Myhre Syndrome (SMAD4)

Progressive multisystem connective tissue disorder caused by heterozygous missense variants at codons 496 and 500 of the SMAD4 gene, with proliferative fibrosis, vascular, airway and gastrointestinal stenoses, joint stiffness, thick skin, short stature and neurodevelopmental impairment; includes the former LAPS syndrome

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Original description and clinical delineation

Selma A. Myhre, Ruvalcaba and Graham described in 1981, in Clinical Genetics, “a new growth deficiency syndrome” in two unrelated men aged 24 and 18 years [2, 24]. Both had prenatal and postnatal growth deficiency, with final heights of 140 and 146 cm, intellectual disability, a face with maxillary hypoplasia, prognathism, short palpebral fissures, short philtrum and small mouth, generalised muscle hypertrophy, reduced joint mobility, cryptorchidism, a cardiac anomaly and early-onset mixed deafness; radiographs showed a thickened calvarium, broad ribs, hypoplastic iliac wings, short tubular bones and large, flattened vertebrae with bulky pedicles [2]. The authors proposed a de novo dominant mutation because the parents were 37 and 38 years old at the time of birth [2]. Over the following twenty years the literature added isolated cases and small series, mostly male, until the first female case was described in 2003, and the syndrome came to be recognised by the combination of short stature with a “square” habitus, characteristic face, muscular pseudohypertrophy, joint stiffness, deafness and variable cognitive impairment [2, 7].

1.2. LAPS syndrome and nosological unification

Hopkin et al. described in 1998 three patients with progressive airway narrowing, short stature and joint stiffness, with no infectious, inflammatory or metabolic cause [2]. Lindor et al. added in 2002 two adult women with the same picture, who needed tracheostomy as young adults, and proposed the name LAPS, an English acronym for laryngotracheal stenosis, arthropathy, prognathism and short stature [25]. The similarity with Myhre syndrome was discussed by Lindor et al. in 2009, in an article entitled “LAPS syndrome and Myhre syndrome: two disorders or one?” [16], and in 2012 Lindor et al. identified in the two original patients SMAD4 variants already described in Myhre syndrome, concluding that this was the same disease [2, 26]. The series of Michot et al. (2014), with 30 patients diagnosed with Myhre syndrome and 2 with LAPS, confirmed the clinical and molecular homogeneity of the group [27]. GeneReviews currently regards LAPS syndrome as allelic to Myhre syndrome, with variants at the same codons, and the term is no longer used [1]. Bone Dysplasias (4th edition, 2018) still treats LAPS as a differential diagnosis and states that laryngeal stenosis is not part of Myhre syndrome, a position that later data do not support: acquired laryngotracheal stenosis is described in about 15% of patients in Smith's Recognizable Patterns and in recent cohorts [7, 16, 28].

1.3. Molecular discovery

In 2011–2012, two teams independently identified the molecular cause by exome sequencing. Le Goff et al. found in 11 patients three heterozygous missense variants at the same codon, Ile500, in the MH2 (Mad homology 2) domain of SMAD4, next to the monoubiquitination site at Lys519, with defective ubiquitination in patient fibroblasts [29]. Caputo et al. identified two recurrent de novo variants at the same residue in eight patients, having selected the genes of the transforming growth factor beta (TGF-β) signalling network by analogy with geleophysic dysplasia [2, 30]. The p.(Arg496Cys) variant was described later and is now the second most frequent [7, 27]. Smith's Recognizable Patterns (8th edition, 2022) swaps the titles of the Le Goff (2011) and Lindor (2012) references and gives the locus as 18q12.2; the correct title of the Le Goff article is “Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome”, and the locus is 18q21.2 [1, 16, 29].

1.4. From case series to natural history

After the discovery of the gene, the literature moved from isolated reports to reviews and cohorts. Michot et al. (2014) analysed 32 patients; Lin et al. (2016) reviewed 54 patients with a confirmed variant, with a cardiovascular emphasis; Garavelli et al. (2016) described the potentially fatal complications in 48 patients; Yang et al. (2022) followed 12 patients from the French reference centre for rare bone dysplasias; Lin et al. (2024) characterised 47 patients assessed at the Myhre Syndrome Clinic of Massachusetts General Hospital (MGH) between 2016 and 2023; and Vanbelleghem et al. (2024) described 24 adults [7, 13, 15, 27, 31, 32]. In December 2025, the American Journal of Medical Genetics Part C devoted a themed issue to the syndrome, with reviews on basic research, therapy, the patient registry, skin, autopsies and familial transmission [9, 19, 33, 34]. GeneReviews counted more than 200 patients with a molecular diagnosis in December 2024, and a 2026 systematic review brought together 217 patients from 55 reports [1, 35].

1.5. Definition and scope

Myhre syndrome is defined by the association of a compatible clinical picture with a heterozygous pathogenic or likely pathogenic SMAD4 variant at codons 496 or 500; there are no consensus clinical criteria, and a diagnosis of “Myhre-like syndrome” without molecular confirmation is discouraged [1, 7]. Loss of function of the same gene causes juvenile polyposis syndrome and the juvenile polyposis–hereditary haemorrhagic telangiectasia overlap, with opposite mechanism and phenotype [1, 36]. In the skeletal classification, Myhre syndrome belongs to the acromelic dysplasias, alongside geleophysic dysplasia, acromicric dysplasia and Weill-Marchesani syndrome, which share thick skin, short stature, short hands and joint stiffness and are treated here as differential diagnoses [1, 3, 37].

2. Molecular Genetics and Pathophysiology

2.1. The SMAD4 gene and TGF-β/BMP signalling

SMAD4 maps to 18q21.2 and encodes the common mediator (co-SMAD) of the canonical TGF-β, bone morphogenetic protein (BMP) and activin pathways [1, 5]. After activation of type I and II receptors, the receptor-regulated SMADs (R-SMADs) are phosphorylated — SMAD2 and SMAD3 in the TGF-β pathway, SMAD1, SMAD5 and SMAD8/9 in the BMP pathway — and form heterotrimeric complexes with SMAD4, which accumulate in the nucleus and bind SMAD-binding elements in DNA to regulate transcription of target genes [5, 19, 38]. The MH1 domain binds DNA and the MH2 domain mediates oligomerisation with the R-SMADs and transactivation; SMAD4 also interacts with transcriptional cofactors such as NKX2-5 and with the inhibitory SMADs SMAD6 and SMAD7 [30, 38]. The TGF-β superfamily includes 33 ligands and 12 receptors, all dependent on SMAD4 in the canonical pathway, which explains the pleiotropy of an alteration of this protein: development of the axial and appendicular skeleton, cardiac muscle and central nervous system, extracellular matrix deposition, immunity and reproductive function [1, 39]. Smith's Recognizable Patterns stresses that the coexistence of congenital anomalies and acquired manifestations shows that SMAD4 is required both for development and for postnatal homeostasis [16].

2.2. Variant spectrum and nomenclature

All variants associated with Myhre syndrome are heterozygous missense substitutions affecting amino acids 496 or 500 of the MH2 domain [1]. Table 2.1 presents the nomenclature normalised in VariantValidator on the MANE Select transcript NM_005359.6 and the current ClinVar classification.

Sources: [6, 7, 40].

The other substitutions at the third nucleotide of codon 500 (c.1500A>T and c.1500A>C) are synonymous, p.(Ile500=), and do not produce p.(Ile500Met) [6]. The legend of Figure 1 in Smith's Recognizable Patterns reads “p.I500V, c.1487A>G”; position c.1487 is a guanine and the only change that produces p.(Ile500Val) is c.1498A>G, so the book's notation should be read as c.1498A>G [6, 16]. In a 2025 report the variant is described on the previous version of the transcript, NM_005359.5:c.1498A>G, with the same coding position [41]. GeneReviews reports that sequencing detected 100% of known pathogenic variants and that no exon-level or whole-gene deletions or duplications have been described, as expected for a mechanism that does not depend on loss of function [1]. In the 2025 Myhre Syndrome Foundation review, about 50% of cases carry p.(Ile500Val), about 40% p.(Arg496Cys) and the remainder the substitutions of Ile500 by threonine, methionine or leucine [39]. The proportion of each variant depends on the cohort: in the Ghent adult study, p.(Arg496Cys) accounted for 14 of 24 patients, compared with 5 of 25 adults in the literature (p<0.01) [13].

2.3. Mechanism: gain of function or dominant-negative effect

The prevailing hypothesis is gain of function. Le Goff et al. observed in patient fibroblasts reduced SMAD4 monoubiquitination, with stabilisation of the mutant protein, increased phosphorylation of several SMAD partners and altered expression of TGF-β and BMP target genes [2, 29]. Piccolo et al. showed increased SMAD4 levels and disorganised extracellular matrix in fibroblasts, corrected by losartan [1, 7, 18]. Lindsay et al. (2025), in nasal epithelial basal cells from three patients with p.(Ile500Val), p.(Arg496Cys) and p.(Ile500Thr), found no change in SMAD4 stability or in R-SMAD phosphorylation, but rather increased transcriptional activity, attributed to greater protein–protein interaction within the SMAD complex; p.(Ile500Val) increases the stability of the SMAD3/SMAD4 transcriptional complex [1, 42]. Conversely, Alankarage et al. (2022) reported that SMAD4-I500V dimerises but has severely impaired transcriptional activity and acts in a dominant-negative manner on wild-type SMAD4, on the R-SMADs and on the function of the transcription factor NKX2-5 [38]. GeneReviews considers this discrepancy unresolved; both hypotheses converge on dysregulated TGF-β/BMP signalling with abnormal extracellular matrix deposition during development and in adult life [1, 43]. The restriction of the spectrum to two residues, which are also hotspots of somatic mutation in neoplasms, suggests that these changes have specific consequences for SMAD4 function, distinct from simple loss of function [7, 30].

2.4. From molecular pathway to tissue

The defining manifestation is an excessive fibroproliferative response: histological specimens show cellular proliferation and excessive extracellular matrix deposition, especially in the heart, lung and upper and lower airways [44]. Skin biopsies reveal pan-dermal thickening of collagen bundles, with an immunohistochemical pattern distinct from the inflammatory scleroderma disorders, and electron microscopy of the dermis showed irregular elastin cores with globular deposits and almost absent microfibrils [45, 46]. The two autopsies published in 2025 documented chronic pericarditis, fibrosing pleuritis, diffuse interstitial pulmonary fibrosis, submucosal bladder fibrosis, nodular medial hypertrophy of the aorta, pericardial and peritoneal adhesions, thickening of the calvarium and dura mater, and ovarian fibrosis with reduced oocyte numbers [47]. In the respiratory epithelium, SMAD4 activation reduces proliferation and mucociliary differentiation of basal cells and impairs bacterial clearance; a 2026 study added increased susceptibility to respiratory syncytial virus through suppression of the innate defence protein BPIFA1, a mechanism reproduced in normal cells by TGF-β1–SMAD4 activation [42, 48]. Smith's Recognizable Patterns summarises the pathophysiological distinction: restrictive proliferative fibrosis around the heart, vessels, skin and other organs separates Myhre syndrome from the TGF-β pathway disorders characterised by weakness of the vascular wall and serosae, such as Marfan, Loeys-Dietz and Shprintzen-Goldberg syndromes [16]. Lin et al. propose, for the vascular phenotype, the term “hypoplastic aortopathy”, in contrast to the dilating aortopathy of these syndromes [7]. The French PNDS summarises the data from mouse models with targeted Smad4 inactivation: in chondrocytes it causes dwarfism with histological changes of the growth plate and sensorineural hearing loss due to cochlear anomalies; in osteoblasts it alters postnatal bone homeostasis, which may contribute to prognathism and maxillary hypoplasia; in the brain, SMAD4 is involved in astrocyte differentiation, oligodendrocyte migration, interneuron genesis and the balance between excitation and inhibition in the hippocampus, functions proposed to explain the neurodevelopmental disorders [14]. These are loss-of-function models, so extrapolation to gain-of-function variants is indirect.

2.5. Inheritance, parental origin and selection in the male germline

Myhre syndrome is autosomal dominant and results, in most patients, from a de novo variant [1]. Wood et al. (2024) analysed 16 informative trios: in all of them the variant arose on the paternal allele, and the fathers of probands were on average 6.3 years older than expected [8]. Using an ultrasensitive assay, they found the codon 500 pathogenic variants at high levels in the sperm of most men, with a strong positive correlation with donor age; these mutations confer a selective advantage on the spermatogonia carrying them, the same “selfish” mechanism previously described only for genes of the RTK-RAS-MAPK pathway [8]. In the MGH cohort, mean maternal and paternal ages at birth were 32 and 37 years [7]. Vertical transmission has been described in several families, all with p.(Arg496Cys): from mother to two children in three families, from a mildly affected mother to a son in a family published in 2025, from father to three children in a Brazilian family, and two adult men with p.(Arg496Cys) had children without fertility problems [1, 9, 10, 13, 46, 49]. Penetrance appears complete, with variable expressivity within and between families [10].

