NORD gratefully acknowledges Angela E. Lin, MD, Medical Genetics, MassGeneral Hospital for Children, Co-Director Myhre Syndrome Clinic, for assistance in the preparation of this report.
Myhre syndrome is a rare, but increasingly diagnosed genetic disorder characterized by short stature, characteristic facial features, distinctive heart and aorta problems, mild to moderate intellectual disability, autism/autistic-like behavior, and various bone and joint abnormalities. The familiar facial features are often mild in very young children, but present in almost all individuals. These include a small narrow eye opening (blepharophimosis, short palpebral fissure), flat facial profile (maxillary hypoplasia), and a relatively prominent nose. The chin is small in young children, but over time, there is often a prominent jaw (prognathism). Other findings include hearing impairment, short fingers and toes (brachydactyly), muscles that appear abnormally large (muscular pseudohypertrophy), joint stiffness, and narrowing (stenosis) of the voice box (larynx) and windpipe (trachea). Abnormalities of the heart structure (congenital heart defects), heart muscle (cardiomyopathy) and pericardium are common and distinctive. A risk for certain types of cancer is recognized. Myhre syndrome is caused by mutations (pathologic variants) in the SMAD4 gene. It was thought that all molecularly proven cases were due to a de novo mutation (a new gene change that arises around the time of conception, not carried by the parents). However, it has been reported that Myhre syndrome can be transmitted from parent to child. A person with Myhre syndrome would have a 50-50 chance of transmitting this to each child.
Myhre syndrome was first described in two unrelated males in 1981 by Drs. Myhre, Ruvalcaba and Graham. In 1998, the first of a series of papers reported on a similar condition consisting of (L)aryngotracheal stenosis (A)rthropathy, (P)rognathism, (S)hort stature syndrome (LAPS), that was recognized to be the same as Myhre syndrome (Hopkins et al., 1998; Lindor et al., 2002, 2009 and 2012). It was proven that both disorders had the same mutation in the same gene (SMAD4). This was viewed as different expression (variants) of the same disorder. Part of the variable expression of Myhre syndrome is related to the age of diagnosis. Of the four variants in SMAD4, it is not yet known whether there are correlations between the specific variant and clinical features.
Although researchers have been able to describe a recognizable syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified patients and the lack of large clinical studies prevent physicians from developing a complete picture of associated symptoms and prognosis. No other genes have been identified to cause Myhre syndrome. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below and that every patient is unique. Parents of affected children and adults with Myhre syndrome should talk to their primary care physician and medical team about their specific case, associated symptoms and overall prognosis.
Growth deficiency is a common finding and usually occurs before birth (prenatally), often resulting in low birth weight. Growth deficiencies continue after birth and most children are shorter than would be expected for age (short stature). Puberty has occurred early in some patients, while in others it has been delayed. Affected females may experience absence of menstruation (amenorrhea), irregular menstruation, or early-onset heavy menstruation. Affected males may experience failure of the testes to descend into the scrotum (cryptorchidism). Some have premature puberty.
Most affected infants and children have distinctive facial features including eyes which are small and narrow (blepharophimosis, short palpebral fissure), underdeveloped midfacial structures (maxillary hypoplasia), and prominent nose. The jaw can be small in childhood, but is usually prominent later in life and occasionally pointed (prognathism). Affected individuals may also have a shorter than normal groove in the upper lip (philtrum), thin lips, an unusually narrow mouth, and small ears.
The airway can be affected at various levels such as narrowing or blockage of the nasal airway by tissue (choanal atresia). Further down, there can be progressive narrowing of the larynx and trachea, a condition known as laryngotracheal stenosis. This results in noisy breathing (stridor), a loud cough (croup) and respiratory insufficiency sometimes requiring oxygen or breathing tubes (tracheostomy). Without treatment, laryngotracheal stenosis can cause life-threatening complications; the condition can recur after treatment. The risk for this condition appears to increase with age and it usually presents in adolescence or young adulthood.
In a few affected individuals, the trachea itself and the branches can be narrowed because of the accumulation of tissue. The lungs may be unable to take in enough air for the affected person to breathe properly (bronchopulmonary insufficiency). This condition may result from obstructive or restrictive disorders of the respiratory system or due to narrowing (stenosis) of the pulmonary arteries. Bronchopulmonary insufficiency can potentially cause life-threatening breathing difficulties. In addition, the rib cage is often stiff which limits breathing.
Most individuals with Myhre syndrome develop hearing loss. In some, it is due to the accumulation of wax-like material or from recurrent ear infections. This prevents sound waves from being conducted through the middle ear (conductive hearing loss). Other individuals may have hearing loss due to an impaired ability of the auditory nerves to transmit sensory input from the ears to the brain (sensorineural hearing loss). A few patients have abnormal inner ear structures (dysplasia). Hearing loss can also be mixed, which means individuals have a combination of conductive and sensorineural hearing loss. Most patients have either conductive or mixed. Hearing loss usually affects both ears (bilateral), although the degree of severity varies from one person to another. Narrowing of the tear ducts can occur, but may not be diagnosed as such. Instead there may be persistent tearing or puffiness of the eyes.
