ERN-Cranio’s EU Clinical Practice Guidelines for Pierre Robin Sequence

When EU Guidelines for a rare disease are officially rejected by the EU’s top two experts on that rare disease, then the EU Guidelines are nonviable.


Wednesday 30 March 2022

From: Philippe Pakter
Date: Wednesday 30 March 2022
Subject: Request for final approval of the European Guideline on Robin Sequence
To: Dr. Irene Mathijssen
CC: All members of the ERN-Cranio Guideline Development Group for Pierre Robin Sequence
Dear Dr. Irene Mathijssen, Coordinator, ERN-Cranio,

Yesterday I asked an ERN-Cranio physician to share with me the final version of ERN-Cranio’s EU Clinical Practice Guidelines for Pierre Robin Sequence, because neither you nor your colleagues gave me access to these files. I went straight to the chapter on first line treatments. I read the following.

“Clinicians and many families will be aware of the general recommendation for infants is to be nursed in the supine position to reduce the risk of sudden death infant syndrome (SIDS), however, prone positioning is widely accepted and effective in up to approximately three-quarter of the RS patients. Close monitoring of O2 saturation should prevent SIDS… Positioning treatment is easily taught and there are few harms associated with this intervention although escalation of care must occur in non-responders.”

Our understanding of evidence-based medicine is that it involves a careful review of the medical literature in order to evaluate the benefits and harms of various interventions, according to objective criteria. Objective criteria in the context of Pierre Robin Sequence is polysomnography, the gold standard for objectively measuring the severity of upper airway obstruction among Pierre Robin Sequence babies.

Concerning benefits: these ERN-Cranio EU Guidelines recommend prone positioning as a first line treatment, based on the claim that prone positioning is “effective in up to approximately three-quarter of the RS patients”. However, a 2021 systematic review study published by the international Pierre Robin Sequence consensus movement – international Pierre Robin Sequence experts from all over the world – stated the following: “Three studies used PSG to estimate the effect of prone positioning and demonstrated that it did not completely resolve OSA in the majority of infants.” Thus, the number of evidence-based studies which actually relied on PSG to objectively gauge the benefits of prone positioning is extremely low – and in these studies, prone positioning failed to resolve OSA in the majority of cases.

Concerning harms: these ERN-Cranio EU Guidelines recommend prone positioning based on the claim that “there are few harms associated with this intervention”. However, according to a landmark paper on SIDS published in the Lancet (“Sudden unexplained infant death in 20 regions in Europe: case control study”), prone sleeping increases a baby’s risk of SIDS by over 13 times. Once again, ERN-Cranio’s EU Guidelines: “there are few harms associated with this intervention”; and the Lancet: a 13 times increase in the risk of SIDS.

ERN-Cranio’s EU Guidelines state that “Close monitoring of O2 saturation should prevent SIDS”. No evidence at all is provided in support of this statement – and it gets worse. This close monitoring of O2 saturation which “should” prevent SIDS is entirely optional: “Consider positioning therapy (either prone or lateral positioning with or without a saturation monitor) as first-line to relieve mandibular-related OSA or UAO”.

The benefits of the intervention are exaggerated; the risks are minimized; contradictory studies are omitted outright – and, for good measure, these Guidelines engage in sheer speculation (monitoring “should” prevent SIDS). Dr. Irene Mathijssen, as Coordinator of ERN-Cranio, you accepted EU funds on the basis that you would produce evidence-based Guidelines of care for the EU. We and others – including some of the most internationally renowned Pierre Robin Sequence experts in the world – believe that this is not evidence-based medicine. What other critical evidence is distorted or omitted, how many other unsupported statements and recommendations might be found, scattered throughout this document?

In a June 2021 letter we warned Dr. Andrzej Rys, Director, European Commission DG SANTE, and Prof. Till Voigtländer, Co-chair of the ERN Board of Member States, that this is exactly what would happen, and this would be the inevitable result, of an allegedly “EU” Guideline development project for a rare disease which intentionally excluded the EU’s top two experts in that rare disease. When an allegedly “patient-centered” Guideline working group included not a single Pierre Robin Sequence patient or parent – not one single Pierre Robin Sequence patient or parent – a shocking situation which continues to this day. “It is expected that all stakeholders should strive to adhere to the recommendations set out in this Chapter”. We who represent the ultimate stakeholders, babies suffering from this life-threatening rare disease, reject this document.

It has been brought to our attention that your hospital, Erasmus Rotterdam Medical Center, and the Great Ormond Street Hospital in London, may be bound together in a relationship with a certain American body, ICHOM, involving common financial and funding interests. This pre-existing relationship between Erasmus Rotterdam MC, and the Great Ormond Street Hospital in London, potentially creates the impression of a perceived conflict of interest. Erasmus Rotterdam MC, which is in charge of ERN-Cranio, favored the Great Ormond Street Hospital, and included the Great Ormond Street Hospital in this EU project – in spite of the fact that the Great Ormond Street Hospital is not a member of ERN-Cranio. At the very same time, Erasmus Rotterdam MC excluded the EU’s top two experts on this rare disease, on the exact same basis – that they were not members of ERN-Cranio. We will ask the research oversight boards to investigate this matter, because if the EU’s top two experts on this rare disease had not been arbitrarily excluded from this EU project by Erasmus Rotterdam MC, then the “final version” of this “EU” Guideline we are discussing today would be a higher quality document.

As ERN-Cranio’s official ePAG patient organization representing Pierre Robin Sequence patients, we request an invitation and link to participate in the upcoming discussion scheduled for 31 March 2022 concerning this EU document which was produced about us, without us.

Best regards,

Philippe Pakter
Philippe Pakter
Chairman, Pierre Robin Europe: ERN-Cranio’s official patient organization for Pierre Robin Sequence
Member, EURORDIS, The European Organisation for Rare Diseases
Member, VSOP, Vereniging Samenwerkende Ouder-en Patiëntenorganisaties
PhD candidate, law: “Access to healthcare in Europe: the effectiveness of EU legislation in the context of rare disease patients”

Friday 18 March 2022

From: Philippe Pakter
Date: Friday 18 March 2022
Subject: Request for final approval of the European Guideline on Robin Sequence
To: Dr. Irene Mathijssen
CC: All members of the ERN-Cranio Guideline Development Group for Pierre Robin Sequence
Dear Dr. Irene Mathijssen, Coordinator, ERN-Cranio,

You have released the final version of the EU Clinical Practice Guidelines for Pierre Robin Sequence.

The EU’s top two experts on Pierre Robin Sequence, Prof. Dr. Christian Poets at the Tübingen University Hospital, and Prof. Dr. Corstiaan Breugem at Amsterdam University Medical Center, have both formally rejected them.

When EU Guidelines for a rare disease are officially rejected by the EU’s top two experts on that rare disease, then the EU Guidelines are nonviable.

As ERN-Cranio’s Coordinator you may now be considering the option of moving forward anyway and rushing to publication, over the serious critiques of your internationally respected colleagues – Prof. Dr. Corstiaan Breugem, Prof. Dr. Siegmar Reinert, Prof. Dr. Christian Poets, Prof. Dr. Bernd Koos, and others. The ERN Coordinator is responsible for the way this project has been managed; in the same way you will be held responsible for what comes next. My colleagues and I are in touch with various Dutch and international bodies, including formal research oversight boards. They will receive a copy of this email and they will consider a number of issues, including the following.

  • In developing these PRS Guidelines, Erasmus MC intentionally excluded the EU’s top two experts on this rare disease: Prof. Dr. Corstiaan Breugem, and Prof. Dr. Christian Poets. Prof. Dr. Corstiaan Breugem organized the world’s first international PRS consensus meeting, thereby launching the international PRS consensus movement; he has also published more research on PRS than any physician we know of in the world today.
  • Erasmus MC also excluded Prof. Dr. Christian Poets, of the Tübingen University Hospital, who manages the multidisciplinary team of highly specialized experts which administers a breakthrough PRS treatment, the Tübingen Palatal Plate. The Tübingen Palatal Plate has been adopted by Stanford University, and by Harvard University – with training and support from Prof. Dr. Christian Poets and his team.
  • Although Erasmus MC excluded these two world-class PRS experts from this EU-funded PRS Guideline development project, Erasmus MC is not itself an Orphanet Center of Expertise for PRS, which makes the exclusion of the EU’s top two PRS experts even more troubling.
  • ERN-Cranio, in order to justify the exclusion of these two world-class PRS experts from this PRS Guidelines project, stated in writing that “we are not allowed to involve centers outside the ERN CRANIO network”. There is no such rule. Furthermore Erasmus MC’s Dr. Eppo Wolvius, who made this statement, knew when writing it that the Great Ormond Street Hospital, which is “outside the ERN CRANIO network”, was involved in this project – because he and others at Erasmus MC were working on the Guidelines alongside the Great Ormond Street Hospital physicians. Openness and transparency are absolutely vital for high quality research; arbitrary decision making based on relationships and politics make it impossible to achieve top quality research results.
  • In September we received a letter from the Dutch Ministry of Health indicating that ERN-Cranio had informed the Dutch Ministry that these top two PRS experts were now a part of this PRS Guideline development project. Nevertheless in November 2021, when ERN-Cranio organized a meeting in Rotterdam to discuss these PRS Guidelines, Prof. Dr. Corstiaan Breugem and Prof. Dr. Christian Poets were both excluded. Prof. Dr. Corstiaan Breugem, whose PRS research volume exceeds that of any living PRS expert, is based in Amsterdam. Thus ERN-Cranio excluded from this important PRS Guideline development meeting a PRS expert with incomparable PRS research experience, who was located only 80 kilometers away.
  • Under additional pressure from the Dutch Ministry of Health, ERN-Cranio finally permitted these two experts to provide written feedback on the draft document which ERN-Cranio had produced without them. In our 13 December 2021 letter to the German Health Minister Dr. Karl Lauterbach, we described some of the serious serious flaws, medical inaccuracies, misinterpreted research, unsupported conclusions, overlooked medical studies, and multiple forms of bias, which the Tübingen University Hospital identified in ERN-Cranio’s late 2021 draft.
  • From the perspective of research quality, the key question is this: what did ERN-Cranio do with this feedback? ERN-Cranio largely ignored it. After reviewing the most recent draft of these PRS Guidelines, the final version, the Tübingen University Hospital indicated the following. “Most of our comments submitted on Nov 4 were not included in the set of documents the Rotterdam team created… They were apparently largely treated as if non-existing.” Once again this is PRS knowledge and expertise submitted by a world-class PRS Center of Expertise, the Tübingen University Hospital, which has achieved a medical breakthrough in PRS care, a breakthrough which has been adopted by Stanford and Harvard. Top quality evidence-based research requires at a bare minimum that all scientific evidence is considered – particularly if the evidence is presented by an internationally recognized expert.
  • The Dutch Ministry of Health asked Erasmus MC if they were including PRS patients in the Guideline Development Group. The response from ERN-Cranio was to bring in Mr. Gareth Davies. Mr. Gareth Davies is a very dear man, but he represents patients with cleft lip/cleft palate. The goal of this project however was to develop Guidelines of care for PRS. There is a stark difference between cleft lip/cleft palate, and PRS – a complex heterogeneous rare disease characterized by high morbidity, high mortality, and a high level of associated conditions.
  • ERN-Cranio has an official patient group representing PRS patients; it is called Pierre Robin Europe. Starting in April 2021 Pierre Robin Europe raised valid, serious questions about the way this research project was being managed. Our most serious concern was the exclusion from the PRS Guideline development group of the EU’s top two PRS experts. Pierre Robin Europe also protested the fact that there were zero patients in the Guideline Development Group. ERN-Cranio responded to the valid concerns we had raised by excluding us completely, and in our place using a substitute who does not represent patients suffering from this complex life-threatening rare disease. ERN-Cranio excluded Pierre Robin Europe from every single meeting which has ever been held in relation to these PRS Guidelines. We at Pierre Robin Europe have not had the opportunity to interact with a single healthcare provider in the Guideline Development Group. Many, perhaps most of the healthcare providers in the Guideline Development Group do not know that we exist. We, ERN-Cranio’s official patient organization representing the PRS rare disease community, were not involved in the discussion of the scope of these PRS Guidelines. We were not involved in the discussion of the clinical questions which the Guidelines would address. We were not permitted to share our perspective on the relative importance of the clinical questions. We were not given the chance to rate the importance of outcomes. A local Dutch company called Qualicura was hired to provide training for the members of the Guideline Development Group, training which was paid for by the EU; we were not told that such training was taking place. We were not invited to the November 2021 meeting in Rotterdam to discuss these Guidelines. We were not even sent a copy of the final version of these EU Guidelines. We are not on the Guideline Development Group’s email recipient list. We are ERN-Cranio’s one and only PRS patient organisation, and ERN-Cranio excluded us altogether. Quality research is absolutely impossible when those who raise valid questions, or who present dissenting views, are marginalized or excluded.
  • The highly respected Coordinator of another ERN, after learning how this project in ERN-Cranio was being managed, signed an official letter of complaint to Prof. Dr. Karl Lauterbach, the German Health Minister, a fact which can be confirmed through the Minister’s office.

