Introduction

Rubinstein-Taybi syndrome (RTS) (MIM (Mendelian Inheritance in Man) #180849; #613684; #610543) is a multisystem disorder with physical, cognitive and behavioural characteristics, which can be caused by variants in two genes that regulate transcription via chromatin remodelling. The condition is named after the US paediatrician Jack Rubinstein and Iranian radiologist Hooshang Taybi who described seven affected infants in 1963.1 There are >800 publications on RTS and related topics. Within the framework of the European Reference Network Ithaca a group of international experts recognised the importance of equal practices regarding diagnostic procedures and care for individuals with RTS. To address this issue, an international consensus group was established, which performed a literature review, evaluated data critically, formulated conclusions and held a face-to-face meeting in the presence of patient group representatives. This has led to the present series of guidelines for diagnostics and care for individuals with RTS. For Methods see online supplemental materials.

Clinical diagnostic criteriaDefinition

The goal of defining an entity is that affected individuals and their caregivers who face similar signs, symptoms and health problems, can meet one another, share knowledge, emotions and experiences about the disorder, support one another, and, this way, facilitate care and research. So the essence of a definition is to allow grouping together individuals with the same diagnosis.

Currently, variants in the genes CREBBP and EP300 are known to cause RTS.2 3 One may argue that the diagnosis of RTS should be based on these molecular findings and clinical diagnostic criteria are no longer needed. Several issues argue against this: there are individuals with a phenotype classically fitting RTS, but without detectable cytogenetic or molecular anomaly; there are individuals with a genuine variant in CREBBP or EP300 but with a phenotype different from the RTS phenotype,4 which can have major consequences in counselling patients and families; there are individuals with either a CREBBP or an EP300 variant of uncertain pathogenicity, and whose phenotype resembles RTS only to a limited extent, leaving it uncertain whether or not the variant is causative for the phenotype; there are many countries worldwide in which the availability of molecular studies is limited, and in which caregivers have to rely on a clinical diagnosis for counselling. For these reasons, we concluded that a clinical definition of the RTS phenotype is still needed and will remain needed.

There is no widely accepted set of clinical diagnostic criteria for RTS. We used the largest published set of data on individuals with RTS and either a CREBBP (n=308) or an EP300 variant (n=52),5 to determine the sensitivity of signs and symptoms (table 1).

Table 1

Main clinical findings in percentages of individuals with molecularly confirmed Rubinstein-Taybi syndrome

We used the scored features as available, to avoid a bias. Signs present in at least 75% of either of the two groups were accepted as being sufficiently characteristic of the condition. In addition, we added three features with a lower frequency but which are highly specific for RTS: (1) radially deviated thumbs; (2) keloid formation; and (3) maternal pre-eclampsia. We considered adding talon cusps to these criteria but refrained from doing so as this sign is not yet present in the age group during which typically a diagnostic question arises. When developing the scoring system, it was observed that the presence or absence of the sign ‘long eyelashes’ did not contribute to sensitivity, and given the low intra-observer reliability of this feature it was excluded from the scoring criteria. Furthermore, the features known to be highly specific for RTS (radially deviated thumbs typical smile; columella below alae nasi, maternal pre-eclampsia keloids) were given a higher weighted value in the scoring system to reflect their diagnostic importance. Features were then subdivided into Cardinal Features, which we considered to be essential for RTS, and Suggestive Features, which are present less frequently but should raise suspicion for RTS (table 2; figure 1). Subsequent discussion of these criteria allowed consensus for the clinical diagnostic criteria, based on the presence of both Cardinal and Suggestive Features (online supplemental R1). If an individual scores 12 or higher, including meeting a score for the Cardinal Features, the diagnosis of RTS can be clinically confirmed irrespective of the results of molecular testing. A score of 8–11 including a positive score for the Cardinal Features indicates a likely diagnosis of RTS which requires further confirmation by molecular testing. A score of 5–7, with or without a Cardinal Feature, indicates that the diagnosis of RTS is still possible and molecular studies are indicated. A score of 0–4 indicates that the diagnosis is unlikely, and other explanations of the phenotype should be explored.

Figure 1

Cardinal features of the clinical diagnostic criteria of face and limbs for Rubinstein-Taybi syndrome (RTS).