2.6. Genotype–phenotype correlations

Correlations are based on small numbers and are still being established [1]. In the MGH cohort, comparing p.(Ile500Val) with p.(Arg496Cys), the following were more frequent in the first group: any cardiovascular anomaly (proportion 0.96 versus 0.50; p<0.001), any vascular hypoplasia (0.78 versus 0.28; p<0.001), arterial anomalies (0.78 versus 0.33; p=0.003), hearing loss (0.48 versus 0.17; p=0.037), short stature below −2 standard deviations (0.96 versus 0.33; p<0.001), sacral dimple (0.78 versus 0.17; p<0.001), hypermetropia (0.65 versus 0.33; p=0.044) and joint stiffness (1.0 versus 0.83; p=0.043); there was no difference in congenital heart disease, moderate to severe aortic hypoplasia, sleep, constipation, precocious puberty, keratosis pilaris, keloids, macrocephaly, astigmatism, contractures or brachydactyly [7]. Of the five patients with p.(Ile500Thr), three (60%) had moderate to severe aortic obstruction and two (40%) duodenal obstruction; the early multisystem phenotype of this variant also appears in the 2025 review of congenital anomalies and in the earliest case of multilevel airway stenosis [7, 50]. In the Ghent adult cohort, the codon 500 group was diagnosed earlier (median age 16 versus 41 years), had shorter stature (−2.8 versus −2.1 standard deviations; p=0.013), more intellectual disability (8 of 9 versus 4 of 11), brachydactyly and hearing loss (100% versus 57% each); however, the authors observed comparable cardiovascular and respiratory involvement in both groups, including an early death from laryngeal stenosis in a patient with p.(Arg496Cys), which contradicts the idea that these complications are restricted to codon 500 [13]. GeneReviews associates p.(Arg496Cys) with more often normal stature, more precocious puberty and heavy menstrual bleeding in women and, to date, with all patients with seizures [1]. The 11 deaths reviewed by Lin et al. occurred in patients with codon 500 variants (eight p.(Ile500Val), two p.(Ile500Thr) and one p.(Ile500Met)), but the authors caution that the table cannot be used to infer correlations, because of publication bias [7]. Skin analysis of 175 patients suggests diagnostic delay and less affected skin with codon 496 [45].

2.7. Allelic disorders and somatic variants

Germline loss-of-function SMAD4 variants, including large deletions and nonsense variants, cause juvenile polyposis syndrome and the juvenile polyposis–hereditary haemorrhagic telangiectasia overlap, with risk of gastrointestinal cancer, arteriovenous malformations, dilating aortopathy and pulmonary arterial hypertension [1, 51, 52]. The phenotypes are opposite: aortic dilatation, joint hypermobility and lax skin are described in the juvenile polyposis–hereditary haemorrhagic telangiectasia overlap, and aortic hypoplasia, joint stiffness and firm skin in Myhre syndrome [36]. Telangiectasias and juvenile polyps have not been described in Myhre syndrome [1]. Clinical Cardiogenetics includes SMAD4 among the TGF-β pathway genes for heritable thoracic aortic disease, associating it with juvenile polyposis, hereditary haemorrhagic telangiectasia, Myhre syndrome and isolated forms [53]. Somatic SMAD4 inactivation occurs in about one third of colorectal cancers and in half of pancreatic tumours, with no hereditary implication [1]. This coexistence of phenotypes has a practical consequence: Myhre variants appear on cancer predisposition panels and are also registered in ClinVar for juvenile polyposis, so the report must be interpreted in the light of the phenotype [40, 54].

3. Clinical Spectrum and Manifestations by System

3.1. Overview and data sources

Myhre syndrome is a progressive multisystem connective tissue disorder; the most characteristic manifestations — joint stiffness, restrictive pulmonary and cardiovascular disease, proliferative fibrosis and skin thickening — usually arise spontaneously, but fibrous proliferation, abnormal scarring and adhesions may follow trauma, invasive procedures or surgery [1]. Effusions of the pericardium, airways, pleura, uterus and peritoneum may occur and progress to fibrosis [1]. The available frequencies come from referral series with different biases: the MGH cohort (47 patients, 2016–2023, recruited by referral to a North American centre, 11% outside the USA, median age at diagnosis 5 years), the French Necker cohort (12 patients, median age of survivors 22 years), the Michot series (32 patients aged 8 to 48 years), the Lin cardiovascular review (54 patients) and the Ghent adult cohort (24 patients, with more p.(Arg496Cys)) [7, 13, 15, 27, 31]. All patients in the MGH cohort followed for at least five years showed symptom progression [7]. The available data mainly describe treated disease; the MGH cohort shows that only 26% of patients have a feature considered severe (requiring invasive treatment or a mortality risk factor), and most live with joint stiffness and neurodevelopmental limitations [7, 39].

Table 3.1 summarises the GeneReviews frequencies, which aggregate more than 200 published patients.

Source: [1].

The background document of the French PNDS adds two literature syntheses. The review of 57 patients published by Yu et al. (2019), including six Chinese patients, recorded intrauterine growth restriction in 76%, stature below −2 standard deviations in 88%, narrow palpebral fissures in 90%, prognathism in 82%, maxillary hypoplasia in 80%, small ears in 81%, short philtrum in 80%, small mouth in 75%, thin upper lip in 70%, thick skin in 82%, pseudomuscular build in 96%, deafness in 74% and visual abnormalities in 50%; the review of the first 61 cases by Le Goff et al. (2014) found narrow palpebral fissures in 90%, prognathism in 85%, intellectual disability in 84%, deafness in 79% and congenital heart disease in 46% [14]. These are frequencies from published cases, biased towards severe forms and codon 500 variants.

3.2. Growth and body composition

Intrauterine growth restriction is present in most pregnancies: 53% in the MGH cohort, 12 of 12 in the French cohort (median −2 standard deviations) and 79.3% in the Smith's Recognizable Patterns synthesis [7, 15, 16]. Short stature becomes more marked after birth, with a stocky habitus and normal head circumference; median postnatal stature was −3.5 standard deviations in the French cohort, and Smith describes a range of −6 to −2 standard deviations [15, 16]. GeneReviews anticipates an adult stature more than two standard deviations below parental target height in more than 80% of patients, especially with codon 500 variants [1]. In the MGH cohort, short stature (below −2 standard deviations) affected 72% overall and, among those under 18 years, 18 of 19 (95%) with p.(Ile500Val) versus 5 of 16 (31%) with p.(Arg496Cys); bone age was advanced in 3 of 9 assessed [7]. Head circumference is proportionally larger than stature in 79% of patients (“relative macrocephaly”), with absolute macrocephaly rare and microcephaly in 6% of the MGH cohort and in 4 of 10 newborns in the French cohort [7, 15]. The pseudomuscular build, with generalised muscle hypertrophy, appears at around 6 years (75% in the French cohort; 97% in the Smith synthesis), and electromyography may show a myopathic pattern [15, 16]. Excess weight begins in adolescence and affects most adults (10 of 15 adults in the literature and 17 of 20 in the Ghent cohort, with a median body mass index of about 29 kg/m²) [1, 13]. One adult woman in the MGH cohort had a fat distribution suggestive of lipodystrophy [7]. The PNDS describes growth restriction as moderate in the prenatal period, at around −2 standard deviations, worsening postnatally to below −3 standard deviations, with final stature between −2 and −4 standard deviations; head circumference at birth lies between −1.5 and −3 standard deviations in half of patients and then keeps the same position; excess weight appears in adolescence in one third of cases [14].

3.3. Face and orofacial region

The face is characterised by short palpebral fissures, deep-set eyes, maxillary hypoplasia, short philtrum, narrow mouth, thin upper lip vermilion, small or widely spaced teeth and prognathism, attributed to disharmonious maxillomandibular growth; there is no facial coarsening [1]. The changes are mild before 3 years and become evident with age, with median identification at 6 years in the French cohort: prognathism in 11 of 12 (92%), maxillary hypoplasia in 9 of 11 (82%), narrow palpebral fissures in 9 of 12 (75%) and small ears in 8 of 11 (73%) [7, 15]. In the MGH cohort, the characteristic face was present in all but one woman, and a prominent chin in 74%, severe in one fifth of these, without the need for orthognathic surgery [7]. Cleft lip and palate is rare, submucous cleft occurs in some patients and velopharyngeal insufficiency is common (19% isolated in the MGH cohort), with hypernasal speech [1, 7, 16]. Limited mouth opening and prognathism justify, according to a 2025 series, maxillofacial assessment with orthopantomography and lateral cephalometric radiography [55].

3.4. Cardiovascular system

Cardiovascular abnormalities may appear at any age and worsen after instrumentation [1]. In Lin's review of 54 patients (2016), 70% had a cardiovascular anomaly, with congenital heart disease, pericardial disease (17%), restrictive cardiomyopathy (9%) and systemic arterial hypertension (15%); pericarditis and restrictive cardiomyopathy each accounted for three of the ten deaths [31]. In the MGH cohort, 77% had at least one cardiovascular anomaly: structural heart disease in 47%, long-segment aortic hypoplasia in 60% (mild in 38%, moderate to severe in 21%), systemic hypertension in 38%, additional arterial stenoses in 13%, pericardial disease in 13% and restrictive cardiomyopathy in 4% [1, 7]. The PNDS estimates congenital heart defects at about 60%; its background document details Lin's review of 54 patients (2016): congenital heart disease in 63%, spontaneously closing septal defects in 10%, ductus arteriosus in 20%, juxtaductal coarctation in 15%, hypoplasia of the descending aorta in 6%, aortic valve stenosis in 15% and mitral stenosis in 4%, abdominal aortic stenosis in 7%, constrictive pericarditis in 7% and recurrent pericardial effusion in 7% [14]. According to the PNDS, arterial stenoses become detectable at around 8–10 years, still asymptomatic, and present in adolescence and young adulthood with chronic hypoperfusion or acute visceral or cerebral ischaemia; pulmonary hypertension is usually recognised in adolescence, but appears in childhood in patients with Shone complex [14].

Congenital heart defects. These include atrial or ventricular septal defect, patent ductus arteriosus, tetralogy of Fallot and left heart obstructive defects — coarctation, long-segment aortic narrowing, aortic valve stenosis, mitral stenosis and multilevel obstruction —, which are more frequent than right-sided obstructions (pulmonary valve and branch stenosis) [1]. In the MGH cohort, the 22 patients with heart disease had septal defects (4), ductus arteriosus (6), pulmonary valve stenosis (2), multilevel left-sided obstruction (10), aberrant right subclavian artery (2) and, in one case each, tetralogy of Fallot, anomalous coronary artery and subaortic membrane; 17% had increased left ventricular trabeculation without criteria for non-compaction cardiomyopathy [7]. The French cohort described two Shone complexes (supravalvular mitral ring, parachute mitral valve, subaortic stenosis and coarctation), both with mitral valve replacement [15]. Cappuccio et al. gathered seven patients with tetralogy of Fallot — classic, with pulmonary atresia and major aortopulmonary collateral arteries (MAPCAs), or with absent pulmonary valve —, half with postoperative cardiac dysfunction more severe than usual; the association with corectopia, heterochromia and congenital miosis suggests a neural crest migration defect [56]. Two fetuses in the MGH cohort had ventricular disproportion with mitral, aortic and arch hypoplasia; after birth they needed only arch repair, with subsequent growth of the left ventricle [7].

Hypoplastic aortopathy. Long-segment aortic hypoplasia is the most frequent vascular manifestation [7]. Of the four patients in the MGH cohort with coarctation, none had the discrete juxtaductal form; all had diffuse arch narrowing with a gradient above 15 mmHg between the four limbs, all needed reintervention for recoarctation, and balloon dilatation failed as initial treatment but was useful after surgery; the surgeon described the aortic wall as thickened in three [7]. One patient with p.(Ile500Thr) had a 7 cm narrowing of the abdominal aorta from the diaphragmatic hiatus to below the renal arteries, with proximal stenosis of the superior mesenteric artery and persistent hypertension despite two cutting balloon angioplasties [7]. On computed tomography angiography (CTA), Figure 1 of Lin (2024) shows diffuse narrowing of the thoracoabdominal aorta in a 21-year-old man with p.(Ile500Thr), with the narrowest point of 6.8 mm at the suprarenal level [7]. Visceral stenoses (coeliac trunk, mesenteric and renal arteries) are accompanied by renal artery stenosis in 13% of the MGH cohort, almost always with moderate or severe aortic hypoplasia; in a boy without aortic obstruction, CTA showed non-obstructive intimal flaps in the renal arteries [1, 7]. Smith's Recognizable Patterns states that vascular stenoses are refractory to balloon dilatation and recur, and illustrates a coarctation that arose after ductus arteriosus surgery through fibrous proliferation [16]. In the French cohort, large and medium vessel stenoses were found in 2 of 7 patients studied, asymptomatic (coeliac trunk, splenic artery and renal polar branches; left common carotid), and one patient died of mesenteric infarction without prior vascular assessment [15]. Smith reports a sudden death from massive mesenteric ischaemia [16].

Pericardial disease. This ranges from transient or recurrent effusion to chronic or progressive constrictive pericarditis requiring surgery [1]. In the MGH cohort, six patients (13%) had pericardial disease: four self-limiting effusions and two cases of constriction treated with pericardiocentesis, pericardial window, decortication or pericardiectomy; non-steroidal anti-inflammatory drugs, high-dose prednisone and colchicine were used without measurable impact [7]. Smith adds cases of tamponade [16]. The background document of the PNDS cites a 7-year-old boy with p.(Ile500Thr) and severe recurrent pericarditis with tamponade, treated with pericardiectomy and corticosteroids, with relapse on corticosteroid withdrawal (Picco et al., 2013) [14]. Pericardial effusion and restrictive cardiomyopathy may occur at any age and be asymptomatic [1].

