A 9-year-old boy presents to the pediatric clinic with family concerns for poor growth and a progressive rash. After an otherwise uncomplicated pregnancy, he was born full term via cesarean delivery for failure to progress. His postnatal course was normal with no abnormal findings or birthmarks identified during his newborn nursery stay. In the office today he is noted to be symmetrically small (weight and height at the 5th and 10th percentiles, respectively) with progressive anthropometric decline from the 75th percentile appreciated since birth. On examination he has mild dysmorphic facial features (high arched palate, low set ears, ocular hypertelorism, broad nasal bridge, bulbous nose), pectus excavatum, and multiple tan macules on his trunk and extremities—sparing his palms, soles, and oral mucosa (see Figs 1 and 2). According to his parents, these macules appeared between 3 and 4 years of age and have gradually increased in number. By history, he also has mild expressive language delay manifested by difficulties remembering certain vocabulary words and producing complex sentences for which he is receiving speech therapy through the school system. The remainder of his examination is completely normal. His past medical history is notable for peripheral pulmonic stenosis identified at 2 months of age by echocardiogram during evaluation of a murmur, which has since resolved. His father has similar skin findings (see Fig 3) with a past medical history of sensorineural hearing loss in his 30s and pulmonary stenosis when he was a child that also resolved spontaneously. Incidentally, both his father and mother had karyotypes completed several years prior to this presentation due to recurrent spontaneous miscarriages. The results were normal. The patient’s laboratory evaluation included a complete blood cell count, electrolytes, and karyotype, which have all shown no abnormalities. Based on the above history and examination, a targeted laboratory test was drawn that confirmed the suspected diagnosis.Genetic testing identified a known disease-causing variant in the protein tyrosine phosphatase nonreceptor type 11 (PTPN11) gene. The variant, c.1403C>T, has been commonly seen in Noonan syndrome with multiple lentigines (NSML).First identified in 1936, NSML is a rare autosomal dominant multisystem disorder characterized by 5 cardinal features: lentigines, cardiac abnormalities (most commonly hypertrophic cardiomyopathy [HCM]), short stature with growth retardation, skeletal anomalies (primarily pectus deformity), and dysmorphic facial features (including ocular hypertelorism and ptosis). (1) Additional common features include café-au-lait and analogous more darkly pigmented café noir spots (see Fig 3), sensorineural hearing loss, isolated electrocardiographic abnormalities, pulmonic stenosis, cryptorchidism, developmental delay, and variable degrees of cognitive deficits. (2) Considered to be fully penetrant but variably expressed, not all patients with NSML demonstrate every feature described above. Lentigines, although not universally identified, are the most common and distinctive feature of this condition occurring in more than 90% of patients. (3) Lentigines present as dispersed, black-brown flat macules primarily located on the face, neck, and upper trunk with occasional involvement of palms, soles, and genitalia. They can involve mucosal surfaces, but this is rare in NSML. Occasionally present at birth, lentigines typically appear around 4 years of age and increase in number into the thousands until puberty. (4) It can be challenging to clinically distinguish lentigines from other hyperpigmented macules such as ephelides (freckles) and junctional nevi. Common differentiating features include timing of presentation (lentigines typically appear earlier), location (ephelides have a proclivity for areas of high sun exposure), phenotype predilection (ephelides appear more commonly in children with blonde or red hair, fair complexion, blue eyes), and seasonal variation (lentigines proliferate and darken independently from sun exposure). In indeterminate cases, skin biopsy can be a helpful diagnostic tool showing increased number of melanocytes and prominent rete ridges at the dermal-epidermal junction for lentigines; normal number of melanocytes with increased melanin content for ephelides; and clustered nests of melanocytes at the dermal-epidermal junction for junctional nevi. (5) Café-au-lait spots are another common cutaneous manifestation that occur in up to 70% to 80% of patients and are similar to those found in neurofibromatosis type 1 (NF1) although typically not in a number that fulfills criteria for NF1. (3) Their presence typically precedes lentigines and they may be useful in the early diagnosis of NSML in children without lentigo demonstrating other cardinal features of the condition.Approximately 200 cases of NSML have been reported in the literature although the true incidence has not been formally assessed. (1) In approximately 90% of patients with NSML, a missense mutation—in which a single nucleotide substitution results in a codon that produces a different amino acid—in the PTPN11 gene on chromosome 12q24 is identified. (6) Mutations in the RAF1, BRAF, and MAP2K1 genes have also been implicated.NSML falls into a subclass of conditions caused by mutations in genes involved in the RAS/mitogen-activated protein kinase pathway, otherwise known as RASopathies. This pathway is activated by extracellular input from growth factors and plays a critical role in regulating cellular proliferation, differentiation, and senescence of several tissue types involved in normal development. (7) The RASopathies include NF1, Noonan syndrome, NSML, capillary malformation–arteriovenous malformation syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, and Legius syndrome. Because they share a common underlying mechanism, the RASopathies often exhibit several overlapping phenotypic features including the presence of facial anomalies, heart defects, and poor linear growth