Clinical characteristics.

Myhre syndrome is a multisystem progressive connective tissue disorder that often results in significant complications. The highly distinctive (and often severe) findings of joint stiffness, restrictive lung and cardiovascular disease, progressive and proliferative fibrosis, and thickening of the skin usually occur spontaneously. Some proliferation such as abnormal scarring or adhesions may follow trauma, invasive medical procedures, or surgery. Effusions of the heart, airways, lungs, uterus, and peritoneum may occur and can progress to fibrosis. Most affected individuals have characteristic facial features (short palpebral fissures, deeply set eyes, maxillary underdevelopment, short philtrum, thin vermilion of the upper lip, narrow mouth, and prognathism) and developmental delay / cognitive disability, typically in the mild-to-moderate range. Neurobehavioral issues may include autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and/or anxiety. Although immunoglobulin (Ig) G and IgA deficiency are rare, affected individuals can experience recurrent infections (including otitis media, sinusitis, mastoiditis, or croup). Hearing loss can progress over time. Growth may be impaired in early life. Most adolescents develop obesity. Eye findings can include refractive errors, astigmatism, corectopia, and optic nerve anomalies. Gastrointestinal (GI) issues may include gastroesophageal reflux disease, constipation, and encopresis. Less commonly, stenosis of the GI tract, Hirschsprung disease, and/or metabolic dysfunction-associated liver disease may be observed.

Diagnosis/testing.

The diagnosis of Myhre syndrome is established in a proband with characteristic clinical findings and a heterozygous (typically recurrent) pathogenic variant in SMAD4 identified by molecular genetic testing.

Management.

Treatment of manifestations: Feeding therapy for those with poor weight gain or feeding issues; gastrostomy tube placement may be required for persistent feeding issues; referral to nutrition for those who develop obesity; consideration of balloon dilation or long-term tracheostomy for those with complete or recurrent tracheal stenosis; use of smaller-size, uncuffed endotracheal tubes for anesthesia; intralesional steroids for some keloids; physical therapy for decreased range of motion of joints; orthotics for tiptoe walking; dietary management, stool softeners, prokinetics, osmotic agents, or laxatives for constipation; guarded treatment with minimal instrumentation of the GI tract for gastrointestinal stenosis. Standard treatment for orofacial clefting, velopharyngeal insufficiency, developmental delay / intellectual disability, cardiovascular disease including systemic/pulmonary hypertension, restrictive lung disease, sleep apnea, immunodeficiency, tethered spinal cord, frequent fractures, eye/vision issues, hearing loss, protein-losing enteropathy, liver dysfunction, diabetes mellitus, cryptorchidism, hypospadias, and epilepsy.

Prevention of secondary complications: Limiting tissue trauma appears to be the single most important preventive measure. When possible, alternative noninvasive approaches should be pursued during diagnosis and management.

Surveillance: At each visit, measure growth parameters; right upper arm blood pressure (if tolerated); monitor for evidence of respiratory insufficiency and obtain pulse oxygen measurement; evaluate for signs/symptoms of upper airway stenosis and sleep apnea; monitor for constipation and signs/symptoms of GI stenosis; monitor developmental progress and educational needs, including mobility and self-help skills; assess for signs/symptoms of anxiety, ASD, and ADHD; assess for signs/symptoms of frequent infections; monitor for premature puberty in childhood; encourage nonstrenuous exercise, healthy eating, and weight management. Annually (or as clinically indicated), pulmonary function studies or impulse oscillometry in children age six years and older, if able to cooperate with test maneuvers; ophthalmology evaluation; hearing evaluation; assessment for abnormal scarring. Every two years, echocardiogram (in an asymptomatic person with a normal echocardiogram at initial diagnosis). Every five to ten years starting in childhood (age 5-10 years), CT or MR angiogram of the aorta, the exact frequency of which is based on the presence and degree of aortic disease. The decision to use CT or MR depends on the age and behavior of individual, the imaging center, and the availability of supportive services ("Child Life") to accomplish without anesthesia. Starting in the second decade, low threshold for fasting blood sugar and hemoglobin A1c to assess for diabetes mellitus; periodic DXA scan to assess bone mineral density; monitor for heavy menses. As clinically indicated, more extensive cardiovascular imaging in persons with abnormal findings at initial diagnosis; renal bladder ultrasound, if there is intractable incontinence. As needed, in the third decade of life, coronary CT angiography; evaluation for sleep apnea and need for intervention.

