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Myhre Syndrome

Synonyms: Laryngotracheal Stenosis, Arthropathy, Prognathism, and Short Stature (LAPS) Syndrome; Myhre-LAPS Syndrome

, MD, , MD, and , MD.

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Summary

Clinical characteristics.

Myhre syndrome is a connective tissue disorder with multisystem involvement, progressive and proliferative fibrosis that may occur spontaneously or following trauma or surgery, mild-to-moderate intellectual disability, and in some instances, autistic-like behaviors. Organ systems primarily involved include: cardiovascular (congenital heart defects, long- and short-segment stenosis of the aorta and peripheral arteries, pericardial effusion, constrictive pericarditis, restrictive cardiomyopathy, and hypertension); respiratory (choanal stenosis, laryngotracheal narrowing, obstructive airway disease, or restrictive pulmonary disease), gastrointestinal (pyloric stenosis, duodenal strictures, severe constipation); and skin (thickened particularly on the hands and extensor surfaces). Additional findings include distinctive craniofacial features and skeletal involvement (intrauterine growth restriction, short stature, limited joint range of motion). To date, 55 individuals with molecularly confirmed Myhre syndrome have been reported.

Diagnosis/testing.

The diagnosis of Myhre syndrome is established by detecting a de novo SMAD4 heterozygous pathogenic variant in a proband with characteristic clinical findings.

Management.

Treatment of manifestations: Symptomatic treatment (with attention to limiting tissue trauma by minimizing instrumentation during diagnosis and management) by specialty experts of the following involvement: cardiovascular, respiratory (including tracheostomy when tracheal stenosis is recurrent or complete), and GI; routine management of speech and language delay, intellectual disability, behavioral problems.

Prevention of secondary complications: Limiting of tissue trauma given the apparent increased risk for proliferative fibrosis following otherwise uncomplicated endotracheal intubation and surgical procedures. When possible, alternative noninvasive approaches should be pursued during diagnosis and management

Surveillance: Cardiovascular: echocardiogram every one to three years in asymptomatic individuals with a normal echocardiogram at the time of initial diagnosis; in individuals with abnormal cardiac findings at the time of diagnosis, more extensive imaging (including possible cardiac MRI) may be considered. Respiratory: oxygen saturation in children with monitoring as needed for symptoms suggestive of restrictive/obstructive pulmonary disease; annual pulmonary function studies in children oldert than age six years if able to cooperate; evaluation of laryngotracheal stenosis based on symptoms. Annual ophthalmology and audiology evaluations.

Agents/circumstances to avoid: Smoking; tissue trauma.

Genetic counseling.

Myhre syndrome is inherited in an autosomal dominant manner. All probands with Myhre syndrome reported to date have the disorder as a result of a de novo SMAD4 pathogenic variant. If the SMAD4 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism. To date, individuals with Myhre syndrome are not known to reproduce and fertility has not been assessed. Once the SMAD4 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at theoretic increased risk for Myhre syndrome and preimplantation genetic diagnosis are possible.

Diagnosis

Formal diagnostic criteria have not been published for Myhre syndrome.

Suggestive Findings

Myhre syndrome should be suspected in individuals with the following clinical and radiographic findings.

Clinical

Cardiovascular

  • Arterial obstruction: juxtaductal coarctation of the aorta, long- and short-segment descending thoracic and abdominal aortic obstruction, and peripheral arteries in various locations; infrequently, branch pulmonary artery stenosis
  • Congenital heart defects:
    • Atrial and ventricular septal defects, patent ductus arteriosus
    • Valvular stenosis: aortic and mitral valves; infrequently, tricuspid and pulmonic valves
  • Pericardial involvement: ranges from effusion to constrictive pericarditis; often chronic and severe
  • Restrictive cardiomyopathy (can be rapidly progressive)
  • Hypertension: systemic and pulmonary

Respiratory (congenital or acquired)

  • Laryngotracheal narrowing (including subglottic stenosis)
  • Choanal stenosis
  • Obstructive airway disease
  • Restrictive pulmonary disease (which appears to increase with age)

