What are the other Names for this Condition? (Also known as/Synonyms)

• Growth Mental Deficiency Syndrome of Myhre
• LAPS Syndrome
• Laryngotracheal Stenosis, Arthropathy, Prognathism, and Short Stature

What is Myhre Syndrome? (Definition/Background Information)

• Myhre Syndrome is an extremely uncommon genetic disorder characterized by several physical abnormalities, often accompanied by impaired intellectual development. Many cases are reported in males
• In majority of cases, spontaneous mutation(s) in the SMAD4 gene cause this disorder. However, it is possible for an affected individual to pass the mutation to his/her child, and hence, a positive family history is a risk factor for developing Myhre Syndrome
• The SMAD4 gene is an integral part of an important signaling pathway, known as the transforming growth factor-β (TGF-β pathway), which modulates several aspects of growth and development. A defective SMAD4 protein interferes with the proper functioning of this pathway, leading to the characteristic symptoms of the disorder
• Symptoms may include growth deficiency, skeletal abnormalities, certain characteristic facial features, stiff joints, abnormalities in formation and function of organs, and intellectual disability
• The diagnosis of Myhre Syndrome may involve a careful physical examination, recurrent clinical evaluations, advanced imaging techniques, and a thorough evaluation of family medical history
• Complications may include impaired movement, difficulty eating or breathing, abnormalities in blood flow, impaired social skills, renal and gastrointestinal system dysfunction, all contributing to a decreased quality of life
• The treatment provided is mostly symptomatic and may include medications, surgery, and physical therapy. The prognosis of Myhre Syndrome is dependent upon the severity of its signs and symptoms. In most cases, a lifelong monitoring of the condition and supportive care is essential

Who gets Myhre Syndrome? (Age and Sex Distribution)

• Myhre Syndrome is an extremely rare disorder, with approximately 30 cases being reported in the scientific literature worldwide
• The disorder manifests at birth (congenital presentation). Both males and females are affected, though many cases are observed in males
• All races and ethnic groups may be affected

What are the Risk Factors for Myhre Syndrome? (Predisposing Factors)

• The risk factors for Myhre Syndrome that arise owing to sporadic gene mutation(s) during conception, are not clearly understood
• However, parents with the disorder may pass on the condition to their children. Under such circumstances, a family history of Myhre Syndrome is a risk factor for being diagnosed with the genetic disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Myhre Syndrome? (Etiology)

Myhre Syndrome is caused by mutation(s) in the SMAD4 gene.

• Under normal circumstances, the SMAD4 gene codes for the SMAD4 protein
  • This protein interacts with other cellular proteins to regulate the function of certain genes, which are involved in growth and development
  • SMAD4 protein is ubiquitous and is an integral part of the transforming growth factor-β (TGF-β) signaling pathway. This pathway modulates cellular function and proliferation, based on conditions outside the cells
• When the SMAD4 gene is mutated, the resultant aberrant protein may
  • Be absent
  • Not interact efficiently with other proteins
  • Remain stable for longer durations than normal
• The aberrant protein leads to improper transmission of chemical cues in cells, leading to abnormalities in cellular growth and development
• In most reported cases, SMAD4 mutation(s) arise spontaneously during conception, with neither parent being affected by Myhre Syndrome. The exact cause of these mutations, in such cases, is not known

However, affected individuals may pass on the syndrome to their children. In such cases, the condition is inherited in an autosomal dominant manner. In this type of inheritance, a single copy of the defective, causative gene in every cell of an individual’s body is sufficient to cause the disorder. The child inherits the disorder from an affected parent.

What are the Signs and Symptoms of Myhre Syndrome?

The signs and symptoms of Myhre Syndrome may vary widely in type and severity, and may include the following:

• Growth deficiency, which may begin prenatally (before birth)
• Low birth weight
• Characteristic facial features such as:
  • Narrow upper and lower eyelid folds
  • Underdeveloped upper jaw; prominent jaw
  • Short upper lip groove
  • Cleft palate
  • Underdeveloped portions of the middle face
  • Thin lips, narrow mouth
  • Drooping of eyes or ears; small ears
• Progressive narrowing of the trachea and/or larynx, which can lead to loud breathing, coughing, or respiratory insufficiencies
• Narrowing of the pulmonary arteries
• Hearing loss affecting both ears (bilateral)
• Chronic nasal passage blockage by tissue
• Farsightedness, astigmatism, strabismus (crossed eyes)
• Mild/moderate intellectual disabilities
• Failure to achieve certain developmental milestones
• Behavioral abnormalities
• Skull bones may be abnormally thick; wide ribs; underdeveloped hip bone
• Narrow, short, and rounded long bones (bones of the arm and leg); stiff joints
• Short stature
• Webbed hands or feet, fingers fixed in a bent position; short fingers and/or toes
• Enlarged vertebrae
• Abnormally large muscles in early childhood
• Progressive skin thickening or hardening
• Congenital heart defects (present at birth)
• Inflammation, swelling, or tightening of the sac around the heart
• High blood pressure
• Absence of a kidney
• Chronic constipation
• Puberty occurring either early or late
• Absence of or light menstruation in females
• Failure of the testes to descend into the scrotum in males

How is Myhre Syndrome Diagnosed?

The diagnosis of Myhre Syndrome may be undertaken through the following tests and exams:

• Complete physical examination and careful evaluation of the individual’s family/medical history
• Assessment of symptoms: Recurrent clinical evaluations to determine the extent of symptoms, such as intellectual disabilities
• X-rays to identify skeletal abnormalities
• Imaging techniques, such as echocardiography, to examine the extent of heart defects during infancy and adulthood

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Myhre Syndrome?

The possible complications associated with Myhre Syndrome include:

• Impaired movement
• Diminished academic performance
• Impaired social skills
• Chronic pain
• Decreased quality of life
• Potentially fatal complications include:
  • Difficulty eating or breathing
  • Acute or chronic impairment in blood flow
  • Impaired renal and gastrointestinal function

How is Myhre Syndrome Treated?

The treatment for Myhre Syndrome vary depending on the type and severity of symptoms, and overall health of the affected individual. It may require a coordinated effort by several specialists, and may be directed towards addressing specific symptoms.

The treatment measures may include:

• Surgery to repair skeletal malformations
• Placement of a feeding tube directly into the stomach, when chewing difficulties exist
• Medications, especially for the treatment of pain
• Physical therapy to improve muscle tone and range of movement
• Correctional lenses for vision-related abnormalities
• Special educational services to ensure that the affected individual reach their maximum intellectual potential

How can Myhre Syndrome be Prevented?

Myhre Syndrome is a genetic disorder; presently, there are no guidelines or methods available for preventing the disorder.

• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as Myhre Syndrome
• Regular medical screening at periodic intervals with tests and physical examinations are recommended

What is the Prognosis of Myhre Syndrome? (Outcomes/Resolutions)

• The prognosis of Myhre Syndrome is determined by the type and severity of symptoms in the affected individual, as well as his/her overall health status
• The disorder may require lifelong monitoring to address symptoms and avoid complications
• With proper support and management, individuals with the syndrome can lead a fulfilling life
• However, there exists an increased risk for respiratory and cardiovascular complications in the affected individuals, which can even be fatal

Additional and Relevant Useful Information for Myhre Syndrome:

Currently, Myhre Syndrome is not a well-understood disorder, due to its extreme rarity.