The EU’s European Reference Networks are legally mandated to produce evidence-based patient-centered rare disease Guidelines of care, drawing upon the top rare disease experts in the EU. ERN-Cranio had all the resources it needed to produce outstanding PRS Guidelines. In support of this work, the European Commission spent approximately 4,000,000 Euros of EU taxpayer money (Tender N° SANTE/2018/B3/030) to create an official EU Methodology for the ERNs to use when developing Clinical Practice Guidelines for the EU’s rare disease community. The European Commission spent 100,000 Euros of EU taxpayer money (Tender N° SANTE/2017/B3/083) to hire a contractor to develop templates and documents for the ERNs. The European Commission DG SANTE informed us, Pierre Robin Europe, in a letter dated 1 October 2021 (Ref. Ares(2021)5983971), that the European Commission spent an additional 50,000 Euros of EU taxpayer money to provide ERN-Cranio with direct financial support, for this PRS Guideline development project. The financial resources were available. The necessary infrastructure and tools were available. Most importantly, the EU’s top two PRS experts were available – and they were ready, willing, able, and eager to contribute. So too was Pierre Robin Europe, ERN-Cranio’s official PRS patient organisation. In spite of the promising opportunity and abundant resources, this project has failed. The failure is managerial in nature, and the responsibility falls upon the Coordinator of ERN-Cranio. A formal, fully open and transparent investigation will follow.

Kind regards,

Philippe Pakter
Chairman, Pierre Robin Europe: ERN-Cranio’s official patient organization for Pierre Robin Sequence
Member, EURORDIS, The European Organisation for Rare Diseases
Member, VSOP, Vereniging Samenwerkende Ouder-en Patiëntenorganisaties
PhD candidate, law: “Access to healthcare in Europe: the effectiveness of EU legislation in the context of rare disease patients”

From: Dr. Corstiaan Breugem
Date: Saturday 12 March 2022
Subject: Request for final approval of the European Guideline on Robin Sequence
To: Dr. Eppo Wolvius; Mr. Gareth Davies
CC: Dr. Irene Mathijssen; All members of the ERN-Cranio Guideline Development Group for Pierre Robin Sequence

Dear Eppo,

I would like to congratulate you and your team for doing a lot of work.

When I support a Guideline, I make sure I support something that we can always comply to. It should not be the “ideal” world, but it should be practical and achievable, based on the current literature or include experts in the field. If I do not follow the guideline, there should be a good reason, and this should not happen regularly. Last year I gave you reasons why I think this current guideline is not a practical guideline. It does also not include some relevant literature.

We were given the opportunity to give suggestions in October 2021. I see that many have not been included. My pediatricians for instance say that it is not practical to say that everybody should have a “PSG” before and after palatoplasties and pharyngoplasties. We work in a National reference centre for Robin sequence and see many patients. This is just not practical. Also simply saying a “PSG” is not enough. What criteria do we agree upon are safe to do surgery. Do we really need a PSG in every patient before and after surgery. Maybe in an ideal world. What other ways eg questionnaires, lab test are more practical and should performed, before we suggest doing a PSG in everybody. We feel that suggestions are made in this guideline that are not in reality with what can be achieved in practical care.

I also have a problem with the name “European Guideline”. The European Reference Network includes specialized centers in Europe and is not representative of the whole of Europe. I think at the most, you can call this a ERN Guideline. I am unsure if the ERN has the authority to call this a European Guideline because no National Cleft Association has been involved in the development of this guideline.

Although I see that you and your team have incorporated a lot of effort in this guideline, I am sorry to say, but we cannot support this in its current form.

Best wishes

Corstiaan

Kind regards

Prof. dr. Corstiaan Breugem (MD PhD)
Professor in Plastic and Reconstructive Surgery
Head Pediatric Plastic Surgery
President Dutch Cleft Palate Craniofacial Association
Vice-president European Cleft Palate Craniofacial Association

Department of Plastic Reconstructive and Hand Surgery
Amsterdam UMC, Emma Children’s Hospital
Location AMC, University of Amsterdam|
Room J1A. 210 | Meibergdreef 9, 1105 AZ Amsterdam
The Netherlands

 

 

 

From: Prof. Dr. Christian Poets
Date: Wednesday 2 March 2022
Subject: Rejection of request for final approval of the ERN Guideline on Robin-Sequence
To: Dr. Eppo Wolvius
CC: All members of the ERN-Cranio Guideline Development Group for Pierre Robin Sequence

Dear Eppo,

Thank you for sending the latest version of this guideline. After careful consideration, the Tuebingen team came to the conclusion that we have to reject this guideline in its present form. Please find our reasons for this decision outlined in the enclosed letter and in our annotations to chapters 1&2 (also enclosed).

We look forward to hearing from you.

Kind regards,

Prof. Christian F. Poets, M.D.
Medical Director
Dept. of Neonatology | Children’s Hospital
Calwerstraße 7 | 72076 Tübingen

A parent’s view on the care of their baby with Pierre Robin Sequence

A patient’s perspective on rare disease care. From “Seminars in Fetal & Neonatal Medicine”.


Feedback:

“Thanks, Philippe – this is tremendous and it emphasises the need or should I say absolute imperative that we obtain and heed the patient / parent perspective in the approach to rare diseases. This certainly provides aspects that we do not read about in the textbooks.”

– Prof. Dr. Peter A. Mossey
Professor and Personal Chair of Craniofacial Development & Dentofacial Orthopaeds, the University of Dundee; Associate Dean for Research; Director of WHO Collaborating Centre for Craniofacial Anomalies and Technology Transfer

 

A parent’s view on the care of their baby with Robin sequence

Abstract

A Robin sequence parent presents the view that Robin sequence healthcare providers are engaging in practices which may be outdated, excessively invasive, and unnecessarily detrimental to quality of life, and proposes possible areas of research to improve patient outcomes.

 

Abbreviations

AHI – Apnoea Hypopnoea Index

CPAP – Continuous Positive Airway Pressure

ICU – Intensive Care Unit

MDO – Mandibular Distraction Osteogenesis

OA – Obstructive Apnoea

RS – Robin sequence

SIDS – Sudden Infant Death Syndrome

TLA – Tongue Lip Adhesion

TPP – Tübingen Palatal Plate

UAO – Upper Airway Obstruction

US – Ultrasound

 

1. Introduction

I am the parent of a child named Lysiane who was born in France in 2017 and diagnosed with Robin sequence (RS). I am the chairman of Pierre Robin Europe, an RS patient advocacy organization based in the Netherlands. I am currently earning a PhD in cross-border healthcare law at the University of Geneva.

In this article I will present thoughts and suggestions concerning RS care, based upon my own experience as an RS parent. I will then conclude with five general recommendations, which may be applied more broadly to all rare disease care.

RS is a rare disease affecting approximately 1 in 10 000 babies. It is characterized by micrognathia, glossoptosis, and Upper Airway Obstruction (UAO). RS presents two main symptoms, of varying severity: UAO, and feeding difficulties. Treatment options include both non-surgical and surgical techniques.

 

1.1. Prenatal diagnosis and counseling

A prenatal diagnosis of RS can reduce trauma, improve care, and save lives; however the prenatal warning signs of RS are sometimes missed. Prenatal ultrasound (US) images showed that my daughter had severe micrognathia; this went unnoticed by the US team. The US team did however make note of polyhydramnios, over multiple screening sessions. Micrognathia and polyhydramnios are known potential warning signs of RS – but no RS flags were raised. This was at a tertiary care hospital in a major European city. Based on my ongoing contact with hundreds of other RS parents across Europe and America, this situation is not uncommon, and suggests that we need better criteria on how RS can be identified during prenatal US.

As a parent I am greatly encouraged by the promising research which is being carried out to improve the prenatal diagnosis of RS [1]. An early diagnosis of any disease benefits healthcare providers, patients and families in multiple ways. Also, many RS babies suffer from one or more associated conditions; a red flag for RS would alert clinicians of the need to vigilantly search for these associated conditions. Finally, the mandible is “a common site for defects associated with genetic conditions, a good number of which can be recognized prenatally” [2]. Additional time invested in studying the mandible, for instance by measuring the inferior facial angle, would not only yield potential warning signs of RS, and by extension various conditions commonly associated with RS; it would also help raise red flags about numerous other potential problems wholly unrelated to RS.

Anatomy does not correlate very well with severity when it comes to RS symptoms; a baby with moderate micrognathia can suffer from severe UAO, and vice-versa. However in carrying out prenatal screening for RS, the goal is not to predict severity; the goal is simply to identify a high risk that the baby will be born with RS. In such cases clinicians can advise the mother to give birth in an RS Center of Expertise, at a hospital offering tertiary level or comprehensive care, rather than at home.

Improving our ability to prenatally diagnose RS is one challenge, but what happens next? What type of counseling should be provided, who should provide it, and what form should it take? In a retrospective analysis of 1530 Dutch babies born with a cleft, the infant mortality rate of RS babies was found to be eight times higher than the infant mortality rate of the general Dutch population [3]. Stark figures like these are likely to horrify the average parent or parent-to-be, but making things even more complicated is RS’s dramatic heterogeneity. RS babies with certain associated conditions will face even higher infant mortality rates, while RS babies with isolated RS will face lower infant mortality rates. What kind of RS counseling is appropriate in the face of such great uncertainty? Further research to develop RS counseling practices, in partnership with the RS patient community, could help to improve patient outcomes.

 

1.2. Postnatal treatment: conventional cleft care versus RS care

Several years ago an international consensus was reached concerning the diagnostic criteria for RS – micrognathia, glossoptosis, and UAO; while most RS babies are born with a cleft palate, a cleft is not required for an RS diagnosis [4]. From my perspective as an RS parent, it seems logical to omit the cleft as a diagnostic criterion; below I will explain why.

