The manuscript by Salima El Chehadeh and colleagues reports clinical and molecular findings of pEDS in 11 individuals from 7 independent families. This is an interesting and relevant study but the manuscript is somewhat superficial and could benefit from a more thoughtful and detailed presentation of data.

The morphological features of pEDS are generally interesting and deserve a detailed description. Nevertheless, the images are very small and fuzzy, and it would be good to have quality images. This should include photographs from other affected individuals to confirm that the depicted features are indeed typical for pEDS, as claimed in the table. Showing more photographs is particularly relevant since F2P1 had anorexia nervosa which in itself may explain part of the phenotype. I assume that all patients provided informed consent for publication of (facial) photographs?

The oral images are rather non-instructive (sometimes useless) and should be replaced by professional photographs. What is the point of showing an X-ray of complete dental loss?

Why was trio exome sequencing performed in family 1 when the diagnosis was made clinically? Individual F1P1 presumable had two children but these are not depicted in the pedigree. How certain are the authors that the healthy 2 year-old daughter and the 11-year-old son with joint hyperlaxity and pectus carinatum are NOT affected by pEDS? Was gingival attachment reliably normal, and if yes was there any particular explanation for the connective tissue abnormalities (? true joint hyperlaxity?) in the boy? F1P1 is one of the individuals depicted in the figure, could there be another connective tissue condition in the family? More interesting than some of the tiny images in the figures would be a high resolution MRI image of individual F1P1 to allow a closer look at the 4 mm white matter lesion. Were there any other white matter abnormalities, as reported in basically all adult persons with pEDS? Same questions is also relevant for individual F4P1.

If I read the case reports correctly, venous insufficiency was only proven in a single patient, F1P1, and full vascular assessment in other individuals gave normal results. It is therefore somewhat premature to claim that pEDS should be added to the rare genetic causes of early-onset venous insufficiency. Rather it would be good to check other affected individuals for venous obstruction or valvular incompetence to confirm that venous insufficiency is present.

In the conclusions the authors recommend early diagnosis for “vascular monitoring, including both arterial and venous assessments”. However, they do not provide any evidence that doing so is helpful for the affected individuals. Are there any data showing that early and presumably regular “vascular monitoring” would be of clinical benefit? What recommendations are given in France for evidence-based clinical management of pEDS patients?

It is a pity that only a minority of individuals in the large families 4 and 7 were studied. It is claimed that several individuals in family had serious arterial manifestations without stating any clinical evidence that they indeed had pEDS. If clinical descriptions are in the supplement only, why not include every affected individual from all families? A detailed pEDS questionnaire has been published that could provide important clinical information if physical examination and genetic confirmation is not possible.
How certain are the authors that younger individuals not marked as affected indeed do not have pEDS?

Would the authors claim that chronic weakness (asthenia?) is a prominent manifestation of pEDS? How as this assessed?

How was it determined that the nails are fragile?

The molecular data are quite superficial. It would be relevant to review the proposed functional effect of the individual variants identified in the patients. Merely stating that the affected cysteines have a “key role … in maintaining the flexibility and the function of the C1 complex” is rather meagre. Functional studies may have been interesting particularly in the affected individuals with C1S variants.

Other details

I would groups methods and results together, rather than giving a very brief “materials and methods” section. Indeed, it would be good to give the relevant clinical information in more detail in the main paper rather than as supplementary material.

The pedigrees should follow the international nomenclature, and the numbering should be in line with the rest of the manuscript. Actually, I do not think that the family trees are necessary when only a small proportion of individuals has been studied – and as the pedigrees make some families identifiable they should be removed. Alternatively the authors should provide informed consent for publication of the pedigrees.

The legend to the table seems to relate to a different text.

I assume that do novo occurrence of the pEDS variants was proven by confirming absence in the parent in all cases? This should be stated.

On protein level the “r” and “s” of C1r and C1s are written with small letters. This should be followed consistently throughout the manuscript
It may be good to give the names of the novel C1R and C1S variants in the abstract.

Abstract line 29: “instigate” (not investigate) vascular monitoring

Thank you for the substantial revision.