Table 2

Clinical diagnostic criteria for Rubinstein-Taybi Syndrome

We realise that the presence of unusual signs and symptoms is not incorporated in the score as a negative feature. Still, these should always also be taken into account. Especially the presence of an unusual sign or symptom in someone with a score indicating a likely or definitive diagnosis of RTS should lead to considering the presence of a co-existing second (possibly Mendelian) disorder. In addition, in scoring signs, especially low-hanging columella, the ethnic background should be taken into account as in some ethnicities a low-hanging columella is a common variant. If uncertainty remains it is often useful to evaluate both parents and other relatives as well (online supplemental R2). Lastly, in the first months of life delayed development and disturbed postnatal growth may not yet present and a definitive score may be only possible at an age when this can be reliably ascertained.

Subsequently, we evaluated whether the set of diagnostic features allowed establishing the diagnosis reliably in a group of 100 individuals with molecularly confirmed RTS, that had not been part of the group of patients on which the criteria were built (online supplemental table S1). All individuals scored 5 or higher, indicating none would have been missed as having RTS based on clinical criteria (complete sensitivity). Only seven patients scored in the group Possibly RTS, others scored in the group Likely RTS (n=38) or Definitively RTS (n=55). Furthermore, we evaluated whether 45 individuals with a specific group of pathological CREBBP or EP300 variants, who have been considered to have a separate entity (Menke-Hennekam syndrome (MKHK); MIM #618332 / #618333),4 would be correctly distinguished from RTS (online supplemental table S1). Results showed that none scored as definitive or likely RTS, 9 as possibly RTS and 36 as unlikely RTS, so the entities could correctly be discerned. To determine the specificity, we reasoned that three entities that may resemble RTS and are not uncommon, that is, Floating Harbour syndrome (FHS; MIM #136140) (n=45), Wiedemann-Steiner syndrome (WDSTS; MIM #605130) (n=46) and Cornelia de Lange syndrome (CDLS; MIM #122470) (n=100), should be reliably discerned from RTS based on the set of weighted clinical features (online supplemental table S2). Results showed that none of the individuals with FHS and CDLS fulfilled the criteria for a definitive diagnosis of RTS, but one of the patients with WDSTS had such a score. In addition, one of the patients with WDSTS had a score within the Likely RTS group but was found by the present authors to have a classical RTS facial gestalt. This has to be expected as RTS is a chromatinopathy, and variants in other genes acting in the same pathway are likely to have consequences for the phenotype as well and rarely may even alter the phenotype significantly. Further studies to explain this unusual phenotype are planned. Furthermore, 8 of the 46 WDSTS individuals, and 1 of the 100 CDLS individuals fulfilled the criteria for Likely RTS, indicating that specificity was very high, but not complete. Due to the overlap in function of the genes involved in the four entities, this is to be expected.6 The results are in agreement with our joint clinical experience that, infrequently, discrimination between RTS and WDSTS based on clinical criteria can be extremely difficult. This happens less frequently in patients with CDLS and in FHS, but the phenotypic overlap is still marked. Obviously, this has consequences for the molecular analyses in someone with such scores (see Molecular diagnostic criteria). We realise that prospective studies will be needed to determine more reliable specificity and sensitivity. In addition, such studies should include individuals of non-European descent, to evaluate whether the scoring system will be equally valid as in individuals of European descent.

Severity score

A major issue for families, especially at the time of diagnosis, is an indication of the severity of RTS. No severity score for RTS has been published to date. In our opinion a comparison and weighing of the severity and influences that various signs and symptoms have on the quality of life of an affected individual can only be made by the affected individuals and their families, and not just by physicians. We suggest that a group of family members should be facilitated to indicate which set of physical, cognitive and behavioural issues influence the life of individuals with RTS most. Ideally, such criteria should be stratified according to the nature of the molecular genetic cause (online supplemental R3).

Molecular diagnostic criteria

RTS has been subdivided into type 1 (RTS1; OMIM #180849) and type 2 (RTS2; OMIM #613684) associated with heterozygous pathogenic variants or re-arrangements in the genes CREBBP and EP300, respectively, typically leading to haploinsufficiency. Both genes encode paralogous transcriptional coactivators with lysine acetyltransferase activity.7 8 The proteins CBP and p300 play a crucial role in transcription initiation by acting as a bridge, linking transcription factors to the transcription machinery, and through acetylation of histones9 10 (figure 2).