Gastrointestinal

  • Congenital or acquired pyloric stenosis
  • Later onset:
    • Duodenal strictures
    • Severe constipation

Skin

  • Stiff and thickened overall, but particularly on the hands and extensor surfaces
  • Facial creases fewer than expected for age

Proliferative fibrosis/scarring

  • May occur spontaneously or following trauma or surgery
  • May involve the serosal surfaces of the heart, airway and lungs, and gastrointestinal tract as well as the skin

Neuropsychiatric

  • Mild-to-moderate intellectual disability
  • Autistic-like behaviors in some

Craniofacial

  • Characteristic facial features including short palpebral fissures, deeply set eyes, maxillary underdevelopment, short philtrum, narrow mouth, thin vermilion of the upper lip, and prognathism (Figure 1, Figure 2, Figure 3, Figure 4, Figure 5). Facial characteristics can progress over time; although classic coarsening of features is not present, mandibular elongation is notable. Note: Craniofacial features can vary considerably.
  • Cleft lip and/or palate and velopharyngeal insufficiency reported in 13% [Lin et al 2016]
Figure 1. . Female with Myhre syndrome at ages seven months, four years, and 16 years.

Figure 1.

Female with Myhre syndrome at ages seven months, four years, and 16 years. Note the short palpebral fissures, thin upper vermilion border and maxillary underdevelopment. She required tracheostomy subsequent to traumatic intubations that resulted in complete (more...)

Figure 2. . Female with Myhre syndrome at ages newborn, 12 months, 3.

Figure 2.

Female with Myhre syndrome at ages newborn, 12 months, 3.5 years, and seven years. Note the short palpebral fissures, thin upper vermilion border, and progression of mild prognathism.

Figure 3. . Female with Myhre syndrome at ages three years, ten years (standing), and 21 years (face, posterior hairline, and hands).

Figure 3.

Female with Myhre syndrome at ages three years, ten years (standing), and 21 years (face, posterior hairline, and hands). Note the short palpebral fissures, broad mid-upper nasal bridge, downward pointing nasal tip, thin upper vermilion border, broad (more...)

Figure 4. . Male with Myhre syndrome at age 12 years.

Figure 4.

Male with Myhre syndrome at age 12 years. Note the mild facial features (mild maxillary underdevelopment and thin upper vermilion border) and finger contractures (hands are on a flat surface).

Figure 5. . Female with Myhre syndrome at age five years.

Figure 5.

Female with Myhre syndrome at age five years. Note the short palpebral fissures, thin upper and lower vermilion borders, left-sided facial palsy, and brachydactyly with otherwise mild features. Facial palsy is observed in 4% of individuals with Myhre (more...)

Skeletal

  • Infants typically have intrauterine growth restriction (IUGR)
  • Short stature (height is significantly less than that predicted by parental heights) with compact body habitus
  • Range of motion of the joints can be limited

Radiographic

Findings include the following:

  • Thickened calvarium
  • Shortened long bones
  • Brachydactyly
  • Broad ribs
  • Enlarged vertebrae with shortened pedicles; vertebral fusion
  • Hypoplastic iliac wings

See Figure 6.

Figure 6.

Figure 6.

Radiographs of a female age 14 years A. Thickened calvaria and anterior cervical vertebral fusion (arrow) of C2 and C3.

Establishing the Diagnosis

The diagnosis of Myhre syndrome is established in a proband with characteristic clinical findings and a de novo heterozygous pathogenic variant in SMAD4 detected by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel or single-gene testing) and genomic testing (comprehensive genome sequencing).

Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Persons with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom a specific diagnosis has been elusive are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and radiographic findings suggest the diagnosis of Myhre syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of SMAD4 is performed first. If no pathogenic variant is found, gene-targeted deletion/duplication analysis may be considered; to date, however, no exon or whole-gene deletions have been reported.
  • A multigene panel that includes SMAD4 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of Myhre syndrome has not been considered, genomic testing (comprehensive genome sequencing), when available, is likely to be the diagnostic modality selected. Comprehensive genome sequencing includes exome sequencing and genome sequencing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Myhre Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
SMAD4Sequence analysis 355/55 4
Gene-targeted deletion/duplication analysis 5Unknown 6
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

54 patients summarized by Lin et al [2016] and one patient reported by Bassett et al [2016]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

Myhre syndrome is a multisystem connective tissue disorder involving: the cardiovascular system, respiratory system, gastrointestinal tract, and skin; progressive and proliferative fibrosis that may occur spontaneously or following trauma or surgery, often resulting in significant complications; mild-to-moderate intellectual disability; and behavioral issues in some. Additional findings include distinctive craniofacial features and skeletal involvement.

Myhre syndrome was first described by Myhre et al [1981] in two unrelated males. Since 2011, when heterozygosity for a SMAD4 pathogenic variant was found to be causative, 55 affected individuals with a molecularly confirmed diagnosis of Myhre syndrome have been reported. Lin et al [2016] reported four affected individuals and summarized findings in 50 previously reported individuals [Le Goff et al 2011, Al Ageeli et al 2012, Asakura et al 2012, Caputo et al 2012, Lindor et al 2012, Picco et al 2013, Ishibashi et al 2014, Kenis et al 2014, Michot et al 2014, Hawkes & Kini 2015, Oldenburg et al 2015, Starr et al 2015]. Subsequently Bassett et al [2016] reported one additional affected individual.

Note: Unless otherwise noted, the following findings are reported in Lin et al [2016].

Infancy and progression of findings. In infancy, characteristic facial features are usually present, but more difficult to recognize than in an older child (see Suggestive Findings and Figure 1, Figure 2, Figure 3, Figure 4, Figure 5). Short stature and hearing loss develop over time as well as the highly distinctive (and often severe) findings of Myhre syndrome: joint stiffness, restrictive lung and cardiovascular disease, progressive and proliferative fibrosis, and thickening of the skin.

Cardiovascular. Of 54 individuals with a confirmed molecular diagnosis of Myhre syndrome, 70% had a cardiovascular abnormality including structural heart defects (63%); pericardial disease (17%), restrictive cardiomyopathy (9%), and systemic hypertension (15%).

Cardiovascular abnormalities include the following:

  • Atrial septal defect (4%) and ventricular septal defect (6%)
  • Patent ductus arteriosus (which can be large) (20%)
  • Obstructive defects of the left heart, such as juxtaductal aortic coarctation (15%), long-segment aorta narrowing (6%), aortic valve stenosis (15%), and mitral valve stenosis (2%). These are more common than obstructive defects of the right-side, such as valvar and branch pulmonary artery stenosis [Michot et al 2014, Hawkes & Kini 2015, Starr et al 2015].
  • Peripheral vascular stenoses (in celiac and/or renal arteries) (7%)

Of note, complex congenital heart defects are not observed.

Pericardial disease (reported in 17%) can present as a short-term or recurrent effusion or as chronic or progressive constrictive pericarditis that may require surgical intervention (see Management).

Restrictive cardiomyopathy, a lethal condition, is the least common form of cardiomyopathy in the general population and can be overlooked unless cardiac catheterization documents the characteristic hemodynamics.

While constrictive pericarditis and restrictive cardiomyopathy can present with similar hemodynamics, they differ in pathogenesis and treatment (see Management).

Pulmonary hypertension has been infrequently reported; however, this may reflect limited evaluation and/or bias toward ascertainment and/or reporting of younger patients (as underlying causes of pulmonary hypertension resulting from involvement of the lungs and cardiovascular circulation may evolve with age).

Progressive cardiovascular issues can appear at any age; those with onset in childhood may worsen following instrumentation: two patients with restrictive cardiomyopathy who were treated with heart and heart/lung transplantation did not survive postoperative complications [Starr et al 2015].

Respiratory. Respiratory issues can be multifactorial. Airway stenosis, typically involving the larynx and trachea, has included subglottic stenosis (17%) that can be recurrent and severe. Less common is upper airway obstruction due to choanal stenosis (11%).