In the Intensive Care Unit (ICU) our daughter was desaturating on a regular basis. The flashing red light, the urgent beeping sound, the doctors and nurses rushing over to silence the terrifying electronic alarms, our knowledge that repeated instances of oxygen desaturation cause brain damage – this was our day to day experience when we visited Lysiane in the ICU. In addition to her breathing difficulties, Lysiane was unable to drink sufficient quantities of milk; in the ICU she never once drank even 20 ml of milk in a single feeding, in spite of the fact that a specialist was doing her best to help her along. Lysiane required machines to meet two of her most basic needs, respiration and nutrition. Her cleft palate, which we knew had to be closed at or around the end of her first year of life, was low on our list of concerns.

While the RS baby’s cleft may be a part of the sequence, a possible result of the RS baby’s tongue position during the prenatal period, the cleft’s importance in the context of actual RS care seems limited. The functional difficulties these babies face, the breathing difficulties and the feeding difficulties, are not primarily a result of the cleft palate; the functional difficulties are more closely associated with glossoptosis and in some cases neurological problems. These are not issues which physicians typically have to address in the context of conventional cleft care, and indeed the breathing and feeding difficulties which we associate with RS can exist even if the baby has no cleft at all. Another characteristic of RS treatment which sets it apart from conventional cleft care is that among RS babies there is a pronounced risk of associated conditions, which can greatly exacerbate the RS baby’s immediate health problems and long term prospects. Taking all of this into account, it seems to make sense that a cleft palate is no longer required as an RS diagnostic criterion.

 
—–

2. RS care

2.1. The RS baby’s need for multidisciplinary care

An RS baby is not a baby with a cleft who happens to have a small chin; an RS baby is a baby with a complex rare disease who happens to have a cleft. Some RS parents do not understand this, or have a hard time accepting it. It is important however that healthcare providers get this message across. Not only is RS rare, and complex, but the dizzying number of conditions which commonly arise in association with RS make it even more complicated and challenging [5]. Through a basic understanding of the complexity of this rare disease, parents may better appreciate the importance of the full multidisciplinary team of experts which RS care requires. Healthcare providers may consider actively engaging RS parents by explaining the role which each expert will play in their baby’s ongoing care.

The RS baby’s feeding difficulties can result not only in a failure to thrive; the feeding difficulties can also be profoundly demoralizing for RS parents. Since the RS baby’s feeding problems are not the same as those of a baby with a conventional cleft, the RS baby’s multidisciplinary team should include highly specialized nurses and speech therapists who have worked specifically with RS babies.

For parents, the RS baby’s feeding difficulties can be demoralizing; the breathing difficulties, terrifying. To treat the RS baby’s UAO, options include both non-surgical and surgical techniques. I will discuss some of these treatments below, from the RS parents’ perspective.

 

2.2. Prone sleeping

Prone sleeping was proposed for RS babies in the early 1900s, half a century before the term Sudden Infant Death Syndrome (SIDS) was ever mentioned in the medical literature. Today prone sleeping is condemned by healthcare providers throughout the entire modern world. This sets the stage for an enduring tension in RS care.

Every time we visited our hospital’s maternity ward for prenatal care, we saw a large poster in the waiting room reminding us: “Couché sur le ventre, votre bébé court un risque mortel. Ne faites pas cette erreur. Couchez toujours votre bébé sur le dos” (in English: “A baby sleeping on her stomach runs a mortal risk. Do not make this mistake. Your baby should always sleep on her back”). After our daughter Lysiane was diagnosed with RS, however, our physicians told us that stomach sleeping was suitable. As parents we were torn. Prone sleeping increases a baby’s risk of SIDS by a factor of five, ten, and possibly more [6]. As RS parents we kept asking ourselves, “if Lysiane’s UAO poses an even greater threat than SIDS, un risque mortel, then shouldn’t her healthcare providers be providing her with some kind of a healthcare treatment?” It seemed to us that with prone sleeping, Lysiane’s physicians were asking us to swap one known danger for another – to resign ourselves and our newborn baby to the lesser of two evils.

In 2019 I attended an RS Symposium at the European Cleft Palate Craniofacial Association’s International Congress. During a period of open discussion between clinicians, one of the physicians insisted that if it were her own baby, she would not place the baby to sleep in the prone position; she therefore refused to recommend this practice to RS parents. I suddenly realized that as RS parents, our serious concerns about prone sleeping had not been unreasonable; the tension between this century old “prone sleeping for RS babies” protocol, and current medical knowledge, is very, very real.

Medical studies which looked at “side sleeping” (“lateral sleeping”) found that it too significantly increased the risk of SIDS [7]. Babies move when they sleep, and when placed on their sides, fall easily into the prone position; exhausted parents cannot stay up all night watching them. Given the notoriety of prone sleeping, the term “side sleeping” may serve to some extent as a polite euphemism for prone sleeping; in practice however this may be a distinction without a difference.

If there were a convincing body of RS medical research demonstrating, with polysomnography, that the clinical benefits of prone sleeping significantly outweighed the risks, then this entire analysis would be different. But the evidence-based research on prone sleeping for RS babies is scarce [8]. Based on its known risks, prone sleeping cannot properly be described as “conservative”; based on its questionable benefits, it may be ambitious to call it a “treatment”.

Years ago the American Academy of Pediatrics, which strongly advises parents to always place babies to sleep on their backs, warned Fisher-Price about the design of its “Rock ‘n Play Sleeper”. The reason: this sleeper was designed in such a way that made it easy for a baby to roll over onto her stomach and fall asleep, in the prone position. Fisher-Price sold the product anyway, all over America, and in Europe as well – and a number of babies did indeed die in these sleepers. Eventually Fisher-Price issued an international recall of over 4.7 million units, at tremendous cost [9]. Here however, in the context of RS care, healthcare providers are actually recommending prone sleeping – at home, without a pulse oximeter, and without any parental training in cardiopulmonary resuscitation. Can this century-old “prone sleeping for RS babies” protocol be reconciled with 21st century medical knowledge? This question seems to call for both evidence-based research, and careful reflection.

 

2.3. Mechanical ventilation assistance

In the COVID-19 era many non-healthcare practitioners have gained at least some passing familiarity with Continuous Positive Airway Pressure (CPAP) and other forms of mechanical ventilation assistance. In CPAP we see a desperate attempt to maintain life, in the absence of any readily available treatment or cure. No COVID-19 patient wants to be hooked up to a breathing machine, but the patient accepts the burden of care – the ongoing hospitalisation, the substantially reduced mobility, the considerable sacrifice in quality of life – because the patient, who wants to live, has no other choice. Most COVID-19 patients receiving CPAP ventilation assistance have indeed lived life to some extent, up to adulthood, and many into their senior years. For RS babies on the other hand life is just beginning; CPAP’s burden of care is particularly painful for the entire RS family.

In addition to its considerable burden of care and reduced quality of life, CPAP has also been shown to create a significant risk of causing facial deformities in children, due to the constant pressure which the CPAP mask exerts on the growing facial structures of the child’s face. “Global facial flattening was observed in 68% of the patients and concerned the forehead (43%), malar area (38%), and maxilla (28%). One or two anatomical regions were concerned in 37% and 18% of the patients, respectively. A concave face was observed in 12% of the patients … This observational study underlines the high prevalence of facial side effects of nasal mask use in children” [10].

The known risk of facial deformities is understated in certain studies proposing CPAP for RS babies. One such study suggests that the risks are minimal, and can be constrained, based upon the relatively short treatment duration required. The authors write, “This relatively short period restricts the potential side effects of long-term noninvasive continuous positive airway pressure such as facial flattening and maxillary retrusion” [11]. To support this conclusion, this CPAP study cites another CPAP study for support [12]. However the study which is cited indicates that the mean duration of treatment was not in fact short; the treatment periods for the observed patients were all at least seven months long, and the majority of patients received ventilation assistance well beyond the one year mark [12].

Furthermore the above-mentioned study on CPAP and facial deformities underscored the fact that maxillary retrusion (“maxillary retrusion was observed in 37% of the patients”) did not correlate with treatment duration at all; “In univariate and multivariate analyses only daily use (>10 h per day) was associated with maxillary retrusion” [10]. The substantial risk of maxillary retrusion was triggered not by months and months of use, but rather by daily use which exceeded 10 h per day. RS babies suffering from UAO require ventilation assistance when they sleep; babies sleep more than 10 h per day. Unless the baby is prevented from falling asleep, the risk of maxillary retrusion seems inescapable. At issue here are facial deformities, among babies who already suffer from facial deformities. “This relatively short period restricts the potential side effects of long-term noninvasive continuous positive airway pressure such as facial flattening and maxillary retrusion” [11]. Such a problematic statement should have raised serious questions during the process of peer review.

High flow nasal cannula exerts less pressure on the baby’s face, but like CPAP, high flow nasal cannula calls for substantial medical equipment, and often requires long term hospitalisation. In the event that the mechanical ventilation equipment is transported into the home, major challenges remain. Even when the baby is not sleeping, the ventilation equipment must be on stand-by, because babies tend to take unscheduled daytime naps; this makes it difficult for the mother to put her baby into a baby carriage and take a quick trip to the supermarket, or take the baby for a stroll in a nearby park.

Lysiane began her life receiving mechanical ventilation assistance, so my family and I know its arduous burdens first hand. Eventually we transferred Lysiane from the French ICU to Tübingen Germany to undergo the Tübingen Palatal Plate (TPP) treatment. The TPP ended Lysiane’s dependance on mechanical ventilation assistance, eliminated the need for prone sleeping, and allowed us to finally leave the hospital, and bring Lysiane home.

 

2.4. Surgery

The majority of RS babies are born with a cleft, so surgery for RS babies is in most cases a given. There seems however to be an increasingly strong push to subject these babies to additional surgeries, to resolve the baby’s UAO. These surgeries are generally performed in the first few months, or even the first few weeks of the baby’s life. How effective are these surgical procedures?

The effectiveness of Tongue Lip Adhesion (TLA) is particularly difficult to gauge. To begin with, TLA studies produce noticeably different results, depending upon which healthcare provider published the study. Furthermore studies published on TLA often present vague and subjective assessments, which can be difficult to understand. Virtually everyone agrees on the importance of practicing evidence-based medicine, using objective criteria. Virtually everyone agrees that polysomnography is the gold standard for measuring the severity of UAO. Nevertheless many TLA studies simply ignore polysomnography altogether.

Some of the more recent TLA studies do mention polysomnography, and emphasize its singular importance in the context of RS research and care. “Tongue-lip adhesion is a surgical technique proposed in the treatment of airway obstruction related to glossoptosis, but few published studies have been based on objective criteria. The purpose of this study was to evaluate the efficacy of tongue-lip adhesion, as determined by polysomnography, in children with Pierre Robin sequence … Preoperative assessment was based on nap polysomnography in the sleep laboratory when the child was stable … Follow-up polysomnography was performed an average of 1 month after tongue-lip adhesion” [13]. These explicit references to polysomnography are reassuring, and this study’s conclusions make TLA appear quite promising: “The postoperative clinical assessment revealed resolution of signs of respiratory distress in 30 cases (81%),” and in the group of 37 babies who underwent the procedure, TLA “resolved obstructive sleep apnoea in 29 patients” [13].

What data did the polysomnography yield? “The apnoea-hypopnoea index (AHI) decreased in all patients. The median postoperative AHI was 27 events per hour (range: 5–65) (P < 0.0001)” [13].