Agents/circumstances to avoid: Smoking; tissue trauma; elective tracheal surgery/intubation (if possible); tracheal resection; growth hormone therapy.

Genetic counseling.

Myhre syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant. De novo SMAD4 pathogenic variants that have been evaluated for parent of origin to date have all been paternal and have been associated with advanced paternal age. A few individuals diagnosed with Myhre syndrome have the disorder as the result of a SMAD4 pathogenic variant inherited from an affected parent. Each child of an individual with Myhre syndrome has a 50% chance of inheriting the SMAD4 pathogenic variant. Once the SMAD4 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Myhre syndrome should be suspected in individuals with the following clinical and imaging findings and family history. Although no single feature is pathognomonic, co-occurrence of some findings is highly suggestive of Myhre syndrome (see Table 2 for frequency of select features).

Clinical findings

• Short stature (height is significantly less than predicted mid-parental height) with compact body habitus
• Characteristic facial features (See Clinical Description, Craniofacial and Figures 1, 2, 3, 4, 5, and 6.)
• Conductive and mixed hearing loss
• Respiratory difficulties, usually due to restrictive thorax or, infrequently, multilevel airway stenosis (including choanal, subglottic, laryngotracheal, and/or bronchial)
• Progressively stiff, thickened skin and subcutaneous tissue
• Limited range of motion of the joints with occasional contractures
• Effusions involving the heart, airways, lungs, uterus, and peritoneum, which may progress to fibrosis
• Mild-to-moderate intellectual disability
• Autism spectrum disorder or neurodivergent behaviors
• Severe constipation and/or encopresis
• Premature puberty

Figure 1.

The same female with Myhre syndrome at ages seven months, four years, and 16 years (lateral and frontal views). Note the short palpebral fissures, thin vermilion of the upper lip, and maxillary underdevelopment. She required tracheostomy at age 13 years (more...)

Figure 2.

The same female with Myhre syndrome as a newborn and at ages 12 months, 3.5 years, and seven years. Note the mild left-sided facial asymmetry (7th cranial nerve palsy), short palpebral fissures, thin vermilion of the upper lip, and progression of mild (more...)

Figure 3.

Male with Myhre syndrome at age 12 years with mild facial features (mild maxillary underdevelopment and thin vermilion of the upper lip) and finger contractures. Reported as Patient 4 in Starr et al [2015]

Figure 4.

Female with Myhre syndrome at age five years. Note the short palpebral fissures, thin vermilion of the upper and lower lips, left-sided facial palsy, and brachydactyly, with otherwise mild features. Reported by Hawkes & Kini [2015]

Figure 5.

The same male with Myhre syndrome at various ages from toddlerhood (lower right corner) to age 19 years (upper left corner).

Figure 6.

Two different women with Myhre syndrome at ages 40 years (A) and 50 years (B). The women are shown together in C.

Imaging findings

• Echocardiographic findings
  • Aortic narrowing, such as typical juxtaductal aortic coarctation, diffuse long-segment aortic hypoplasia, or segmental stenosis (branch arteries)
  • Congenital heart defects (See Clinical Description, Cardiovascular.)
  • Pericardial involvement ranging from transient effusion to chronic severe constrictive pericarditis
  • Restrictive cardiomyopathy and diastolic dysfunction
  • Pulmonary hypertension
• Skeletal radiographs (See Figure 7.)
  • Thickened calvarium
  • Shortened long bones
  • Enlarged (tall) or flattened (platyspondyly) vertebrae with shortened pedicles
  • Cervical vertebral fusion
  • Hypoplastic iliac wings
  • Absent or extra ribs
  • Small exostoses and/or enostoses (bone islands)

Figure 7.

Radiographs of a female with Myhre syndrome at age 14 years A. Lateral cervical spine shows thickened calvaria and anterior cervical vertebral fusion (arrow) of C2 and C3.