Restrictive and obstructive pulmonary disease are major causes of morbidity at all ages. Interstitial lung disease has been described. Severe pulmonary fibrosis has been noted on autopsy [Starr et al 2015].

Gastrointestinal involvement

Cutaneous. Generalized thickening/stiffness of the skin is seen in nearly all individuals with Myhre syndrome. Various terms used to describe the skin include thick, stiff, firm, rough, keratotic, and inelastic. Additional findings are minimal creasing of the facial skin and fibrous and keloid-like scar formation.

Skin changes may not be apparent in infancy; they are often first noted on extensor surfaces, palms, and soles. The changes progress with age.

Neuropsychiatric. Data are limited. Mild-to-moderate intellectual disability and global developmental delay are common; however, cognition can be within the normal range. Of note, acquired and unrecognized hearing loss may also contribute to speech delay and academic and social challenges.

Findings of autism spectrum disorder have been noted in a minority of affected individuals [Michot et al 2014].

Skeletal. The majority of affected infants have intrauterine growth restriction (41/49; 84%). Short stature with compact body habitus (with normal head circumference) becomes more apparent over time. Adult height is expected to be more than two standard deviations below what is predicted by parental heights.

Small hands and feet with brachydactyly is usually notable (see Figure 3, Figure 4, Figure 5).

Posture may be distinct with flexed elbows and bending forward at the hips (see Figure 3 and Ishibashi et al [2014], Figure 1).

Reduced range of motion of large and small joints is characteristic and is exacerbated with age. Walking on tiptoes is common.

Immune system. Recurrent infections (especially otitis media and pneumonia) have been reported in 19 of 34 individuals. Increased susceptibility to infection has been associated with immunoglobulin deficiency in three affected individuals; IVIG was utilized with reported benefit in one affected individual [Starr et al 2015]. At this point, it is unknown if immune deficiency is associated with Myhre syndrome or if it is an incidental finding [Michot et al 2014, Starr et al 2015].

Ophthalmologic. At least one abnormal eye finding was reported in 53% (26/49) of affected individuals:

  • Strabismus 13/53 (24%)
  • Refractive errors in 17/53 (31%)
  • Other. Cataracts, astigmatism, and optic nerve sheath meningioma

Hearing loss is observed in most (83%) individuals with Myhre syndrome.

Hearing loss is predominantly conductive, but can be sensorineural and mixed. The underlying etiology of the hearing loss is often unclear or unknown; most often patients have a history of bilateral myringotomy tube placement.

Of note, most infants pass their newborn hearing screen. In the authors' experience hearing loss usually becomes evident in early childhood and is typically present in adults.

Endocrine. Puberty has been reported to be normal, premature, or delayed. Secondary amenorrhea has been reported.

Neoplasia

Genotype-Phenotype Correlations

The gain-of-function SMAD4 pathogenic variants that cause Myhre syndrome involve only two protein residues (codons 496 and 500). To date, no clear genotype-phenotype correlations are evident in affected individuals with either codon abnormality.

Of note, although the three individuals reported with the p.Arg496C variant do not have cardiovascular involvement and are taller in stature – two on the growth curve (2nd-25th centile) and one <1st centile [Michot et al 2014, Caputo et al 2014] – the data are too limited to draw any conclusions about genotype-phenotype correlations.

Penetrance

Penetrance appears to be complete; however, no familial cases of Myhre syndrome have been reported.

Nomenclature

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

Prevalence

The prevalence is unknown.

Since 2011 when a heterozygous pathogenic variant in SMAD4 was discovered to be the cause of Myhre syndrome, 55 affected individuals with a molecularly confirmed diagnosis have been reported worldwide with no apparent ethnic or sex predilection (54 summarized in Lin et al [2016] and one reported by Bassett et al [2016]).

Differential Diagnosis

The disorders that most closely resemble Myhre syndrome are the other acromelic dysplasias: geleophysic dysplasia, acromicric dysplasia, and Weill-Marchesani syndrome, which share the findings of thickened skin, short stature, short hands, and stiff joints. MULIBREY nanism should also be considered.

Table 2.

