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Exact prevalence and incidence rates for Noonan syndrome with multiple lentigines (NSML) are not known. About 300 cases have been described to date. A slight male predominance has been reported.

Patients with NSML have a characteristic facial appearance including a broad forehead, hypertelorism, ptosis, down-slanting palpebral fissures, a high-arched palate, and low-set posteriorly rotated ears. Pectus deformity is common. Multiple lentigines, presenting as flat, black-brown macules, are located mainly on the face, neck, and upper trunk, sparing the mucosa, and constitute a hallmark feature of the syndrome. Lentigines appear at 4 to 5 years of age and increase in number until puberty. Café-au-lait spots may also be observed alone or along with lentigines. About one quarter of patients show growth delay with short stature in adulthood. Cardiac defects include ECG (electrocardiogram) anomalies, pulmonary valve stenosis, progressive conduction defects and hypertrophic cardiomyopathy, and are found in about 50% of patients. Some affected individuals have abnormal genitalia: unilateral or bilateral cryptorchidism and hypospadias in about one third of affected males; urinary tract defects and, less commonly, ovarian abnormalities. Sensorineural hearing loss is a less common feature (20%). Intellectual disability is generally mild and affects about 30% of cases. NSML can be associated with the development of neuroblastoma, acute myeloid leukemia, and acute lymphoblastic leukemia.

NSML is mainly caused by mutations in the PTPN11 gene (12q24.1). Mutations are different from those known to cause Noonan syndrome, explaining the distinct clinical phenotype. Some cases are reported to involve mutations in RAF1 (3p25) , BRAF (7q34), or MAP2K1 (15q22.1-q22.33; one patient). There may be other currently unidentified causative genes.

Clinical diagnosis may be difficult because of the absence of characteristic lentigines. Patients may have an initial diagnosis of Noonan syndrome. Molecular genetic testing may be useful to confirm diagnosis or to distinguish between overlapping syndromes.

The clinical presentation overlaps significantly with Noonan syndrome and the main distinguishing manifestation is multiple lentigines. Other differential diagnoses include cardio-facio-cutaneous, Costello, and Turner syndromes.

Prenatal diagnosis is possible if a causative gene mutation has been identified in an affected family member.

NSML follows an autosomal dominant pattern of inheritance. The proportion of de novo mutations is unknown. Genetic counseling should be provided to affected families informing them that there is a 50% risk of transmission from an affected individual to their offspring.

Isolated lentigines may be treated with cryosurgery or laser treatment. Treatment of lentigines may also include tretinoin and hydroquinone creams. Treatment of cardiovascular manifestations follows standard methods and periodic cardiac monitoring is recommended. Cryptorchidism in affected males is also treated with conventional techniques. Hearing loss may require hearing aids, educational support, or cochlear implantation.

Life expectancy is normal in most affected patients, with the exception of patients with severe hypertrophic cardiomyopathy. The prognosis is mainly related to the severity of cardiac manifestations.