Figure 2

Structures and functions of CBP/p300. (A) The proteins CBP and p300 are composed of 2442 amino acids (AA) and 2414 AA, respectively, with 58% of sequence similarity within their domains. The various domains are represented by their position in the AA sequence: N-terminal nuclear receptor interaction domain (NRID or RID), cysteine-histidine rich region 1 (C/H1) containing the transcriptional adapter zinc finger 1 (TAZ1), kinase-inducible domain (KID) interacting domain (KIX), Bromodomain, C/H2 containing a plant homeodomain (PHD), lysine acetyltransferase domain (KAT), C/H3 containing the zinc finger (ZZ) and TAZ2 domains and interferon-binding transactivation domain (IBiD). The Menke-Hennekam syndrome (MKHKS) region corresponds to the location of the missense variants leading to the MKHKS. (B) CBP and p300 act as transcriptional co-activators of target genes by different mechanisms: (1) Binding function by facilitating the physical and functional interactions of TF; (2) scaffolding function allowing the recruitment of TF and in particular CREB; (3) KAT function by catalysing the transfer of acetyl groups on lysine residues of both histone tails and non-histone proteins such as the RNApolII complex and TF. Ac, acetyl group; TBP, TATA binding protein; TF, transcription factors. Adapted from a study by Van Gils et al.15

Mutation spectrum

Variants in CREBBP and EP300 have been identified in 55–75%,2 3 11 12 and 8–11%,3 5 13 14 of individuals with RTS, respectively, of whom 2–3% have deletions of the complete gene. In 5–20% no molecular anomaly can be detected (online supplemental R4). To date, over 500 CREBBP and over 100 EP300 pathogenic variants are known, distributed along all 31 exons (figure 3). Several recurrent CREBBP variants have been reported, ~50% of missense variants are localised in the KAT domain,15 and recurrent rearrangements occur between introns 1 and 2 of CREBBP due to the high frequency of repeated or palindromic sequences in this region.16 17

Figure 3

Mutation spectrum of CREBBP and EP300 in individuals with Rubinstein-Taybi syndrome (RTS) (referenced in HGMDPro variant database and/or LOVD). (A) Repartition of 500 pathogenic variants in CREBBP referenced as causing RTS1 including 84 non-sense variants, 192 frameshift variants, 46 splicing variants, 84 missense variants, 75 intragenic deletions, 14 deletions including CREBBP completely, 2 intragenic duplications and 3 complex rearrangements. (B) Repartition of 118 pathogenic variants in EP300 referenced as causing RTS2 including 26 non-sense variants, 56 frameshift variants, 6 splicing variants, 16 missense variants, 11 intragenic deletions and 3 deletions encompassing EP300 completely. Adapted from a study by Van Gils et al.15

Genotype-phenotype correlation

Individuals with RTS1 and RTS2 both may show the classical phenotype but this may also vary. Individuals with RTS2 demonstrate in general less marked typical facial characteristics, no radial deviation of the thumbs, have infrequently keloids and a higher average cognitive level.5 13 14 However, maternal pre-eclampsia, intrauterine growth retardation and microcephaly are more common in RTS2 compared with RTS1.5

The type and site of variants in CREBBP and EP300 do not associate with a specific phenotype with respect to external morphology, malformations, cognition or behaviour,5 11 13 18 19 (online supplemental R5). The exception is formed by missense variants between the end of exon 30 and the beginning of exon 31 of both CREBBP and EP300, which both lead to a phenotype that differs from RTS (table 1) and has been designated as MKHK (OMIM #618332, #618333).4 20 These missense variants hypothesised to affect specifically the binding properties of the ZNF2 (zinc finger, ZZ type) and ZNF3 (zinc finger, TAZ type) domains to different CBP partners by affecting their own folding.21 22

RTS shows broad phenotypic overlap with other Mendelian disorders affecting the structure of chromatin genome-wide called ‘chromatinopathies’, such as FHS (OMIM #136140), CDLS (OMIM #122470, #300590, #610759, #614701, #300882, #608749), WDSTS (OMIM #605130), Kabuki syndrome (OMIM #147920, #300867), genitopatellar syndrome (OMIM #606170), Biesecker-Young-Simpson syndrome (OMIM #603736) and Gabriele-de Vries syndrome (OMIM #617557).