Restrictive cardiomyopathy. This is rare (under 5%), lethal and difficult to diagnose without catheterisation; constrictive pericarditis and restrictive cardiomyopathy can have similar haemodynamics, but differ in pathogenesis and treatment [1, 7]. One patient in the MGH cohort had raised filling pressures at catheterisation without echocardiographic signs of restriction, such as biatrial dilatation [7]. A woman with restrictive cardiomyopathy and uncorrected descending aortic hypoplasia developed protein-losing enteropathy at 15 years, controlled for 11 years with fluid management, diuretics and budesonide [7]. The two patients with restrictive cardiomyopathy treated with heart and heart–lung transplantation died of postoperative complications, with marked fibrosis [1, 16]. The PNDS describes restrictive cardiomyopathy mainly in young adults, with restrictive filling and reduced diastolic volume of one or both ventricles, preserved wall thickness and systolic function, and lists atrial fibrillation and thromboembolic events as complications; fatigue, dyspnoea, palpitations and presyncope in an adolescent or young adult should prompt a search for it [14]. The combination of aortic obstruction with restrictive cardiomyopathy is associated with greater morbidity and mortality [7].

Pulmonary hypertension and coronary disease. Pulmonary hypertension, primary or secondary to left ventricular dysfunction, severe left-sided obstruction or airway disease, is probably under-assessed [1]. In the French cohort, five of eight patients assessed by echocardiography (63%) had pulmonary hypertension with a mean pressure of 40–50 mmHg, of various causes (stenosis of one pulmonary artery, mitral disease of Shone complex, pulmonary sequestration, chronic airway obstruction), with onset in adolescence, and one patient died in a pulmonary hypertensive crisis [15]. In the MGH cohort, pulmonary hypertension accompanied the two cases of restrictive cardiomyopathy (sildenafil in one) [7]. Coronary atherosclerosis was detected in two adults aged 37 and 50 years, one with severe stenosis of a posterolateral branch in a woman with insulin-treated diabetes and obesity, without demonstrable ischaemia [7]. Monozygotic twins with p.(Ile500Val) had different courses: one developed symptomatic aortic stenosis at 37 years and was managed conservatively, with transoesophageal echocardiography deferred; the other, who underwent a posterior pharyngeal flap and right heart catheterisation with a pulmonary artery stent in childhood, had progressive pulmonary arterial hypertension and died at 31 years [57].

3.5. Airways, lung and sleep

Respiratory disease is multifactorial [1]. Airway stenosis may affect several levels, from the choanae to the bronchi — laryngotracheal, subglottic (from mild to complete) and bronchial —, of unknown cause; a congenital predisposition aggravated by trauma or infection is assumed, although many children have been intubated several times without traumatic stenosis [1]. Smith reports progressive acquired laryngotracheal stenosis in 15% and obstructive and restrictive bronchopulmonary insufficiency in 21.8% [16]. In the MGH cohort, four patients had mild subglottic stenosis suspected after an intubation, without progression, even with repeat intubation; one man developed multilevel stenosis from the age of 8 years, after adenotonsillectomy and ventilation tubes, with complete closure of the posterior nasal cavity at 10 years, repeated choanal and tracheal surgery, tracheostomy at 24 years, molecular diagnosis at 25 and serial dilatations until his death at 32 years [7]. In the Mayo Clinic series (1981–2014), the four women with multilevel stenosis, mainly subglottic and glottic, had previously been intubated; two became tracheostomy-dependent and one had six endoscopic treatments in four years with rapid recurrence, and nasotracheal intubation preceded choanal stenosis in one case [58]. The earliest form was identified at birth in an infant with p.(Ile500Thr) [7]. The PNDS estimates obstructive airway involvement in 13% of patients, often at several levels (choanae, larynx, trachea), with a congenital component and a component acquired after trauma such as intubation [14]. The MGH authors propose that multilevel stenosis results from a developmental anomaly vulnerable to proliferative desquamation, with debris successively occluding the external auditory canals, mastoids, nasolacrimal ducts, sinuses, choanae, nasopharynx, larynx, trachea and bronchi; it is not possible to predict who will be affected [7].

Restrictive lung disease is mainly due to thoracic restriction: all 17 patients in the MGH cohort who underwent spirometry had a restrictive pattern, with a mean forced vital capacity of 57.2% of predicted (standard deviation 14.4) [7]. “Asthma” (36% of the cohort) responds poorly to bronchodilators (response in 5 of 17 tested), and computed tomography shows mosaic attenuation in 22% of those studied [1, 7]. Biopsies and autopsies revealed diffuse interstitial fibrosis with abundant collagen and airway smooth muscle hyperplasia, obliterative bronchiolitis and, in one case diagnosed posthumously, fibrothorax with “trapped lung” [7, 41, 44]. Pleural effusions occurred in 6 of 10 patients in the French cohort, one recurrent, and the combination of obstruction with recurrent effusions led to chronic respiratory failure in adolescence in two [15]. The PNDS also mentions emphysema in some patients, possibly due to distal airway stenosis, non-specific pulmonary microcalcifications on computed tomography and a multifactorial restrictive pattern (short stature, small thoracic cage, broad ribs, low chest wall compliance) [14]. Obstructive sleep apnoea was described in 34% of the MGH cohort, and disturbed sleep, common in autism spectrum disorder, in 66%; 19% had restless legs syndrome or periodic limb movements, and ferritin was low in at least 9% [1, 7].

3.6. Ear, nose and infections

Hearing loss occurs in most patients in GeneReviews (83% in Smith), in 38% of the MGH cohort (with incomplete ENT follow-up) and in 58% of the French cohort, detected from the age of 2 years [1, 7, 15, 16]. Most newborns pass newborn hearing screening; the loss appears between early childhood and the end of adolescence, is bilateral, conductive or mixed (isolated sensorineural rare) and progressive in some patients [1, 7]. Dysplasia of the lateral semicircular canal and otosclerosis-like thickening and fusion of the ossicles, middle ear fibrosis and inner ear anomalies in 19% of the MGH cohort have been described [7, 16]. Recurrent otitis media affects 77% and 55% needed ventilation tubes; cerumen is abundant and mixed with keratinous debris, and in a boy with ichthyosis the hearing loss normalised after removal of the plugs under anaesthesia [7]. Stenosis or atresia of the nasolacrimal duct is common and recurs [1]. Recurrent respiratory infections (otitis, sinusitis, mastoiditis, laryngitis with stridor) are explained in part by mechanical factors and by impaired epithelial innate immunity [1, 42]. Hypogammaglobulinaemia has been described: in the MGH cohort, 7 of 13 patients assessed at other institutions had low IgG, 3 of them also low IgA, and in the French cohort 4 of 12 had immunoglobulin deficiencies, two with global IgG deficiency treated with intravenous immunoglobulin until the end of school age; no severe, invasive or opportunistic infections have been described [7, 15].

3.7. Skin, wound healing and serosae

Thick, firm, rough and inelastic skin, described in almost all patients in GeneReviews and in 76% of 175 patients in the literature, may be absent in infancy; it starts on the extensor surfaces, palms and soles and progresses with age [1, 45]. In the French cohort it appeared at school age (67%) [15]. Keratosis pilaris is extensive (chest, back, legs) and thicker than in the general population (22% in the literature review) [7, 45]. Abnormal scars range from hypertrophic scars and keloids after surgery to fine white linear scars after trivial activities; the face has few creases [1, 7]. Proliferative fibrosis also affects the large airways and the serosae of the heart, lungs and peritoneum [1]. Postoperative adhesions with serositis have been described after bowel resection and after appendicectomy, while other patients undergoing major abdominal surgery did not develop them [7].

3.8. Musculoskeletal system

Reduced mobility of large and small joints is characteristic and worsens with age, with a posture of flexed elbows and forward hip flexion [1]. In the MGH cohort, 94% had stiff joints with abnormal gait, 49% less severe contractures and 11% severe diffuse arthropathy; contractures were detected from 26 months, and the “stiff” gait is characterised by absence of heel strike, trunk rotation and arm swing, short steps and externally rotated hips [7]. In the 6-minute walk test, all nine patients tested walked less than predicted [7]. Hands and feet are small, with brachydactyly (64% in the MGH cohort; 11 of 11 in the French cohort), clinodactyly (70%), camptodactyly (17%) and cutaneous syndactyly of the 2nd and 3rd toes (66%) [7, 15]. Radiological findings include a thickened calvarium, short long bones, tall or flattened vertebrae with short or prominent pedicles, cervical vertebral fusion, hypoplastic iliac wings, broad, absent or supernumerary ribs (eleven pairs in 49% of the MGH cohort), broad or short femoral necks, cone-shaped epiphyses of the phalanges and small exostoses (34%) or enostoses [1, 7, 15, 28]. Bone Dysplasias illustrates the progressive thickening of the calvarium and the prognathism, more marked in older patients, prominent vertebral pedicles with mild anterior wedging of the thoracolumbar vertebrae and a short, deformed middle phalanx of the 5th finger [28]. Scoliosis affects 21% of the MGH cohort and was described as a new manifestation in the Ghent adults; fractures (28%) usually follow minor trauma and heal [7, 13]. Severe calf pain, not relieved by common analgesics, affects 26% and may be associated with low spinal cord compression [1, 7]. A 2026 report described congenital proximal radioulnar synostosis [59].

3.9. Central nervous system, neurodevelopment and behaviour

Developmental delay in several domains is almost universal in the MGH cohort, but formal intellectual disability, which requires cognitive and adaptive assessment, was diagnosed in 32%; 94% had school adaptations and 91% marked social difficulties [7]. Autism spectrum disorder meeting full criteria affected 72% of the MGH cohort (40–70% according to GeneReviews), attention deficit hyperactivity disorder 53% (treated pharmacologically in only 15%) and anxiety disorders 40% [1, 7]. About one third of patients have normal intellectual development and attend mainstream education; most adults remain under parental guardianship, but some have completed higher education, work and have families [1, 16]. In the Ghent adult cohort, intellectual disability depended on the variant: 89% at codon 500 and 36% with p.(Arg496Cys) [13]. Acute psychosis, not otherwise specified or associated with bipolar disorder, has been described in seven patients aged 13 to 24 years (mean age 18.7 years), with variable response to treatment, which warrants prompt psychiatric assessment in the face of acute behavioural changes [60]. The PNDS describes, in adolescence, anxiety disorders and psychotic episodes with delusions and visual hallucinations, sometimes preceded by thought disorganisation, which should be looked for; the autistic traits of childhood make it difficult to assess negative symptoms [14]. Two thirds of children have learning difficulties requiring therapy and educational support, and difficulties with social adaptation become more visible on entry to primary school than in preschool [14]. Epilepsy is uncommon (8% in the MGH cohort, three with p.(Arg496Cys)), and 19% have paroxysmal movements with a normal or not performed electroencephalogram [7].

Brain magnetic resonance imaging (MRI) frequently shows white matter hyperintensities, interpreted as injury from intrinsic cerebral microvasculopathy and not as birth trauma (53% of those studied in the MGH cohort) [1, 7]. In patients who underwent angiography, the MGH cohort found large-vessel arteriopathy with reduced tortuosity and branching anomalies in 9 of 9, and small-vessel disease in 18 of 34, with prominent perivascular spaces and lacunar infarcts; a French patient had recurrent strokes from the age of 26 years due to moyamoya syndrome [7, 15]. Other findings include corpus callosum anomalies (21%), Chiari I malformation, syringomyelia, idiopathic intracranial hypertension and pseudopapilloedema [7, 15, 16]. Caudal spinal cord pathology is common: deep sacral dimple in 55%, low-lying conus medullaris in 17% (33% of those studied) and filum lipoma in 15%, with tethered cord release in seven patients; spinal stenosis with cord compression affected three adults [7]. Toe walking, which is common, may reflect autistic behaviour, tethered cord or autonomic dysfunction [1, 7].

3.10. Eyes

In the MGH cohort, 91% had at least one ocular abnormality: astigmatism (64%), hypermetropia (55%), myopia (13%), esotropia (19%), amblyopia (11%), lacrimal drainage abnormalities (45%) and optic nerve anomalies, described as blurred margins or pseudopapilloedema (36%) [7]. Corectopia, cataracts and abnormal retinal pigmentation are less frequent; in the MGH cohort, the two cataracts had an alternative explanation (age and a pathogenic PITX3 variant) [1, 7, 16]. Bilateral foveal hypoplasia was described in 2025 in an 8-year-old boy, possibly underdiagnosed owing to the lack of optical coherence tomography [61]. The PNDS highlights hypermetropia, sometimes with strabismus, as the most frequent refractive error, cataract as a possible complication in adolescence and papilloedema as a sign to look for because of idiopathic intracranial hypertension; its background document also cites cases of pigmentary retinopathy, bilateral glaucoma with Axenfeld-Rieger anomaly and congenital cortical cataract with bilateral papilloedema [14].