At issue here is a surgical procedure which is being proposed for newborn babies with a rare disease. How can a median postoperative AHI of 27 events per hour support a finding that TLA “revealed resolution of signs of respiratory distress in 30 cases (81%)” and “resolved obstructive sleep apnoea in 29 patients” out of this group of 37? [13] It cannot. Serious questions should have been raised during the process of peer review.

Another study, carried out by Harvard/Boston Children’s Hospital, which looked at both TLA and Mandibular Distraction Osteogenesis (MDO), and which focused on the exact same variable – pre- and postoperative AHI – indicated that TLA failed to do its job over half of the time: “Successful resolution of OA [Obstructive Apnoea] occurred in 9 patients (47%) in the TLA group and 22 patients (92%) in the MDO group” [14]. Given the inconsistent results across the various TLA studies, and the inconsistent ways in which the researchers arrived at their conclusions, it is not easy for an RS parent to have faith in this particular procedure. An RS mother does not want to send her newborn baby into two rounds of TLA surgery, three rounds or more in the event of dehiscence, if she knows that the odds of success are at about the same level as a coin toss.

The studies on MDO tend to show a greater reliance on polysomnography than the studies on TLA. Also, MDO’s success rate, based upon pre- and post-intervention AHI, appears to be higher, and also more consistent from one study to the next. However compared with TLA, MDO is a more aggressive surgical procedure; even the physicians who express enthusiasm for MDO readily admit that this invasive procedure is associated with various risks, and various unknowns, some of which are long-term.

As pointed out by the President of the International Confederation of Cleft Lip and Palate and Related Craniofacial Anomalies, Dr. Felicity Mehendale, “surgery is trauma; it is always good to remember that” (presentation at the 2019 European Cleft and Craniofacial Initiative for Equality in Care COST Action). When the surgery is performed on a newborn baby, then the surgery is not just traumatic for the patient, it is also traumatic for the parents as well. Surgery on newborn babies should only be performed when reasonably necessary. An emergency decision to carry out tracheostomy to save a baby’s life stands out as a relatively straightforward call, based upon the necessity and proportionality of the intervention. The rationale for MDO is less clear, because the TPP treatment offers, in most cases, a completely viable non-surgical alternative [15]. MDO is perhaps most questionable for RS babies in the European Union; in the EU, patients have a legal right to access cross-border healthcare in another EU Member State. The parents of an RS baby in France, wishing to avoid TLA and/or MDO, have a legal right, under EU cross-border healthcare law, to travel to Germany, and receive the non-surgical TPP treatment in Tübingen.

 

2.5. Access to rare disease care – Lysiane’s patient journey

Lysiane did not have the benefit of a prenatal diagnosis; as a result she was born in a hospital which was not an RS Center of Expertise. Every single day we would go to the ICU in order to spend time with her. When visiting hours were over we had to leave the ICU and go home without her, a difficult separation which we were forced to repeat every single evening. Lysiane remained in that French ICU for five straight weeks, receiving mechanical ventilation assistance; there was no release date in sight. The ICU became our second home. It would be difficult to adequately convey the boundless pain of that time period.

After five weeks in the ICU, we submitted an application to the French healthcare authorities requesting prior authorisation for Lysiane to receive the TPP treatment in Tübingen Germany. That is, we asked that Lysiane be transferred from her hospital in Lyon, which was not a Center of Expertise for RS, and which could offer her nothing more than to keep her in the ICU indefinitely, connected to a mechanical breathing machine – to a hospital in Tübingen, which was a Center of Expertise for RS, and which offered a highly specialized, medically proven, safe, non-surgical, cost-effective treatment for her rare disease. In our application we included a letter from the coordinator of the Tübingen RS Center of Expertise, translated to French, distinguishing the TPP from other RS treatments. We also included four internationally peer reviewed medical studies, all evidence-based (with pre- and post-intervention polysomnography data, and weight gain data), demonstrating the safety and efficacy of the TPP treatment [16,17,18,19].

France’s main RS Center of Expertise in Paris, which does not offer the TPP treatment, would not support the transfer to Tübingen. Instead of providing the medical referral letter we required as part of our application, they instead issued a statement suggesting that France’s treatment, CPAP, and Germany’s treatment, the TPP, are equally effective.

The French healthcare authorities subsequently refused our request for prior authorisation. The basis of the refusal was that France’s treatment is equally effective as Germany’s treatment, echoing France’s main RS Center of Expertise in Paris. My father took out a bank loan, using his home as security for the loan; we transferred Lysiane to Tübingen and paid for the TPP treatment ourselves, using the borrowed funds. The TPP did its job; it resolved Lysiane’s breathing difficulties, liberated Lysiane from the breathing machine, and permitted us to finally take Lysiane home, changing her life, and changing our lives too. We documented our rare disease patient journey in meticulous detail in an open letter to the President of the French Republic Emmanuel Macron [20].

The European Commission’s SOLVIT Network, after carefully analyzing Lysiane’s case, formally concluded that France, in refusing Lysiane’s application for the TPP treatment in Germany, violated EU cross-border healthcare law (SOLVIT Case Number 2569/17/DE). We, Lysiane’s parents, are now engaged in an appeal procedure to reverse France’s refusal. Our supporters and allies include Members of European Parliament from every major EU political party; the executive directors of the two largest patient organizations in Europe, the European Patients’ Forum and EURORDIS; professors of EU law, human rights law, health care policy, and medical ethics, from the Sorbonne, Sciences Po, Erasmus University, Oxford, New York University, and elsewhere; a major international law firm supporting our case on a pro-bono basis; as well as physicians, medical researchers, patient organizations and patient advocates, demonstrating a consensus that crosses all political, professional and national boundaries [21].

 

2.6. Tübingen Palatal Plate: international uptake of the TPP treatment

RS was named after a stomatologist, Dr. Pierre Robin, who studied the condition almost a century ago. It is perhaps fitting that RS care has now been transformed by an orthodontist, Dr. Margit Bacher, who invented a safe and effective way to save these babies from their breathing difficulties, and facilitate feeding, without machines or surgery. A prospective multicenter study as well as a retrospective study analyzing longitudinal data from 307 RS babies admitted to the Tübingen University Hospital both demonstrated that the TPP not only resolves UAO, but also improves weight gain in RS babies [16,22]. In addition to its safety and efficacy, the TPP comes with a relatively low burden of care, and improved quality of life: limited hospitalisation, unrestricted mobility, no cumbersome equipment, and no surgery. Babies from around Europe and Russia and even America have been transferred to Tübingen to benefit from the TPP treatment, which is now administered by multiple healthcare providers in Germany. Recent advances have rendered this already economical treatment even more economical to administer [23,24].

In most of Europe’s RS Centers of Expertise, however, the TPP remains unavailable. As an RS parent who has seen the remarkable effectiveness of the TPP treatment first hand, I sometimes wonder why this is the case. The European Union is supposed to function as a union. In medicine in particular, the European Reference Network system was established, and receives EU funding, precisely in order to promote collaboration and pooling of rare disease knowledge and expertise. In practice, the TPP treatment will likely have to travel from Tübingen, across the Atlantic ocean to America, and then back across the Atlantic ocean to Europe once again, before babies in major EU Member States outside of Germany can expect to benefit from the breakthrough TPP. What can explain this inertia?

The English author and philosopher Gilbert Keith Chesterton wrote: “It isn’t that they can’t see the solution. It is that they can’t see the problem” [25]. As an RS parent I believe this strange situation applies in the world of RS care. Every healthcare provider in the international community of RS experts knows about the efficacy, safety, and quality of life benefits which the TPP treatment provides. Even physicians lacking any familiarity with RS can readily learn about the TPP’s medically proven ability to resolve UAO and increase weight gain by accessing the numerous, peer-reviewed, evidence-based medical studies which have been published on this highly effective technique [15,16,17,18,19,22,23,24,26,27].

However, RS experts are familiar with the TPP, they do see it; but they do not see the problems inherent in their own RS treatments of choice. They do not see that parents are terrified about placing their baby to sleep in the notorious prone position. They do not see that parents do not want their baby to depend upon and remain attached to a mechanical breathing machine, turning the hospital into a second home, or the home into a second hospital. Parents do not want their baby to undergo Tongue Lip Adhesion, a hideous procedure first proposed a century ago, whose benefits remain in question. Parents do not want to send their newborn baby into even more aggressive surgery, such as MDO, unless there really are no other good options.

 

3. Conclusion

Using Lysiane’s experience as a case study, what useful lessons can be drawn? First, as noted in the beginning of this article, an improved RS prenatal screening protocol could reduce trauma, improve care, and save lives. At the same time, there seems to be a need for further research to determine what kind of pre- and postnatal RS counseling would be appropriate in the face of this complex and heterogenous rare disease [28].

Second: by actively involving rare disease patients and parents as engaged participants and stakeholders in a collaborative rare disease care team which includes researchers, clinicians, genetic counsellors, psychosocial counsellors, and other healthcare providers, we may gain greater visibility on patients’ needs and concerns, and produce better patient outcomes.

Third: the vast majority of rare diseases lack any approved treatment or cure. Lysiane’s case may serve as a useful reminder that when a safe, medically proven, economical rare disease treatment has been developed, healthcare providers should facilitate access to that treatment. Unless there is a strong justification for denying access to a particular treatment – danger, questionable efficacy, excessive cost – a family should not have to take out a personal bank loan as a condition for accessing safe and medically proven rare disease care [29].

Fourth: Lysiane’s experience demonstrates that in Europe there is a promising opportunity to facilitate access to cross-border healthcare for rare disease patients, through a properly designed program of education and training. In the EU, prior authorisation for cross-border healthcare is subject to strict legal scrutiny. EU law states that “individual decisions of refusal to grant prior authorisation shall be restricted to what is necessary and proportionate to the objective to be achieved, and may not constitute a means of arbitrary discrimination or an unjustified obstacle to the free movement of patients” (Directive 2011/24/EU on the application of patients’ rights in cross-border healthcare). The EU Court of Justice specifies that every refusal to grant prior authorisation must be justified by “an overriding reason in the public interest” (Case C-173/09 Georgi Ivanov Elchinov v Natsionalna zdravnoosiguritelna kasa [2010] ECR I-08889). These standards for refusal are high and very difficult to meet, because by EU design, refusals should be exceptional events. In order for rare disease patients to benefit from meaningful access to care, these rules must be respected – but in order for healthcare administrators to respect these rules, they must first understand them. How can the legal standards governing EU cross-border healthcare be clearly and effectively explained to Europe’s numerous and diverse healthcare funds and administrators? Who should provide the training? What form should it take? And how can this information be communicated to EU citizens, including those from socially and economically disadvantaged backgrounds, so that they too can benefit from European advances in rare disease care? These questions call for further research and action, preferably on an EU level.

Fifth: Lysiane’s case demonstrates the limits of digital healthcare, and the idea that “information and knowledge should travel, so the patient doesn’t have to.” Sometimes the patient does have to travel. The patient has to travel to receive treatment at a light ion hadron therapy facility; likewise, the patient has to travel to receive a highly specialized rare disease treatment such as the TPP. The TPP treatment requires a relatively large team of individuals and disciplines and concentrated expertise, including neonatologists trained in upper airway nasopharyngeal fiber optic endoscopy, pediatric sleep medicine, orthodontics, cranio-maxillofacial surgery, neonatal nursing, and speech therapy. A treatment like the TPP cannot be offered in every hospital, or even in every country, and it does not need to be. The important point though is that if the patient does have to travel to access one of these highly specialized treatments, then the patient, especially the rare disease patient, should be helped, not hindered.