Diagnostic approach

There are two main entry points for molecular genetic testing in RTS: clinical suspicion of RTS or no clinical suspicion (figure 4). If clinical presentation suggests RTS, the first-line tests are either targeted analysis of CREBBP and EP300 by Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) or by high throughput analysis (array Comparative Genomic Hybridisation (aCGH); whole-exome sequencing (WES) if accessible). If RTS is not suspected in an individual with intellectual disability and/or malformations, the first tier is high throughput analyses (aCGH; WES or whole-genome sequencing). Evaluation of variant should be performed using the ACMG (American College of Medical Genetics and Genomics) classification.23 Additional RNA studies are needed in case of unknown splicing variants. Suspicion of somatic mosaicism should be confirmed in more than a single tissue (buccal swab; bladder epithelium cells; skin biopsy). The phenotype should be re-evaluated after the identification of a (possibly) pathogenic variant to confirm that the molecular finding fits the clinical phenotype. If targeted analyses yield negative results and high throughput analyses are not available, the diagnosis remains dependent on the clinical phenotype and a definitive diagnosis may not be possible.

Figure 4

Molecular diagnostic pathways for Rubinstein-Taybi syndrome. In individuals with clinically classic RTS phenotype, the first-line molecular diagnostic approach is targeted analysis of CREBBP and EP300 by Sanger sequencing and MLPA or by high throughput analysis (aCGH; WES). In individuals in whom RTS is not suspected, aCGH and WES or WGS are performed. a Including analysis of CREBBP / EP300 and genes causing related entities; b evaluation of results using ACMG classification23; c episignature specific for RTS24 ; d RNA studies; searches for mosaicism. aCGH, array Comparative Genomic Hybridisation; ACMG, American College of Medical Genetics and Genomics; MLPA, Multiplex Ligation-dependent Probe Amplification; RTS, Rubinstein-Taybi syndrome; WES, whole-exome sequencing; WGS, whole-genome sequencing

If the clinical diagnosis cannot be confirmed molecularly, molecular analyses yield a variant of unknown significance, or the phenotype does not fit the molecular finding, analysis of a genome-wide methylation pattern (epigenetic signature) can be performed as individuals with RTS have a specific pattern.24

If all studies are negative, one should consider other diagnoses. Still, currently, not all molecular mechanisms leading to RTS are known, and if the clinical diagnostic criteria for RTS are met (see Clinical diagnostic criteria), the diagnosis of RTS remains the standard in guiding management and follow-up of the patient.

Recurrence risk

RTS is inherited as an autosomal dominant trait and occurs de novo in over 99% of patients. However, familial occurrence does occur, either if a parent is relatively mildly affected or due to somatic or germ-line mosaicism.25 26 To date, eight instances of somatic or germ-line mosaicism and seven instances of parent-to-child transmission have been described in over 2000 reported affected individuals, indicating the empirical recurrence risk is 0.5–1%.27 The recurrence risk for offspring of an affected individual is 50%, although it may be lower due to a spontaneous miscarriage (online supplemental R6).

Prenatal diagnosis

Without a positive family history, the prenatal diagnosis of RTS is only infrequently made as there are few reliable antenatal signs. Truly detailed three-dimensional ultrasonography may allow suggestive facial characteristics, but the morphology of the extremities, and specifically the radially deviated thumbs, are the main diagnostic handles.28 29 Additional findings that may be helpful are intrauterine growth retardation, polyhydramnios, underdevelopment of the cerebellum and gallbladder anomalies.26

The main reason to perform prenatal diagnostics for RTS is the birth of a previous child with RTS in the family. If a causative variant in CREBBP or EP300 has been detected, reliable molecular prenatal diagnostics can be performed in samples obtained by chorionic villus sampling or amniocentesis, or in embryonic cells obtained by in vitro fertilisation (online supplemental R7).

Prenatal testing in families without a previous child with RTS and a known pathogenic variant, by non-invasive cell-free fetal DNA screening, is not advocated, as an interpretation of the pathogenicity of variants detected this way may be extremely difficult. This limits the validity and informative value of the prenatal testing and may cause ethical issues for the families in deciding whether or not a pregnancy should be continued. Any prenatal testing needs to be discussed carefully with the couple before the procedure and should take into account the differences in perspective of couples and national legislation.