along with frequent association of skin, skeletal, and genitourinary abnormalities as well as variable degrees of intellectual disability. (1)The diagnosis is established either based on clinical findings or, if clinical findings are insufficient, by identification of a pathogenic mutation in 1 of 4 genes (PTPN11, RAF1, BRAF, and MAP2K1) (see Table 1). Because some features manifest with advancing age, the diagnosis may be problematic in very young patients with only partial phenotypes. Some authors have suggested that diagnosis in infancy should be considered with the combination of HCM, distinct facial features, and café-au-lait spots. (8)Important to include in the differential diagnosis for children with multiple lentigines are Carney Complex (lentigines associated with cardiac and endocrine tumors), Peutz-Jeghers syndrome (lentiginouslike lesions around oral mucosa associated with intestinal polyposis), PTEN hamartoma tumor syndrome (lentigines with macrocephaly, lipomatosis, pigmentation of glans penis, vascular malformations), and premature aging with multiple nevi (no associated cardiac defects/syndromic features) (see Table 2). (9) All RASopathies are also important to consider as well but often difficult to distinguish from NSML during infancy based on physical features alone. In particular, there is strong phenotypic overlap between NSML, Noonan syndrome, and cardio-facio-cutaneous syndrome due to shared germline pathogenic gene variants. (2) These conditions become more easily differentiated when genetics are investigated, and specific patterns develop later in childhood. Specifically, key features that help to distinguish NSML from other RASopathies include the more common association with distinct cutaneous findings (such as lentigo and café-noir spots), proclivity for HCM as opposed to other cardiac abnormalities, and associated hearing loss in NSML.Management of children with NSML requires multidisciplinary involvement and a fundamental understanding of involved systems as well as characteristic features. Anthropometric data should be plotted on growth charts designed for children with Noonan syndrome. (10) Baseline cardiac evaluation with echocardiography and electrocardiography as well as ophthalmologic and audiology assessments should be pursued. Renal ultrasound (with urinalysis if urinary tract abnormalities are identified on either clinical examination or imaging), clinical and radiographic assessment of spine and rib cage, a dental examination (risk for malocclusion has been noted in the literature), and a detailed developmental evaluation with consultation with a clinical geneticist are also part of the assessments recommended at initial diagnosis. (2) Although intrinsic risk for skin malignancies is thought to be no different than the general population, recent case reports suggest a potential higher risk for melanomas, (11) highlighting the importance of careful serial skin examinations in patients with NSML and close involvement with a dermatologist. If anomalies are discovered in any system, periodic follow-up should be planned and lifelong monitoring may be necessary, especially of cardiovascular abnormalities. (2) Of note, although the onset of HCM usually precedes multiple lentigines, the hypertrophic process may start or often worsen in parallel with lentigines appearing. (1) As such, a complete cardiology assessment should be performed annually and particularly at the appearance of multiple lentigines. (1) Annual hearing assessment should also be performed and, if hearing loss is detected, twice-yearly evaluations by a physician familiar with hereditary hearing impairment and repeat audiometry to confirm stability of the hearing loss is recommended. (2) Treatment of cardiovascular anomalies and cryptorchidism is the same as in the general population. Surveillance for intellectual and developmental disabilities can be performed per routine pediatric care and is of particular importance due to the higher prevalence of these issues in individuals with NSML. Adult height and response to growth hormone therapy have not been studied in NSML. If considered, it should be done in close consultation with a cardiovascular subspecialist due to the theoretical progression of ventricular wall thickness. (1) In general, long-term prognosis for people with NSML is favorable and linked to the degree and severity of cardiac involvement. Future research into gene therapy targeted at known missense mutations offers a promising therapeutic direction in the treatment of select patients with NSML. Because NSML is inherited in autosomal dominant fashion with potential for a de-novo pathogenic variant reported in the literature (although the proportion of cases caused by de-novo mutations is unknown), a proband with NSML should also have parents evaluated for clinical features of the condition as well as pathogenic genetic variants. (2) If a parent of the proband is affected, the risk to the siblings is 50%. When parents are clinically unaffected, the risk to the siblings of a proband appears to be low but greater than that of the general population because of the possibility of germline mosaicism. (2) It is therefore appropriate to evaluate relatives at risk in order to identify, as early as possible, those who would benefit from initiation of treatment and preventive measures.The patient’s echocardiogram at the time of diagnosis was normal. His electrocardiography showed left axis deviation, which has remained unchanged on serial evaluations. Audiology, ophthalmology, renal, and musculoskeletal assessments were all normal. His development progressed in age-appropriate fashion with height, weight, and head circumference all notably remaining within the 10th, 25th, and 90th percentiles, respectively, when plotted on Noonan-specific growth curves. His father had been followed annually in the cardiology clinic, due to his childhood history of pulmonic stenosis; he was also found to meet clinical criteria for NSML after a detailed evaluation by a geneticist.