3.11. Gastrointestinal tract and liver

Faltering growth and feeding difficulties are common in infancy, sometimes requiring tube feeding; dysphagia affects 26% of the MGH cohort [1, 7]. Constipation is almost universal and may be severe, with faecal incontinence and delayed toilet training; 57% of patients in the MGH cohort used drugs for constipation or reflux [7]. Duodenal atresia, congenital or late-onset pyloric stenosis, duodenal, jejunal, anal and oesophageal stenoses, fatal oesophageal atresia, intestinal malrotation and Hirschsprung disease have been described [1, 7, 15, 16]. Abnormal liver tests sometimes suggest metabolic dysfunction-associated steatotic liver disease (fatty liver in two and steatohepatitis in three patients in the MGH cohort), and protein-losing enteropathy may accompany the right heart failure of restrictive cardiomyopathy [1, 7]. In 2026 the first case of rapidly progressive biliary cirrhosis due to fibro-obliterative cholangiopathy after an infection was published, in a 15-year-old boy with p.(Ile500Val), treated with living-donor liver transplantation; in the accompanying review of 217 patients, previous liver abnormalities were mild and secondary [35].

3.12. Endocrine, reproductive and urinary systems

Precocious puberty, described in both sexes, affected 31% of girls and 24% of boys in the MGH cohort, with gonadotrophin-releasing hormone analogues in 4 of 12 children with true precocious puberty, and mean menarche at 9.5 years; in the French cohort, eight girls had precocious puberty from the age of 8 years [7, 15]. Adult women frequently have macromastia (with reduction mammoplasty in some), menometrorrhagia, diagnoses of polycystic ovary syndrome, premature ovarian insufficiency and secondary amenorrhoea [1, 7]. Female fertility appears reduced: autopsies showed ovarian fibrosis with fewer oocytes, the pregnancies described in affected women occurred after medically assisted reproduction and after spontaneous miscarriages, and the 2025 review suggests an increased risk of infertility and pregnancy loss [9, 13, 46, 47]. Glucose intolerance and adult-onset diabetes, sometimes difficult to control and requiring high-dose insulin, are associated with excess weight; one adolescent girl had hyperinsulinism with an abnormal glucose tolerance test [1, 7]. In boys, cryptorchidism (38% in the MGH cohort) and hypospadias (10%) are more frequent than in the general population [7]. The PNDS considers advanced puberty very common in girls and associates female infertility with ovarian insufficiency; from adolescence it describes excess weight, dyslipidaemia and type 2 diabetes as cardiovascular risk factors to monitor [14]. Urinary incontinence after 4 years of age affected 55% of the MGH cohort, with poor response to the usual measures; urinary lithiasis occurred in about 10%, and chronic kidney disease in 6% [7].

3.13. Neoplasms

Lin et al. (2020) described neoplasms in 6 of 61 patients (9.8%) and endometrial cancer in 3 of 34 women (8.8%), with a mean age of 40 years; a 2024 corrigendum clarified that one of these women had p.(Ile500Thr) and not p.(Arg496Cys) [7, 54, 62]. The adults in the literature reviewed in Ghent included two endometrial carcinomas, an optic nerve sheath meningioma and a vestibular schwannoma; adding cohort and literature together, 3 of 29 women had endometrial cancer, compared with a lifetime risk of about 3% in the general population [13]. In 2025 a further endometrioid carcinoma was published in a 43-year-old woman diagnosed posthumously, and GeneReviews mentions anecdotal cases of hypothalamic hamartoma [1, 41]. Smith also includes midbrain glioma [16]. These figures come from small referral series, without a comparison group, and do not allow a risk to be calculated; the relationship with polycystic ovary syndrome and obesity is unclear [7]. The background document of the PNDS, based on Lin (2020), stresses that the endometrial cancers described were diagnosed at an advanced stage and lists precocious puberty, obesity, polycystic ovary syndrome and a family history of gynaecological cancer as possible risk factors [14].

4. Clinical Recognition and Warning Signs

4.1. When to suspect it, by age

Diagnosis is difficult in the first years: according to Yang et al., Garavelli et al. found, among 69 patients in the literature, no diagnosis before 2 years and only eight before 8 years, and in the French cohort the median age at suspicion was 12 years and at molecular confirmation 14 years [15]. In the prenatal period, suspicion may arise in the presence of severe intrauterine growth restriction, increased nuchal translucency, pericardial effusion, myocardial thickening, aberrant right subclavian artery, tetralogy of Fallot with pulmonary atresia or hypoplasia of left-sided structures, with confirmation by fetal exome or genome [7, 63, 64]. In the newborn and infant, the signs are not very specific: low birth weight, faltering growth, congenital heart disease, short palpebral fissures and brachydactyly with hyperconvex nails, which Garavelli et al. point to as early clues [16, 32]. In the preschool years, developmental delay, autism spectrum disorder, recurrent otitis and respiratory infections and hearing loss predominate [1, 15]. At school age the face becomes recognisable, the pseudomuscular habitus, thick skin and joint stiffness appear at around 6 years, and the thickened calvarium, widened vertebral pedicles and cone-shaped epiphyses become visible on radiographs [15]. In adolescence and adulthood, obstructive or restrictive respiratory disease, pulmonary hypertension, vascular stenoses, systemic hypertension, diabetes, obesity, menstrual disorders and infertility appear [13, 15]. With p.(Arg496Cys), the presentation may be mild and the diagnosis made only in adulthood, sometimes after an affected child (median age 41 years in the Ghent cohort) [13, 45]. The French PNDS proposes cumulative clues by age: in the perinatal period, the combination of growth restriction, brachydactyly and heart disease; in early childhood, the same combination with neurodevelopmental delay and deafness; and, at around 6 years, joint limitation and skin thickening, which it considers the most specific signs, with widened vertebral pedicles, cone-shaped epiphyses and a thickened calvarium as radiological arguments [14].

4.2. Contexts that should prompt the hypothesis

GeneReviews lists the suggestive findings: short stature well below target height with a stocky habitus, characteristic face, conductive or mixed hearing loss, respiratory difficulties due to a restrictive chest or, rarely, multilevel stenosis, progressively thickened skin and subcutaneous tissue, limited joint mobility, serous effusions, mild to moderate intellectual disability, autism spectrum disorder, severe constipation or encopresis and precocious puberty; on echocardiography, aortic narrowing (coarctation, long-segment diffuse hypoplasia, branch stenoses), congenital heart disease, pericardial disease, restrictive cardiomyopathy and pulmonary hypertension; and, on radiographs, a thickened calvarium, short long bones, tall or flattened vertebrae, cervical fusion, hypoplastic iliac wings, absent or supernumerary ribs and exostoses [1]. Cappuccio et al. recommend considering the syndrome in a child with tetralogy of Fallot, short stature, unusual face and developmental delay, because of the higher risk of postoperative morbidity [56]. The syndrome was mistaken for mucopolysaccharidosis in an 11-year-old boy [59] and, according to Lin et al., may be taken for Williams syndrome, Alagille syndrome or a RASopathy, which are also associated with coarctation, a small-calibre aorta and valvular dysplasia [7]. Laryngotracheal or choanal stenosis after intubation, aortic recoarctation, recurrent pericardial effusion or extensive adhesions after surgery in a person with short stature and joint stiffness are clues to an abnormal fibroproliferative response [7, 58, 65]. A SMAD4 variant at codons 496 or 500 found on a cancer predisposition or polyposis panel should suggest the syndrome rather than juvenile polyposis [40, 54].

4.3. Warning and emergency signs

The warning signs are stridor, noisy breathing, increased work of breathing, desaturation and progressive nasal obstruction, which may indicate airway stenosis; retrosternal pain, dyspnoea, unexplained fatigue (especially after a viral infection), oedema and hepatomegaly, which may indicate pericarditis, constriction or restrictive cardiomyopathy; new-onset arterial hypertension and asymmetry of pulses or blood pressure between limbs, which suggest aortic or renal stenosis; recurrent vomiting, abdominal distension and pain, which may correspond to gastrointestinal stenosis, adhesions or mesenteric ischaemia; and acute changes in behaviour or thinking, which may be psychosis [1, 13, 15, 60]. The deaths described resulted mainly from cardiovascular (64%) or respiratory (27%) failure, including death after choking, intracerebral haemorrhage on extracorporeal membrane oxygenation and presumed arrhythmia [7]. Any intubation, airway endoscopy or elective surgery should be treated as a high-risk situation and planned by an informed team [1, 7]. The PNDS integrates recognition of these signs into therapeutic education: the patient and carers should be able to identify deterioration requiring an urgent consultation, for example increasing dyspnoea in a valvulopathy under surveillance, and acute dyspnoea or acute chest pain should prompt a search for pericarditis [14]. There is no newborn screening.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no consensus clinical criteria, and no sign is pathognomonic; the co-occurrence of several findings is suggestive [1]. The diagnosis is established in a proband with characteristic clinical findings and a heterozygous pathogenic or likely pathogenic SMAD4 variant, usually recurrent [1]. Under the interpretation rules of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), the pathogenic and likely pathogenic classes are equivalent for clinical decision-making; a SMAD4 variant of uncertain significance (VUS) neither establishes nor excludes the diagnosis [1]. Patients described as having “Myhre-like syndrome” need genetic confirmation, and Lin et al. ask that this label not be used when testing is negative or has not been done [1, 7]. The Michot series included three patients with a typical phenotype without a SMAD4 variant, which indicates that a negative result does not completely exclude a similar disorder of another cause [27]. The French PNDS takes the same position: without established clinical criteria, the diagnosis rests on a set of clinical and radiological arguments and is confirmed by testing for a SMAD4 variant; it recommends requesting molecular testing for any patient with suspected disease, at any age, because the result has prognostic value, and referring the patient to the nearest reference or competence centre [14].

5.2. Molecular tests and algorithm

When the findings suggest the syndrome, SMAD4 sequencing targeted to the recurrent variants may be requested, or a multigene panel that includes SMAD4 and the differential diagnosis genes (ADAMTSL2, FBN1, LTBP3, ADAMTS10, ADAMTS17, LTBP2, TRIM37), which reduces the number of VUS and of findings unrelated to the phenotype [1]. When the syndrome has not been considered — a common situation in children with developmental delay, autism or multiple congenital anomalies —, exome or genome sequencing is the usual route, and the 2021 ACMG guideline recommends it as a first- or second-tier test in children with congenital anomalies or intellectual disability [1, 17]. In the MGH cohort, 72% of diagnoses were made by exome; the remainder came from autism/intellectual disability, deafness or cancer panels, targeted SMAD4 analysis or genome, often after other first-line tests [7]. The MGH cohort found a second genetic diagnosis in 6% of patients (for example, a PITX3 variant that explained congenital cataracts) and a chromosomal translocation in one patient, so an atypical finding should prompt reanalysis [7].

Sources: [1, 7, 17, 27].

5.3. Test limitations

Sequencing detected 100% of published pathogenic variants, but this proportion describes the known mutational spectrum and not clinical sensitivity, which depends on the starting phenotype [1]. Deletion/duplication methods are of no diagnostic value, because no variants of this type have been described and the mechanism is not loss of function [1]. The variants lie in the coding region and are captured by the exome [1]. Leucocyte DNA may fail to detect somatic mosaicism in the parents, and the disease may result from gonadal mosaicism [1]. McGowan et al. described in two patients streaky skin with plaque-like thickening, suggestive of mosaicism [66]. ClinVar classification is heterogeneous: p.(Ile500Val) and p.(Ile500Thr) are pathogenic without conflict, p.(Arg496Cys) has conflicting classifications (with submissions for cancer predisposition, aortic aneurysm and pancreatic carcinoma), p.(Ile500Met) is registered as pathogenic for juvenile polyposis and p.(Ile500Leu) as a VUS for juvenile polyposis [40]. A laboratory interpreting these variants on a cancer panel may therefore relate them to juvenile polyposis; the report must be read with the phenotype, and the clinician should state the suspicion of Myhre syndrome on the request form [40, 54]. gnomAD v4 contains seven carriers of p.(Arg496Cys) and one of p.(Ile500Val) among 807,162 individuals, which indicates a spectrum with mild forms in adults and should not lead to downgrading the classification [13].

5.4. Report content and further assessment

The report should state the gene, the transcript with version (NM_005359.6), Human Genome Variation Society (HGVS) cDNA and protein nomenclature, zygosity, ACMG/AMP class and, where available, the result of parental testing [1, 6]. There are no diagnostic biochemical biomarkers; serum TGF-β, fibrillin-1, type I collagen and metalloproteinases have been proposed only as possible markers of fibrotic activity under investigation [19]. Molecular confirmation is followed by the systematic assessment described in section 7.1, which defines the extent of the disease [1, 7].