Family history. Because Myhre syndrome is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Infrequently, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations) [Meerschaut et al 2019, Demir et al 2023, Vanbelleghem et al 2024].

Establishing the Diagnosis

The diagnosis of Myhre syndrome is established in a proband with characteristic clinical findings and a heterozygous (typically recurrent) pathogenic (or likely pathogenic) variant in SMAD4 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous SMAD4 variant of uncertain significance does not establish or rule out the diagnosis. (3) Individuals described as having "Myhre-like syndrome" require genetic testing for confirmation.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Myhre syndrome is a multisystem progressive connective tissue disorder that often results in significant complications. The highly distinctive (and often severe) findings of joint stiffness, restrictive lung and cardiovascular disease, progressive and proliferative fibrosis, and thickening of the skin may occur spontaneously or following trauma, invasive medical procedures, or surgery. In most, short stature and hearing loss also develop over time.

To date, more than 200 affected individuals with a molecularly confirmed diagnosis of Myhre syndrome have been reported [Bassett et al 2016, Lin et al 2016, Lin et al 2020, Cappuccio et al 2021, Cappuccio et al 2022, Yang et al 2022, Lin et al 2024, Vanbelleghem et al 2024]. The following descriptions of the phenotypic features associated with Myhre syndrome are based on these reports, which will not be cited again unless there is specific or unique data pertaining to a particular citation.

Craniofacial. The craniofacial features of Myhre syndrome (see Figures 1, 2, 3, 4, 5, and 6) can vary considerably and progress over time (see also Figure 5 in Lin et al [2024]), which make the features more apparent in older individuals. Although classic coarsening of features is not present, mandibular prominence is notable and attributed to disharmonic maxillary/mandibular growth. Facial features typically also include:

• Short palpebral fissures (See Figure 4.)
• Deeply set eyes
• Maxillary underdevelopment
• Short philtrum
• Narrow mouth
• Thin vermilion of the upper lip (See Figure 3.)
• Small and/or widely spaced teeth
• Prognathism

While cleft lip and palate is rare, velopharyngeal insufficiency is common.

Developmental delay and intellectual disability. Mild-to-moderate developmental delay and intellectual disability are common. Cognition can be within the normal range, although this is not the most common outcome. Delayed speech can be significant. Most affected individuals are ultimately verbal, using verbal communication as their primary means of communication, although some remain essentially nonverbal. Most affected individuals are supported by parents and under guardianship of their parents. Activities of daily living are achieved by many adults, although delayed toilet training and hygiene (e.g., bathing, dental care, menstrual assistance) can be a challenge to independence. Less commonly, affected individuals have attended college (generally smaller schools or two-year programs that provide accommodations for individuals with learning challenges). Several adults have been employed, have a partner, reproduced, and engaged in recreational activities such as musical theater, singing, and writing.

Other neurodevelopmental features

• Abnormalities of tone can include low truncal tone (hypotonia) transitioning to high tone (hypertonia).
• Tiptoe walking is observed often, but not well understood. In many children, it is viewed as an autism spectrum disorder behavior. In a few affected individuals, MRI imaging shows a form of tethered cord (rarely, classic) for which surgery is performed (see Management).
• Balance issues are attributed to lack of general fitness and stiff joints.
• Epilepsy is not common. Some affected individuals have had abnormal movements and staring spells, during which EEG was either not completed or was normal.

Neurobehavioral/psychiatric. Autism spectrum disorder (ASD) has been noted in 40%-70% of affected individuals and may range from mild social disability to severe autism. Attention-deficit/hyperactivity disorder (ADHD) and anxiety have also been observed in affected individuals. Psychosis has been rarely observed.

Neuroimaging. When performed, brain MRI has commonly found white matter hyperintensities, which are better characterized as white matter injury related to intrinsic cerebral microvasculopathy and not true external injury or birth trauma.

Growth. Intrauterine growth restriction (IUGR) has been found during the pregnancies of the majority of affected infants. Short stature with compact body habitus (with normal head circumference) becomes more apparent over time.

