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 " Ł 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. Cafe au lait spots may also be present (70 " ô80%).
- 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 é á
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. é á
ETIOLOGY AND PATHOPHYSIOLOGY
- In most individuals, NSML syndrome 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 Ä ▓-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 cafe 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 " ômediated 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.
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 features develop during puberty or later in life, which may delay diagnosis.
- Clinical diagnosis: Must have lentigines plus two cardinal features OR, in the absence of lentigines, must exhibit three cardinal features plus one first-degree relative diagnosed with NSML.
- Cardinal features are lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness.
- Generally a clinical diagnosis, but if suspected in young children, confirmation by genetic testing is appropriate.
- Other associated findings that are not cardinal features but should increase suspicion for NSML:
- Other cutaneous abnormalities
- Axillary freckling
- Interdigital webbing
- Cafe au lait spots
- Localized hypopigmentation
- Hyperelastic skin
- Onychodystrophy
- Other genitourinary abnormalities such as hypospadias
- Endocrine abnormalities
- Low follicle-stimulating hormone, luteinizing hormone, thyrotropin
- Elevated 17-hydroxy and 17-ketosteroids
- Neurologic defects
- Seizures
- Nystagmus
- Hyposmia
- Cephalofacial dysmorphisms
- Mandibular prognathism
- Broad nasal root
- Dysmorphic skull
- Low-set ears
- High palate arch
- Epicanthal folds
- Ptosis
- Corneal tumors
- Other skeletal abnormalities
- Pectus excavatum or carinatum
- Kyphoscoliosis or winging of scapulae
- Syndactyly
- Delayed development or agenesis of permanent or supernumerary teeth
Note:These features are recognized as minor manifestations of this complex and highly variable syndrome. é á
HISTORY
- Family history of cardiac arrhythmias or abnormalities of skin pigmentation
- Multiple lentigines present as dispersed flat, black-brown macules, mostly on the face, neck, and upper part of the trunk with sparing of the mucosa (4) but may not be present before age 4 to 5 years, may darken with age, and number in the thousands by puberty.
PHYSICAL EXAM
- Complete physical and neurologic examination
- Skin: multiple lentigines of face, neck, and upper torso, sparing mucosa: dispersed, flat brown-black macules numbering in the thousands by puberty; cafe au lait spots, hyperelastic skin
- Cardiovascular: conduction abnormalities, pulmonary valve stenosis
- Height: postnatal growth retardation; plot growth on NS growth charts (5)
- Skeletal examination: pectus excavatum or carinatum, kyphoscoliosis, syndactyly, careful assessment of spine and ribs
- HEENT: characteristic facial features similar to those of NS (although less prominent), inverted triangle-shaped face, downslanting palpebral fissures, ocular hypertelorism, ptosis, broad nasal root, high-arched palate, low-set posteriorly rotated ears
- Ophthalmologic examination
- GU: abnormalities of genitalia, especially cryptorchidism, hypospadias
DIFFERENTIAL DIAGNOSIS
- NS: characterized by short stature, congenital heart defects, webbed neck, pectus deformities, variable developmental delay, cryptorchidism, and characteristic facial features; also autosomal dominant with variable expressivity; NS shares features of NSML but without lentigines, cafe au lait spots, or deafness. NS without multiple lentigines may be associated with PTPN11, RAF1, MAP2K1 (as well as other genes SOS1, KRAS, NRAS, BRAF).
- Ephelides (freckles)
- Lentigo
- Neurofibromatosis
- Carney syndrome: multiple familial neoplasia and lentiginosis syndrome associated with Carney complex gene 1, a PRKAR1A gene on 17q22 " ô24
- Albright syndrome
- Cardiofaciocutaneous syndrome
- Turner syndrome
- Watson syndrome: phenotypically similar to neurofibromatosis 1
- Costello syndrome: shares features of NSML, NS, and cardiofaciocutaneous syndromes but lacks PTPN11 mutation
- Williams syndrome
DIAGNOSTIC TESTS & INTERPRETATION
- Molecular genetic testing is informative in approximately 90% of individuals who meet clinical criteria for NSML.
- Molecular diagnostic testing strategy to confirm (or establish) diagnosis in a proband
- PTPN11 sequence analysis of coding exons 7, 12, and 13. No causative mutations (for NSML) have been identified in any other exons.
- If no mutation is identified in PTPN11, perform sequence analysis of coding exons 6, 13, and 16 of RAF1 and coding exons 6 and 11 to 17 of BRAF.