6. Differential Diagnosis

6.1. The acromelic dysplasias

The closest entities are the other acromelic dysplasias — geleophysic dysplasia, acromicric dysplasia and Weill-Marchesani syndrome —, which share thick skin, short stature, short hands and feet and joint stiffness and result, like Myhre syndrome, from disturbances of TGF-β/BMP signalling and of the extracellular matrix [1, 3, 37]. Geleophysic dysplasia has a different face, with a “happy” appearance, full cheeks and a short nose (the origin of the name), progressive cardiac valve thickening, hepatomegaly and delayed bone age; the main findings appear in the first year, and cardiac, airway and pulmonary involvement causes death before 5 years in about one third of patients [1, 67]. Bone Dysplasias distinguishes Myhre syndrome from geleophysic dysplasia by muscle hypertrophy, thick calvarium and broad ribs, and from acromicric dysplasia by the face, deafness and muscle hypertrophy, with thick calvarium and broad ribs as discriminating radiological signs [68, 69]. Acromicric dysplasia has characteristic notches on the 5th metacarpal (lateral) and the femoral head (medial), has no deafness or calvarial thickening and has fewer congenital heart defects [1]. Weill-Marchesani syndrome is distinguished by lens abnormalities recognised in childhood — microspherophakia, myopia, ectopia lentis and glaucoma, which can lead to blindness — and by the absence of deafness [1]. Bone Dysplasias mentions “LTB3” in acromicric dysplasia, a typographical error for LTBP3; in OMIM, acromicric dysplasia #102370 is associated only with FBN1, and LTBP3 variants are associated with geleophysic dysplasia 3 (#617809), while GeneReviews also describes an acromicric form due to LTBP3 based on McInerney-Leo et al. (2016) [1, 28, 70, 71]. The French PNDS adds useful details for the distinction. In geleophysic dysplasia, the face is round, with a “jovial” expression, small nose with anteverted nares, long flat philtrum, thin upper lip and narrow palpebral fissures; in acromicric dysplasia, the eyebrows are well defined, the eyelashes long, the nose bulbous, the lips thick and the philtrum long and prominent; in both, growth delay begins in the first year with preserved head circumference and psychomotor development is normal, and the cardiorespiratory course (valvulopathy, pulmonary hypertension, asthma, laryngotracheal stenosis) is more severe and progressive in geleophysic dysplasia [14]. The PNDS estimates the prevalence of these two dysplasias at about 1/1,000,000 and that of Weill-Marchesani syndrome at about 1/100,000 [14]. Weill-Marchesani syndrome, described by two ophthalmologists in 1932 and 1939, has a mean adult height of 1.40–1.70 m in men and 1.30–1.60 m in women, secondary phacogenic glaucoma due to pupillary block and angle closure, valvular heart disease (pulmonary or aortic stenosis, mitral regurgitation), ductus arteriosus and ventricular septal defect, cases of thoracic aortic aneurysm and carotid dissection, occasional tracheal stenosis and rare, mild intellectual disability; it has recessive (ADAMTS10, ADAMTS17, LTBP2) and dominant (FBN1) forms [14].

6.2. Other overlapping disorders

Stiff skin syndrome (FBN1) has “stone-hard” skin and stiff joints, but is not dysmorphic, has few cardiovascular abnormalities and no calvarial thickening [1, 72]. MULIBREY nanism (TRIM37, autosomal recessive, with about 85 of the 110 described patients in Finland, most homozygous for a founder variant) shares intrauterine growth restriction, a relatively large head, constrictive pericarditis, restrictive cardiomyopathy and hearing loss; it is distinguished by even shorter stature, a small tongue, absence of calvarial thickening, a bell-shaped chest with thin ribs, failure of sexual maturation, liver disease and frequent tumours [1, 7, 73]. Pericardial disease also occurs in Cantú syndrome and in camptodactyly-arthropathy-coxa vara-pericarditis syndrome [7]. Hypoplastic aortopathy brings Myhre syndrome close to Williams syndrome (elastin arteriopathy), Alagille syndrome, neurofibromatosis type 1 and the RASopathies (RAS-MAPK pathway disorders), which combine coarctation, a small-calibre aorta and valvular dysplasia; restrictive cardiomyopathy may occur in inborn errors of metabolism [7]. Marfan, Loeys-Dietz and Shprintzen-Goldberg syndromes, also of the TGF-β pathway, have vascular wall weakness, aortic dilatation and hypermobility, the opposite of Myhre syndrome [7, 16]. The juvenile polyposis–hereditary haemorrhagic telangiectasia overlap due to SMAD4 loss of function has aortic dilatation, hypermobility, lax skin, polyps and telangiectasias [1, 36]. In clinical practice, juvenile scleroderma, mucopolysaccharidosis and inflammatory arthropathies enter the discussion in the presence of thick skin and joint stiffness; skin biopsy in Myhre syndrome shows a pattern distinct from the inflammatory scleroderma disorders [45, 59]. Cerebellar ataxia with atrophy, described in a 2011 case, was not found in the MGH cohort, and the old hypothesis of identity with GOMBO syndrome was not confirmed [2]. The background document of the PNDS collects other diagnoses discussed in the literature: OSMED syndrome, Moore-Federman syndrome, Léri pleonosteosis, Schwartz-Jampel syndrome, Brosnan XY gonadal dysgenesis and Berardinelli congenital lipodystrophy, as well as juvenile scleroderma, in which a case with p.(Ile500Thr) was treated without response with corticosteroids and methotrexate before the molecular diagnosis [14]. It also records the controversy over including Myhre syndrome among the segmental progeroid syndromes, proposed by Kandhaya-Pillai et al. (2021) on the basis of a patient with p.(Arg496Cys) initially classified as having Werner syndrome and of fibroblasts with accelerated senescence, and contested by Lin et al. (2021) because of the lack of phenotypic similarity to Werner syndrome [14].

6.3. Differential diagnosis table

IUGR: intrauterine growth restriction; NF1: neurofibromatosis type 1; HHT: hereditary haemorrhagic telangiectasia; AVM: arteriovenous malformations; AD: autosomal dominant; AR: autosomal recessive. Sources: [1, 7, 16, 36, 52, 53, 67, 70–78].

7. Treatments and Risk Management Strategies

7.1. Framework and sources of recommendations

There is no cure and no approved disease-modifying therapy, and no formal evidence-based guidelines have been published [1, 19]. The available recommendations are expert consensus: GeneReviews (December 2024 update), Table 5 of Lin et al. (2024), based on the experience of the MGH multidisciplinary clinic and presented by the authors as pragmatic suggestions and not as a guideline, and Table 2 of Vanbelleghem et al. (2024), aimed at adults [1, 7, 13]. Care is supportive, multidisciplinary and oriented towards quality of life, function and prevention of complications; Lin et al. propose a “medical home” model in a specialised centre, which coordinates care with local professionals [1, 7]. In September 2025, the French reference centre for constitutional bone diseases published with the HAS the first national diagnosis and care protocol (PNDS) devoted to the syndrome, developed according to the 2012 HAS method and reviewed by paediatric cardiology, child psychiatry, paediatric pulmonology, rheumatology, general practice, ophthalmology, otorhinolaryngology, paediatric endocrinology and the patient association; it is expert consensus, without grading of evidence, supported by a background document of reports and series [14]. The PNDS assigns coordination to the specialist physician in concert with the reference or competence centre, with multidisciplinary consultations in day hospital, and assigns to the primary care physician routine follow-up, vaccination, the growth chart, detection of complications (falling off the growth curve, worsening contractures, murmurs, hypertension, dyspnoea, apnoeas, infections, precocious puberty) and prevention of cardiovascular risk factors [14].

7.2. Initial assessment after diagnosis

Sources: [1, 7, 55].

The French PNDS defines an initial work-up with similar content, but with some differences of detail, gathered in Table 7.3.

Source: [14].

7.3. The central principle: limiting tissue trauma

Limiting tissue trauma is, according to GeneReviews, the most important preventive measure, and should be communicated to all professionals involved; whenever possible, a non-invasive alternative is preferred in diagnosis and treatment [1]. Starr et al. observed a progressive fibroproliferative response to surgery in all five patients in their series and recommended approaching any surgery with extreme caution and minimal invasiveness [65]. Shared decision-making with the family should include non-intervention as an option, for example for piercings, orthodontic appliances (which may stimulate gingival hypertrophy), exploratory procedures or surgical correction of velopharyngeal insufficiency [1]. Abdominal and pelvic procedures should be minimised, because of the risk of extensive and potentially fatal adhesions, and hysterectomy for menorrhagia should be the last resort [1]. The different courses of two monozygotic twins — the one who had pharyngeal surgery and catheterisation with a stent in childhood died at 31 years with pulmonary arterial hypertension, while the other, managed conservatively, was alive at 37 — illustrate the argument, without proving causality [57]. The agents and circumstances to avoid are tobacco (with active counselling), unnecessary tissue trauma, elective tracheal surgery and intubation whenever possible, tracheal resection (contraindicated) and growth hormone [1]. Vaccinations are recommended [1].

7.4. Airway, anaesthesia and procedures

Complete or recurrent tracheal stenosis can be treated by balloon dilatation, and long-term tracheostomy is an alternative; tracheal resection is contraindicated [1, 58]. To avoid traumatic intubation, GeneReviews recommends a smaller, uncuffed endotracheal tube, or careful monitoring of cuff pressures; elective tracheal surgery or intubation should be avoided and, when necessary, prepared in a preoperative multidisciplinary discussion [1]. MGH Table 5 adds: use mask ventilation when possible; when intubating, use the smallest possible tube, keep cuff pressure at or below 15 cmH₂O, entrust intubation to the most experienced professional and pass these precautions on to each anaesthetist; laryngoscopy and bronchoscopy are performed only when clinical assessment confirms symptoms and, if stenosis is confirmed, require serial assessments [7]. Vanbelleghem's Table 2 recommends non-surgical options in adults when feasible and atraumatic intubation by an experienced team [13]. Gastrointestinal endoscopy should be performed with caution to avoid airway manipulation, and non-invasive three-dimensional imaging may be preferable [1]. The Oldenburg series shows that intubation frequently precedes stenosis, but the MGH cohort shows that many children were intubated without stenosis and that mild post-intubation subglottic stenosis did not progress with repeat intubation; the relationship is probably multifactorial [7, 58]. In the French series, a subcannular stenosis required endoscopic treatment and a custom-made cannula [15]. The French PNDS details the perioperative approach. Any intervention should be discussed at the reference or competence centre, and the preoperative work-up, at any age, includes a cardiology review with echocardiogram and electrocardiogram, a pulmonology review, an ENT review and an anaesthetic review; the airway is assessed by oropharyngeal examination with a tongue depressor and awake nasal, pharyngeal and supraglottic laryngeal fibroscopy in clinic, with cervicothoracic CT and estimation of laryngotracheal calibre if there is doubt, and laryngotracheal endoscopy under general anaesthesia may be performed before surgery [14]. In general anaesthesia, the PNDS prefers the laryngeal mask airway when possible and, failing that, an endotracheal tube of smaller calibre than expected for age and weight, with restricted indication for intubation and minimal duration [14]. In laryngotracheal stenosis, treatment should be as minimally invasive as possible: nebulised topical corticosteroids, non-invasive mask ventilation or balloon dilatations; in severe subglottic or high tracheal stenosis, prolonged tracheostomy may be needed, with its own risk of subcannular stenosis from irritation, which is treated, in addition to topical corticosteroids and dilatations, by changing the material, diameter or length of the cannula [14]. The background document cites a 25-year-old man with p.(Ile500Val), bilateral choanal and laryngotracheal stenosis and recurrent pericardial effusions after pericardiectomy, who needed a tracheostomy and progressed favourably with etanercept 50 mg subcutaneously once weekly and repeated tracheal dilatations with local injection of methylprednisolone (20 mg in each quadrant), a regimen that the PNDS considers non-standardised [14].

7.5. Cardiovascular disease

All patients should be followed by a cardiologist with experience in congenital heart disease, pericardial disease and restrictive cardiomyopathy; all unnecessary instrumentation should be avoided [1]. Congenital heart defects are treated conventionally, anticipating greater postoperative morbidity (for example, more severe dysfunction after repair of tetralogy of Fallot) [56]. In coarctation and aortic hypoplasia, the MGH cohort showed recurrence after every surgical repair, failure of balloon dilatation as initial treatment and usefulness of the balloon after surgery; Lin et al. recommend anticipating a second procedure and treating postoperative systolic hypertension [7]. In severe valvular aortic stenosis, they recommend referral to a specialised valve programme [7]. Systemic arterial hypertension is treated medically according to its cause, with assessment for renal stenosis; in the MGH cohort, 36% were treated, 53% of these with more than one drug, mainly losartan (47%), amlodipine (35%) and atenolol (29%) [1, 7]. Pericardial effusion and pericarditis were treated with non-steroidal anti-inflammatory drugs; high-dose prednisone and colchicine had no measurable impact in the two patients in whom they were used, and constriction required pericardiocentesis, pericardial window, decortication or pericardiectomy [7, 19]. Restrictive cardiomyopathy requires catheterisation for haemodynamic characterisation; patients in heart failure should be followed at a transplant centre, but heart and heart–lung transplantation have been associated with high mortality and have not been shown to prolong life, although families may wish to discuss it with the transplant team [1, 7]. Protein-losing enteropathy associated with right heart dysfunction was controlled in one patient with fluid management, diuretics and budesonide [7]. Pulmonary hypertension is treated according to its cause; one patient with repaired tetralogy of Fallot received sildenafil [1, 7].

Cardiological and vascular guidance in the French PNDS. The PNDS considers that most patent ductus arteriosus require surgical closure, that atrial and ventricular septal defects without haemodynamic consequences can simply be monitored clinically and by ultrasound, because they close spontaneously in most cases, and that valvulopathies and complex heart defects, such as Shone complex, are operated on at a reference centre after discussion at a multidisciplinary meeting [14]. In pericarditis, recurrent or chronic, it considers oral non-steroidal anti-inflammatory drugs and colchicine of little efficacy; most patients need pericardiocentesis, and pericardiectomy is discussed in constrictive pericarditis [14]. In restrictive cardiomyopathy, symptomatic treatment relies on diuretics, prevention of atrial fibrillation and anticoagulation [14]. In pulmonary arterial hypertension without an identified aggravating factor, it proposes diuretics, a salt-free diet and oxygen therapy to reduce right ventricular overload, with specific therapy only after invasive haemodynamic assessment at an expert centre, and contraindicates physical exertion and situations that worsen hypoxia [14]. In systemic arterial hypertension, which is common in adults, it indicates diuretics and calcium channel blockers, with control of excess weight, dyslipidaemia and type 2 diabetes as in the general population, and cardiology follow-up at least annually [14].

