Noonan syndrome with multiple lentigines

Overview

Noonan syndrome with multiple lentigines (NSML), formerly known as LEOPARD syndrome, is a rare genetic disorder that shares many features with Noonan syndrome but is distinguished by the presence of numerous dark skin spots called lentigines. It is a multisystem condition that affects the skin, heart, facial structure, growth, and development. The term LEOPARD is an acronym describing its major features: Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retarded growth, and Deafness (sensorineural).

NSML is part of a group of conditions known as RASopathies, which are caused by mutations affecting the RAS/MAPK signaling pathway—a critical regulator of cell growth and development. Symptoms often begin in early childhood, and early recognition is essential for monitoring and treating potentially serious complications such as cardiac abnormalities and hearing loss.

Causes

NSML is primarily caused by mutations in the PTPN11 gene, which encodes the SHP-2 protein involved in the RAS/MAPK signaling pathway. Less commonly, mutations in RAF1 or BRAF genes have been implicated. These mutations lead to abnormal signaling that affects cell development and differentiation in various tissues, contributing to the clinical features of the disorder.

The condition is inherited in an autosomal dominant manner, meaning a mutation in just one copy of the gene from either parent can cause the disorder. In many cases, the mutation occurs de novo (spontaneously) without a family history.

Symptoms

The symptoms of Noonan syndrome with multiple lentigines vary widely in severity and presentation, even among individuals with the same genetic mutation. They typically appear in early childhood and may become more prominent with age.

Dermatologic Features

• Multiple lentigines: Small, dark brown to black flat spots on the skin, often appearing by age 4–5 and increasing in number over time

• Café-au-lait spots: Light brown patches may also be present

• Skin findings often cluster on the face, neck, trunk, and limbs

Cardiovascular Abnormalities

• Hypertrophic cardiomyopathy (HCM): Thickening of the heart muscle, a serious complication in many patients

• Pulmonary valve stenosis: Narrowing of the pulmonary valve, leading to heart murmur and reduced blood flow

• Electrocardiographic abnormalities: Including conduction defects and abnormal ECG patterns

Facial and Craniofacial Features

• Ocular hypertelorism (widely spaced eyes)

• Low-set, posteriorly rotated ears

• Ptosis (drooping eyelids)

• Short nose with broad nasal root

• Webbed neck or low posterior hairline

Growth and Development

• Short stature or delayed growth

• Failure to thrive in infancy

• Delayed puberty or genital abnormalities (e.g., undescended testes in males)

Hearing and Vision

• Sensorineural hearing loss: Often bilateral and may present in infancy or early childhood

• Strabismus (crossed eyes) or refractive errors may also occur

Other Possible Features

• Learning difficulties or mild intellectual disability

• Hypotonia (low muscle tone)

• Feeding difficulties in infancy

Diagnosis

The diagnosis of NSML is based on a combination of clinical evaluation, family history, and confirmatory genetic testing. The presence of multiple lentigines along with characteristic cardiac, facial, and developmental features raises clinical suspicion.

Diagnostic Criteria

• Presence of multiple lentigines (usually more than 20)

• Family history of NSML or features consistent with Noonan syndrome spectrum

• At least two of the following:

  • Cardiac anomalies (HCM or pulmonary stenosis)

  • Facial dysmorphism

  • Growth retardation

  • Sensorineural deafness

  • Genital anomalies

Confirmatory Testing

• Genetic testing: Identification of a pathogenic variant in PTPN11, RAF1, or BRAF confirms the diagnosis

• Echocardiogram and ECG: To assess for heart abnormalities

• Hearing evaluation: Audiometry to detect sensorineural hearing loss

• Growth charts and endocrine workup: To monitor height and development

Treatment

There is no cure for Noonan syndrome with multiple lentigines, and treatment is supportive and symptom-based. A multidisciplinary care approach is essential for managing the wide range of clinical features.

Cardiac Management

• Regular follow-up with a cardiologist for hypertrophic cardiomyopathy or valve issues

• Beta-blockers or surgical intervention may be necessary for significant cardiac obstruction

Growth and Hormonal Therapy

• Growth hormone therapy may be considered in children with growth hormone deficiency

• Endocrinologic support for delayed puberty or genital anomalies

Hearing and Developmental Support

• Use of hearing aids or cochlear implants for hearing loss

• Speech therapy, occupational therapy, and special education for developmental delays

Dermatologic and Cosmetic Management

• No treatment is typically required for lentigines, but cosmetic removal may be considered

• Sun protection is advised to prevent darkening of pigmented lesions

Psychosocial and Genetic Counseling

• Counseling for affected individuals and families to manage chronic care and inheritance risks

• Support groups and educational resources for coping and advocacy

Prognosis

The prognosis for individuals with Noonan syndrome with multiple lentigines depends largely on the severity of cardiac involvement and the presence of other complications such as hearing loss or developmental delay. With early diagnosis and appropriate medical care, many individuals can lead fulfilling lives.

Regular cardiac and developmental monitoring is essential to manage potential complications. Most people with NSML have normal intelligence and life expectancy, especially if major cardiac issues are addressed promptly. Supportive therapies and a strong care team can greatly improve long-term outcomes and quality of life.