I appreciate this opportunity to contribute the patients’ perspective, and I hope that it fosters useful dialogue. A healthcare provider’s work can be extremely difficult. The responsibility you have taken on is profound. I wish you strength and courage as you face the tremendous moral challenges which constitute such a routine part of your day-to-day job.

 

Funding

This work received no grant from any funding agencies in the public, commercial, or not-for-profit sectors.

 

Declaration of competing interest

The author has no conflict of interest to declare.

 

Acknowledgements

I sincerely thank Mr. Americanos, Dr. Barman, Dr. Breugem, Mr. Davies, Mr. deBronkart, Mr. Elffers, Dr. Graeβner, Ms. Harris, Mr. Houÿez, Dr. La Scala, Dr. Logjes, Dr. Mossey, Dr. Oosterwijk, Ms. and Mr. Pakter, Dr. Palmier, Dr. Persson, Dr. Railavo, Dr. Resnick, Dr. Römmler-Zehrer, Mr. Russell, Dr. Sireau, Mr. Tavin, Dr. Wong- Rieger, and my beloved Delphine. Ms. Kumsal Bayazit, CEO of Elsevier, my family, and our friends and colleagues in the rare disease patient community, will never forget your kindness and support. Thank you.

 

References

[1] Nguyen JQN, et al. Can Robin sequence Be predicted from prenatal
ultrasonography? J Oral Maxillofac Surg 2020;78.

[2] Paladini D. Fetal micrognathia: almost always an ominous finding. Ultrasound
Obstet Gynecol 2010;35.

[3] van Nunen DPF, et al. Elevated infant mortality rate among Dutch oral cleft cases: a
retrospective analysis from 1997 to 2011. Front Surgery 2014;1.

[4] Breugem CC, et al. Best practices for the diagnosis and evaluation of infants with
Robin sequence. JAMA Pediatrics 2016;170.

[5] Logjes RJH, et al. The ontogeny of Robin sequence. Am J Med Genet 2018;176.

[6] Carpenter R, et al. Sudden unexplained infant death in 20 regions in Europe: case
control study. Lancet 2004;363.

[7] Moon RY. SIDS and other sleep-related infant deaths: evidence base for 2016
updated recommendations for a safe infant sleeping environment. Pediatrics 2016;
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[8] Poets CF, Wiechers C. Reappraising prone positioning for infants with Robin
sequence: a cautionary tale. Arch Dis Child 2021;106.

[9] U.S. Consumer Product Safety Commission. Fisher-Price Recalls Rock ‘n Play
Sleepers Due to Reports of Deaths. CPSC.gov.; 2019.
https://www.cpsc.gov/Recalls/2019/Fisher-Price-Recalls-Rock-n-Play-Sleepers-Due-to-Reports-of-Deaths/

[10] Fauroux B, et al. Facial side effects during noninvasive positive pressure ventilation
in children. Intensive Care Med 2005;31.

[11] Amaddeo A, et al. Continuous positive airway pressure for upper airway
obstruction in infants with Pierre Robin sequence. Plast Reconstr Surg 2016;137.

[12] Leboulanger N, et al. Physiologic and clinical benefits of noninvasive ventilation in
infants with Pierre Robin sequence. Pediatrics 2010;126.

[13] Broucqsault H, Lamblin M-D, Hosana G, Fayoux P. Evaluation of the efficacy of
tongue-lip adhesion in Pierre Robin sequence. Euro Annals Otorhinolaryngol Head
Neck Disease 2018;135.

[14] Resnick CM, Calabrese CE, Sahdev R, Padwa BL. Is tongue-lip adhesion or
mandibular distraction more effective in relieving obstructive apnea in infants with
Robin sequence? J Oral Maxillofac Surg 2019;77.

[15] Poets CF, Koos B, Reinert S, Wiechers C. The Tübingen palatal plate approach to
Robin sequence: summary of current evidence. J Cranio-Maxillofacial Surg 2019;
47.

[16] Poets CF, et al. Multicenter study on the effectiveness of the pre-epiglottic baton
plate for airway obstruction and feeding problems in Robin sequence. Orphanet J
Rare Dis 2017;12.

[17] Müller-Hagedorn S, Buchenau W, Arand J, Bacher M, Poets CF. Treatment of
infants with Syndromic Robin sequence with modified palatal plates: a minimally
invasive treatment option. Head Face Med 2017;13.

[18] Buchenau W, et al. Functional treatment of airway obstruction and feeding
problems in infants with Robin sequence. Arch Dis Child Fetal Neonatal Ed 2017;
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[19] Maas C, Poets CF. Initial treatment and early weight gain of children with Robin
Sequence in Germany: a prospective epidemiological study. Arch Dis Child Fetal
Neonatal Ed 2014;99.

[20] Pakter P. Letter to French President Emmanuel Macron, “Lysiane – French baby
with a rare disease”. Pierre Robin Europe; 2018.
https://pierrerobineurope.com/letter-to-macron/pdf/

[21] Pakter P. Letter to EU Health Commissioner Stella Kyriakides, “Rare Disease
Patients and Access to Care”. Pierre Robin Europe; 2019.
https://pierrerobineurope.com/kyriakides-pdf/

[22] Wiechers C, et al. Retrospective study on growth in infants with isolated Robin
sequence treated with the Tuebingen Palate Plate. Orphanet J Rare Dis 2021;16.

[23] Müller-Hagedorn S, Arand J, Scholz T, Poets CF, Wiechers C. An innovative method
for manufacturing the Tuebingen palatal plate for infants with Robin sequence.
BMC Pediatr 2020;20.

[24] Xepapadeas AB, et al. Technical note on introducing a digital workflow for
newborns with craniofacial anomalies based on intraoral scans – part II: 3D printed
Tübingen palatal plate prototype for newborns with Robin sequence. BMC Oral
Health 2020;20.

[25] Chesterton GK. The collected works of G.K. Chesterton. Ignatius Press; 1986.

[26] Wiechers C, et al. Mandibular growth in infants with Robin sequence treated with
the Tübingen palatal plate. Head Face Med 2019;15.

[27] Naros A, et al. Perioperative complications in cleft palate repair with Robin
sequence following Tuebingen palatal plate treatment. J Cranio-Maxillofacial Surg
2021;49.

[28] Sandow R, Kilpatrick NM, Tan TY, Raj S, Forrest LE. Parental experiences and
genetic counsellor roles in Pierre Robin sequence. J Commun Genetics 2020;11.

[29] Pakter P, Sadek J, Miller N. Rare Revolution Magazine: “Crossing Borders to Access
Rare Disease Care, Lysiane’s Story”. Pierre Robin Europe; 2020.
https://pierrerobineurope.com/rare-revolution-pdf/


Pierre-Robin-Sequence-patient-perspective-Fetal-and-Neonatal-Medicine

Prenatal Diagnosis of Pierre Robin Sequence: an Interview with Dr. Cory Resnick

Dr. Cory M. Resnick, Oral & Maxillofacial Surgeon at Boston Children’s Hospital and Assistant Professor at Harvard Medical School, describes the exciting progress he has made on the Prenatal Diagnosis of Pierre Robin Sequence.

Read more

Letter to EU Health Commissioner Kyriakides

On 5 December 2019 we sent a letter to EU Health Commissioner Stella Kyriakides…
Read more

Rare Revolution Magazine article

RARE Revolution Magazine article, Clinical Spotlight: “Crossing borders to access rare disease care: Lysiane’s Story” Read more

Pierre Robin Sequence – Information Document for Parents

> Lire la version française ici
> Lees hier de Nederlandse versie

Dear Fellow Parents,

Although Pierre Robin Sequence is described in Europe’s Orphanet Rare Disease Database, and in America’s NORD Rare Disease Database, and in the GARD Genetic and Rare Diseases Database, the information provided in these databases seems to be written for physicians, and not for parents. Our goal was to produce the kind of document each of us wishes we as parents could have had, when the doctors first told us that our baby had Pierre Robin Sequence.

To create the document we collaborated with healthcare providers – doctors, nurses, surgeons and orthodontists – and also parents and Pierre Robin Sequence patient groups. The document went through many drafts but we’re now sharing it with others. The current version provides information about Pierre Robin Sequence, and various treatments, both surgical and non-surgical. Since the document is for parents like us, without a medical background, we used plain language and clear explanations. And thanks to the continuous and ongoing involvement of all the different healthcare providers, the document has been confirmed as being medically accurate and objective. We know there’s always room for improvement and we will definitely keep trying to make it better, so we welcome all feedback, both positive and negative, on the Contact Page.

We send each of you fellow Pierre Robin parents out there our very best wishes and encouragement.

Kind regards,

Philippe Pakter
Pierre Robin Europe Foundation (Stichting Pierre Robin Europe)

Pierre Robin Sequence
The Condition, and Various Treatments

Pierre Robin Sequence Information Document for Parents

Introduction to Pierre Robin Sequence

Pierre Robin Sequence is a rare condition, and although exact figures are unknown, it is only believed to affect approximately 1 in 8,500 babies. It is named after a dentist, Pierre Robin, who worked in Paris, France, and who studied and wrote about the condition during the 1920’s and 1930’s. Pierre Robin Sequence is characterized by a set of oral and facial deformities: a small lower jaw (the medical term is “micrognathia”); the baby’s small lower jaw is set back in the baby’s face (the medical term is “retrognathia”); the baby’s tongue, instead of sitting flat in the mouth, sits up, in the back of the throat, in an angled or vertical position (the medical term is “glossoptosis”); and in most cases, the baby has a cleft palate, not outside, but inside of the baby’s mouth. The problems these babies face include upper airway obstruction, breathing difficulties, and feeding difficulties. The severity of these difficulties varies from baby to baby.

Micrognathia – the medical term for a small lower jaw.

 

The baby’s tongue, instead of sitting flat in the mouth, sits up, in the back of the throat, in an angled or vertical position; the medical term is “glossoptosis”.

Pierre Robin Sequence actually goes by several slightly different names. Some healthcare providers refer to it as Pierre Robin Sequence; others call it Pierre Robin Syndrome, or Robin Sequence, Robin Anomalad, RS, PRS, etc. In this document, we will use the simple and abbreviated name, “Robin Sequence”.

While Robin Sequence falls under the broad category of rare diseases, and is included in the major European and American rare disease databases (Orphanet, NORD, and GARD), it can also be described as a condition, and as a sequence. But why is Robin Sequence described as a “sequence”? The reason is that with Robin Sequence, one problem leads to another problem, in a chain of events – in a “sequence”. For example: during the normal development of a baby inside of the mother’s womb, babies begin the growth process with a divided, open palate; the roof of the baby’s mouth is open. At around 8 to 12 weeks into the pregnancy, the two sides of the baby’s palate normally join together, and close. However, in babies with Robin Sequence, the baby’s lower jaw is very small. Because the lower jaw is very small, there is almost no space for the baby’s tongue; the baby’s tongue can’t lay down flat in a flat, horizontal position, inside of the baby’s mouth. Instead, the baby’s tongue gets bunched up, and pushed to the back of the baby’s mouth, in an angled, upright, vertical position. The problem is that if the baby’s tongue is in this vertical position, then the baby’s palate can’t join together and close – because the tongue is in the way. Thus, the small lower jaw leads to a sequence of events: with a small lower jaw, the tongue doesn’t have enough space; therefore it’s pushed up, in a vertical position; this in turn prevents the palate from closing, because the tongue is in the way. The result is a small cleft, a hole, in the roof of the baby’s mouth, the palate.

