NORD gratefully acknowledges Noralane M. Lindor, MD, Mayo Clinic, Department of Health Sciences Research, Scottsdale, Arizona for assistance in the preparation of this report.
Myhre syndrome is an extremely rare genetic disorder characterized by short stature, characteristic facial features, mild to moderate intellectual disability and various bone (skeletal) abnormalities. Characteristic facial features may include abnormally narrow skin folds (palpebral fissures) between the upper and lower eyelids (blepharophimosis), underdevelopment of the upper jaw bone (maxillary hypoplasia), and an unusually prominent jaw (prognathism). Other findings may include hearing impairment, short fingers and toes (brachydactyly), congenital heart defects, muscles that appear abnormally large (muscular pseudohypertrophy), joint stiffness, and narrowing (stenosis) of the voice box (larynx) and windpipe (trachea). Myhre syndrome is caused by mutations in the SMAD4 gene. All molecularly proven cases have been due to a de novo mutation (a new mutation that arises around the time of conception, not carried by the parents). A person with Myhre syndrome would have a 50-50 chance of transmitting this to each child.
Myhre syndrome was first described in the medical literature in 1981 by Drs. Myhre, Ruvalcaba and Graham. In 1998, Hopkin et al., reported on a condition that in 2002 would be termed (L)aryngotracheal stenosis (A)rthropathy, (P)rognathism, (S)hort stature syndrome or LAPS by Lindor et al. Researchers eventually learned that Myhre and LAPS syndromes were caused by mutations in the same gene and are different expressions (variants) of the same disorder at different ages.
Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below and that every case is unique. Parents should talk to their children’s 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 cases, while in others it has been delayed. Affected girls may experience absence of menstruation (amenorrhea) or infrequent or light menstruation (oligomenorrhea). Affected males may experience failure of the testes to descend into the scrotum in males (cryptorchidism).
Most affected infants and children have distinctive facial features including include upper and lower eyelid folds (palpebral fissures) that are narrower than normal (blepharophimosis), underdevelopment of the upper jawbone (maxillary hypoplasia), an unusually prominent jaw (prognathism), and underdevelopment of the middle of the face (midface hypoplasia). Affected individuals may also have a shorter than normal groove in the upper lip (philtrum), thin lips, an unusually narrow mouth, and small ears.
Some affected individuals experience progressive narrowing of the larynx and trachea, a condition known as laryngotracheal stenosis. This condition can cause noisy breathing (stridor), a loud cough (croup) and respiratory insufficiency sometimes needing 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 some affected individuals, the bronchial tubes and the lungs may be unable to take in enough air in order 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.
Some individuals may develop hearing loss. Some individuals have hearing loss due to the failure of sound waves to be 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). Hearing loss can also be mixed, which means individuals have a combination of conductive and sensorineural hearing loss. Most cases are either conductive or mixed. Hearing loss usually affects both ears (bilateral), although the degree of severity varies from one person to another.
Mild to moderate intellectual disability has been reported and, in some cases, affected infants and young children may experience delays in reaching developmental milestones. Behavioral abnormalities including difficulties with social interactions, poor communications skills, hyperactivity, stubbornness, and/or repetitive behaviors have also been described.
Several skeletal abnormalities have been described in individuals with Myhre syndrome including bones on top of the skull (calvaria) may be abnormally thick. 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, and fifth fingers that are fixed in a bent position (clinodactyly) are also common findings. In some affected individuals, the bones that surround the spinal cord (vertebrae) may be unusually large. Joint disease is also a common finding 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.
Affected individuals may have an increased susceptibility to infections, particularly of the ears and lungs. Children are particularly prone to recurrent infections. Narrowing of the airways and the anatomy of the ear may predispose individuals to respiratory and ear infections.
In some cases, affected individuals may exhibit additional symptoms including abnormalities of the heart that are present at birth (congenital heart defects), swelling, tightening, or inflammation of the sac around the heart (pericarditis), and high blood pressure (hypertension). Pericarditis can be recurrent and progress to cause life-threatening complications.
Less common signs and symptoms include cleft palate, cleft lip, drooping of the upper eyelids (ptosis), and intestinal or renal abnormalities such as chronic constipation or absence (agenesis) of a kidney. Narrowing or blockage of the nasal airway by tissue (choanal atresia) has been reported in rare cases and can contribute to breathing difficulties and susceptibility to respiratory infections. Eye (ophthalmologic) abnormalities can develop including refraction abnormalities such as an inability to focus on close up objects (hypermetropia or farsightedness) or an imperfection in the curvature of the eye leading to blurred vision (astigmatism) and, less often, crossed eyes (strabismus) or cataracts at young ages.
Myhre syndrome is caused by a mutation 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.
All reported mutations have occurred as new (sporadic or de novo) mutations, which means that in these cases the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not thought to be inherited from or “carried” by a healthy parent. Affected individuals 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.
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.
Myhre syndrome is an extremely rare inherited disorder that, in theory, affects males and females in equal numbers. More than 60 cases have been reported in the medical literature. 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 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).
Intellectual disability may present at birth, but is usually not detected until the infant is old enough to respond to clinical testing. Clinical 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. Such evaluation can help ensure that appropriate steps are taken to help affected individuals reach their potential.
Characteristic facial features, skeletal malformations, and/or heart defects may also be present at birth. Specialized X-ray tests may be used to identify skeletal malformations. Advanced imaging techniques (e.g., echocardiogram) may help to determine the exact nature of heart defects.
Growth retardation, 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. In early childhood, muscle enlargement (muscular pseudohypertrophy) may also be observed.
The treatment of Myhre syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who diagnose and treat skeletal disorders (orthopedists), specialists who diagnose and treat disorders of the heart (cardiologists), specialists who assess and treat airways and lung disorders (otolaryngologists and pulmonologists), specialists who assess and treat hearing problems (audiologists), specialists who assess and treat eye disorders (ophthalmologists), speech pathologists, physical therapists and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling will be of benefit for affected individuals and their families.
As it appears that individuals with Myhre syndrome are susceptible to development of excessive scar tissue (fibrosis) related to tissue injury such as from surgery, efforts should be made to avoid anything but the most necessary of invasive interventions, including endoscopic procedures.
There are no standardized treatment protocols or guidelines for affected individuals. 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., malformation of the jaw, syndactyly, congenital heart defects, cleft palate or lip, 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 difficulties swallowing and/or feeding. In some cases, this may necessitate placing a tube through a small insertion in the abdominal wall and directly into the stomach (gastrostomy tube).
Early intervention is important to ensure that children with Myhre syndrome reach their potential. Special services that may be beneficial to affected children may 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. Basic immunologic tests should be conducted to detect possible immunodeficiency, specifically humoral immunodeficiencies. Humoral immunity affects the differentiation of certain white blood cells (B cells) and the production of antibodies.
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.
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
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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