• Most affected individuals have shortened long bones.
• Adult height is expected to be more than two standard deviations below what is predicted by parental heights in more than 80% of affected individuals, particularly in those who have a pathogenic variant at codon position 500 (see Genotype-Phenotype Correlations).
• Although head circumference is rarely greater than or equal to two standard deviations above the mean for age and sex, it is commonly proportionally greater than height ("relative macrocephaly").
• Although Myhre syndrome-specific growth charts have not been developed, growth is expected to be at the lower end or below the typical growth charts for weight and length/height for infants and children.
• Overweight (BMI >25, or >99th centile) may begin in adolescence and is found in most adults.

Gastrointestinal/feeding. Many infants and children have difficulty with poor feeding and weight gain and some may benefit from a feeding tube (see Growth in this section and Management). Other gastrointestinal findings may include:

• Choking, coughing, and/or dysphagia
• Mild-to-severe constipation
• Duodenal atresia
• Late-onset and congenital pyloric stenosis; less commonly stenosis may involve the duodenum, jejunum, and anus.
• Protein-losing enteropathy associated with right heart failure and restrictive cardiomyopathy (Patient 1 in Lin et al [2016])
• Hirschsprung disease
• Abnormal liver function tests can suggest a pattern of metabolic dysfunction-associated steatotic liver disease (MASLD); however, this is an emerging observation.

Cardiovascular. Progressive cardiovascular issues can appear at any age; those with onset in childhood may worsen following instrumentation. Two affected individuals with restrictive cardiomyopathy (which is rare) who were treated with heart and heart/lung transplantation did not survive due to postoperative complications [Starr et al 2015], and thus, transplantation has not been used in other reported affected individuals.

In 47 individuals with confirmed Myhre syndrome evaluated at Massachusetts General Hospital [Lin et al 2024], 77% had a cardiovascular abnormality including structural heart defects (47%), mild long-segment aorta hypoplasia (60%), systemic hypertension (38%), moderate-to-severe narrowing including coarctation (21%), additional arterial stenoses (13%), pericardial disease (13%), and restrictive cardiomyopathy (4%).

• Congenital cardiovascular abnormalities can include the following:
  • Atrial septal defect or ventricular septal defect
  • Patent ductus arteriosus
  • Tetralogy of Fallot
  • Obstructive defects of the left heart, such as juxtaductal aortic coarctation, long-segment aortic narrowing, aortic valve stenosis, mitral valve stenosis, and multiple levels of obstruction. These are more common than obstructive defects of the right side, such as valvar and branch pulmonary artery stenosis.
  • Visceral vascular stenoses (in celiac, superior mesenteric, inferior mesenteric, and/or renal arteries)
• Pericardial disease can present as short-term or recurrent effusions, or as chronic or progressive constrictive pericarditis that may require surgical intervention (see Management).
  • Restrictive cardiomyopathy, a lethal condition, can be difficult to diagnose without cardiac catheterization to assess hemodynamics.
  • While constrictive pericarditis and restrictive cardiomyopathy can present with similar hemodynamic impairment, they differ in their pathogenesis and treatment (see Management).
• Pulmonary hypertension, either primary or as a result of left ventricular dysfunction, has been infrequently reported; however, this may reflect limited evaluation and/or bias toward ascertainment and/or reporting of younger affected individuals (as underlying causes of pulmonary hypertension resulting from involvement of the lungs and cardiovascular circulation may evolve with age). It is unknown how often this is secondary to right-sided cardiac dysfunction or severe left-sided obstruction, although both have been observed.

Respiratory. Respiratory findings are usually multifactorial. The cause of multilevel airway stenosis ranging from the choanae distally to include laryngotracheal narrowing, subglottic stenosis (ranging from mild to complete), and the bronchi is unknown. There may be a congenital predisposition, which is exacerbated by trauma or infection. However, many children have had numerous intubations without developing "traumatic" stenosis. There can be mild stridor and croup in childhood, which rarely progresses to a severe multilevel form. Upper airway obstruction caused by choanal stenosis progressing to atresia is rare and a dramatic manifestation of airway occlusion from the proliferative process.