It is important to note that not all babies with Robin Sequence have a cleft palate. Some just suffer from the very small lower jaw (“micrognathia”), which is deeply set back and receded (“retrognathia”), and a tongue which is in the raised, vertical position, in the rear of the baby’s throat (“glossoptosis”). Since not all Robin Sequence babies have a cleft palate, recent efforts have been made to focus not on the presence or absence of a cleft palate; instead, doctors are focusing more on whether the baby is showing signs of upper airway obstruction, which can create very serious risks to the baby’s life and long-term health. At a May 2017 meeting in Toronto Canada, doctors from all over the world who treat Robin Sequence and who study Robin Sequence got together to discuss the way forward. The doctors reached a general agreement, a consensus – the three characteristics which are necessary for a diagnosis of Robin Sequence are micrognathia, glossoptosis, and upper airway obstruction; a cleft palate is not required for a diagnosis of Robin Sequence.

Robin Sequence often appears together with other medical conditions. According to Orphanet, Europe’s database of rare diseases, approximately half of the babies who are born with Robin Sequence are also born with another condition. The other condition could be Stickler Syndrome, or Treacher-Collins Syndrome, or any of a number of other rare conditions. These are serious conditions all by themselves; each one presents its own symptoms and problems. Thus, babies suffering from Robin Sequence show a great deal of variation in terms of exactly which symptoms each baby has. Since associated conditions can create so many additional medical risks, it is critical for the doctors treating your baby to take a hands on, active approach. Your baby’s breathing problems are probably taking center stage, because breathing problems are of immediate, grave concern – babies, like all humans, need air – but your doctors should also look for associated conditions, carry out genetic testing, and perform neurological examinations, at the same time that they are dealing with your baby’s breathing difficulties.

In addition to breathing difficulties, babies suffering from Robin Sequence may also face feeding difficulties. A cleft palate, if present, can aggravate the baby’s feeding difficulties, since a cleft makes it difficult for your baby to create a suction effect inside of his or her mouth. Also, the extra effort your baby needs for breathing can itself be exhausting, leaving him or her less energy and enthusiasm to feed.

Feeding difficulties can interfere with weight gain and normal growth (the medical term is “failure to thrive”). These feeding difficulties can be serious, and may require the use of a nasogastric tube – a tube which enters the baby’s nose and goes all the way down into the baby’s stomach, to deliver milk, and ensure that the baby receives adequate nutrition. If feeding difficulties continue, the baby may undergo surgery and receive a gastrostomy tube – a feeding tube which enters the baby’s body through the tummy, and goes directly into the baby’s stomach.

Most children with a cleft palate suffer from a build-up of fluid behind the eardrum. Normally, the muscles in the palate make sure that fluid is drained from the middle ear, to the throat. However, in a baby with a cleft palate, the muscles in the palate are not in their normal, natural position; this makes it difficult or impossible for these muscles to do their job, and drain the fluid. This can lead to a build-up of fluid behind the eardrum. If this fluid build-up behind the eardrum causes hearing problems, it may be necessary to surgically insert a tiny tube into each eardrum. These tiny tubes help provide ventilation, air flow between the inside of the ear and the outside world, which reduces fluid build-up. Babies with Robin Sequence may also suffer from ear infections. Ear infections can cause temporary hearing loss, which can lead to problems with speech and language development.

If your baby does have a cleft palate, then the cleft will have to be closed with surgery. This is often done when the baby is approximately 1 year old, depending on various factors, including the child’s weight – does the baby have enough weight and strength to endure surgery – and whether your baby still has breathing difficulties at that time. Children with a cleft palate have a higher risk of delayed or defective speech development; your baby may in the future need assistance from speech therapists.

Treatments for Robin Sequence

Feeding Difficulties
When a baby with Robin Sequence faces difficulties feeding, it can place a tremendous burden on you, the parents. You may try every single baby bottle available on the market, and spend an hour or more trying to feed your baby every single meal, four or five times a day – and still find it difficult or even impossible to provide your baby with the milk he or she needs. Making things even harder, vomiting can be a common occurrence – sometimes daily, sometimes several times a day. Babies with Robin Sequence also face an increased risk of gastroesophageal reflux disease, or “GERD”. GERD is a condition in which the contents of your baby’s stomach – not only the milk, but also your baby’s natural stomach acids – flow up into the esophagus, the tube which runs between your baby’s stomach and mouth. This stomach acid can irritate your baby’s esophagus and cause your baby a great deal of discomfort and pain. For you as a parent, all of this this can be both physically challenging and emotionally depressing. Patience, and the faith that things will gradually improve, are critical.

If your baby is unable to consume a sufficient volume of milk, you may be able to add nutritional supplements to the milk – for instance, Duocal, a special powder which is rich in protein and fats. Another possibility is to feed your baby a specially formulated, highly enriched milk substitute. The names of these products will be different from country to country, but one example is Infatrini. This medical product comes in a liquid form, and is particularly rich in the type of nutrition which a growing baby needs. Do not wait until your baby loses a lot of weight before taking action. If your baby is suffering from feeding difficulties, maintain close and ongoing contact with the nursing staff and doctors; tell them about your difficulties, and ask them for help.

If feeding difficulties make it difficult or impossible for the baby to drink enough milk, then the baby may receive a nasogastric tube, which enters the baby’s nose, and descends down into the baby’s stomach.

If feeding difficulties make it difficult or impossible for the baby to drink enough milk, then the baby may receive a nasogastric tube, which enters the baby’s nose, and descends down into the baby’s stomach.

For long term feeding difficulties, the baby may undergo surgery and receive a gastrostomy tube, which enters the baby’s body through the tummy, and goes into the baby’s stomach.

For oral feeding, special bottles and techniques may be required; specialised assistance is strongly advised, because the feeding difficulties of a baby with Robin Sequence can be highly challenging, even for the experts.

Playtex

The Playtex Nurser bottle has an internal plastic liner or bag. This internal plastic bag can be gently pressed with your fingers when you are feeding your baby, which causes the milk to gently flow.

 

The small plastic bag drops into the bottle, from the top. On the bottom, the Playtex bottle is actually open, which means you can insert your fingers into the bottle.

 

By gently pressing on the flexible plastic bag inside of the Playtex nurser bottle, the milk will slowly flow into your baby’s mouth.

 

Medela

The Medela bottle – a bottle which is specially designed for babies with feeding difficulties. Applying gentle pressure just next to the yellow ring will cause the milk to slowly flow.

 

Medela bottle – the nipple. The flow of the milk through the Medela bottle’s nipple can be adjusted by aligning the baby’s nose with one of the three lines on the base of the nipple; each line on the nipple produces a different flow rate. Slow flow: the short line. Medium flow: the middle line. High flow: the long line.

 

Dr. Brown’s

The “Specialty Feeding System”, produced by a company called “Dr. Brown’s”, looks like a regular baby bottle. In fact, it works differently…

 

The Dr. Brown’s “Specialty Feeding System” uses an “Infant Paced Feeding Valve”, a small, blue plastic disk which fits inside of the base of the nipple. The manufacturer, “Dr. Brown’s”, describes this as a compression based system. Essentially, the baby gets the milk to flow from the nipple by applying compression – by gently chewing on the nipple – rather than by suction (suction can be difficult for babies with Pierre Robin Sequence and cleft palate). Important note: Dr. Brown’s sells many different types of baby bottles. If you are interested in this “Specialty Feeding System”, make sure that you are ordering the Dr. Brown’s Specialty Feeding System with the blue valve (the “Infant Paced Feeding Valve”) and the blue insert.

 

 

Breathing Difficulties
When it comes to Robin Sequence breathing difficulties, different doctors favor different treatment strategies. However, no matter which treatment or treatments your local healthcare provider prefers, the first step is to determine how severe your baby’s breathing difficulties are. At this time, the most objective and scientific way to measure the severity of your baby’s breathing difficulties is through a test called a “polysomnography”, a “PSG”. A PSG is often referred to as a “sleep study”, because this test is carried out while your baby sleeps. To carry out a PSG/sleep study, your baby will be connected to various sensors right before he or she goes to sleep. Then, all through the night, while your baby sleeps, the sensors will monitor and record your baby’s breathing patterns, chest movements, oxygen levels, and other vital signs.

A baby who is about to undergo a sleep study. The sleep study is a painless test – and it is a very important and fundamental procedure for Robin Sequence babies to undergo.

The data which your baby’s PSG/sleep study produces will help show whether your baby’s breathing is mildly obstructed, moderately obstructed, or severely obstructed. Doctors do not yet agree on exactly what level of breathing obstruction qualifies as mild, or moderate, or severe, but in any case, the information produced by the PSG/sleep study serves as a guide, helping doctors to determine which treatments might be appropriate. This type of approach is called “evidence-based decision making”. What this means is that the healthcare decisions which you and your physicians make about your baby are based on objective, scientific data – the results of the PSG/sleep study – rather than on this person’s feeling, or that person’s opinion. Evidence-based decision making is strongly favored in medicine today, so in treating Robin Sequence, the PSG/sleep study plays a fundamental role.

The results of a sleep study. This data provides medical evidence of the Robin Sequence baby’s breathing difficulties, allowing both you and the physicians to see whether your baby’s breathing problems are mild, moderate, or severe. For treating Robin Sequence babies, the sleep study is absolutely fundamental; this is called “evidence-based medicine”.

A baby suffering from Robin Sequence should undergo a PSG/sleep study before undergoing treatment for breathing difficulties, and after the treatment as well, to see whether the treatment relieved that baby’s breathing difficulties, and if so, by how much. Since the PSG/sleep study is currently the most objective and scientific way of measuring the severity of your baby’s breathing difficulties, it is not just used in the treatment of individual babies. This same tool, the PSG/sleep study, is also used when doctors carry out medical studies to scientifically evaluate the effectiveness of a particular Robin Sequence treatment. The PSG/sleep study is a standard Robin Sequence tool, and it is a very important test which your baby should undergo. If your local hospital is unable to carry out a PSG/sleep study, ask your doctor whether the test can be carried out at another hospital nearby.

To deal with the breathing difficulties of babies suffering from Robin Sequence, a number of different treatments have been used, depending on how serious the baby’s breathing difficulties are. Which treatment you choose for your baby is a critical decision which you should think about very carefully, and also discuss with your healthcare provider. Robin Sequence is rare, and when it comes to a rare disease or complex condition, expert help may be difficult to find. If your local healthcare provider does not have specialised knowledge of Robin Sequence, it is very important that you look for and find specialists who are familiar with it, and who do have experience treating it.

While prone (stomach) position was used for many years as a default way of trying to relieve the baby’s upper airway obstruction and breathing difficulties, other methods have been developed. In actual practice, the doctors in your local hospital will most likely propose the treatment which they happen to be familiar with – because they received training in that particular technique. However, if you reach out to other parents, on RareConnect, or in a Facebook group focusing on Robin Sequence, you might discover that the doctors in a different hospital, in your same exact country, propose a different treatment – because that is the treatment which they happen to know, and which they use in that hospital. It is a good idea to use the internet and reach out to other families, and other experts, to learn about the various treatments which might be available for your baby. This way you can learn about the experience which other parents like you had, with each of these different treatments.