Disorders to Consider in the Differential Diagnosis of Myhre Syndrome

DisorderGene(s)MOIClinical Features of the Disorder
Overlapping with Myhre SyndromeDistinguishing from Myhre Syndrome
Acromicric dysplasia
(OMIM 102370)
FBN1AD
  • IUGR
  • Short stature
  • Brachydactyly
  • Joint stiffness
  • Thickened skin
  • Characteristic external notch of the fifth metacarpal and internal notch of the femoral head
  • Absence of hearing loss
  • Less frequent cardiac anomalies
  • Absence of calvarial thickening
Geleophysic dysplasia 1ADAMTSL2AR
  • IUGR
  • Short stature
  • Short hands and feet
  • Progressive joint limitation and contractures
  • Progressive cardiac valvar thickening
  • Thickened skin
  • Hepatomegaly
  • Characteristic facies
FBN1AD
Weill-Marchesani syndrome 2ADAMTS10
LTPBP2
AR
  • IUGR
  • Short stature
  • Brachydactyly
  • Joint stiffness
  • Distinctive lens abnormalities 2
  • Lack of hearing loss
FBN1AD
MULIBREY nanism
(OMIM 253250)
TRIM37AR
  • IUGR
  • Short stature
  • Relatively large head
  • Constrictive pericarditis
  • Restrictive cardiomyopathy
  • Shorter stature
  • Small tongue

IUGR = intrauterine growth restriction

1.

Geleophysic dysplasia. Major findings are likely to be present in the first year of life. Cardiac and respiratory involvement result in death before age five years in approximately 33% of individuals with geleophysic dysplasia 1.

2.

Weill-Marchesani syndrome. The ocular problems, typically recognized in childhood, include microspherophakia (small spherical lens), myopia secondary to the abnormal shape of the lens, ectopia lentis (abnormal position of the lens), and glaucoma, which can lead to blindness.

Management

Evaluations Following Initial Diagnosis

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

Cardiovascular

  • Upper- and lower-extremity blood pressure measurements
  • Two-dimensional echocardiography with Doppler
  • For those with abnormal findings, more extensive imaging if indicated including cardiac catheterization to document the characteristic hemodynamics of restrictive cardiomyopathy

Respiratory

  • Assessment for airway stenosis by the least invasive means possible with assessment for signs of upper-airway obstruction including noisy breathing, work of breathing, and oxygen saturation
  • Assessment of pulmonary function and oxygen saturation for evidence of obstructive or restrictive lung disease

Gastrointestinal. Based on clinical indication (by least invasive means possible), evaluate for evidence of stenosis.

Neuropsychiatric. Neuropsychometric evaluation may be indicated for individuals with autistic behaviors and/or cognitive involvement.

Other

  • Ophthalmology evaluation
  • Speech evaluation
  • Audiology evaluation
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Treatment is largely symptomatic and may include the following.

Cardiovascular

  • Management by a cardiologist trained in congenital heart disease, including pericardial disease and restrictive cardiomyopathy. At present, no evidence suggests that in Myhre syndrome management of specific lesions would differ from standard care in current clinical practice, except that any unnecessary instrumentation should be avoided as associated tissue trauma may induce stenosis and the scarring-type tissue response unique to Myhre syndrome.
  • Affected individuals who are in heart failure should be under the care of a cardiovascular specialist with access to a transplant center.
  • Maximize all medical treatment and minimize instrumentation for all cardiac studies and therapies.
  • Medical treatment of systemic hypertension and pulmonary hypertension (based on underlying cause).

Respiratory

  • Affected individuals have required long-term tracheostomy due to complete and recurrent tracheal stenosis following multiple and/or traumatic intubations [McGowan et al 2011, Oldenburg et al 2015, Starr et al 2015]. To avoid traumatic intubation, consider using a size-smaller uncuffed endotracheal tube. Elective tracheal surgery/intubation should be avoided; tracheal resection is contraindicated [Oldenburg et al 2015].
  • Symptomatic treatment of restrictive lung disease
  • Oxygen supplementation as necessary

Gastrointestinal

  • Minimal instrumentation of the gastrointestinal tract is advised because post-operative adhesions can be fatal [Lindor et al 2012].
  • Endoscopy should be approached with caution to avoid airway manipulation which increases the risk for tracheal/laryngeal scarring/stenosis [Oldenburg et al 2015]. Noninvasive 3D imaging may be preferred.
  • Aggressive management of constipation (through dietary means or medication if necessary) is indicated.

