The molecular basis of human congenital limb

The molecular basis of human congenital limb malformations
Aimée Zuniga
*
, Rolf Zeller, Simone Probst
published online: 26 APR 2012 DOI: 10.1002/wdev.59
Article/wisId-WDEV59.html

Term Brief definition Human syndrome (Example) Gene affected (Examples)
Amelia Absence of at least one limb Tetra-amelia: all four limbs missing
(OMIM 273395); very rare
WNT3
Micromelia or
brachymelia
Global term for abnormally
small and imperfectly
developed limbs.
See specific terms below
Proximal and Long Bone Defects
Shoulder
girdle/pelvis
defects
Scapula and clavicle; or
pelvic and pubic bones are
malformed.
Cleidocranial dysplasia (OMIM 119600) RUNX2
Frequency 1:10
6
Ectromelia Long bones are missing or
shortened
See specific terms below
Phocomelia Long bones are shortened
or absent in one or several
of the extremities. Hands
and/or feet are present, but
often malformed.
The teratogen thalidomide can cause
limb phocomelia (Box 1)
Hemimelia Shortening or absence of
one of the distal long bones
(ulna, radius, tibia or fibula).
Holt-Oram syndrome (OMIM 142900) TBX5
Frequency 1:10
5
Synostosis Fusion of adjacent bones. Craniosynostosis type 1 (OMIM
123100)
TWIST1
Sirenomelia
(Symmelia)
Legs are fused. Sacra defect with anterior meningocele
(OMIM 600145)
Unknown
Mostly fatal due to kidney
malformations
Hand and Foot Anomalies
Adactyly All digits are absent Unknown
Acheiria Missing hands or feet Acheiropody (OMIM 200500); very rare. SHH enhancer (Box 2)
Syndactyly Fusion of digits. In ‘osseous
syndactylies’ bones are
fused. In ‘cutaneous
syndactylies’ the soft tissue
is affected
Cenani-Lenz syndrome (OMIM
212780); rare
LRP4 gene or GREM1-FMN1 landscape

Hypodactyly or
Oligodactyly
Fewer than five digits. Cenani-Lenz syndrome patients can be
affected by oligodactyly
See above
Brachydactyly Digit length shorter than
usual.
Autosomal-dominant Brachydactyly
(BDA), several types
IHH (BDA1) BMPR1 , GDF5 (BDA2), ROR2 (BDB1)
NOG (BDB2) GDF5 (BDC) HOXD13 (BDD, BDE1)
OMIM 112500, 112600, 113000,
611317, 113100, 113200, 113300,
613382
Ectrodactyly/Split
-hand and split-
foot
malformations
Deficiency or absence of
middle digits resulting in a
split autopod.
Split-hand and split-foot malformation
(SHFM1-6, OMIM 183600, 313350,
246560, 605289, 606708, 225300)
DLX5/6 (SHFM1)
TP63 (SHFM4)
HOXD cluster (SHFM5)
WNT10B (SHFM6)
Polydactyly: pre-
axial, post-axial,
central
Formation of additional
digits.
Greig's Cephalopolysyndactyly (OMIM
175700)
GLI3
The number of
supernumerary digits can
vary from one to several.
‘Pre-axial’ refers to extra
digits on the side of the
thumb and ‘post-axial’ refers
to extra digits on the side of
the little finger. ‘Central’
polydactylies result in
duplications of middle digits.
Mutations altering SHH directly or indirectly
!