Some of the treatment methods described below date back many years, and are being reviewed by medical professionals to find more effective and less invasive techniques. Not all doctors and not all parents agree on the best ways to treat Robin Sequence, but almost everyone agrees on one general principle: whenever possible, non­surgical treatments should be tried first, in order to avoid performing surgical operations on these small babies. Generally speaking, non-surgical techniques require months of devoted treatment, which does put a certain burden on you, the parents. However, those who support these non-surgical treatments point out that it allowed their baby to avoid invasive surgery. As a general trend, hospitals first try to treat a baby without using surgery, and reserve surgery for those babies where the non-surgical options could not be used, or failed.

 

Prone Positioning (placing the baby on their stomach)
A baby suffering from Robin Sequence tends to have the greatest difficulties breathing when the baby is placed on his or her back. This is because when the baby is laying on his or her back, the baby’s tongue, which is already in a raised position, blocking the entrance to the throat, can fall back even further, and seriously obstruct the baby’s airway. For this reason, babies suffering from Robin Sequence are often placed to sleep on their stomach, in the “prone” (stomach) position, or on their side. The practice of placing Robin Sequence babies to sleep on their stomach was first proposed by Pierre Robin himself, in 1934, over 80 years ago.

The prone sleeping position – placing the baby to sleep on her stomach. This practice has become highly controversial, because medical studies have consistently found that prone (stomach) sleeping substantially increases the risk of SIDS (Sudden Infant Death Syndrome, also known as “Crib Death”).

 

A poster in America, urging parents to only let babies sleep on their back.

 

A poster in France, with a strong warning about prone (stomach) sleeping: “Even if everything in this room looks perfect… a baby sleeping on her stomach runs a mortal risk. Do not make this mistake! Your baby should ALWAYS sleep on her back.”

Based on what we have learned over the last 80 years concerning the serious risks of placing babies to sleep on their stomach, this practice of prone (stomach) positioning for babies suffering from Robin Sequence has become highly controversial. It offers a possible improvement, but it is not ideal. Prone (stomach) positioning should only be done when your baby is connected to a machine which monitors your baby’s pulse and oxygen level.

OTHER OPTIONS WITHOUT AN OPERATION:

Nasopharyngeal Airway (also called “NPA tubes”)
In order to maintain an open channel between your baby’s nose and your baby’s upper throat (the medical term is “nasopharynx”), doctors may insert a flexible tube into and through one of your baby’s nostrils. This soft flexible tube is called a nasopharyngeal airway; it ends just above the baby’s “epiglottis”. The “epiglottis” is the medical term for the small flap inside of the throat, which acts like a lid on the top of the baby’s windpipe. The nasopharyngeal airway, also called the “NPA” tube, helps to relieve the Robin Sequence baby’s upper airway obstruction, by keeping the baby’s tongue from falling back, and blocking the top of the baby’s throat. The NPA tube is a widely used treatment for babies suffering from Robin Sequence in the United Kingdom. Most parents say that their baby tolerated it well, and that they were happy that it allowed their baby to avoid surgery. If the NPA tube gets filled with mucous, or milk, a portable suction machine can be used to clear the tube. Parents also learn how to change the NPA tube themselves, and insert a new tube – a process which can be difficult and scary for parents in the beginning, but which becomes much less difficult with experience and practice. Depending on the baby’s breathing difficulties, the baby may use the NPA tube for anywhere from 3 months to 6 months to 9 months, or some period of time in between.

The NPA tube is a flexible tube which enters the nose and ends just above the baby’s “epiglottis”, the small flap inside of the throat which acts like a lid on the top of the baby’s windpipe. The purpose of the NPA is to maintain an open channel between your baby’s nose and your baby’s upper throat

 

Breathing machines (including “CPAP”)
A Robin Sequence baby suffering from moderate to severe breathing difficulties can be attached by tubes to a breathing machine, in order to receive manual breathing assistance. The umbrella term for ventilation assistance using breathing machines is “non­invasive respiratory support” – “non-invasive”, because surgery is not required in order to provide this breathing assistance. One form of non-invasive respiratory support, Continuous Positive Airway Pressure (“CPAP”), involves the application of a flow of air, at a specific pressure and rate, into the baby’s airway. The air is literally pushed from the machine, into a set of tubes, through a mask which is attached to the baby’s face, and into the baby’s lungs.

A Robin Sequence baby receiving respiratory support with Continuous Positive Airway Pressure (“CPAP”).

Generally speaking, CPAP requires long-term hospitalisation. Long-term hospitalisation prevents the newborn baby from going home to his or her parents, comes at a high financial cost, and exposes the baby to the risk of hospital borne illnesses. Ventilation assistance also requires the baby to be attached for long periods of time each day to an external breathing machine, which substantially reduces mobility, for both the baby, and the parents.

A Robin Sequence baby receiving respiratory support in the ICU.

In countries such as Australia, where vast distances may separate patients and their hospitals, babies are often hospitalised at home. With home hospitalisation, the hospital’s ventilation machines are transported to and installed inside of the parents’ home. The CPAP is then administered to the baby by the parents, who are trained how to operate the breathing machine and equipment. In the beginning, the baby must be connected to the breathing machine 24 hours a day. When your baby’s breathing improves, this can be reduced, so that your baby only needs to be connected to the breathing machine when he or she sleeps.

The aim of CPAP’s breathing machines is to avoid invasive surgery, including tracheostomy, which will be described below; almost every doctor agrees that non­surgical treatments should be tried first, in order to avoid performing surgical operations on these small babies.

 

Tübingen Palatal Plate (also called the “TPP”)
A “palatal plate” is a small device made of plastic or other durable material which is worn inside of the mouth, on the palate, or roof of the mouth. Robin Sequence experts in Tübingen, Germany have developed a specially modified version of the palatal plate, for babies suffering from Robin Sequence: the Tübingen Palatal Plate (the “TPP”). The TPP is a small oral device worn inside of the baby’s mouth; it resembles the oral retainers which children wear after their teeth-straightening dental braces have been removed. The TPP is not surgically attached – instead it sticks to the baby’s palate with denture adhesive, and two adhesive strips. Like dentures, the TPP can be inserted or removed by the parents whenever they want, without requiring doctors or nurses. The difference between the TPP device and other palatal plates is that the TPP has a small extension in the rear, an extension whose shape, angle and length are precisely designed and manufactured for each baby by a multidisciplinary German team. The purpose of this extension is to push the baby’s tongue down, in a flat, horizontal position, out of the way of the baby’s throat. By actively pushing your baby’s tongue down into its normal and natural position, the TPP unblocks the throat, eliminates your baby’s breathing difficulties, and allows your baby to sleep safely and silently, even on his or her back – without any tubes, machines, or other equipment.

Above, a Tübingen Palatal Plate.

 

An illustration of how the Tübingen Palatal Plate (TPP) works. The large pink/red object is the baby’s tongue. In the cross-section image on the left, the Pierre Robin Sequence patient has no TPP device; the abnormal rear position of the tongue blocks the upper airway, creating potentially life-threatening breathing and eating difficulties. In the illustration on the right, the TPP device is in place; it is represented by a dark blue line. The dark blue line begins at the upper alveolar ridges (where the upper front teeth will eventually grow), continues along the upper palate, covers the cleft in the palate, and then extends down. In the image on the right, toward the right side, we can see this downward dipping dark blue line extension pushing the base of the tongue left, toward the front of the mouth. By shifting the tongue forward, the TPP device instantly liberates the throat – without surgery.

The TPP is removed by the parents once a day for cleaning, using a toothbrush, the way one would clean a set of dentures. After the first 2 months of wearing the TPP, the baby has to return to the hospital for an examination of the baby’s breathing – a “polysomnography”, also called a sleep study. The sleep study is done in order to confirm that the baby’s breathing is still unobstructed and free. If necessary, the TPP will be slightly modified, to account for the natural growth of the baby’s mouth. Altogether, the TPP is worn for a period of between 3 to 5 months. After this period is over the lower jaw has grown forward, so the tongue has enough space to lay down horizontally and flat, and not cause breathing problems any more. The baby no longer needs to wear the TPP in his or her mouth; the therapy is complete.

OPTIONS WITH AN OPERATION:

Tongue-Lip Adhesion (also called “Labioglossopexy”)
Another Robin Sequence treatment, first proposed over 100 years ago, is the practice of removing the baby’s upper airway obstruction by literally sewing the baby’s tongue down, onto the baby’s lower lip. The goal is to force the tongue to remain in a horizontal position, down and out of the way of the baby’s airway and throat.

Tongue-Lip Adhesion (also called “Labioglossopexy”).

 

Tongue-Lip Adhesion involves sewing the baby’s tongue down, onto the baby’s lower lip. The goal is to force the tongue to remain in a horizontal position, down and out of the way of the baby’s airway and throat.

Tongue-lip adhesion, also called labioglossopexy, has mixed results in relieving breathing problems; in some hospitals the success rate has been approximately 70%, while in other hospitals the success rate has been lower. Babies can experience complications from this operation; “dehiscence” is when the stitches accidentally come out of the baby’s tongue, several weeks or several months after the initial surgery; the surgeon then has to sew the baby’s tongue back down again. All babies undergoing tongue-lip adhesion eventually have to have a final surgery, in order to remove the stitches, and release the tongue from the lip. Tongue-lip adhesion is less invasive than other surgical techniques, but when tongue-lip adhesion fails, the next step, generally speaking, is for the surgeon to carry out a more invasive surgical treatment – mandibular distraction osteogenesis, which is also called “jaw distraction”.

 

Mandibular Distraction Osteogenesis (also called “Jaw Distraction”)
Another surgical option to relieve the Robin Sequence baby’s upper airway obstruction is to physically lengthen the baby’s undersized lower jaw using a procedure called “Mandibular Distraction Osteogenesis”. Mandibular Distraction Osteogenesis is also referred to as “Jaw Distraction”. While the baby is under general anesthesia, a surgeon cuts through the bones in the baby’s undersized, lower jaw, the mandible. The surgeon then installs a device called a distractor, which uses special screws called “pins.” In the week or two following the initial surgery, the screws on the distractor are turned, approximately 1 to 2 millimeters per day. This creates tension, and moves the bones of the baby’s mandible apart. New bone then grows (“osteogenesis”) and fills in the gaps created by the distractor. While the new bone is growing, the baby continues wearing the distractor device at all times.

Mandibular Distraction Osteogenesis. The surgeon installs a device called a distractor, which uses special screws called “pins.”

 

Following the initial surgery, the screws on the distractor are turned, approximately 1 to 2 millimeters per day. This creates tension, and moves the bones of the baby’s lower jaw (“mandible”) apart.

 

New bone then grows (“osteogenesis”) and fills in the gaps created by the distractor. While the new bone is growing, the baby continues wearing the distractor device at all times.

Surgeons performing Mandibular Distraction Osteogenesis / Jaw Distraction emphasize its proven ability to relieve upper airway obstruction by physically increasing the length of the lower jaw, giving the tongue more space to lay down in a flat, horizontal position. Mandibular Distraction Osteogenesis is an invasive surgical procedure, and complications can occur: infections where the pins enter the bones, scarring on the baby’s face, tooth damage, facial nerve damage, and device failure.

 

Tracheostomy
A tracheostomy is a surgical procedure which involves the creation of a surgical incision in the baby’s throat, in order to place a tube directly into the baby’s windpipe. The tube is inserted through the incision, just below the baby’s vocal cords. The tube allows air to enter the baby’s lungs and bypass the baby’s upper airway, which remains obstructed. According to one surgeon, “Unfortunately, several morbidities have been associated with tracheostomy, including increased risk for tracheomalacia, chronic pneumonia, laryngeal stenosis, intellectual and physical impairments, compromised social interactions, and a requirement for complex nursing care and parental education. In addition, the long-term benefit of tracheostomy is questionable, as tracheostomy is associated with increased cost of medical care due to frequent emergency room visits for treatment of pneumonia.” The tendency today is to reserve tracheostomy for critical situations where other treatments could not be used, or did not work.

