Noonan Syndrome with Multiple Lentigines (LEOPARD Syndrome)

Basics

  • Noonan syndrome with multiple lentigines (NSML), commonly known as LEOPARD syndrome, is a genetically heterogeneous syndrome caused by a mutation in one of four distinct genes.
  • Cardinal features of NSML include multiple lentigines, hypertrophic cardiomyopathy (HCM), short stature, pectus deformity, and dysmorphic facial features, including hypertelorism and ptosis.
  • LEOPARD is an acronym for a constellation of cardinal features: Lentigines, ECG abnormalities, Ocular hypertelorism, Pulmonic valve stenosis, Abnormalities of male genitalia, Retardation of growth, sensorineural Deafness, and autosomal Dominant hereditary pattern (1).
  • NSML is one of a group of disorders called the neurocardiofaciocutaneous syndromes.
  • Synonym(s): The term “LEOPARD syndrome” is being phased out because some families of affected children find it offensive. NSML is also formerly known as progressive cardiomyopathic lentiginosis, familial multiple lentigines syndrome, lentiginosis profusa syndrome, Gorlin syndrome II, Capute-Rimoin-Konigsmark-Esterly-Richardson syndrome, Moynahan syndrome.

Description

  • Lentigines (often appear during childhood) progress to thousands of brown-black macules by adolescence; mucosa is spared. >90% of patients (but not all) have lentigines. Café au lait spots may also be present (70–80%).
  • Heart defects found in 85%, including HCM, which typically appears in infancy and may be progressive, also pulmonic valve stenosis
  • Facial dysmorphism includes hypertelorism (50%).
  • Growth retardation (<50%) is postnatal, less common in NSML than in related RASopathies.
  • Sensorineural deafness (20%) is poorly characterized as a manifestation of NSML syndrome; typically mild
  • Intellectual disability is (30%) typically mild.

Epidemiology

  • Penetrance is high but difficult to quantify due to ascertainment bias and variable expressivity. Often, the diagnosis is made in an adult only after the diagnosis of a more severely affected child.
  • When a child of apparently unaffected parents is diagnosed with NSML, consider genetic testing for parents and other first-degree relatives. Nonpenetrance, nonpaternity, or undisclosed adoption may explain apparently sporadic cases.
  • No clear racial predilection
  • Predominant sex: male > female, possibly due to ascertainment bias

Prevalence
Unknown prevalence in the United States and internationally

General Prevention

Prenatal diagnosis or preimplantation genetic testing is possible in families when the disease-causing mutation is known. An unknown percentage of cases are due to de novo mutations.

Etiology and Pathophysiology

  • In most individuals, NSML and Noonan syndrome (NS) are allelic disorders resulting from different missense mutations. 90% of these mutations are in the PTPN11 gene.
  • The PTPN11 gene product, tyrosine phosphatase, participates in the transduction of intracellular signals essential for diverse developmental processes, including cardiac development.
  • Melanocytic hyperplasia resulting in lentigines is postulated to result from abnormal neural crest cell development.
  • Increased β-adrenergic effector activity in the myocardium has been shown on histology.
  • Electron microscopic examination of lentigines shows large accumulations of melanosomes containing giant granules of pigment, similar to those found in café au lait spots in neurofibromatosis.

Genetics

  • Genetically heterogeneous syndrome caused by one of the four described genes
  • Autosomal dominant with high penetrance and highly variable expressivity
  • Unknown percentage of cases due to new mutations
  • Mutation in the PTPN11 gene (LS1, OMIM #151100) on chromosome 12q24 (2)
    • 90% of NSML is caused by PTPN11 mutations.
    • >90% of these mutations are detectable by sequence analysis (especially sequence variants of exons 7, 12, or 13).
    • NSML caused by PTPN11 is allelic to NS (NS1; OMIM #163950).
    • PTPN11 mutations in NSML are dominant-negative mutations that interfere with growth factor/ERK-MAPK–mediated signaling; NS PTPN11 mutations are activating.
    • NSML and NS mutations are located in different exons of this gene.
  • Mutation in the RAF1 gene (LS2, OMIM #611554) on chromosome 3p25.2
    • <5% of NSML is caused by RAF1 mutations.
    • >90% of these mutations are detectable by sequence analysis (especially sequence variants of exons 6, 13, or 16).
    • NSML caused by RAF1 is allelic to NS5 (OMIM #611553).
  • Mutation in the BRAF gene (LS3, OMIM #613707) on chromosome 7q34 (in two individuals)
    • >90% of these mutations are detectable by sequence analysis (especially sequence variants of exons 6 and 11 to 17).
    • NSML caused by BRAF is allelic to NS7 (OMIM #613706).
  • A mutation in MAP2K1 (chromosome 15q22) has been reported in one individual with NSML (3).
    • NSML caused by MAP2K1 is allelic to NS.

Commonly Associated Conditions

  • Variable cognitive deficits: intellectual disability (usually mild) in 30%
  • Skeletal abnormalities
  • HCM
  • Malignant melanoma
  • Risk of malignancy in NSML is no greater than the general population.

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