Neonatal careRecognition

86% of children present within the first month of life and 70% of these on the first day of life; prolonged hospital admission after birth was reported in 61%.30 Early recognition of RTS may help identify complications and assist families to cope.31 The typical facial features of RTS evolve with time.32 The characteristic appearance in the neonatal period differs somewhat as it is mainly characterised by a prominent forehead with haemangiomas (‘stork-bite naevus’) in the glabella region, (apparent) hypertelorism, epicanthi and at that age up-slanting palpebral fissures. The nasal bridge tends to be straight, the tip short and upturned, and the nasal septum is not or only slightly extending beyond the alae.32 A small mouth, highly arched palate and small mandible are also present. Additional features can be unusually thick, black hair, a large anterior fontanelle and long eyelashes. Newborns with a variant in EP300 tend to have a less obvious phenotype.5 The distal limb anomalies are the most characteristic of RTS in the neonatal period and are similar to those at an older age (see Clinical diagnostic criteria). Cryptorchidism is common.

Feeding

Neonatal feeding difficulties are common (71–80%), due to swallowing incoordination, poor nipple grasp, hypotonia and gastro-oesophageal reflux.33 Nutritional supplementation including gastric tube feeding is required in 40% of cases, as are occasionally percutaneous tubes, but most feeding challenges will have resolved within the first year of life.30 Should feeding difficulties persist, additional professionals should be consulted (see Gastroenterology). Still, half of the mothers report a sufficient suck and were pleased with their breastfeeding experience.33 Adequate breastfeeding instructions, proper positioning and ongoing encouragement are indicated (online supplemental R8).

Birth parameters

At birth most infants fall within the normal range for weight, length and head circumference,34 although a higher incidence of microcephaly and growth restriction has been reported in infants with EP300 variants, possibly related to the frequently occurring pre-eclampsia.5 There is no increased risk of preterm birth.35 The use of RTS-specific growth charts is encouraged to monitor growth adequately (online supplemental R9).

Systemic manifestations

The various systemic manifestations of RTS are described elsewhere in the guidelines. The work-up of every newborn with suspected or confirmed RTS should include ophthalmological exams (glaucoma; coloboma); cardiac assessment (malformations); and renal ultrasound (malformations) (online supplemental R10). Obviously, further care such as the baseline newborn hearing screening and vaccinations should be performed as per the general population.

EndocrinologyHypoglycaemia

Transient hypoglycaemia occurs with a low frequency in newborns with RTS and responds well to usual management schemes (online supplemental R11). Hypoglycaemic hyperinsulinism (HH) is very rare, may occur after birth or in the first years of life, is sometimes associated with concurrent illness, and can be transient or permanent.36 37 It has mainly been described in children with EP300 variants.5 Early diagnosis and treatment of HH is crucial to avoid permanent brain damage.38 Treatment is as in the general population: frequent enteral feeding, continuous glucose infusion and diazoxide). Usually, specialist consultation is needed.39

Growth

Postnatal growth retardation is a hallmark of RTS.34 Usually within months after birth, the length, weight and head circumference drop from normal values to ~ −2SDS. Neither boys nor girls show a pubertal growth spurt, which contributes to a subsequent average adult height of −3SDS for both men and women.34 The use of growth charts specific for RTS, based on molecularly confirmed patients, facilitates adequate monitoring of growth (online supplemental R9). Growth hormone (GH) deficiency is infrequent but has been reported in few individuals, in whom GH therapy resulted in an increase in height SDS.40 Every child in whom growth differs markedly from the growth pattern of the dedicated growth charts needs to be evaluated for GH deficiency (online supplemental R12). If present, treatment is as in the general population. Prepubertal boys and girls may develop an unusual body shape due to increased fat tissue around the abdomen and hips, which disappears in puberty in boys, but often persists throughout life in girls.41

Puberty

The timing of puberty and the development of secondary sex characteristics usually falls within normal limits. The mean age of onset of puberty was 12.2 years,35 with a mean age of menarche at 13.6 years.41 There is no indication that fertility has decreased, although formal studies are lacking. About 25% of adult males and females with RTS are sexually active.42 Sexual education should be proposed according to the level of emotional and cognitive functioning,43 and contraceptive options are recommended as in the general population taking the level of developmental functioning into account (online supplemental R13).

