Summary
A bioRxiv preprint analyses 435 thalidomide-affected limbs and proposes that the unusual order of bone reductions follows the sequential exit of developing bones from a sensitive window.
A bioRxiv preprint proposes a developmental explanation for the unusual order in which thalidomide-related limb reductions appear. The analysis covered 435 affected limbs from published records between 1962 and 2025, including 269 upper limbs: 142 from humans and 127 from non-human primates.
The authors argue that the pattern reflects when different bone precursors leave a period of developmental sensitivity. In this model, exposure during limb growth affects structures that are still within that sensitive window, while structures that have matured earlier are less affected.
From the thumb towards the little finger
The reconstructed order of upper-limb reduction is:
Digit 1 → radius → humerus → digit 2 → ulna → digit 3 → digit 4 → digit 5
Digit 1 is the thumb and digit 5 is the little finger. The radius and ulna are the two forearm bones, while the humerus is the upper-arm bone. The sequence therefore begins with structures on the thumb side, reaches the upper arm, and then returns through the ulna and the remaining digits towards the little-finger side.
The order was reconstructed using what the preprint calls forward-chain assembly. The analysis also examined co-reductions, in which more than one bone is reduced together. It identified two ordering rules. Within a limb segment, a bone is not reduced before every bone positioned anterior to it has also been reduced. Among the most posterior bones of the three major limb segments—digit 5, the ulna and the humerus—a bone is not reduced before all bones closer to the body have been reduced.
In developmental anatomy, the hand is the distal limb segment, the forearm is the intermediate segment and the upper arm is the proximal segment. This terminology helps describe the second part of the proposed pattern.
A two-axis maturation wave
The preprint interprets the rules as the result of a maturation wave moving in two directions. Within the hand, the proposed progression runs from digit 5 towards digit 1. Across the forearm, it runs from the ulna towards the radius. Across the limb segments, it moves from the hand towards the upper arm.
Combined into one sequence, the proposed order of exit from the sensitive window is:
Digit 5 → digit 4 → digit 3 → ulna → digit 2 → humerus → radius → digit 1
A sensitive window is a period during embryonic development when a tissue or structure is especially vulnerable to a particular disturbance. The paper's model treats a co-reduction as a snapshot of the bones that are still sharing such a window when exposure occurs.
The model also uses the concept of a progress zone, the actively growing region of a developing limb. According to the proposed explanation, exposure while the limb is elongating can truncate structures proximal to that zone. If exposure occurs later, only the bone precursors that have not yet matured are reduced. This timing-based mechanism is intended to explain why thalidomide-related reductions can follow a characteristic but apparently non-linear order.
The evidence is a retrospective reconstruction of published human and non-human-primate limb records, not a new exposure experiment or clinical study. The work is currently presented as a bioRxiv preprint, so its proposed sequence and developmental interpretation remain subject to peer review and further testing.