By Keith S. Wexler, MBA, Maternal Fetal Medicine, Prenatal Diagnosis and Biotech/Life Sciences Consultant, GENASSIST, Inc.
Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.
Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center
Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital
- Dwarfism: Short stature that results from a medical or genetic condition, usually defined as 4 feet 10 inches or less.
- Dysplasia: Term used to define abnormal growth or development.
- Achondroplasia: Most common form of short stature with short arms and legs.
- Thanatophoric Dysplasia: [Thanatos (death); Phoric (bearing] – A severe form of congenital dwarfism which results in early death. Second most common form of fatal dysplasia to Osteoporosis Imperfecta.
Background: We saw a couple for a prenatal consultation due to the father of the baby having a family history of a female paternal cousin that died in the neonatal period of a fatal form of dwarfism. The family wanted to know the recurrence risks even though the child was never tested to see which type of dwarfism she had.
There are many types of abnormal growth or development resulting in short stature. Most cases of dwarfism are not fatal. Most causes of dwarfism are not from a chromosomal abnormality. Causes of dwarfism can be genetic, familial, environmental, dietary or metabolic.
Early Fatal types of dwarfism are uncommon with most being due to spontaneous or new (denovo) mutations in genes which control growth and other vital organ functions.
Thanatophoric Dysplasia usually results in fetal demise or early neonatal loss usually due to pulmonary insufficiency. Mutations in the FGFR3 gene on chromosome 4p16.3 have been described. Mutations in this same gene are believed to be responsible for Achondroplasia.
Thanatophoric Dysplasia is one of the rare dysplasias (the incidence of occurrence is approximately 1 in 20,000 to 1 in 50,000 births). Theoretically, the risk of recurrence is approximately the same as the mutation happening the first time. The greatest risk for recurrence quoted in the literature is approximately 2% which is at the low end for the birth of a child with a birth defect (general population risk 3% to 5% for a birth defect).
Fatal Achondroplasia is usually due to the inheritance two abnormal genes, one from each parent with Achondroplasia.
Microcephalic Osteodysplastic Primordial Dwarfism recently has been described as an autosomal recessive inherited disease due to a mutation in the RNU4ATAC gene on chromosome #2q14.2.
Many types of non-fatal dysplasia have been attributed to mutations in the COL2A1 gene on chromosome 12q11. Autosomal dominant types include:
- Kniest Dysplasia
- Legg-Calve-Perthes Disease
- Platyspondylic Lethal Skeletal Dysplasia
- Spondyloepimetaphyseal Dysplasia
- Spondyloperipheral Dysplasia
- Spondyloepiphyseal Dysplasia
- Stickler Syndrome
Autosomal Dominant Pseudoachondroplasia is believed to be due to a mutation in the cartilage oligomeric matrx protein (COMP) gene.
X-Linked Spondyloepiphyseal Dysplasia has been attributed to a mutation in the TRAPPC2 gene on the X chromosome.
Great care needs to be taken during pregnancy especially when ultrasound is performed to make sure that “ultrasound markers” that might be an indication for a chromosomal abnormality (ie. Down Syndrome) are not confused with a baby that is simply “short stature”.
Trisomy 21 (Down Syndrome) “Ultrasound Markers”:
- Nuchal fold equal or greater than 5 mm up to 18 weeks gestation , equal to or greater than 6 mm at 18 to 22 weeks gestation
- Echogenic bowel
- Frontal lobe greater than or equal to 2 weeks smaller than dates
- Tricerebellar diameter greater than or equal to 2 weeks smaller than dates
- Bilateral hydronephrosis/pyelectasis greater than or equal to 4 mm
- Missing, small bone or triangular middle phalanx in the fifth digit (pinky)
- Splaying of hips greater than or equal to 90 degrees
- Big toe spread from the rest of the toes
- Humerus greater than or equal to 2 weeks smaller than dates
- Femur greater than or equal to 2 weeks smaller than dates