On the vascular side, the PNDS recommends a first work-up from 8 years of age with Doppler ultrasound of the abdominal aorta, renal arteries and carotids, repeated annually and supplemented by CTA if stenosis is suspected, and cerebral MR angiography from 10 years of age [14]. Prevention of ischaemic complications relies on antiplatelet agents and control of cardiovascular risk factors; acute ischaemic stroke is treated in a stroke unit, with thrombolysis to be considered; chronic hypoperfusion with impaired vascular reserve may justify surgical revascularisation, decided at a multidisciplinary meeting [14]. The PNDS specifies neither an antiplatelet drug nor a dose; Table 7.4 presents the reference doses of acetylsalicylic acid for the prevention of arterial ischaemic events, extrapolated from other arteriopathies.

7.6. Lung disease, sleep and infections

Restrictive lung disease is treated symptomatically and in a standardised way by pulmonology, with oxygen when necessary; sleep apnoea is treated with continuous or bilevel positive airway pressure ventilation, or oxygen [1]. “Asthma” responds poorly to bronchodilators [7]. Disturbed sleep was treated in the MGH cohort with trazodone, suvorexant, ramelteon and melatonin, and iron was replaced in 40% of patients, empirically or in the presence of iron deficiency, mainly associated with heavy menstrual bleeding or prematurity [7]. Humoral immunodeficiency is treated as advised by the immunologist and may include intravenous immunoglobulin, with benefit reported in at least two patients; antibiotic prophylaxis and additional vaccination are options in the immunology clinic [1, 7]. Persistent otitis media with effusion is treated with ventilation tubes and removal of cerumen; cerumen softeners are of little efficacy and contraindicated with tubes or tympanic perforation [1, 7]. Hearing loss benefits from hearing aids, including bone conduction aids, and early intervention services should include hearing support [1, 7]. The French PNDS describes a mixed ventilatory disorder: multifactorial restriction, upper or lower airway stenoses with obstructive sleep apnoea, reversible bronchial hyperreactivity and bronchiolar changes with a mosaic appearance on CT [14]. It recommends lung function tests from 6 years of age, or from 3 years if there are symptoms, polysomnography (or, failing that, polygraphy) in the presence of apnoea symptoms, non-systematic chest CT, inhaled corticosteroids and inhaled β2-agonists for bronchial hyperreactivity, nocturnal non-invasive ventilation for obstructive apnoea and oxygen therapy for respiratory failure; if stenosis is suspected, cervical and chest CT with endoscopic assessment [14]. Repeated bronchopulmonary infections are treated with targeted antibiotic therapy, with testing for hypogammaglobulinaemia and immunoglobulin replacement when indicated, and pleural effusions require microbiological documentation [14]. In otorhinolaryngology, the PNDS asks for annual hearing assessment from the first year of life, because hearing loss compromises language and neurodevelopment, hearing aids and speech and language therapy according to the type of deafness, antibiotic treatment of acute otitis and transtympanic tubes for recurrent, complicated or chronic otitis, and an ENT review before any planned intubation [14].

Ophthalmology and intracranial hypertension. In addition to the ophthalmological examination at diagnosis, the PNDS proposes systematic examinations in the first week of life and at 2 months (usually by the paediatrician), and by an ophthalmologist between 9 and 15 months, between 2.5 and 3 years and at 6 years; any warning sign justifies prompt examination outside the schedule [14]. The appearance of papilloedema requires assessment at a reference centre, for possible idiopathic intracranial hypertension, whose pharmacological treatment is acetazolamide; the PNDS gives no dose, so Table 7.4 uses the British consensus on idiopathic intracranial hypertension and the IIHTT trial in adults and the drug label in children [14, 79, 80].

7.7. Gastrointestinal tract and nutrition

Faltering growth is treated with feeding therapy and, if persistent, gastrostomy, with a low threshold for swallowing assessment; food may be thickened or chilled [1]. Obesity, which is difficult to control, requires nutritional support [1]. Constipation requires aggressive management with diet, stool softeners, prokinetics, osmotic or stimulant laxatives; in the MGH cohort, polyethylene glycol, bisacodyl and senna, home or hospital disimpaction and, in one case of functional sphincter obstruction, botulinum toxin were used [1, 7]. Gastrointestinal stenoses are treated with caution and minimal instrumentation, because postoperative adhesions can be fatal [1]. Liver disease is usually associated with cardiac or metabolic factors; fibro-obliterative cholangiopathy with biliary cirrhosis required liver transplantation in one case [1, 35].

7.8. Growth, puberty, gynaecology and metabolism

Growth hormone is not recommended: there is no systematic study in Myhre syndrome, its anabolic action may interact with SMAD4 activation, the MGH centre did not observe a consistent increase in height in treated children and the French cohort described one treated patient without benefit [1, 7, 15]. A 2021 case report of growth hormone combined with letrozole, cited by Lin et al. as anecdotal evidence, does not change this position [7]. True precocious puberty is treated with gonadotrophin-releasing hormone analogues, as advised by the endocrinologist [7]. The French PNDS recommends monitoring height monthly until 6 months, quarterly until 2 years, six-monthly until 3 years and then annually until final height; if the curve falls off, it requests a paediatric work-up with IGF-1 and a growth hormone stimulation test [14]. It considers growth hormone treatment non-standardised and its efficacy difficult to assess; a single patient reportedly improved in height with growth hormone combined with letrozole, which is insufficient to recommend the combination [14]. The PNDS stresses that aromatase inhibitors have no paediatric marketing authorisation, that their long-term risk in children is unknown, that reports in boys describe vertebral deformities, possible impairment of bone mineralisation at puberty, a fall in HDL cholesterol and a rise in haemoglobin (with a potential thrombotic risk, in a patient already at increased cardiovascular risk), and that they are contraindicated in girls, save exceptionally, because of the risk of ovarian cyst [14]. The background document also cites a Korean boy with precocious puberty at 8 years treated with growth hormone and a GnRH analogue, with a favourable response at 15 years [14]. Tanner stage should be assessed from 6 years of age; if advanced puberty is suspected, an LH-RH test is performed and blockade of the gonadotrophic axis is discussed [14]. Menometrorrhagia was treated with oral contraceptives (27% of women in the MGH cohort) or a hormonal intrauterine device; hysterectomy is a last resort, because of the risk of postoperative fibrosis [1, 7]. Dysfunctional uterine bleeding may reflect endometrial cancer and should be investigated [1]. Adult-onset diabetes may be difficult to control and require insulin pumps, high-dose insulin or a glucagon-like peptide-1 receptor agonist [1, 7].

7.9. Skin, musculoskeletal system and rehabilitation

Some keloids can be treated with intralesional corticosteroid, and removal of lesions should be minimally invasive; emollients reduce keratosis pilaris, although the sensory hypersensitivity associated with autism makes topical treatments difficult [1, 7]. Physiotherapy is recommended from diagnosis in all patients, with home programmes of range of motion, stretching, core strengthening and breathing exercises, orthoses and equipment, and activities such as swimming and dance; it is unknown whether passive exercises preserve flexibility, but physical activity to maintain fitness is encouraged, and a sedentary life should be avoided [1, 7]. Toe walking can be treated with orthoses, once tethered cord has been excluded; tethered cord is treated neurosurgically, and symptomatic spinal stenosis may require surgery [1, 7]. Fractures are treated conventionally; no effective prevention is known, and periodic bone densitometry is recommended from the second decade [1]. Occupational therapy helps with fine motor difficulties and adaptation of daily activities [1]. The French PNDS sets an annual orthopaedic review in children and every 2–3 years in adults (every 3 years without new symptoms, in the adult schedule), with assessment of spinal alignment, stiffness and pain at each review and referral to a chronic pain clinic when the usual measures are insufficient [14]. Physical medicine and rehabilitation coordinates care: early and regular physiotherapy aims to limit contractures and improve functional capacity, with endurance and resistance training; occupational therapy proposes orthoses, technical aids and home adaptation, with a home visit if necessary, for short stature and hand function; adapted physical activity adjusts exercise to motor and cardiorespiratory limitations, respecting pain and joint limitations [14]. On losartan, the PNDS states that studies showed a positive effect on extracellular matrix disorganisation and joint stiffness and that no therapeutic trial is under way, without making a recommendation for use [14].

7.10. Neurodevelopment, behaviour and mental health

Children should be referred to early intervention (physiotherapy, occupational therapy, speech, language and feeding therapy, special education) and then to adapted educational support, with assessment for augmentative and alternative communication, which does not impair speech development, and sign language in patients with hearing loss and minimal expressive language [1]. Interventions used in autism spectrum disorder, including applied behaviour analysis, are indicated [1]. Attention deficit hyperactivity disorder appears undertreated (pharmacological treatment in 15% in the MGH cohort), and anxiety, mood disorders and psychosis require psychiatric assessment; the psychotic episodes described had a variable response to drugs and behavioural interventions [7, 60]. Epilepsy is treated with antiseizure medication as advised by the neurologist; in the MGH cohort lamotrigine and levetiracetam were used [1, 7]. Psychological distress should be assessed regularly in adults [13]. The French PNDS adds practical guidance: psychomotor therapy or motor physiotherapy for hypotonia in the first months; testing for hearing impairment in the presence of language delay, especially with no first words at 18 months, with assessment and therapy by speech and language therapy; augmentative communication with picture exchange or Makaton if the oral language deficit persists after 3 years; psychometric assessment before entry to primary school and systematic neuropsychological assessment in the year preceding each change of school stage (at around 5–6 and 10–11 years), with reassessment of school placement if the child is struggling [14]. Schooling is adapted to the profile: mainstream class with a support assistant if there are learning difficulties without intellectual disability, school inclusion units for mild intellectual disability (intelligence quotient between 55 and 70) and specialised establishments for moderate to severe disability (quotient below 50), with support until entry into employment [14]. In the presence of communication disorders, the PNDS indicates assessment at an autism resource centre. In psychosis, treatment relies on atypical antipsychotics, with a good response described to risperidone; as risperidone may worsen stiffness, the PNDS proposes replacing it with aripiprazole if motor tolerance is poor [14]. The reference doses are given in Table 7.4. Patients and families should have psychological support from the time the diagnosis is disclosed [14].

7.11. Palliative care and family support

Social services should connect families with local resources, carer respite and support, and care coordination should organise the multiple appointments, equipment and medications [1]. Palliative and supportive care should be offered when there are severe airway, cardiovascular or neoplastic complications, or progressive chronic disease; Lin et al. stress its role in helping the patient and family to “live their best life” and anticipate end-of-life events, and encourage the participation of adolescents and young adults in decisions [1, 7]. Discussion of autopsy can be incorporated into end-of-life planning, because autopsies have added knowledge about the disease [7, 47].

7.12. Therapy targeting the TGF-β pathway: losartan

Losartan is an angiotensin II type 1 receptor antagonist which, in addition to its antihypertensive effect, attenuates TGF-β-mediated fibrosis by reducing TGF-β activators and the total and active forms of the factor and its receptors [18]. In fibroblasts from patients with Myhre syndrome, it corrected the imbalance between metalloproteinases and their inhibitors and the deposition of fibrillin-1 and type I collagen [1, 18]. Cappuccio et al. (2021) treated three patients (a child aged 3 years and 10 months and two adults) with oral losartan for 12 months, off-label and with ethics committee approval; a fourth patient stopped the drug shortly after starting because of dizziness [18]. The dose was titrated to maintain baseline blood pressure: the child tolerated 0.7 mg/kg per day, one adult 100 mg per day and the other 50 mg per day, after orthostatic hypotension with 100 mg per day [18]. At 6 and 12 months, the modified Rodnan score fell in all three patients, range of motion measured by goniometry improved in all three (especially in the upper limbs), and global longitudinal strain by speckle-tracking echocardiography improved significantly in one patient, with a trend in the other two; patients reported functional improvements, such as climbing stairs and swimming [18]. The authors stress the absence of a control group and the minimal sample, and conclude that, with the available data, treatment with losartan is not recommended, and randomised, blinded trials are needed [18]. GeneReviews classifies losartan as an investigational therapy [1]. Lin et al., taking a different view, recommend using an angiotensin II receptor antagonist because of the link with the TGF-β pathway, although they did not identify any superior or harmful drug in the MGH cohort, and describe a man with severe aortic disease in whom losartan lowered systolic pressure but raised diastolic pressure [7]. Aortic stenosis increases the risk of hypotension with losartan [18]. In summary, losartan in Myhre syndrome is a reasonable first-choice antihypertensive in hypertensive patients and an experimental treatment for fibrosis, without demonstrated clinical benefit.

Table 7.1 compares the dose used in the pilot study with those of the US label and the Portuguese Summary of Product Characteristics (SmPC) for hypertension, the reference approved indication.

Sources: [18, 81, 82].