Other findings can include the following:

• Restrictive pulmonary disease, often associated with restrictive thorax
• "Asthma" that does not always respond to bronchodilator therapy, as in typical reactive airway disease
• Interstitial lung disease and severe pulmonary fibrosis on autopsy [Starr et al 2022].
• Abnormal sleep, most often associated with autism. In some instances, a sleep study may reveal obstructive sleep apnea.
• Sleep apnea

Immune system. The precise immunologic profile in people with Myhre syndrome has not been fully studied. Increased frequency of infections involving the respiratory tract (including otitis media, sinusitis, mastoiditis, or croup) has been reported and may result from mechanical factors. For example, ear canals, sinuses, and mastoid cells may be opacified from proliferative debris. Compromised innate immunity originating from epithelial cells may contribute to increased susceptibility to upper respiratory tract infections [Lindsay et al 2024]. Serum immunoglobulin (Ig) G and IgA deficiency have been noted in a small number of affected individuals [Lin et al 2024]. Intravenous Ig was utilized with reported benefit in at least two affected individuals [Lin et al 2024] (see Management).

Cutaneous and serosal findings. Thick, firm skin is seen in nearly all individuals with Myhre syndrome, and stiffness may progress in many adults. Various terms used to describe the skin include thick, stiff, firm, rough, hyperkeratotic, and inelastic. Skin changes may not be apparent in infancy; they are often first noted on the extensor surfaces, palms, and soles. The changes progress with age. Additional skin findings include minimal creasing of the facial skin and unusual white linear scars.

Proliferative fibrosis / abnormal scarring can occur following trauma or surgery. Some individuals develop hypertrophic, keloid-like scars. In addition to the skin, proliferation can also involve the large airways (trachea and bronchi) and the serosal surfaces of the heart, lungs, and peritoneum.

Musculoskeletal. Reduced range of motion of large and small joints is characteristic of Myhre syndrome and is exacerbated with age. Posture may be distinct, with flexed elbows and bending forward at the hips (see Ishibashi et al [2014], Figure 1). Other features that may be present include:

• Small hands and feet with brachydactyly, found in most individuals (See Figures 3 and 4.)
• Clinodactyly
• Syndactyly of the toes, usually 2-3
• Scoliosis
• Absence of normal lumbar lordosis and straight spine
• Sacral dimple, sometimes associated with a tethered spinal cord
• Bony fractures, which may be associated with childhood activities and/or trauma
• Leg pain involving the calf, which can be severe. Pain is not relieved with standard analgesics and is poorly understood. It can be associated with lower spinal cord compression.

Characteristic radiographic findings in affected individuals are listed in Suggestive Findings.

Ophthalmologic. Refractive errors are common and usually include hyperopia with astigmatism. Other findings may include strabismus, cataracts, corectopia, and optic nerve anomalies. Nasolacrimal duct stenosis or atresia is common and may be difficult to manage due to recurrent stenosis related to progressive fibrosis.

Hearing. Hearing loss is observed in most individuals with Myhre syndrome. Most newborns pass their neonatal hearing screen; hearing loss usually becomes evident in early childhood to late teens.

• Hearing loss is predominantly conductive or mixed; affected individuals most often have a history of bilateral myringotomy tube placement.
• The underlying etiology of the hearing loss is often unclear or unknown and may require inner ear imaging to diagnose structural anomalies, although this is thought to be rare.

Endocrine. Endocrine findings may include premature puberty (reported in both sexes), early menarche, meno- or metrorrhagia, and macromastia, the latter prompting reduction mammoplasty in some. Both premature ovarian failure and secondary amenorrhea have been observed.

Glucose intolerance in adults may be more common than the few reports of diabetes. One teenage girl had hyperinsulinism and an impaired glucose tolerance test, which may indicate insulin resistance [Kilci et al 2022].

Genitourinary. Genitourinary findings are infrequent but have included mild hypospadias and undescended testes in males.

Neoplasia. Since a report of neoplasia in six individuals with Myhre syndrome (3 of whom were women with endometrial cancer) [Lin et al 2020], there have been no additional reports of affected individuals with neoplasia. Anecdotally, there are additional cases, including one further person with endometrial cancer and two with hypothalamic hamartoma.