Global developmental delay / intellectual disability educational issues. The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

  • Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the United States, early intervention is a federally funded program available in all states.
  • Ages 3-5 years. In the United States, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.
  • Ages 5-21 years. In the United States, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
  • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
  • All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life. Some issues to consider:
    • Private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • In the United States:
      • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
      • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Social/behavioral issues

  • Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is individualized therapy targeted to each child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
  • Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavioral management strategies or providing prescription medications when necessary.
  • Individualized behavioral therapy or pharmacologic treatment for anxiety, depression, or other psychological manifestations as per current clinical practice is appropriate.

Hearing

Craniofacial

  • Individuals with orofacial clefting or velopharyngeal insufficiency should be referred to a craniofacial clinic with pediatric experience. These individuals benefit most from a multidisciplinary approach to care.
  • A craniofacial clinic associated with a major pediatric medical center usually includes a surgical team (craniofacial surgeon and neurosurgeon), clinical geneticist, ophthalmologist, otolaryngologist, pediatrician, radiologist, psychologist, multiple dental specialists, audiologist, speech therapist, and social worker.

Skeletal

  • Consider physical therapy to keep joints mobile (no study has been done on efficacy). Note: It is not known if passive range of motion exercises help maintain flexibility.
  • A systematic study of growth hormone treatment for short stature has not been done. One affected individual has been noted to have anecdotal improvement in growth velocity; however, it is unknown if adult height would be affected [Starr et al 2015].

Ophthalmology. Routine treatment of strabismus and refractive errors. Note: Complications from surgical repair have not been reported.

Prevention of Secondary Complications

Limiting tissue trauma appears to be the single most important preventive measure: The literature suggests increased risk of proliferative fibrosis following otherwise uncomplicated endotracheal intubation and surgical procedures. 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 post-surgical fibrosis is highly likely.

Surveillance

Cardiovascular

  • After normal baseline evaluations of upper- and lower-extremity blood pressure measurements, two-dimensional echocardiography with Doppler, and cardiology evaluation
  • In asymptomatic individuals with a normal echocardiogram at the time of initial diagnosis, repeat echocardiogram every 1-3 years. Note that pericardial effusion and restrictive cardiomyopathy may occur at any age and may be clinically asymptomatic [Starr et al 2015, Garavelli et al 2016, Lin et al 2016].
  • In individuals with abnormal findings at the time of initial diagnosis, more extensive imaging may be indicated given the progressive nature of the disorder (e.g., MRI to evaluate for pericardial thickening or effusion).

Respiratory

  • Consider oxygen saturation in children, with monitoring as needed for symptoms suggestive of restrictive/obstructive pulmonary disease and annual pulmonary function studies in children older than age six years if able to cooperate with test maneuvers.
  • Evaluation for upper airway stenosis (e.g., laryngotracheal stenosis) should be considered based on symptoms.

Other

  • Annual ophthalmologic and audiology evaluations
  • Monitoring of physical skill development and joint mobility

Agents/Circumstances to Avoid

Patients should be aggressively counseled not to smoke.

Limiting tissue trauma appears to be the single most important preventive concept in this disorder to communicate to all health care providers involved in their care (see Prevention of Secondary Findings).

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Myhre syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

Sibs of a proband. If the SMAD4 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.

Offspring of a proband. To date, individuals with Myhre syndrome are not known to reproduce and fertility has not been assessed.

Other family members. The risk to other family members is presumed to be low given that all probands with Myhre syndrome reported to date have the disorder as a result of a de novo SMAD4 pathogenic variant (i.e., no familial cases of Myhre syndrome have been reported).