Gastroenterology

Malformations of the gastrointestinal tract such as a duodenal web and malrotation occur at a low frequency in newborns with RTS, although the frequency of the malrotation may be higher than in the general population.44 45 Symptomatology is similar to in newborns without RTS and should be managed as in the general population.41 45

Feeding problems are very frequently present at birth and may remain present for a prolonged period of time.41 45 46 Oral feeding is preferred if it is safe and feasible, while tube feeding may be needed and a gastrostomy for long-term use. The involvement of dieticians is often helpful (online supplemental R14). Although feeding problems are in part explained by recurrent respiratory infections and hypotonia, also gastro-oesophageal reflux (GOR) may play a role.46 Limited GOR occurs in all healthy infants and children; if causing excessive symptoms it is referred to as GOR disease (GORD).47 The symptomatology of GORD may vary widely, from feeding problems, dental enamel erosions and recurrent pneumonias to restlessness and poor sleep. The pathogenesis remains uncertain.46 GOR(D) should be differentiated from excessive regurgitation after feeds in otherwise asymptomatic infants, which is usually indicated as infant rumination syndrome.48 Extremely rarely, oeosinophilic oesophagitis may develop.49 Given the lack of evidence for the management of GORD specifically in RTS, management of GORD should be as in the general population,47: thickening of food and reassurance of parents as a first step. If symptoms persist, an initial trial with PPI (Proton Pump Inhibitors) treatment can be considered. If problems continue, further evaluation should be considered. If a PPI trial improves symptomatology, this does not conclusively prove acid-related GORD. Long-term use of PPI may cause side-effects,50 thus in successful PPI trials individuals should undergo weaning trials regularly (eg, after 6 months and yearly thereafter) to evaluate the utility of continuing PPI treatment, while mitigating rebound effects by dose tapering. If symptoms persist or recur, additional testing, such as pH-impedance testing and/or endoscopy can be considered (online supplemental R15). Fundoplication and other surgical interventions are not recommended in an early phase of management, as these have a relatively high failure rate, commonly cause complications and can induce dysphagia and subsequent feeding problems; it should be reserved for patients with proven GORD unresponsive to optimal nutritional and medical therapy.51 Fortunately, complications of long-term GORD such as Barrett’s oesophagus are rare in RTS,52 and oesophageal cancer has not been reported.

Constipation is extremely prevalent in RTS across all age groups throughout the lifespan.41 45 The cause remains unknown, Hirschsprung disease or other identifiable aetiologies do not occur more frequently than in the general population. Additional investigations are only indicated if symptomatology suggests an underlying disease. Long-term treatment with increased dietary fibres and fluid intake, and oral osmotic laxatives remain the cornerstone of treatment53 (online supplemental R16). In severe cases, stimulant laxatives may be added, and further management schemes are as in the general population.

Cardiology and pulmonologyCardiovascular system

Congenital heart defects (CHDs) occur in 30% of cases, without a genotype–phenotype correlation.18 54–56 The reported differences in incidence according to ethnicity can be explained by ascertainment bias and differences in methodology.57 The typical CHDs are patent ductus arteriosus, persistent foramen ovale and atrial and ventricular septal defect.5 13 19 55 58–60 Individuals with a CHD do not have a higher rate of other malformations or are associated with impaired cognitive function.

The cardiovascular system should be evaluated at diagnosis, including cardiac sonography (online supplemental R17). Treatment is as in the general population, including endocarditis prophylaxis as indicated. Surgery is needed in 15–22% of patients.42 61 CHDs do not cause unexpected complications in adults.42

Cardiovascular problems typical for the general adult population occur in adults with RTS at a lower frequency. Hypertension is reported in 10% of adults,42 and surveillance and treatment are as in the general population (online supplemental R18).