The child's dose in the pilot study coincides with the weight-based starting dose on the FDA label, but was given below 6 years of age, an age for which neither label recommends the drug; the Portuguese SmPC uses weight bands instead of a per-kilogram dose [18, 81, 82]. Both labels contraindicate losartan in the second and third trimesters of pregnancy (FDA boxed warning for fetal toxicity: discontinue as soon as pregnancy is detected), in severe hepatic impairment (SmPC) and in combination with aliskiren in diabetic patients [81, 82]. In Portugal, losartan is available as a generic (50 and 100 mg tablets); in Infomed, the Cozaar® brand appears only in the combination Cozaar Plus® [82].

Table 7.4 brings together the doses of the drugs that the French PNDS names without giving a dose. As there are no published doses for Myhre syndrome, the guideline for the analogous condition is used as the reference and the label as the comparison; the extrapolation is explicit in each row.

Sources: [14, 79, 80, 83–87].

7.13. Other drugs used or proposed

Etanercept, a tumour necrosis factor alpha inhibitor, was given to a patient with recurrent airway stenoses, with reported improvement in joint mobility and inflammatory symptoms; the observation is anecdotal, without objective measures or prolonged follow-up [19]. De Falco et al. discuss the repurposing of TGF-β inhibitors already developed (antibodies, antisense oligonucleotides, type I receptor kinase inhibitors) and of antifibrotic agents, subject to their safety profile [19]. Intravenous immunoglobulin is used in documented humoral deficiencies, at the usual doses for primary immunodeficiency, under immunology guidance [1, 15]. The remaining drugs (antihypertensives, laxatives, hypnotics, antiseizure medications, psychotropic drugs, gonadotrophin-releasing hormone analogues, contraceptives, insulin) are used according to the usual indications and doses for each problem, with no data to distinguish them in Myhre syndrome [7, 19].

7.14. Regulatory status

Sources: [1, 81, 82].

7.15. Clinical trials

Sources: [18, 23, 34].

There are no interventional trials registered in ClinicalTrials.gov or in the European trials register for Myhre syndrome (search of 31 October 2026); this negative search does not prove the absence of unregistered studies [23]. The pilot study does not allow an effect to be estimated: without a control, with three heterogeneous patients, assessment by a single examiner and no blinding, the improvement may reflect regression to the mean or an observer effect [18, 19].

7.16. Developments in the last 12 months and research

The December 2025 themed issue of the American Journal of Medical Genetics Part C brought together recent research [33]. In terms of level of evidence, all therapeutic developments are preclinical. The Myhre Syndrome Foundation, founded in 2019, has created a preclinical platform with cellular models and conditional knock-in mouse models of the p.(Ile500Val) and p.(Arg496Cys) variants, with the last two exons humanised, an international trial design group that defined four outcome domains (skin and joints; cardiac and respiratory; gastrointestinal; behaviour and cognition) and a multidomain response index, and a project portfolio that includes CAR-T cells (chimeric antigen receptor T lymphocytes) directed against fibroblast activation protein (FAP), gene repair and screening of small molecules that bind the MH2 domain of SMAD4, carried out at the Institute for Research in Biomedicine (IRB) Barcelona on libraries of 100,000 compounds [39]. The foundation rejects strategies of silencing the mutant allele by antisense oligonucleotides, small interfering RNA (siRNA) or CRISPR deletion, because of the risk of haploinsufficiency, the cause of juvenile polyposis [39]. De Falco et al. regard the disease as a candidate for base editing or prime editing, given the recurrence of the variants, but note that the cells and tissues to be corrected have yet to be identified, that gene replacement is unsuitable for a gain of function, that established fibrosis appears largely irreversible and that validated biomarkers and outcomes are lacking [19]. In 2026, BPIFA1-derived peptides reduced respiratory syncytial virus infection in nasal epithelial cultures from patients [48]. Recent clinical research has added to the phenotype psychosis, fibrothorax, biliary cirrhosis with liver transplantation, foveal hypoplasia, radioulnar synostosis, autopsy findings and a severity scale showing a milder phenotype in familial cases [9, 35, 41, 47, 59–61].

7.17. Pregnancy, perioperative care and transition

Pregnancies described in women with Myhre syndrome are few, often after medically assisted reproduction and spontaneous miscarriages, and the 2025 review recommends taking obstetric complications into account in counselling [9, 13, 46]. The sources consulted do not describe obstetric series or specific recommendations for delivery; the general principles — avoid unnecessary instrumentation, plan anaesthesia for an anticipated difficult airway and a small tube — also apply to caesarean section and obstetric anaesthesia [1, 7]. Losartan should be stopped in pregnancy [81, 82]. In the perioperative setting, the principle common to all sources is prior multidisciplinary discussion, the professional most experienced with the airway and communication of the precautions to the whole team [1, 7]. Transition to adult medicine should provide for adult-specific surveillance (Vanbelleghem's Table 2): annual clinical examination with attention to weight, musculoskeletal complications and neurobehavioural symptoms, cardiovascular, metabolic and gynaecological surveillance, and counselling on parenthood, fertility and preconception strategies in early adulthood [13].

7.18. Divergences between recommendations

The three consensus sources agree on the principles (initial multisystem assessment, cardiovascular and respiratory surveillance, limitation of tissue trauma, no growth hormone), but differ on intervals, as shown in Table 7.2.

ABPM: ambulatory blood pressure monitoring; CT: computed tomography; ECG: electrocardiogram; ENT: otorhinolaryngology. Sources: [1, 7, 13, 14].

The difference in the intervals for aortic and echocardiographic imaging reflects different populations (children with more codon 500 variants at MGH, adults with more p.(Arg496Cys) in Ghent) and the absence of data on the rate of progression; the schedule adopted in section 11 follows GeneReviews and MGH Table 5 in children and Vanbelleghem's Table 2 in adults [1, 7, 13].

The 2025 French PNDS differs from the other sources on several points. It prefers annual vascular surveillance by Doppler ultrasound from 8 years, with cerebral MR angiography from 10, whereas GeneReviews and MGH space CTA or MRA of the aorta at 5–10 years and MGH performs vascular neuroimaging at diagnosis; Doppler ultrasound does not replace CTA in the assessment of the thoracic aorta and arch, where the hypoplasia is concentrated, and the section 11 schedule keeps CTA or MRA and adds Doppler ultrasound as an option [1, 7, 14]. It sets cardiology follow-up at least annually, more frequent than the two-yearly echocardiogram of GeneReviews and MGH and the three-yearly one of Ghent [1, 7, 13, 14]. In systemic hypertension it indicates diuretics and calcium channel blockers, whereas MGH recommends an angiotensin II receptor antagonist because of the link with the TGF-β pathway; neither position has comparative data [7, 14]. On losartan, the PNDS mentions a positive effect on the matrix and stiffness, but the pilot study on which it relies concluded that losartan should not be recommended outside a trial, and GeneReviews classifies it as an investigational therapy [1, 14, 18]. In anaesthesia, it favours the laryngeal mask airway, whereas MGH favours face-mask ventilation and GeneReviews the uncuffed tube or one with monitored pressures; all three converge on avoiding intubation and, when unavoidable, using the smallest tube by the most experienced professional [1, 7, 14]. The background document of the PNDS cites Lin's (2016) recommendation to measure B-type natriuretic peptide at least every 3 years, even without symptoms, which the 2024 MGH cohort no longer considers useful as a baseline test [7, 14]. In gynaecology, it proposes endometrial cancer screening in adults without defining age or method, unlike the annual review with transvaginal ultrasound from 30 years proposed in Ghent [13, 14].

The PNDS text also contains inconsistencies and errors that should not be reproduced. It attributes lower severity to an “Arg486” variant, instead of Arg496; it places SMAD4 at 18q12.2, when the locus is 18q21.2 (the same error as Smith's Recognizable Patterns); it lists only four variants, without p.(Ile500Leu); it classifies glioma among benign tumours; it includes chest CT and sleep polygraphy in the systematic initial work-up, but states in another section that CT is not systematic and that polysomnography is performed when there are symptoms; and it sets annual hearing assessment from the first year in the text and systematic assessment at 2 years in the schedule [1, 6, 7, 14].

8. Reproductive Options and Family Counselling

8.1. Inheritance mechanism and risks

Myhre syndrome is autosomal dominant and usually results from a de novo variant [1]. All de novo variants whose parental origin was studied were paternal and were associated with advanced paternal age, through positive selection of the spermatogonia carrying them; the mean paternal age excess was 6.3 years, and codon 500 variants accumulate in sperm with age [1, 8]. In the Ghent cohort, median paternal age in presumed de novo cases was 35 years, with 2 of 10 fathers over 40 years [13]. In the MGH cohort, 11% of patients were conceived by in vitro fertilisation or intrauterine insemination, and dizygotic twins were over-represented (five pairs, all with an affected female twin and an unaffected male twin) [7].

If the variant is not found in either parent, it should be considered de novo or inherited from a parent with gonadal, or somatic and gonadal, mosaicism, which leucocyte DNA may fail to detect [1]. The risk to other relatives depends on the status of the parents [1]. The French PNDS considers penetrance complete with variable severity and estimates the recurrence risk for the parents of a proband with a de novo variant at about 1%, because of the possibility of germline mosaicism, a value matching that of GeneReviews [1, 14].

8.2. Familial transmission

The families with vertical transmission described up to 2025 all carry p.(Arg496Cys): transmission from an affected mother to two children in three families (in one of them after medically assisted reproduction), from a mildly affected 38-year-old mother to a 4-year-old son in a family published in 2025, from a father to three children in a Brazilian family, and two adult men with p.(Arg496Cys) had children without fertility problems [1, 9, 10, 13, 46, 49]. On the severity scale of Brand et al., familial cases were milder than sporadic ones, which explains how a parent may have gone unnoticed [9]. For this reason, MGH Table 5 recommends, in the presence of p.(Arg496Cys), heightened attention and testing of parents and children, and the Brazilian study reinforces the need to investigate the parents for correct counselling [7, 10].

8.3. Fertility and pregnancy in the affected person

Female fertility appears reduced: women in the MGH cohort who tried to conceive did not succeed before diagnosis, Lin et al. were not aware of spontaneous conception in an affected woman, the pregnancy described by Meerschaut followed medically assisted reproduction and recurrent miscarriages, and autopsies showed ovarian fibrosis with fewer oocytes [7, 13, 46, 47]. The 2025 review associates affected mothers with a possible increased risk of infertility and pregnancy loss and proposes counselling that includes dominant transmission, paternal age risk and obstetric complications [9]. In men, fertility is documented at least in carriers of p.(Arg496Cys) [10, 13]. Adults should receive, in early adulthood, counselling on parenthood, fertility and preconception strategies [13].

8.4. Prenatal diagnosis and preimplantation genetic testing

Once the variant has been identified in an affected relative, prenatal diagnosis and preimplantation genetic testing are possible; the ideal time to discuss the risk and these options is before pregnancy [1]. Couples with an affected child and negative parents, whose empirical risk is around 1%, may wish to discuss prenatal diagnosis [1]. Without a family history, the syndrome has been diagnosed in the fetus by exome or genome in the presence of ultrasound findings: nuchal translucency of 5.7 mm with a 1.2 mm pericardial effusion, thickened right ventricular myocardium, aberrant right subclavian artery and persistent left superior vena cava (de novo variant p.(Ile500Thr), termination at 23 weeks); severe intrauterine growth restriction with crossed fused renal ectopia; and pulmonary atresia with ventricular septal defect [63, 64]. Two fetuses in the MGH cohort had hypoplasia of left-sided structures and the arch [7]. The fetal findings described are severe and may not represent the postnatal spectrum, which includes adults with working and family lives; differences in perspective between professionals and families on the use of these tests should be respected [1, 7].

8.5. Content of counselling

Counselling should explain the difference between the germline gain-of-function variants of Myhre syndrome, the germline loss-of-function variants of juvenile polyposis and the somatic variants of cancers, because the same gene name appears in all three contexts [7]. It should be repeated to ensure understanding, inform about the paternal age effect and the possibility of a mildly affected parent, and include psychological and social support for the family [1, 7]. Testing of asymptomatic siblings is justified only when a parent carries the variant or in the presence of compatible signs, given the low risk in other cases [1]. The French PNDS recommends that the diagnosis be disclosed at a dedicated consultation, by the specialist who suspected it or the clinician who requested the test, with information on the disease, transmission, warning signs, treatments, the follow-up schedule and social and educational or occupational support; it recommends psychological support, a letter to the patient's doctors and, given the complexity of the information, a second consultation a few weeks later [14]. Pregnancy may be addressed at that consultation as circumstances dictate, and a genetics clinic appointment should be offered before a future pregnancy [14].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

There are no population-based studies [7]. GeneReviews gives a rough estimate of 1:900,000, and Orphanet classifies the worldwide point prevalence as less than 1 per 1,000,000, citing GeneReviews [1, 12]. Lin et al. estimated a minimum prevalence in Massachusetts of about 1 per 1.4 million, counting state residents followed at the MGH clinic (five patients for seven million inhabitants); the same article gives 1 per 1.2 million elsewhere, and the authors consider the figure an underestimate, because there are undiagnosed or unreferred patients [7]. The presence of seven carriers of p.(Arg496Cys) and one of p.(Ile500Val) among 807,162 individuals in gnomAD v4, which excludes paediatric cohorts, suggests that prevalence may exceed 1 per million, mainly through mild forms with p.(Arg496Cys) [13]. The number of patients with a published molecular diagnosis rose from about 80 in 2023 to more than 200 in 2024 and 217 in 55 reports in 2026, reflecting the increase in diagnosis by exome [1, 13, 35]. The Myhre Syndrome Foundation registry held in 2025 self-reported data on 105 patients from 24 countries [34]. Prenatal diagnosis followed by termination may reduce birth prevalence [7].