Developmental delays occur in all people with Myhre syndrome. Mild to moderate intellectual disability occurs in most people. Behavioral abnormalities including difficulties with social interactions, poor communication skills, hyperactivity, stubbornness, and/or repetitive behaviors are common. Many patients are considered to be on the autism spectrum.
Several skeletal abnormalities have been described in individuals with Myhre syndrome. Bones of the skull (calvaria) may be abnormally thick, but this does not harm a person. The ribs may be abnormally broad and wide, and the upper portions of the hip bone may be underdeveloped (hypoplastic iliac wings). The long bones of the body (i.e., those in the arms and legs) may be unusually narrow, round (tubular) and short. The fingers and toes may be short (brachydactyly). Webbing (syndactyly) of the hands and feet, fifth fingers that are curved inward (clinodactyly), and fingers which are stiff and contracted (camptodactyly) are also common findings. Joint involvement is also common and affected individuals may experience stiff joints eventually resulting in limited mobility of small or large joints that may increase with age.
In early childhood, certain muscles may look abnormally large (muscular pseudohypertrophy), especially those of the arms and legs, giving affected individuals a muscular appearance. Progressive stiffening or thickening of the skin may also be noticeable and is quite common. Scars may thicken.
Affected individuals may have an increased susceptibility to infections, particularly of the ears and lungs. Narrowing of the airways and the anatomy of the ear may predispose individuals to respiratory and ear infections.
Most people with Myhre syndrome have at least one problem involving the heart or aorta. These can be very mild or occasionally severe. Congenital heart defects are structural problems that are usually present at birth. Later in life there can be pericarditis which involves tightening, or inflammation of the sac around the heart. Pericarditis can be recurrent and progress to cause life-threatening complications and may be associated with pleural effusion (fluid buildup in the chest cavity outside of the lungs). The aorta can have areas of narrowing (stenosis, coarctation). High blood pressure (hypertension) can be present.
Less common signs and symptoms include cleft palate, cleft lip, and drooping of the upper eyelids (ptosis). Intestinal problems include chronic constipation, which can lead to inability to be toilet trained. There can be obstruction of the duodenum and pylorus. Renal abnormalities include absence (agenesis) of a kidney or obstruction (hydronephrosis). Eye (ophthalmologic) abnormalities are common and include refraction abnormalities such as an inability to focus on objects which are close (hypermetropia or farsightedness) or an imperfection in the curvature of the eye leading to blurred vision (astigmatism); less often, there can be crossing of the eyes (strabismus) or cataracts at a young age. Rarely, the optic nerves at the back of the eye can appear enlarged (pseudopapilledema).
Myhre syndrome is caused by a gain-of-function mutation (pathogenic variant) in the SMAD4 gene. It is the only gene known to cause the disorder. Genes provide instructions for creating (encoding) proteins that play a critical role in many functions of the body. When a mutation occurs, the protein product of the gene may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
The SMAD4 gene contains instructions for creating (encoding) a protein that is expressed throughout the developing fetus and in most adult tissue and cell types. Mutations in the SMAD4 gene lead to insufficient levels of working (functional/normal) copies of the protein. Because this protein is expressed throughout the body (ubiquitously), this accounts for the widespread and varied symptoms that are potentially associated with Myhre syndrome.
Until recently, all reported mutations have occurred as new (sporadic or de novo) mutations, which means that in these patients, the gene mutation occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. However, a family with an affected mother and two affected children was reported in Belgium (Meerschaut et al., 2019). We know now that an affected individual (at least with the variant in the reported family) could potentially pass on the gene that causes Myhre syndrome in an autosomal dominant manner.
Genetic diseases are determined by two genes, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual (as described above). The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
Myhre syndrome is an extremely rare inherited disorder that, in theory, affects males and females in equal numbers. Fewer than 100 patients have been reported in the medical literature, but cases are being steadily published. Because some cases of Myhre syndrome most likely go undiagnosed or misdiagnosed, determining the true frequency of the disorder in the general population is difficult.
A provisional clinical diagnosis of Myhre syndrome is usually confirmed on the basis of a thorough clinical evaluation, identification of characteristic physical findings, a detailed patient history, and/or specialized tests (particularly advanced imaging techniques). All patients must have molecular genetic testing which is rarely done as a targeted gene analysis (for SMAD4). Currently, testing is performed as either whole exome sequencing (WES) analysis or using a panel of genes related to intellectual disability and autism.
