Myhre syndrome is a rare genetic disorder inherited in an autosomal dominant fashion. It is caused by mutation in SMAD4 gene. Signs and symptoms
The clinical presentation is variable but includes
developmental and growth delay
athletic muscular built
skeletal anomalies
joint stiffness
characteristic facial appearance
deafness
variable cognitive deficits
tracheal stenosis
aortic stenosis
pyloric stenosisThe facial abnormalities include:

blepharophimosis (an abnormally narrow gap between the upper and lower eyelids)
maxillary hypoplasia (underdevelopment of the upper jaw)
prognathism (prominent lower jaw)The skeletal abnormalities include:

short stature
square body shape
broad ribs
iliac hypoplasia
brachydactyly
flattened vertebrae
thickened calvariaCongenital heart disease and undescended testes have also been reported in association with this syndrome. Genetics
Myhre syndrome is due to mutations in the SMAD4 gene. This gene encodes a protein - transducer mediating transforming growth factor beta. Some researchers believe that the SMAD4 gene mutations that cause Myhre syndrome impair the ability of the SMAD4 protein to attach (bind) properly with the other proteins involved in the signaling pathway. Other studies have suggested that these mutations result in an abnormally stable SMAD4 protein that remains active in the cell longer. Changes in SMAD4 binding or availability may result in abnormal signaling in many cell types, which affects development of several body systems and leads to the signs and symptoms of Myhre syndrome.The patients of this disease exhibit hypertrophic phenotype in their muscle tissues. Myostatin target genes are found to be downregulated while bone morphogenetic protein (BMP) target genes display both upregulated and downregulated genotypes. Diagnosis
Treatment
History
This disorder was first reported in 1981. It has many similarities to LAPS Syndrome and they both arise from the same mutations in the SMAD4 gene.
Tepotinib, sold under the brand name Tepmetko, is a medication used for the treatment of adults with non-small cell lung cancer (NSCLC).Tepotinib first received marketing approval in Japan, in March 2020, as a "line-agnostic" drug, meaning it is approved both for treatment-naive patients and for those in whom previous attempts at treatment have failed. U.S. approval followed in February 2021. It is the second therapy approved by the U.S. Food and Drug Administration (FDA) to treat non-small cell lung cancer with these particular mutations, after capmatinib. Medical uses
Tepotinib is indicated for the treatment of adults with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping. Adverse effects
The most common side effects seen in clinical trials were edema, fatigue, nausea, diarrhea, muscle aches, and shortness of breath. Like capmatinib, tepotinib can also cause interstitial lung disease and liver damage, and is toxic to a developing fetus. The most common treatment-related adverse effect in a 2021 study were peripheral edema (54.1%), nausea (20.0%), diarrhea (19.6%), blood creatinine increased (17.6%), and hypoalbuminemia (14.5%), which were mostly mild or moderate. Society and culture
Legal status
On 16 December 2021, the Committee for Medicinal Products for Human Use (CHMP)  of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Tepmetko, intended for the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring alterations leading to mesenchymal-epithelial transition factor gene exon 14 (METex14) skipping.