9.2. Geographical distribution and populations studied

The syndrome has been described in several populations without a known founder, as expected for a usually de novo disease [1, 8]. North American data come mainly from the MGH cohort (47 patients, with five residents outside the USA: three from Canada, one from the United Kingdom and one from South America) and from the Mayo Clinic series [7, 58]. European data include the French series (32 patients of Michot, 12 of Yang at the Necker reference centre), the adult cohort coordinated in Ghent (Belgium) with collaborators from several countries, the Italian series of Garavelli and of Cappuccio, the British cases of McGowan and the second family with vertical transmission [13, 15, 27, 32, 49, 56, 66]. In Asia, the sources consulted include patients from Hong Kong (figures in Bone Dysplasias and a prenatal diagnosis) and Taiwan [28, 59, 63]. In Brazil, Spineli-Silva et al. (2025) described the first Brazilian patients: seven people, including three siblings with p.(Arg496Cys) inherited from their father, with intra- and interfamilial clinical heterogeneity, developmental delay or intellectual disability in five and autism spectrum disorder diagnosed in one [10]. The sources consulted include no data from Portugal. The background document of the PNDS also gathers reports of first cases in several populations: the first Japanese patient (p.(Ile500Thr), diagnosis at 9 years, with precocious puberty), the first woman described, Mexican, in 2003, the first Korean patient (p.(Ile500Val), with an operated ductus arteriosus), the first Chinese patients with p.(Ile500Val) and the 2019 Chinese review [14]. Lin et al. stress the lack of racial and geographical diversity in the cohorts and the need for larger studies to calculate survival [7].

9.3. Sex and special populations

The first cases described were men, and the first woman was described only in 2003; in recent series there is a female predominance (55% in the MGH cohort, 9 of 12 in the French cohort, 17 of 25 adults in the literature), which may reflect referral bias [2, 7, 13, 15]. The muscular build appears more marked in men [2]. Women have their own problems (precocious puberty, menometrorrhagia, macromastia, ovarian insufficiency, infertility and endometrial cancer) [1, 7, 13]. Adults diagnosed late have milder phenotypes and lower mortality than adults in the literature (1 of 24 versus 6 of 25; p=0.098) [13]. People with autism and intellectual disability require adaptation of examinations (rapid CTA without anaesthesia, support from child preparation specialists, measurements under anaesthesia when unavoidable) [7].

9.4. European networks and patient associations

The European Reference Network ERN-ITHACA (rare malformation syndromes, intellectual disability and other neurodevelopmental disorders) is the main reference network, and has funded recent work on therapy for the syndrome [19, 20]. ERN BOND (rare bone diseases) covers the acromelic dysplasias, and VASCERN, ERN-Skin and ERKNet took part in the European adult cohort [13, 21]. The Myhre Syndrome Foundation, an international organisation founded in 2019, supports families, maintains the patient registry with the Coordination of Rare Diseases at Sanford, a network of professionals and a research portfolio [22, 23, 39]. The MGH Myhre Syndrome Clinic, in Boston, functions as a multidisciplinary referral centre [1, 7]. In France, the PNDS entrusts coordination to the reference centre for constitutional bone diseases (CRMR MOC), with its coordinating centre at Necker-Enfants malades Hospital (AP-HP, Paris), constituent sites at the Cochin and Lariboisière hospitals (Paris), the Hospices Civils de Lyon and the CHRU de Montpellier, and 20 competence centres (Amiens, Bordeaux, Brest, Caen, Clermont-Ferrand, Dijon, Grenoble, Lille, Nancy, Nantes, Paris-Trousseau, Poitiers, Rennes, Réunion, Rouen, Saint-Étienne, Strasbourg, Toulouse, Tours and Marseille), integrated into the OSCAR filière de santé for rare diseases of bone, calcium and cartilage [14]. The PNDS refers to the Myhre Syndrome Foundation and the Association française du syndrome de Myhre [14]. On the social side, the syndrome is not on the list of the 30 long-term conditions, but can be recognised as a long-term condition outside the list or through multiple pathology, with continuous care anticipated for more than 6 months; children up to 6 years can be followed at an early medico-social action centre, families can apply to the Maison départementale des personnes handicapées for recognition of disability and the corresponding support (including the disabled child education allowance and recognition as a disabled worker), and the school draws up an individualised reception plan with material adaptations and an emergency protocol [14].

10. Illustrative Clinical Case

Lin et al. (2024) described in detail the oldest known patient with Myhre syndrome, a 53-year-old woman with the rare variant c.1498A>C p.(Ile500Leu) [7]. A graduate, married and active as a patient advocate for the Myhre Syndrome Foundation, she had searched for three decades for a genetic explanation for multiple problems, especially deafness; chromosomal microarray and expansion testing for myotonic dystrophy types 1 and 2 had been normal, and the diagnosis was made only at 49 years by exome sequencing, which also excluded other causes of sensorineural deafness [7]. She measured 154.1 cm and had progressive bilateral sensorineural deafness, with good speech discrimination with hearing aids, hypernasal speech due to mild velopharyngeal insufficiency, poorly controlled insulin-treated diabetes, a body mass index above 40 kg/m², thick skin, urinary incontinence and sleep apnoea treated with continuous positive airway pressure [7]. The course included progressive joint contractures, restrictive lung disease due to progressive chest wall restriction, cervical and lumbar stenosis with cord compression (with a favourable outcome from spinal surgery) and severe chronic pain; she had multiple fractures between 18 months and 28 years, from minor trauma, with good healing, treated vitamin D deficiency and a recent normal bone densitometry [7]. Thelarche occurred at 8 years and menarche at 9, with heavy and irregular flow, and menstruation ceased at 15 years owing to ovarian insufficiency; at 23 years she used oral contraceptives to regulate the cycle, and five artificial inseminations did not result in pregnancy [7]. The echocardiogram showed a small ascending aorta (23 mm in the proximal portion and 26 mm in the mid portion), and CTA a descending thoracic aorta of 20 mm proximally and 15 mm in the mid and distal portions; mild airway narrowing is followed by serial laryngoscopies, and CT showed mild bronchial thickening [7]. At 30 years she had frequent ventricular extrasystoles treated with metoprolol, at 44 years non-sustained ventricular tachycardia after an exercise test, and coronary CTA showed very mild non-obstructive coronary disease [7]. After working into her fifth decade, fatigue and walking difficulty came to require almost constant medical assessments and prevented her from working; the team includes cardiology, pulmonology, spinal surgery, sleep medicine, pain management and rehabilitation, and mental health and palliative care services have begun advance care planning [7].

The case illustrates the adult spectrum that is under-represented in paediatric series: preserved intelligence and social life with a rare variant, late diagnosis by exome, musculoskeletal and respiratory progression over decades, reproductive problems, diabetes and hypoplastic aortopathy without significant obstruction [7, 13]. The figures in the same article, consulted on the PMC page, show the hypoplastic aortopathy in other patients of the cohort: Figure 1 presents CTA with three-dimensional reconstruction of a 21-year-old man with p.(Ile500Thr), with diffuse narrowing of the thoracoabdominal aorta (narrowest point of 6.8 mm at the suprarenal level) and proximal stenosis of the coeliac trunk (https://pmc.ncbi.nlm.nih.gov/articles/PMC11586855/figure/F1/), and Figure 2 the MR angiography of the aorta of a 21-year-old woman (https://pmc.ncbi.nlm.nih.gov/articles/PMC11586855/figure/F2/) [7]. The French cohort illustrates cerebral vasculopathy with the carotid arteriography of a patient with moyamoya syndrome, with stenosis of the terminal portion of the left internal carotid artery and “puff of smoke” collateral circulation (https://pmc.ncbi.nlm.nih.gov/articles/PMC9338657/figure/Fig2/) [15]. The measures in the report (metoprolol for ventricular arrhythmia, spinal surgery, oral contraception) correspond to conventional treatment of each problem, not to a syndrome-specific recommendation [7].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Myhre syndrome is progressive: in the MGH cohort, all patients followed for at least five years showed symptom progression, and joint stiffness is the manifestation whose progression is most predictable [7]. Severity is highly variable: 74% of the 47 patients had no severe feature, and the remaining 26% had restrictive cardiomyopathy (4%), pericardial disease requiring invasive treatment (6%), severe left-sided outflow defects (21%), tetralogy of Fallot with MAPCAs (2%) or multilevel airway stenosis requiring a procedure (2%), some with more than one [7]. Mortality in the MGH cohort was 2 of 46 patients with longitudinal data (4%), a 32-year-old man with multilevel stenosis and an 8-year-old boy with tetralogy of Fallot, pulmonary hypertension and restrictive cardiomyopathy [7]. In the French cohort, 3 of 12 patients died (pulmonary hypertensive crisis and mesenteric infarction in late adolescence or early adulthood; oesophageal atresia in early childhood) [15]. In the 11 deaths reviewed by Lin et al., the mean age was 18 years (eight patients with known age), the cause was cardiovascular in 64% and respiratory in 27%, and only 18% had an autopsy [7]. The Ghent adults, generally diagnosed late and with more p.(Arg496Cys), had a mortality of 1 in 24, compared with 6 in 25 adults in the literature, who died between 22 and 53 years of respiratory failure, progressive pulmonary vascular disease or presumed arrhythmia [13]. The oldest known patient was 53 years old in 2024 [7]. The combination of aortic obstruction with restrictive cardiomyopathy predicts greater morbidity and mortality, but it is not possible to predict who will develop multilevel airway stenosis [7]. Survival has not been calculated, because there are no population cohorts of sufficient size [7]. Established fibrosis appears cumulative and largely irreversible, which gives importance to early diagnosis and prevention of tissue trauma [1, 19].

11.2. Surveillance schedule

Table 11.1 brings together the recommendations of GeneReviews and MGH Table 5 for children and adolescents and Vanbelleghem's Table 2 for adults; where they differ, both are given, as in Table 7.2. The final rows marked “PNDS” add the examinations and intervals specific to the 2025 French protocol.

DXA: dual-energy X-ray absorptiometry; HbA1c: glycated haemoglobin A1c. Surveillance for neoplasms has no basis beyond the gynaecology review proposed for adult women; the Ghent experts suggest attention to gliomas and endometrial neoplasia, and consider the evidence insufficient for preventive hysterectomy [13]. B-type natriuretic peptide, erythrocyte sedimentation rate and C-reactive protein have not proved useful as baseline tests [7].

11.3. Transition and quality of life

Most adults remain under parental guardianship, but many achieve independence in daily activities, and some work, live as couples, have children and take part in activities such as musical theatre, singing or writing [1]. The French cohort described two adults with social and occupational integration [15]. The burdens most often cited by patients and carers, according to surveys and the FDA patient listening session, are respiratory and cardiac manifestations and problems of behaviour, autism, intellectual disability and speech [39]. Chronic pain, fatigue, loss of mobility and musculoskeletal limitations dominate adulthood, as the case in section 10 shows [7]. The French PNDS includes among the aims of follow-up preparation for transfer to adult medicine, strengthening of social, educational and occupational support and therapeutic education of the patient and family, so that both recognise the signs of deterioration and take part in decisions [14].

12. Summary and Final Considerations

Myhre syndrome is an autosomal dominant disease, almost always de novo and of paternal origin, caused by a very limited number of SMAD4 missense variants at codons 496 and 500, which dysregulate TGF-β/BMP signalling through a gain-of-function or dominant-negative mechanism, opposite to that of the juvenile polyposis and hereditary haemorrhagic telangiectasia caused by the same gene [1, 8, 38, 42]. The picture combines prenatal and postnatal growth restriction with a stocky, pseudomuscular habitus, a face that becomes recognisable at around 6 years, thick skin, progressive joint stiffness, conductive or mixed deafness, developmental delay with frequent autism and a fibroproliferative response of the serosae, airways, vessels and skin, spontaneous or triggered by trauma and surgery [1, 7, 15]. The complications that determine prognosis are hypoplastic aortopathy with recoarctation, pericardial disease, restrictive cardiomyopathy, pulmonary hypertension and multilevel airway stenosis; they affect about a quarter of patients and are concentrated in codon 500 variants, although p.(Arg496Cys), milder and the only one transmitted so far, can cause any manifestation [7, 13]. The diagnosis is confirmed by SMAD4 sequencing, often by an exome requested for developmental delay or autism, and must be interpreted in the light of the phenotype, because the same variants appear on cancer and polyposis panels with discordant classifications [1, 40, 54]. Management rests on an initial multisystem assessment, a schedule of cardiovascular, respiratory, sensory, endocrine, renal and neurodevelopmental surveillance and, above all, on limiting tissue trauma: avoid unnecessary procedures, plan the airway with a small tube and low cuff pressures, never resect the trachea, minimise abdominal and pelvic surgery and do not use growth hormone [1, 7]. There is no disease-modifying therapy; losartan showed improvement in skin and joints in a pilot of three patients, but is not recommended outside the treatment of hypertension, and gene editing, antifibrotic immunotherapy and small-molecule strategies are at the preclinical stage [18, 19, 39]. Counselling should cover the possible dominant transmission with p.(Arg496Cys), the risk of about 1% to siblings when the parents are negative, reduced female fertility and the risk of endometrial cancer in adult women [1, 9, 13].

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