Developmental delays which typically present in some form in infancy and into the toddler years persist. Intellectual disability may not be detected until the child is in school and old enough to participate in clinical testing. Clinical evaluation, ideally a neuropsychologic evaluation, should be conducted early in development and on a continuing basis to help determine the presence and extent of certain findings such as intellectual disability and behavioral issues which are on the autism spectrum. Such evaluations can help ensure that appropriate steps are taken to help affected individuals reach their potential. It is important to emphasize that the vast majority of people living with Myhre syndrome are active and engaged in social activities. They can make progress living with their challenges. A small number of adults have married, others have jobs.
Characteristic facial features, and/or heart defects may also be present at birth. X-ray testing (skeletal survey) may be used to identify skeletal malformations which are usually mild. A baseline echocardiogram and complete cardiology consultation is essential for all patients at time of diagnosis and may help to determine the exact nature of heart defects. This should be repeated on a regular basis (every 1-2 years) since some features can progress, but the exact schedule is determined by the cardiologist.
Growth delay, abnormally stiff joints, and hearing impairment may not become obvious until late infancy or early childhood. Periodic testing of an infant’s or child’s hearing is essential to detect any loss in hearing capability.
The treatment of Myhre syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment requires the coordinated efforts of a team of specialists. Pediatricians are key to providing standard health maintenance (including vaccinations). Primary care providers need the insights of specialists. These include orthopedic specialists and rheumatologists who treat skeletal and joint problems, cardiologists who diagnose and treat disorders of the heart, otolaryngologists and pulmonologists who assess and treat ear, nose, airway and lung disorders, audiologists who assess and treat hearing problems, ophthalmologists who assess and treat eye disorders. Other specialists may be needed for skin problems (dermatologists), puberty issues (endocrinologists), kidney problems (nephrologists). To evaluate and treat problems related to development, behavior and school, neuropsychologists, speech pathologists, physical therapists and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.
Genetic counseling is recommended for affected individuals and their families. There should be a care coordinator to assist the primary care physician, a role which is often performed by the medical geneticist.
As it appears that individuals with Myhre syndrome are susceptible to development of excessive scar tissue (fibrosis) related to tissue injury which might be related to surgery. Efforts should be made to avoid anything but the most necessary of invasive interventions, including endoscopic procedures. As needed, anesthesiologists should use the smallest sized endotracheal tube.
There are no standardized treatment protocols or evidence-based guidelines for affected individuals. The recommendations in GeneReviews (Starr, Lindor and Lin) provide pragmatic guidance. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with Myhre syndrome.
Certain abnormalities (e.g., small mouth with narrow palate, syndactyly, congenital heart defects, cleft palate or lip, duodenal atresia, pyloric stenosis, and/or cryptorchidism) may require surgical intervention. Affected infants should be evaluated for choanal atresia which can be fixed by surgery and has led to improved feeding. Other conditions that can be treated surgically include scoliosis, congenital cataracts and hypospadias.
Laryngotracheal stenosis may require surgical treatment; however, the condition may recur after successful treatment. In affected individuals who require a tube to be inserted into the windpipe to assist breathing (as might be needed when undergoing anesthesia), special care must be taken because of the risk of developing laryngotracheal stenosis. Ultimately, affected individuals may require a tracheostomy in which a tube is surgically implanted through a cut in the throat to allow direct access to the windpipe.
Some individuals with Myhre syndrome may have difficulty swallowing and/or feeding. In some patients, this may necessitate placing a tube through a small insertion in the abdominal wall and directly into the stomach (gastrostomy tube). It is not known if there is an immune deficiency in Myhre syndrome. As indicated, appropriate immunologic tests should be conducted with consultation from an immunologist.
Early intervention is important to ensure that children with Myhre syndrome reach their potential. Special services that may be beneficial include special remedial education, special social support, physical therapy, and other medical, social, and/or vocational services. Long-term follow up and regular clinical evaluation of affected individuals is required to detect specific symptoms or complications potentially associated with Myhre syndrome. Applied Behavioral Analysis (ABA) has been reported by providers and families to be of great help, although this has not been formally studied. When possible, it should be included.
Females who have early onset puberty and menstruation, and those who had heavy, painful periods, should be evaluated by a gynecologist. Although endometrial cancer and some forms of brain tumor have been reported, cancer remains a rare event and surveillance has not been addressed. Affected females have specific requirements for follow up because of abnormalities involving the beginning of puberty and possible early development of menopause.
One patient with Myhre syndrome received treatment with anakinra for recurrent pericarditis. Anakinra is a drug that is an interleukin-1 receptor antagonist (i.e. it blocks the activity of interleukin-1). Interleukin-1 is a cytokine, a specialized protein secreted from certain immune cells that either stimulate or inhibit the function of other immune system cells. Interleukin-1 is known to mediate cell response to inflammation. Patients with Myhre syndrome and high blood pressure have been treated with losartan which is suitable for this particular pathway; there are no indications to use it for prevention.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For more information about clinical trials conducted in Europe, contact:
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., short stature, intellectual disability, etc.].)
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