Myhre syndrome (LAPS syndrome) - SMAD4 gene
Myhre syndrome or LAPS syndrome (laryngotracheal stenosis, arthropathy, prognathism and short stature) is a disorder that affects many systems and functions of the body. Associated signs and symptoms may include delayed development of language and motor skills; mild to moderate intellectual disability; behavioral problems such as autism or disorders that affect communication and social interaction; hearing loss due to sensorineural deafness, conductive hearing loss, or mixed hearing loss; stunted growth; and skin stiffness. Regarding the skeletal abnormalities associated with this disease, these include thickening of the skull bones, platyspondyly, wide ribs, hypoplastic iliac wings, brachydactyly and arthropathy.
Other associated features include short palpebral fissures, short nasolabial fold, midface hypoplasia, a small mouth with a thin upper lip, prognathism, cleft palate, and cleft lip. Additionally, affected individuals may develop laryngotracheal stenosis, hypertension, interstitial lung disease, restrictive lung disease, cardiac or ocular abnormalities, and, in males, cryptorchidism. A condition sometimes referred to as laryngotracheal stenosis, arthropathy, prognathism, and short stature syndrome (LAPS) is generally regarded as the same disease as Myhre syndrome because it has similar symptoms and the same genetic cause.
This process is due to mutations in the SMAD4 gene (SMAD family member 4), located on the long arm of chromosome 18 (18q21.1). This gene encodes a protein involved in the transmission of chemical signals from the cell surface to the nucleus. This signaling pathway, called the transforming growth factor beta (TGF-β) pathway, allows the environment outside the cell to affect the way the cell encodes other proteins. The signaling process begins when TGF-β activates the Smad group of proteins. Smad proteins bind to specific areas of DNA where the activity of certain genes is controlled and regulates cell growth and division. By controlling the activity of the SMAD4 gene and regulating cell division, the protein serves as both a transcription factor and a tumor suppressor.
At least 5 mutations in the SMAD4 gene have been identified in people with Myhre syndrome. Each of these mutations affects the isoleucine amino acid at position 500 of the protein by replacing it with a different amino acid. These genetic changes are likely to adversely affect the protein´s ability to bind properly with the other Smad proteins and other proteins involved in the signaling pathway. Other studies have suggested that these mutations lead to an unstable SMAD4 protein that remains active in the cell longer. Changes in the SMAD4 junction or its availability can cause abnormal signaling in many cell types, affecting the development of many body systems and leading to the signs and symptoms of Myhre syndrome.
This disease is inherited in an autosomal dominant pattern, which means that one copy of the altered gene in each cell is sufficient to express the disease. Most cases of Myhre syndrome are due to new mutations in the gene that occur during the formation of reproductive cells or early embryonic development. These cases occur in people with no history of the disease in their family.
Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Myhre syndrome, by means of the complete PCR amplification of the exons of the SMAD4 gene, and their subsequent sequencing.
Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).