Noonan syndrome with multiple lentigines: Have you heard of this disorder before?

About 70% of cases of the Noonan syndrome with multiple lentigines have a family history. It can also result from a new mutation. Read on to know more about this rare genetic disorder.

By: Longjam Dineshwori | | Updated: November 18, 2020 9:04 am

NSML affect males and females in equal numbers.

Noonan syndrome with multiple lentigines (NSML), formerly known as LEOPARD syndrome, is a very rare genetic disorder that is characterised by abnormalities of the skin, heart, ear, genital, head and facial area. Affected individuals may have brown “freckle-like” spots called lentigines that are similar to freckles, heart defects, widely spaced eyes (ocular hypertelorism), a sunken chest (pectus excavatum) or protruding chest (pectus carinatum), and short stature. However, the range and severity of symptoms and physical characteristics may vary from person to person. Also Read - Researchers discover role of mutation in blood cancers

Know the causes of NSML

NSML is caused by mutation in one of two genes: PTPN11 (protein-tyrosine phosphatase, nonreceptor type 11) or RAF1 (a protein coding gene). The mutations in these genes lead to dysregulation of cell division and differentiation. Abnormalities in these genes also cause a different genetic condition called Noonan syndrome. Also Read - Father's X chromosome holds clues to autoimmune disease in women

Majority of the individuals with NSML have a mutation in the PTPN11 gene (approximately 75%), while 10% have mutations in the RAF1 gene. Mutations in BRAF and MAP2K1 genes, belonging to the same molecular pathway as PTPN11 and RAF1, are also implicated, but such cases are rare. Also Read - Researchers identify gene that can alleviate fear and increase social interaction ability

One can inherit the abnormal gene from either parent, or it can be the result of a new mutation (gene change) in the affected person. If one parent is affected there is a 50% chance of passing the abnormal gene to each child. About 70% of cases have a family history, others are sporadic cases occurring from new mutations. NSML affect males and females in equal numbers.

Signs & Symptoms of NSML

The characteristic abnormalities associated with the Noonan syndrome with multiple lentigines is described by the acronym “LEOPARD” which stands for:

L – Lentigines (multiple brown-black spots on the skin)
E – Electrocardiographic conduction defects (abnormalities of the electrical activity and the coordination of proper contractions of the heart)
O – Ocular hypertelorism (widely-spaced eyes)
P – Pulmonary stenosis (obstruction of the normal outflow of blood from the right ventricle of the heart)
A – Abnormalities of the genitals
R – Retarded growth resulting in short stature
D – Deafness or hearing loss due to inner ear malfunction (sensorineural deafness).

Some individuals with the disorder may also exhibit mild intellectual disability, speech difficulties, and/or additional physical abnormalities.

The lentigines typically first appear in mid-childhood (after age four to five) and increase in number with age, usually until puberty. They develop mostly on the face, neck and upper body. Many with the disorder exhibit thousands of small, flat discolorations. Unlike freckles, lentigines tend to be darker, and range from approximately one to five millimeters (mm) in size. Some affected individuals may exhibit larger, dark brown discolorations on the skin. However, all affected individuals develop lentigines.

Approximately 85% of affected individuals have heart defects, including hypertrophic cardiomyopathy and pulmonary valve stenosis. Growth retardation that results in short stature is reported in fewer than 50% of affected persons. Sensorineural hearing deficits seen in approximately 20%, while Intellectual disability is observed in approximately 30% of individuals with NSML.

Diagnosis of NSML

Diagnosis is mainly based on clinical features. A person is suspected to be affected by Noonan syndrome with multiple lentigines if he/she demonstrates one or more of the following basic features:

Lentigines
Cardiac abnormalities
Short stature
Pectus deformity
Facial dysmorphia.

NSML may be suspected in newborns if there’s pale tan or light brown discolorations on the skin (café-au-lait spots), characteristic facial features and hypertrophic cardiomyopathy (thickened heart muscle).

Symptoms of NSML may be similar to other disorders such as Noonan syndrome, Centrofacial lentiginosis, Neurofibromatosis type 1, Peutz-Jeghers syndrome (PJS) and Carney complex.

Published : November 17, 2020 1:08 pm | Updated:November 18, 2020 9:04 am

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