A baby with a tracheostomy.

 

A Multidisciplinary Team of Experts
Robin Sequence is a complicated medical condition which can have effects on different parts of your baby’s body. Often, the baby’s breathing is affected, and these breathing difficulties can be dangerous. Babies with Robin Sequence also tend to have problems with sucking, swallowing, and feeding. But in addition to this, your baby could potentially suffer from central nervous system issues, neurologic abnormalities, or other medical conditions. For you, the parent of a newborn baby, this may sound terrifying – but the point is not to scare you. The point is to emphasize how important it is to find a real multidisciplinary team of highly specialised doctors who have experience dealing with this particular medical condition, Robin Sequence – and to make sure that the multidisciplinary team acts now, not later, in order to ensure the health and to promote the proper development of your newborn child.

Early intervention by a multidisciplinary team of experts, in close and ongoing collaboration with you and your family, is absolutely critical. A baby with a simple case of cleft palate, and a baby with cleft palate and Robin Sequence, a rare and complex disease, have very different medical needs. The proper treatment of Robin Sequence requires more than just a general pediatrician and a surgeon. The team treating your baby should also include specialists from neonatology (doctors who specialize in treating newborn babies with problems or illnesses of some kind), genetics (to test whether your baby may be suffering from an associated genetic condition), a pediatric sleep specialist (who will use special equipment to study your baby’s breathing and oxygen levels during a full night of sleep), an ophthalmologist (who will study your baby’s eyes, and check for signs of Stickler’s Syndrome), a speech therapist (who doesn’t just help with speech, but also with feeding problems), a developmental pediatrician (who will monitor your baby’s physical and intellectual development), an otolaryngologist (an ear/nose/throat specialist, who will watch for problems with your baby’s ears, and hearing), an orthodontist (who may need to carry out dental work, or create an oral palatal plate)… this is the type of team which a baby with Robin Sequence needs in order to have the best possible chance in life.

As part of your baby’s multidisciplinary team of experts, experienced nurses will be absolutely critical; they are among your most important allies. Whether your baby is in the intensive care unit, or at home, with you, the nurses caring for your baby are like the soldiers on the front line. Nurses will be the ones who struggle to help you manage your baby’s Robin Sequence feeding difficulties, who closely monitor your baby’s weight and growth, who train you, the mother and the father, how to care for your baby on a day-to-day basis, who will give you precious tips and advice based on years of experience caring for countless children… and they will be the bridge connecting you with the various specialists in the multidisciplinary team.

One of the hardest things about having a baby with Robin Sequence is that since the condition is rare, expertise about the condition is difficult to find. Treating a baby with Robin Sequence requires a special concentration of expertise, and your local healthcare center may not have the special concentration of expertise which your baby needs. If your local healthcare provider’s experience with Robin Sequence is limited, then it would be a good idea for you or your local doctor to make contact with one of your country’s centres of expertise for this rare condition. In the European Union, you can visit the Orphanet website, at Orpha.net, look up Pierre Robin Sequence, and scroll through the results to find a centre of expertise located near you.

Conclusion
Preferences, familiarity and availability of treatment methods can vary widely from country to country and region to region. As mentioned earlier, you can use RareConnect, as well as Facebook’s Robin Sequence support groups, to reach out to other families. You can ask them, honestly and directly, what they think of various treatments, based on the actual experiences they had. Many, many parents out there have gone through exactly what you are going through right now. You will be surprised and encouraged to find out how eager they are to share information with you, and support you, during this confusing, painful and often overwhelming time. Do not lose hope. Reach out, and connect with other parents. It will really give you a lot of relief when you see that you are not alone.

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This document was produced as part of a joint collaborative effort involving a number of doctors, nurses, surgeons and orthodontists, including Corstiaan Breugem, Peter A. Mossey, Sirpa Railavo, Pia Vuola, Ulla Elfving-Little, Elina Swan, Janne Suominen, as well as parents, Robin Sequence patient groups, and Facebook groups, in the European Union and beyond. Thank you to each and every one of you who helped. If you would like to provide feedback on this document, or about your own experience with Robin Sequence, please send a message to Stichting Pierre Robin Europe (the Pierre Robin Europe Foundation) on the Contact Page.

European Parliament’s Implementation Report on the 2011 Cross-border Healthcare Directive

In a time of growing populist movements, deepening economic uncertainty, and foreboding Euroscepticism, the EU’s 2011 Cross-border Healthcare Directive was intended to serve as a prime example of the real and tangible benefits which the European Union could bring to its citizens. Leveraging the power of Europe’s common market, and solidly grounded in the EU’s four fundamental freedoms – including the free movement of goods and services, and the free movement of people – the 2011 Directive boldly declared that EU citizens had the right to access medical services anywhere in Europe, without facing undue resistance, obstacles, obstruction or delay.

Eight years later, the great optimism engendered by the 2011 Directive has for many EU citizens given way to frustration, disappointment and cynicism.

An official report has just been published by the European Parliament on the implementation of the 2011 Directive.

European Parliament’s Implementation Report on the 2011 Directive

In the report, the authors underscore the importance of the 2011 Directive in the everyday lives of EU citizens: “Cross-border patient mobility is an important policy issue”. The report also points out that for EU citizens seeking highly specialised medical services, cross-border healthcare is often the best and only option for obtaining a life-changing treatment: “…for certain groups of patients, due to rare diseases… cross-border healthcare is the most appropriate and accessible care.” However, the parliamentary committee:

“Regrets that patient mobility for planned healthcare, and especially specialised care, in other Member States remains low… the number of patients availing themselves of their right to cross-border care, as provided for under the directive, including preventive medical tests, scans and health checks, is only growing very slowly…”

The parliamentary committee observes that:

“…in a considerable number of Member States, the obstacles that patients encounter when dealing with health systems remains significant… certain prior authorisation systems appear to be unduly burdensome and/or restrictive…”

And:

“Notes with concern that in some Member States insurance companies have discriminated arbitrarily or created unjustified obstacles to the free movement of patients and services…”

In the understated language typical of such official reports, the parliamentary committee:

“…expresses disappointment that a significant number of Member States have not effectively implemented the requirements for guaranteeing patients’ rights; urges Member States therefore to ensure its proper implementation… while respecting the principle of the free movement of persons within the internal market…”

And the committee reminds Member States that:

“…any limitation on the application of the directive, such as prior authorisation requirements or limitations on reimbursement, should be necessary and proportionate and not give rise to arbitrary or social discrimination, must not put up unjustified obstacles to the free movement of patients and services…”

The committee, recognising that such polite reminders may fail to bring Member States into compliance with the 2011 Directive:

“Calls on the Commission and the Member States to put in place or to enhance an appropriate complaint mechanism for patients seeking treatment abroad, should their rights not have been respected…”

This official EU report published by the European Parliament – the same EU body that debated, drafted, voted on and passed this legislation – expresses both disappointment and concern.

For us, a European family, this much celebrated law, the 2011 Cross-border Healthcare Directive, has been nothing more than a false hope, a cruel and cynical façade, covering up the non-cooperation and outright obstruction which we actually faced right here in Western Europe. In theory, planned cross-border healthcare is possible in the EU, especially for patients seeking highly specialised treatments. In practice, EU citizens avoid it almost entirely. Our horrendous experience in France, struggling unsuccessfully to obtain authorisation for cross-border healthcare in Germany, helps explain why.

While our daughter Lysiane’s case is well documented, the stark reality is that our experience in France – the resistance, non-cooperation and obstruction we faced – is not exceptional at all. The European Parliament just confirmed this fact in their official 2011 Directive Implementation Report, and almost any man woman or child suffering from a rare disease or complex condition can confirm this fact for you as well, first-hand.

My family certainly wants justice – we want our S2, the cross-border healthcare authorisation form which the French government illegally and shamefully denied. But as we have stated elsewhere, our struggle to exercise our legally guaranteed right to access cross-border healthcare in the EU is not just about our daughter Lysiane. And it is not just about us. And it is not just about other babies who happen to be suffering from this particular rare disease, Pierre Robin Syndrome. It is broader than that.

Lysiane’s case raises an issue of wider principle which matters to all EU citizens, and which affects their daily lives: if a newborn baby suffering from a rare disease, immobilized in an intensive care unit and connected to a ventilator machine, doesn’t have the right to obtain a highly specialised, medically proven and cost-effective treatment for her rare disease in another EU Member State – then who does have the right to cross-border healthcare?

The European Parliament’s 2011 Directive Implementation Report paints an unflattering portrait of Member State commitment to EU law. The experts will say there are many complex issues involved here, which is true, but what it comes down to is this: either EU law means something, or it does not. If it means something, then France and other Member States should respect it. And if they do not respect it, then the European Commission should do its job, and enforce it. As the European Commission declared in an official statement (2017/C 18/02):

“The European Union is founded on the rule of law and relies on law to ensure that its policies and priorities are realised in the Member States. The effective application, implementation and enforcement of the law is a responsibility entrusted to the Commission by Article 17(1) of the Treaty on European Union… Infringements must be dealt with promptly. The Commission and the Member States need to proceed expeditiously in investigating breaches of the law.”

EU Health Commissioner Andriukaitis, in 2017 we formally alerted you to Lysiane’s case. It is 2019 now and we are still struggling to obtain justice in this case. The European Parliament’s Implementation Report on the Cross-border Healthcare Directive makes it clear that there are many other cases just like ours: ongoing illegal obstruction by Member States which are violating patients’ rights to access cross-border healthcare, even for rare disease treatments, in spite of EU law. During a European Parliament debate held on 12 February 2019, you Commissioner Andriukaitis solemnly declared the following:

“I would like to stress once again that the Commission will take deliberate action when the spirit and letter of the Directive is not upheld.”

Both the spirit and letter of the Directive were violated when the French government rejected our newborn baby daughter Lysiane’s request for cross-border healthcare in Germany, for her rare disease. Will you Commissioner Andriukaitis please take deliberate action? If so, exactly what deliberate action will you take to bring Lysiane justice – justice now, and not 10 years from now?

Rare Disease Collaboration… and Obstruction

Even if global policies support rare diseases, all the way up to the UN level – and even if various tools have been created to promote the rare disease agenda – in Europe I am thinking of Orphanet, Clinical Patient Management Systems, European Reference Networks, the 2011 Cross-border Health Directive, etc… what should rare disease patients do when local doctors do not want to cooperate? Read more

Rare Diseases Denmark – letter of support

Rare Diseases Denmark, a leading rare disease advocacy group from Scandinavia, is a highly respected voice in the international rare disease movement. In their letter of support, they point out that the case of Lysiane “is a devastating example of the struggle that many rare disease patients and families have faced, and continue to face, right here in Europe.”

Read more

Pro Rare Austria – letter of support

Pro Rare Austria took center stage at the European Conference on Rare Diseases which was recently held in Vienna. As explained by Pro Rare Austria’s Chairman, Dr. Rainer Riedl, “With rare diseases, the sharing of knowledge, the exchange of expertise, as well as networking and cooperation, are particularly important.” In their letter to France’s L’Assurance Maladie, they ask the Director, Nicolas Revel, to revise the unfounded rejection of Lysiane’s right to a safe and medically proven treatment in Germany.

Read more