Noonan syndrome with multiple lentigines

Noonan syndrome with multiple lentigines (NSML) is a rare genetic disorder that affects many parts of the body, especially the skin, heart, inner ear, and genitals [5]. It is characterized by small, dark brown spots called lentigines, which are flat, black-brown macules located mainly on the face, neck, and upper trunk, sparing the mucosa [2].

The cardinal features of NSML include lentigines, hypertrophic cardiomyopathy (a type of heart disease), short stature, pectus deformity (a condition where the chest is sunken or protruding), and dysmorphic facial features, such as widely spaced eyes and ptosis (drooping eyelids) [1][3][14]. Café-au-lait spots may also be observed alone or along with lentigines.

NSML is a rare inherited disorder that can be inherited from an affected parent or due to a new genetic change in a person with no family history of the condition. It belongs to a group of related conditions called the RASopathies, which are caused by mutations in genes involved in the Ras/MAPK signaling pathway [12][13].

The symptoms of NSML can vary widely among affected individuals and may include skin abnormalities, heart problems, ear issues, genital abnormalities, head and facial features, and other systemic manifestations. It is essential to note that NSML is a complex condition with multiple features, making diagnosis and management challenging.

References: [1] - Description of the cardinal features of NSML [2] - Location and characteristics of lentigines in NSML [3] - Additional facial features associated with NSML [5] - General description of NSML [12] - Classification of NSML as a RASopathy [13] - Inheritance pattern of NSML [14] - List of cardinal features of NSML

Noonan syndrome with multiple lentigines (NSML) is a condition that affects many areas of the body, and its signs and symptoms can vary greatly from person to person.

Common Signs and Symptoms:

• Multiple Lentigines: These are flat, black-brown macules that appear on the face, neck, and upper part of the trunk. They may increase in number to the thousands by puberty.
• Hypertrophic Cardiomyopathy: This is a condition where the heart muscle becomes thickened, which can lead to heart problems.
• Short Stature: People with NSML often have shorter-than-average height.
• Pectus Deformity: This refers to a deformity of the chest wall, which can be either protruding or sunken.
• Dysmorphic Facial Features: These include widely spaced eyes (hypertelorism), ptosis (drooping eyelids), and down-slanting palpebral fissures (the openings between the eyelids).
• Genital Abnormalities: In some cases, people with NSML may have abnormalities of the genitals.
• Hearing Loss: This can be caused by abnormalities in the inner ear.

Other Possible Signs and Symptoms:

• Extra Folds of Skin on the Back of the Neck
• Mild Learning Problems
• Fertility Problems

It's worth noting that the signs and symptoms of NSML can vary greatly from person to person, and not everyone with the condition will exhibit all of these features. Additionally, some people may have no noticeable symptoms at all.

References:

• [1] Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome) is a condition that affects many areas of the body.
• [3] The cardinal features consist of lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features including widely spaced eyes and ptosis.
• [6] Other signs and symptoms of this condition include heart defects, unusual facial features, genital abnormalities, and shorter-than-average height.
• [8] Patients with NSML have a characteristic facial appearance including a broad forehead, hypertelorism, ptosis, down-slanting palpebral fissures, ...

Noonan syndrome with multiple lentigines (NSML) can be diagnosed through a combination of clinical evaluation and molecular genetic testing.

Clinical Evaluation

The diagnosis of NSML is often established in a proband (an individual with the condition) who presents with multiple lentigines, which are benign growths on the skin. Other clinical features that may be present include:

• Undescended testicle
• Heart defects, such as electrocardiogram (ECG) and echocardiogram abnormalities
• Hearing loss or other ear-related issues
• Abnormalities in brain function, as detected by CT scan of the brain, skull x-ray, or EEG

Molecular Genetic Testing

Molecular genetic testing can be used to confirm the diagnosis of NSML or to distinguish it from overlapping syndromes. This type of testing may involve:

• BRAF genetic test
• Next-generation sequencing to detect single nucleotide and copy number variants in 20 genes associated with Noonan syndrome and related disorders

Diagnostic Tests

The following diagnostic tests may be used to evaluate individuals suspected of having NSML:

• Electrocardiogram (ECG) and echocardiogram to check the heart
• Hearing test
• CT scan of the brain
• Skull x-ray
• EEG to check the brain's function
• Blood tests to check certain hormone levels
• Removing a small amount of skin for examination

Confirmation of Diagnosis

Diagnosis is made either on clinical grounds or by identification of a pathogenic variant in PTPN11, RAF1, BRAF, or MAP2K1 by molecular genetic testing. Many cases are confirmed through the presence of a pathogenic variant in one of these genes.

References:

• [1] - Diagnosis/testing
• [3] - Differential diagnosis
• [5] - Molecular genetic testing may be useful to confirm diagnosis or to distinguish between overlapping syndromes.
• [9] - Diagnosis is made either on clinical grounds or by identification of a pathogenic variant in PTPN11, RAF1, BRAF, or MAP2K1 by molecular genetic testing.

Treatment Options for Noonan Syndrome with Multiple Lentigines

Noonan syndrome with multiple lentigines (NSML) is a rare inherited disorder that affects various parts of the body, including the skin, heart, and inner ears. While there is no cure for NSML, several treatment options are available to manage its symptoms.

Cardiovascular Treatment

Individuals with NSML often experience hypertrophic cardiomyopathy, which can lead to heart failure. Low-dose Dasatinib has been shown to be effective in ameliorating this condition [7]. Additionally, other cardiovascular treatments may be necessary to manage related complications.

Skin Treatment

Lentigines, a hallmark feature of NSML, can be treated with cryosurgery or laser treatment

Noonan syndrome with multiple lentigines (NSML) is a rare genetic disorder that can be challenging to diagnose due to its overlapping features with other conditions. The differential diagnosis for NSML includes several conditions that share similar symptoms, such as:

• Turner syndrome: A chromosomal disorder that affects females, characterized by short stature, heart defects, and infertility.
• Williams syndrome: A genetic disorder that causes intellectual disability, distinctive facial features, and cardiovascular problems.
• Monogenic disorders with overlapping features: Such as Aarskog syndrome, Baraitser-Winter syndrome, and actinopathies, which can present with similar symptoms to NSML.

According to [4], the differential diagnosis for NSML should also include other RASopathies, specifically Noonan syndrome and neurofibromatosis type 1. This is because these conditions share a common genetic pathway and can exhibit overlapping features.

Additionally, molecular studies have proven that LEOPARD syndrome and Noonan syndrome are allelic disorders caused by different missense mutations in PTPN11 [9]. This suggests that the differential diagnosis for NSML should also consider other RASopathies, particularly those caused by mutations in the same gene.

In terms of specific features to look out for when diagnosing NSML, multiple lentigines are a hallmark characteristic of the condition. These flat, black-brown macules typically appear on the face, neck, and upper trunk, sparing the mucosa [12]. They can be present at birth or develop later in childhood.

It's essential to consider these differential diagnoses when evaluating patients with suspected NSML, as accurate diagnosis is crucial for providing appropriate treatment and management.