Y279C, T468M, A461T, G464A, and Q510P which seems to be a unique familial mutation, in that all other variants are caused by transition errors, rather than transversion. Treatment
It is suggested that, once diagnosed, individuals be routinely followed by a cardiologist, endocrinologist, dermatologist, and other appropriate specialties as symptoms present. It is recommended that those with the syndrome who are capable of having children seek genetic counseling before deciding to have children. As the syndrome presents frequently as a forme fruste (incomplete, or unusual form) variant, an examination of all family members must be undertaken. As an autosomal dominant trait there is a fifty percent chance with each child that they will also be born with the syndrome. Although fully penetrant, since the syndrome has variable expressivity, one generation may have a mild expression of the syndrome, while the next may be profoundly affected. Once a decision to have children is made, and the couple conceives, the fetus is monitored during the pregnancy for cardiac evaluation. If a gross cardiac malformation is found, parents receive counseling on continuing with the pregnancy. Other management is routine care as symptoms present:
For those with endocrine issues (low levels of thyrotopin [a pituitary hormone responsible for regulating thyroid hormones], follicle stimulating hormone) drug therapy is recommended. For those who are disturbed by the appearance of lentigines, cryosurgery may be beneficial. Due to the large number of lentigines this may prove time-consuming. An alternative treatment with tretinoin or hydroquinone creams may help.
Additional dermatologic abnormalities (axillary freckling, localized hypopigmentation, interdigital webbing, hyperelastic skin)
Mild mental retardation is observed in about 30% of those affected by the syndrome
Nystagmus (involuntary eye movements), seizures, or hyposmia (reduced ability to smell) has been documented in a few patients
In 2004, a patient was reported with recurrent upper extremity aneurysms that required surgical repairs. In 2006, a NSML patient was reported with acute myelogenous leukemia.Due to the rarity of the syndrome itself, it is hard to determine whether certain additional diseases are actually part of the syndrome. With a base population of possibly less than one thousand individuals, one or two outlying cases can skew the statistical population very quickly. Pathophysiology
In the two predominant mutations of NSML (Y279C and T468M) the mutations cause a loss of catalytic activity of the SHP2 protein (the gene product of the PTPN11 gene), which is a previously unrecognized behavior for this class of mutations. This interferes with growth factor and related signalling. While further research confirms this mechanism, additional research is needed to determine how this relates to all of the observed effects of NSML. Diagnosis
The presence of the disease can be confirmed with a genetic test. In a study of 10 infants with clinical indications of NSML prior to their first birthday, 8 (80%) patients were confirmed to have the suspected mutation. An additional patient with the suspected mutation was subsequently found to have NF1, following evaluation of the mother.There are 5 identified allelic variants responsible for NSML.