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the SMAD4 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at theoretic increased risk and preimplantation genetic diagnosis for Myhre syndrome are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Alexander Graham Bell Association for the Deaf and Hard of Hearing
    3417 Volta Place Northwest
    Washington DC 20007
    Phone: 866-337-5220 (toll-free); 202-337-5220; 202-337-5221 (TTY)
    Fax: 202-337-8314
    Email: info@agbell.org
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    Suite 2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Myhre Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Myhre Syndrome (View All in OMIM)

139210MYHRE SYNDROME; MYHRS
600993MOTHERS AGAINST DECAPENTAPLEGIC, DROSOPHILA, HOMOLOG OF, 4; SMAD4

Molecular Genetic Pathogenesis

Myhre syndrome is caused by a heterozygous SMAD4 gain-of-function pathogenic variant that confers stability on the abnormal SMAD4 protein due to an apparent decrease in monoubiquitination. This disrupts TGFβ signaling, thus altering expression of downstream target genes encoding TGFβ and bone morphogenic proteins (BMP), resulting in abnormal development of the axial and appendicular skeleton, cardiac muscle, and central nervous system [Caputo et al 2012, Le Goff et al 2014].

In contrast, heterozygosity for a loss-of-function SMAD4 pathogenic variant has been well established as the cause of a spectrum of acquired cardiac diseases, including cardiac fibrosis and hypertrophy, aortopathies, atherogenesis, and pulmonary artery hypertension.

Gene structure. The coding exons 2-12 of SMAD4 constitute a 552-residue protein composed of two domains. Exon 1 is noncoding.

Pathogenic variants. The four pathogenic variants reported to date are missense variants that are restricted to residues 496 and 500 (Table 3). No inactivating deletions or duplications have been reported in individuals with Myhre syndrome.

Since 2011, when heterozygosity for a SMAD4 pathogenic variant was found to be causative, 55 affected individuals with a molecularly confirmed diagnosis of Myhre syndrome have been reported. Lin et al [2016] reported four affected individuals and summarized findings in 50 previously reported individuals [Le Goff et al 2011, Al Ageeli et al 2012, Asakura et al 2012, Caputo et al 2012, Lindor et al 2012, Picco et al 2013, Ishibashi et al 2014, Kenis et al 2014, Michot et al 2014, Hawkes & Kini 2015, Oldenburg et al 2015, Starr et al 2015]. Subsequently Bassett et al [2016] reported one additional affected individual.

Table 3.

SMAD4 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.1486C>Tp.Arg496CysNM_005359​.5
NP_005350​.1
c.1498A>Gp.Ile500Val
c.1499T>Cp.Ile500Thr
c.1500A>Gp.Ile500Met

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The three functional classes of SMADs are:

  • SMAD4 that encodes a SMAD protein known as the co-mediator of the SMADs;
  • SMAD1, SMAD2, SMAD3, SMAD5, and SMAD8 that are the receptor-regulated SMADs (or R-SMADs);
  • SMAD6 and SMAD7 that are inhibitory SMADs.

SMAD4 (mothers against decapentaplegic homolog 4) forms heterodimers with the receptor-regulated SMADs, which are translocated to the nucleus of the cell, which then (via an unclear mechanism) regulates the expression of TGBβ and BMP pathway genes.

The 11 coding exons of SMAD4 constitute a 552-residue protein composed of two domains [Shi & Massague 2003, Le Goff et al 2011, Caputo et al 2012]:

  • Mad homology 1 (MH1), which contributes to DNA binding
  • Mad homology 2 (MH2), which activates transcription

Abnormal gene product. Codons 496 and 500 are in the Mad homology 2 domain; pathogenic variants in these codons confer a gain of function to the protein. The work of Le Goff et al [2011] indicated that defective transcriptional regulation during development plays a significant role in the disorder.

Cancer and benign tumors. Although germline SMAD4 loss-of-function (inactivating) pathogenic variants predispose to hamartomatous polyps in the gastrointestinal track (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. See Chen et al [2014] and references therein.

References

Literature Cited

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Chapter Notes

Acknowledgments

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

Revision History

  • 13 April 2017 (bp) Review posted live
  • 11 July 2016 (ljs) Original submission
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