Pulmonary system

Mild respiratory distress in the first hours of life is common in RTS neonates. Treatment is only needed if other risk factors such as prematurity are present. Upper respiratory infections are common (see Immunology). Infections of the lower respiratory system are uncommon,42 and are explained by feeding problems, microaspirations and gastro-oesophageal reflux. Exceptionally, immunodeficiency may play a role; the reported higher frequency of lower respiratory infections was caused by a study bias.62 In case of recurrent pneumonia with wheezing, hoarseness or stridor, the patient should first be evaluated for microaspirations and gastro-oesophageal reflux49 (online supplemental R19). If negative, a search for immunodeficiency is indicated. Bronchiectasis has been described only in individuals with severe immunological malfunctioning.63

Interstitial lung disease that becomes evident either in childhood,64 or adulthood,65 is uncommon but potentially severe. The diagnosis is made through the radiological characteristics of CT and can be confirmed by biopsy.64 Management is as in the general population and is problematic.

Pulmonary functioning can also be compromised secondary to restrictive pulmonary diseases related to scoliosis,66 and pulmonary hypertension caused by chronic sleep apnoea (obstructive sleep apnoea (OSA))67 (see Otolaryngology and Anaesthesiology).

Ophthalmology

Ocular abnormalities and/or reduced vision are reported in 20–80% of individuals with RTS.55 57 61 68–72 An overview of ocular anomalies is presented in online supplemental table S3 (online supplemental materials). Every child with RTS needs to be referred for ophthalmological evaluation once the diagnosis is suspected (online supplemental R20).

Eye abnormalities were reported to be more common in individuals from Asia and Latin America than those from Africa and the Middle East, but this may be biased.57 Both individuals with CREBBP and EP300 variants present ocular anomalies, but due to small numbers of data on individuals with EP300 variants differences in occurrence remain uncertain.

Anatomical anomalies

Congenital nasolacrimal duct obstruction by a persistent membranous obstruction at the entrance of the duct into the nose causes a watery eye from birth. It is mostly unilateral, with the incidence between 11% and 47%.55 57 59 71–74 Treatment follows international guidelines (Nasolacrimal Duct Obstruction in Children - American Academy of Ophthalmology aao.org) but the surgeon should be aware of the thicker bones and brittle lacrimal sacs in children with RTS.75

The reported frequency of congenital glaucoma varies from 4% to 11%.55 57 61 72 75 The glaucoma can be unilateral or bilateral and be associated with anterior segment anomalies such as iris coloboma or lens luxation. Symptoms include tearing, blepharospasm and photophobia, and enlargement of the eye, manifesting as megalocornea and rapidly increasing myopia. Treatment should be as soon as possible after birth as it can lead to a marked loss of vision (www.eugs.org. Congenital Glaucoma - Europe - American Academy of Ophthalmology aao.org).

Cataracts has been reported in 6–25% of individuals with RTS,19 57 61 72 75 and is usually congenital.72 Reliable incidence figures are lacking. Early diagnosis and treatment in the first 2 months of life are mandatory to avoid visual deprivation, treatment is as in the general population (Pediatric Cataracts: Overview - American Academy of Ophthalmology aao.org). Frequent follow-up is needed for appropriate refractive correction and monitoring of secondary complications. Cataracts may also develop later in life71 (online supplemental R21).

Coloboma is reported in 10% of individuals.19 57 59 71–73 The coloboma can affect the iris, choroid, retina and/or optic nerve. Symptoms depend on location and size and may include visual field loss, reduced vision and photophobia. There is no curative therapy, but sometimes glare can be reduced by wearing sunglasses.

Retinal abnormalities occur frequently,72 but are often subtle, so may go unnoticed, without severe loss of vision, except for macular degeneration secondary to high myopia (online supplemental R21). Evidence may be present in the abnormal distribution of pigment in the macula and a subnormal electroretinogram. In some patients, the abnormal aspect of the macula is caused by foveal hypoplasia (Van Genderen, unpublished).

Functional anomalies

Visual impairment (best corrected binocular visual acuity <6/18) occurs in 20% of individuals,72 and typically is caused by anatomical abnormalities. Bilateral severe anomalies may lead to infantile nystagmus because of decreased sensory input from birth. Refractive errors and strabismus are very common, both occurring in 50–75% of individuals, and may change rapidly with age indicating the need for frequent controls, especially under 5 years of age13 55 57 61 71 72 (online supplemental R21). In young children, high refractive errors need correction to prevent amblyopia. Children may however refuse to wear glasses if improvement of vision is not immediately evident. Gradual introduction in situations in which the child benefits most from glasses may allow the child to get accustomed to wearing spectacles (online supplemental R22).

