Updated: 3/8/2019

Achondroplasia

Topic
Review Topic
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Questions
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Evidence
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Snapshot
  • A 10-year-old boy is brought to the pediatric endocrinologist due to short stature. The mother reports that her son is not as tall as his classmates, and this is causing him stress. On physical exam, there is macrocephaly with frontal bossing, shortening of the arms and legs, and lumbar lordosis. Arrangements are made for genetic molecular testing.
Introduction
  • Clinical definition
    • a congenital skeletal dysplasia that results in shortened extremities and macrocephaly
      • also known as dwarfism
  • Etiology
    • autosomal dominant gain-of-function mutation in fibroblast growth factor receptor (FGFR3)
  • Pathogenesis 
    • constitutively active FGFR3 activity impairs chondrocyte proliferation and differentiation
      • this in turn leads to
        • impaired long bone formation (via endochondrial ossification)
        • enlarged head relative to limbs (via membranous ossification)
  • Associated findings
    • most common cause of dwarfism
    • normal life span, intelligence, and reproduction
Presentation
  • Symptoms
    • asymptomatic
  • Physical exam
    • macrocephaly
    • frontal bossing
    • shortening of arms and legs
      • proximal/rhizomelic segments are more notable
    • lumbar lordosis
    • kyphoscholiosis
Treatment
  • Conservative
    • monitoring, preventing, and addressing complications
      • e.g., leg bowing is managed with physical therapy
 

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Questions (4)
Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Volume  
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Urine  
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2
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(M1.MK.72) A young boy presents to your office for evaluation. He is not growing as quickly as his twin brother (Figure A). Genetic testing reveals a mutation in the fibroblast growth factor receptor gene.

What is the most likely mode of inheritance?

Review Topic

QID: 106538
FIGURES:
1

Autosomal dominant

79%

(85/108)

2

Autosomal recessive

12%

(13/108)

3

X-linked recessive

4%

(4/108)

4

X-linked dominant

3%

(3/108)

5

Mitochondrial

2%

(2/108)

M1

Select Answer to see Preferred Response

PREFERRED RESPONSE 1

(M1.MK.4722) A 3-year-old male is brought in to his pediatrician by his mother because she is concerned that he is not growing appropriately. Physical examination is notable for frontal bossing and shortened upper and lower extremities. His axial skeleton appears normal. He is at the 7th percentile for height and 95th percentile for head circumference. He demonstrates normal intelligence and is able to speak in three-word sentences. He first sat up without support at twelve months and started walking at 24 months. Genetic analysis reveals an activating mutation in a growth factor receptor. Which of the following physiologic processes is most likely disrupted in this patient’s condition? Review Topic

QID: 108535
1

Intramembranous ossification

12%

(32/274)

2

Osteoblast maturation

10%

(27/274)

3

Endochondral ossification

62%

(171/274)

4

Production of type I collagen

10%

(27/274)

5

Bone resorption

3%

(9/274)

M1

Select Answer to see Preferred Response

PREFERRED RESPONSE 3

(M1.MK.27) A 9-month-old female infant is brought in by her mother to the pediatrician because she is concerned that her daughter is not growing normally. On physical exam, the head circumference is 95th percentile and the height is 5th percentile. The child has disproportionate growth such that both the upper and lower extremities show a rhizomelic pattern of shortening, but the axial skeleton appears to be normal. The child appears to have normal intelligence, but has delayed motor milestones; specifically, she is not able to roll or sit up by herself. Which of the following best describes the mode of inheritance for this disorder? Review Topic

QID: 107010
1

Autosomal recessive

20%

(24/119)

2

Autosomal dominant

59%

(70/119)

3

X-linked recessive

6%

(7/119)

4

X-linked dominant

4%

(5/119)

5

Mitochondrial pattern of inheritance

8%

(10/119)

M1

Select Answer to see Preferred Response

PREFERRED RESPONSE 2
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