Genotype-Phenotype Correlations

Genotype-phenotype correlations are still emerging [Yang et al 2022, Lin et al 2024] with a detailed analysis in adults [Vanbelleghem et al 2024].

c.1498A>G (p.Ile500Val). Based on limited data, individuals with the highly recurrent c.1498A>G (p.Ile500Val) pathogenic variant are more likely to have prenatal growth deficiency with postnatal short stature and severe aortic obstruction.

c.1486C>T (p.Arg496Cys). Individuals with the c.1486C>T (p.Arg496Cys) pathogenic variant are more likely to have a height within the normal range for age and sex. Females with this pathogenic variant are more likely to have premature puberty and heavy menses (see Management). Of the six individuals reported with neoplasia, three were women with endometrial cancer, two of whom were heterozygous for the c.1486C>T (p.Arg496Cys) pathogenic variant. To date, all known affected individuals who have developed seizures have had this specific pathogenic variant.

Nomenclature

In the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023], Myhre syndrome is referred to as SMAD4-related Myhre dysplasia and included in the acromelic dysplasias group [Table 1 in Costantini et al 2023].

LAPS (laryngotracheal stenosis, arthropathy, prognathism, and short stature) syndrome was determined to be allelic to Myhre syndrome with pathogenic variants in the same codons [Lindor et al 2012, Picco et al 2013, Michot et al 2014] (see Genetically Related Disorders); the term is no longer in use.

Prevalence

The prevalence of Myhre syndrome is unknown. A rough estimate of the prevalence is 1:900,000 individuals.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Myhre syndrome, the evaluations summarized in Table 5 (if not completed previously as part of the diagnostic evaluation) are recommended.

Treatment of Manifestations

There is no cure for Myhre syndrome. Supportive care to improve quality of life, maximize function, and reduce complications is recommended, ideally involving multidisciplinary care by specialists in relevant fields (see Table 6).

Prevention of Secondary Complications

Limiting tissue trauma appears to be the single most important preventive measure. When possible, alternative noninvasive approaches should be pursued during diagnosis and management [Oldenburg et al 2015, Starr et al 2015].

• Extreme care with intubation and use of an endotracheal tube without a cuff (or careful monitoring of pressures with a cuff) may help prevent airway stenosis [Oldenburg et al 2015].
• Minimize abdominal and pelvic procedures as extensive adhesions may develop postoperatively [Lindor et al 2012].
• Hysterectomy should be an option of last resort for treatment of menorrhagia as postsurgical fibrosis can occur.
• Recognize risk of thickened scars or keloids with ear or other piercings.
• Use of orthodontic braces may stimulate gum hypertrophy.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Agents/Circumstances to Avoid

Affected individuals should be aggressively counseled not to smoke.

Limiting tissue trauma (injury) appears to be the single most important preventive concept in this disorder to communicate to all health care providers involved in an individual's care (see Prevention of Secondary Complications). Decision making with affected individuals and their families should include nonintervention as an option in, for example, ear piercing, orthodontic braces, exploratory procedures, or surgical repair of velopharyngeal insufficiency.

Elective tracheal surgery/intubation should be avoided when possible. Tracheal resection is contraindicated.

Growth hormone therapy is not currently recommended for affected individuals with short stature.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

The antihypertensive drug losartan is an angiotensin II type 1 receptor blocker. Through this mechanism, it also indirectly antagonizes transforming growth factor beta (TGF-β) signaling. In Myhre syndrome fibroblasts, losartan corrected an extracellular matrix deposition defect [Piccolo et al 2014]. Thus, in a small uncontrolled open-label pilot study, three individuals with Myhre syndrome were treated with losartan. Improvements in skin thickness, joint range of motion, and myocardial strain were observed [Cappuccio et al 2021]. However, long-term controlled clinical trials with a larger number of affected individuals are needed to establish the efficacy of losartan on skin, joint, and heart abnormalities in Myhre syndrome.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Myhre syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with Myhre syndrome have the disorder as the result of a de novo SMAD4 pathogenic variant [Lin et al 2016]. De novo SMAD4 pathogenic variants that have been evaluated for parent of origin to date have all been paternal and have been associated with advanced paternal age [Wood et al 2024].
• A few individuals diagnosed with Myhre syndrome have the disorder as the result of a SMAD4 pathogenic variant inherited from an affected parent. Transmission from an affected mother to two affected children has been reported in three families segregating the p.Arg496Cys SMAD4 pathogenic variant [Meerschaut et al 2019, Demir et al 2023, Vanbelleghem et al 2024].
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the SMAD4 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the SMAD4 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for Myhre syndrome because of the possibility of parental gonadal mosaicism.

