Thanks to the collective expert appraisal process set up by Santé publique France and ANSES, the study was conducted with full independence and transparency, and with the involvement of all the stakeholders. Two committees were set up: the Expert Committee (CES), which brings together 20 experts from different disciplines, and the Steering and Monitoring Committee (COS), which brings together all the stakeholders concerned by these cases of TAUL, including parents of children with this malformation.
A collective expert appraisal taking citizens’ hypotheses into account
In accordance with its mission, the Expert Committee has endeavoured to identify and analyse the hypotheses on the causes of these possible clustered cases of Transverse Agenesis of the Upper Limbs. Its work and recommendations have taken into account all the available data and hypotheses without exclusion. To achieve this objective, the Expert Committee relied in particular on the questions formulated by the COS and the work carried out by Santé publique France and ANSES in their fields of expertise, in addition to data from the registers.
To take citizens’ contributions and expectations into account, a temporary reporting system was also set up. In all, 143 reports concerning individuals with malformations and 43 contributions on hypothetical causes were analysed and addressed during the expert appraisal.
The need to accurately define and diagnose TAUL
The CES first endeavoured to clarify the definition of Transverse Agenesis of the Upper Limbs (TAUL). TAUL is a transverse anomaly, affecting only one limb. It is also isolated, which means that no other tissue or organ is involved. It may be difficult to diagnose because it can be confused with other types of defects whose genetic or mechanical origins are known. It is therefore important to ensure that there are no associated malformations, however minor they may be, that could lead to another diagnosis.
Birth defects, including TAUL, remain rare. They account for 3% of births in the world (TAUL affects 1.7 births per 10,000) and their prevalence rate is generally stable.
It is the occurrence of a greater number of cases than expected clustered in time and space that constitutes an alert that may justify additional investigations.
The CES considered it necessary for a group of experts to review all the medical records of children with TAUL reported in Brittany and the Ain département. This review, which was carried out anonymously and without geographical affiliation, revealed that some of the cases reported as TAUL were not actually TAUL. On the basis of this review, the CES validated three cases of TAUL in the town of Guidel, Brittany, over an 18-month period between 2011 and 2013, and confirmed the suspicion of a cluster for these cases. Additional investigations will therefore be carried out in this region to further explore any possible common exposures.
For the Ain département, the Expert Committee confirmed six cases of TAUL between 2011 and 2015 but, after statistical analysis, concluded that these did not represent a cluster.
As Loire Atlantique does not have a malformation register, the collection and examination of medical records is ongoing.
In the event of an alert, this analysis highlighted the importance of providing an accurate diagnosis of congenital malformations. This diagnosis must be made by a geneticist from one of France’s Rare Disease Reference Centres certified for developmental defects.
Stepping up monitoring and care for the families concerned
Following a detailed analysis of the surveillance and warning system for congenital malformations in France, the Expert Committee has put forward a series of recommendations to strengthen monitoring and provide rapid assessment in the event of an alert. In addition to the creation of a seventh register and better coordination of the registers, the CES recommends using the French National Health Data System (SNDS) and health professionals — in particular sonographers and multidisciplinary prenatal diagnosis centres — to set up a nationwide system for reporting suspected clustered cases.
The Expert Committee has also proposed ways of improving the support and counselling given to the families affected by TAUL and other congenital malformations. Information and training initiatives for health professionals should also be developed.
Identification of possible environmental risk factors: work on an unprecedented scale
In order to identify possible new risk factors for these malformations, an in-depth literature review taking into account citizens’ hypotheses was initiated by ANSES and Santé publique France. More than 20,000 scientific articles were selected based on keywords validated by the CES. Regulated chemicals were also reviewed. Ongoing work will better characterise and prioritise potential environmental risk factors, which will be the subject of a second report.
Because no risk factors for TAUL have yet been identified, and due to the rarity of these malformations, the CES does not recommend carrying out a large-scale epidemiological investigation, which would require several decades of observations. However, the CES considers that there is currently insufficient knowledge on the environmental causes of developmental defects and recommends increasing the research capacity on this subject.
 A cluster (or “clustered case”) is the grouping in time and space of cases of diseases, symptoms or health events within a local population.
 The space-time scan statistic (Kulldorff, 1998) was used to identify clustering.