis through positioning and back support
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11
Q

What is the most common mutation causing Achondroplasia?

A

99% have one of two pathogenic variants in FGFR3:
* c.1138G>A p.Gly380Arg
* c.1138G>C p.Gly380Arg

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12
Q

What percentage of Achondroplasia is de novo?

A

80% de novo

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13
Q

What are the disorders caused by FGFR3 mutations?

A
  • Achondroplasia
  • Hypochondroplasia
  • Thanatophoric dysplasia
  • Crouzon
  • Muenke
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14
Q

What is the result of Homozygous achondroplasia?

A

Usually causes respiratory insufficiency and neonatal death

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15
Q

How is Hypochondroplasia different from achondroplasia?

A
  • Lack of rhizomelia / brachydactyly
  • Craniofacial findings subtle or absent
  • Head size more proportional
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16
Q

What is the phenotype of Hypochondroplasia?

A
  • Other changes in FGFR3
  • Milder short stature
  • CNS issues more prominent
  • Seizures, developmental delay
17
Q

What kind of skeletal dysplasia is characterized by:
* Respiratory insufficiency
* “Telephone receiver” femurs
* Often identified by prenatal ultrasound
-“Short long bones”

A

Thanatophoric dysplasia

18
Q

What is the phenotype of Campomelic Dysplasia “Bent limb”?

A
  • Autosomal dominant, SOX9
  • Distinctive facies
  • Pierre Robin sequence with cleft palate
  • Shortening and bowing of long bones, and clubfeet
  • Laryngotracheomalacia with respiratory compromise—often lethal
  • Ambiguous genitalia or 46,XY sex reversal
19
Q

What are the characteristics shared between Osteogenesis Imperfecta Types I and IV?

A
  • Multiple fractures, minimal trauma
    -Type I often improves over time
  • Short stature
  • Blue or gray sclerae (whites of eyes)
  • Weak teeth (dentinogenesis imperfecta)
  • Progressive, postpubertal hearing loss
  • Loose joints
  • Low bone density
  • Wormian bones
  • Often evaluated non-accidental trauma cases
20
Q

What are the eye findings in OI Types I and IV?

A
  • Type I: Blue sclerae, mild
  • Type IV: Gray or normal sclerae, mild-moderate
21
Q

What is the phenotype of OI Type II?

A
  • Perinatal lethal. 60% die on day 1, 80% die by 1 week, survival past 1 year very rare
  • Respiratory distress/insufficient aeration due to small rib cage
  • Dark blue sclerae
  • Extremities short, bowed
  • Thin skull, wide fontanelle
  • X-rays show “crumpled” long bones and multiple fractures
  • More recent recessive forms
22
Q

What is the phenotype of OI Type III?

A
  • Progressive deforming
  • Can have fractures from newborn handling
  • Over 200 fractures in a lifetime common
  • Bones progressively change even without fractures—70 to 90 degree angulation
  • Short stature common
  • Often require wheelchair
23
Q

What are the Intervention / screening / treatment for OI?

A
  • Orthopedic referral
  • PT/OT
  • If neurologic signs, CT scan for basilar impression
  • Bisphosphonate infusions lead to stronger bones
    -Does not decrease risk of fracture
    -Now fractures occur with higher stress
  • Family testing/tracing
24
Q

What is the phenotype of Stickler syndrome?

A
  • Micrognathia with Pierre Robin
  • High myopia – leading to retinal detachment
  • Hearing Loss
  • Hypermobility
  • Epiphyseal dysplasia – arthritis
  • Short stature
25
Q

What genes cause Stickler syndrome?

A
  • COL2A1. Autosomal dominant
  • Also, COL11A1, COL11A2 (AD), COL9A1, COL9A2, COL9A3 (AR)
26
Q

What are the facial features of Stickler syndrome?

A

Malar flattening
Flattened nasal bridge

27
Q

What are the treatments/screening for Stickler syndrome?

A
  • Orthopedics
  • Ophthalmology—protect retina with cryotherapy
  • Audiology for hearing loss
28
Q

You have a child that presents with Macrocephaly, Wide anterior fontanel, Short stature, Absent clavicles, and Abnormal dentition. What do you suspect?

A

Cleidocranial Dysplasia

29
Q

What is the genetic cause of Cleidocranial Dysplasia?

A

Loss of function alleles of the RUNX2 gene

30
Q

What is an interesting fact about SHOX deletion (Leri-Weill)?

A

SHOX is in the pseudoautosomal region
* Deletion or loss of function can be passed on as X-linked or Y-linked!

31
Q

What is a Madelung deformity and where do you see it?

A

A rare arm condition that affects the growth plate of the radius, a bone in the forearm.

SHOX deletion (Leri-Weill)

32
Q

What causes Langer Mesomelic Dysplasia?

A

Homozygous loss of SHOX

33
Q

What are cardiac defects seen in Noonan Syndrome?

A

Congenital Heart defect (50-80%)
* Pulmonic valve stenosis (20-50%)
* Hypertrophic Cardiomyopathy (20-30%)

34
Q

What are the features of Noonan Syndrome?

A
  • RASopathy
  • Short stature
  • Macrocephaly
  • Congenital Heart defect (50-80%)
  • Pectus excavatum
  • Webbed neck
  • Craniofacial: Downslanting palpebral fissures, low set posteriorly rotated ears
  • ¼ with mild intellectual disability
  • Cryptorchidism
  • Bleeding defects
  • Predisposition to juvenile myelomonocytic leukemia (JMML) with specific mutations
35
Q

What are the features of Cardiofaciocutaneous syndrome?

A
  • “Neuroectodermal Noonan”
  • BRAF, MAP2K1, MAP2K2, KRAS
  • Heart issues similar to Noonan
  • Dry skin issues—hyperkeratosis, eczema,
    ichthyosis
  • Sparse eyelashes/eyebrows
  • Sparse hair but curly, wooly, brittle
  • Neurologic problems: Dev delay,
    seizures, abnormal MRI
36
Q

What are the features of Costello syndrome?

A
  • “Noonan syndrome-cutis laxa”
  • Loose, soft skin
  • Papilloma of face and perianal region
  • Joint laxity
  • Hypertrophic cardiomyopathy
  • Arrhythmia
  • HRAS
  • Solid tumors
    -rhabdomyosarcoma and neurblastoma
    -Transitional cell carcinoma of bladder

Survey of Human Genetic Disorders Second Half (10 decks)

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