Offspring of a proband. Each child of an individual with Myhre syndrome has a 50% chance of inheriting the SMAD4 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the SMAD4 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the SMAD4 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for Myhre syndrome are possible.

Note: Severe features (e.g., tetralogy of Fallot with pulmonary atresia, severe growth restriction) have been reported in prenatally diagnosed fetuses not known to be at increased risk of Myhre syndrome [Hui et al 2023, Jury et al 2024].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

SMAD4 encodes mothers against decapentaplegic homolog 4 (SMAD4), signal transduction protein that has roles in many diverse signaling pathways including canonical transforming growth factor beta (TGF-β), bone morphogenetic protein (BMP), and activin signaling. Heterozygous gain-of-function pathogenic variants in SMAD4 that cause Myhre syndrome have been thought to confer stability of the resulting abnormal protein due to an apparent decrease in monoubiquitination. The SMAD4 pathogenic variant p.Ile500Val increases stability of the SMAD3/SMAD4 transcriptional complex [Lindsay et al 2024]. Both of these biochemical activities may be at play, as they would both affect the TGF-β signaling pathway, altering expression of downstream target genes. Signaling perturbations result in altered development of the axial and appendicular skeleton, cardiac muscle, and central nervous system during development and abnormal extracellular matrix deposition during early development and adulthood [Caputo et al 2012, Le Goff et al 2014, Piccolo et al 2014].

In contrast, heterozygous loss-of-function SMAD4 pathogenic variants have been well established as the cause of a spectrum of acquired cardiac and neoplastic diseases, including arteriovenous malformations, aortopathies, pulmonary artery hypertension, and colon cancer susceptibility in the context of juvenile polyposis and hereditary hemorrhagic telangiectasia syndromes [Andrabi et al 2011, Nasim et al 2011, Heald et al 2015].

Mechanism of disease causation. Gain of function (increased TGF-β signaling potency) has been demonstrated in some studies [Lindsay et al 2024]; however, other research suggests a dominant-negative mechanism causing an interruption of typical TGF-β and BMP signaling [Alankarage et al 2022]. Resolution of the observed differences is still outstanding.

Cancer and benign tumors. Although germline SMAD4 loss-of-function (inactivating) pathogenic variants predispose to hamartomatous polyps in the gastrointestinal tract (see Juvenile Polyposis Syndrome), the gain-of-function pathogenic variants associated with Myhre syndrome show no such associations (see Clinical Description, Neoplasia).

Note that somatic inactivation of SMAD4, a gastrointestinal malignancy-specific tumor suppressor gene, is found in one third of colorectal cancer specimens and half of pancreatic tumors [Chen et al 2014].

Author Notes

Myhre Syndrome Clinic at Massachusetts General Hospital

Lindsay Lab at Massachusetts General Hospital

Acknowledgments

The authors are indebted to the people living with Myhre syndrome and their families who have provided consent, motivation, contributions, and advocacy.

Author History

Nicola Brunetti-Pierri, MD (2022-present)
Angela E Lin, MD (2017-present)
Noralane M Lindor, MD; Mayo Clinic (2017-2022)
Mark E Lindsay, MD, PhD (2022-present)
Lisa A Schimmenti, MD (2022-present)
Lois J Starr, MD, PhD (2017-present)

Revision History

• 12 December 2024 (ma) Comprehensive update posted live
• 24 November 2022 (ma) Comprehensive update posted live
• 13 April 2017 (bp) Review posted live
• 11 July 2016 (ljs) Original submission

Literature Cited

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