Treatment of strabismus to prevent amblyopia is as in the general population, provided the affected eye has no congenital anomaly that inhibits amelioration of vision.

Photophobia is common due to cataracts, glaucoma or trichiasis.72 Treatment is by treating the cause. Photophobia secondary to coloboma or retinal dysfunction can be ameliorated by shielding the eyes from direct (sun) light or wearing sunglasses.

Otolaryngology and anaesthesiologyHearing

The typical facial characteristics in individuals with RTS include a small chin and small oral cavity which can result in airway difficulties and, together with gastro-oesophageal reflux, can result in complications such as recurrent middle ear infections.76 Conductive, sensorineural and mixed hearing loss may result.77–79 Regular auditory evaluation is therefore recommended (online supplemental R23).

Sleep

Abnormal facial anatomy and increased collapsibility of the laryngeal walls predispose individuals with RTS to higher rates of sleep-disordered breathing and OSA.80 81 Sleep disorders are frequent in children, and occur in 62% of adults.42 61 OSA is typically characterised by snoring and excessive daytime sleepiness and affects 25% of adults with RTS.42 61 If present in children the facial anatomy is often markedly abnormal and accompanied by obesity, hypotonia and adenotonsillar hypertrophy.81 As with the general population, management should take into account the various causal factors as well as potential difficulties in treating both children and adults with RTS67 (online supplemental R24). Assessment of the sleep patterns using a validated questionnaire, such as the Sleep Disturbance Scale for Children,82 may offer information on both sleep patterns and response to therapy (online supplemental R25). Prior to a major surgical intervention, polysomnography should be considered.83 Management of sleep disorders is aimed at implementing healthy sleep practices, particularly position during sleep, behavioural strategies and the use of and education on pharmacological interventions. Melatonin should be used appropriately in individuals with specific types of insomnias and sleep rhythm disturbances.

Anaesthesiology

Approximately 48% of adults with RTS require surgery at least once, with half of those requiring two or more surgeries during their lifetime.42 Children with RTS are no exception as they receive a higher fraction of anaesthetics relative to their age-matched cohorts.35 As a result of the multisystemic manifestations of RTS, anaesthesiologists should be prepared to provide a tailored anaesthetic for this population (online supplemental R26).

Premedication and behavioural therapy support may prove beneficial in the preoperative setting. A single case series described complications such as cardiac arrhythmias associated with intraoperative administration of atropine and succinylcholine, but other studies have shown the safe and efficacious use in RTS,84 85 and this is also our joint personal experience. The altered facial anatomy may make mask ventilation, laryngoscopy and intubation challenging, and coupled with positioning limitations that may be present due to scoliosis, kyphosis, hypermobility and obesity, may warrant the use of video-laryngoscopy or fiberoptic intubation.35 86 Rarely, transnasal placement of a nasopharyngeal airway or nasogastric tube is inhibited due to narrow or atretic choanae.

Intraoperative management of ventilation and postextubation care can be complicated by the presence of laryngotrachomalacia and augmented airway reactivity. In the immediate postoperative period, opioid use, while not contraindicated, should be used judiciously to prevent exacerbation of obstructive symptoms and hasten potential apnoeas. The perioperative use of analgesic and anxiolytic adjuncts such as non-steroidal anti-inflammatory drugs, acetaminophen and dexmedetomidine are encouraged, if not contraindicated secondary to other comorbidities or surgical considerations. Initiation of transient, non-invasive positive airway pressure may be helpful. Secondary to the elevated risk of complications with anaesthesia and airway manipulation, particular efforts should be made to bundle non-emergent procedures into a single anaesthetic to mitigate potential morbidity (online supplemental R27).

Dermatology

The main skin problem in RTS is the propensity to develop keloid. Keloids are non-malignant fibrous growths resulting from an abnormal response to skin injuries or inflammation that extend beyond the borders of the original wound. The pathogenesis of keloids is thought to involve multiple patient-specific factors (genetics, age, hormones, ethnicity), and environmental factors (trauma, surgery, inflammation) which collectively stimulate wound healing and persistent inflammation.87 Spontaneous keloids occur only in genetic syndromes,88 raising the question whether they are truly spontaneous, or whether unrecognised triggering environmental factors occur.

RTS is the syndrome considered to have the highest risk of keloid development.89 The frequency of Dutch and UK RTS i