- If no mutation is identified, perform sequence analysis of the remaining coding exons of PTPN11, RAF1, and BRAF.
- Approximately 5% of individuals with NSML do not have identifiable PTPN11, RAF1, BRAF, or MAP2K1 mutations. It is likely that other as yet unidentified genes related to RAS signal transduction may be implicated in these cases.
Diagnostic Procedures/Other
- ECG (especially before any surgical procedure), echocardiography; consider Holter monitoring.
- Hearing evaluation: age-appropriate assessment of auditory acuity (may include auditory brainstem response, auditory steady-state response, pure tone audiometry); audiovestibular testing
- Radiographic assessment of spine and rib cage if clinically indicated
- Developmental assessment
- Renal ultrasound or urographic examination, especially in males or those with known urologic abnormalities, urinalysis
- MRI of brain and cervical spine if neurologic symptoms are present
TREATMENT
Most patients are able to live normal lives and have a normal lifespan. Treatment of individual manifestations as in the general population é á
- Cardiovascular abnormalities
- Cryptorchidism
- Hearing loss: hearing aids, education for hearing impaired, cochlear implant if appropriate
- Developmental disability: early intervention and individualized educational plan
- Histology of a lentigo biopsy demonstrates hyperpigmentation of the basal membrane, with increased numbers of melanocytes and slight acanthosis and diffuse lymphohistiocytic infiltrate with some scattered melanophages (6).
MEDICATION
- Lentigines
- Tretinoin cream or hydroquinone cream to help lighten lesions
- Cryotherapy or laser therapy may be impractical due to large number of lesions.
- Structural cardiac anomalies
- Ä ▓-Adrenergic receptor blockers or calcium channel blockers for outflow tract obstruction as appropriate
- Arrhythmias: appropriate antiarrhythmics (6)
ADDITIONAL THERAPIES
Treatment of manifestations é á
- Hearing loss: hearing aids, education for hearing impaired, sign language; consider cochlear implantation.
- Developmental disabilities: early intervention, individualized education planning
ISSUES FOR REFERRAL
- Cardiology: dysrhythmias, cardiomyopathy
- Genetics: genetic counseling
- Urology: genital abnormalities
- Audiology: sensorineural deafness
- Dermatology: lentigines of cosmetic concern or lesions suspicious for malignancy
ONGOING CARE
- Management of individuals with NSML is based on the phenotype rather than on the molecular diagnosis per se.
- Cardiac conduction abnormalities merit special attention.
- Monitor lentigines for appearance of malignant melanoma or nevocellular nevi; incidence increases with increasing number of lentigines.
FOLLOW-UP RECOMMENDATIONS
- Developmental evaluation and follow-up
- Hearing loss: twice-yearly exams and routine audiometry to assess degree of loss
- Cardiology for conduction abnormalities: cardiomyopathy, structural heart disease, as appropriate
- Dermatology: surveillance of lentigines
- Endocrinology: as indicated
PATIENT EDUCATION
- Genetics Home Reference: http://ghr.nlm.nih.gov/condition/multiple-lentigines-syndrome
- Genetic and Rare Diseases (GARD) Information Center: http://rarediseases.info.nih.gov/GARD/
- MedlinePlus. LEOPARD syndrome: http://www.nlm.nih.gov/medlineplus/ency/article/001473.htm
REFERENCES
11 Gorlin é áRJ, Anderson é áRC, Blaw é áME. Multiple lentigines syndrome. Am J Dis Child. 1969;117(6):652 " ô662.22 Ogata é áT, Yoshida é áR. PTPN11 mutations and genotype-phenotype correlations in Noonan and LEOPARD syndromes. Pediatr Endocrinol Rev. 2005;2(4):669 " ô674.33 Nishi é áE, Mizuno é áS, Nanjo é áY, et al. A novel heterozygous MAP2K1 mutation in a patient with Noonan syndrome with multiple lentigines. Am J Med Genet A. 2015;167A(2):407 " ô411.44 Gelb é áBD, Tartaglia é áM. Noonan syndrome with multiple lentigines. In: Pagon é áRA, Adam é áMP, Ardinger é áHH, et al, eds. Gene Reviews. Seattle, WA: University of Washington; 1993 " ô2016.55 Witt é áDR, Keena é áBA, Hall é áJG, et al. Growth curves for height in Noonan syndrome. Clin Genet. 1986;30(3):150 " ô153.66 Mart â şnez-Quintana é áE, Rodr â şez-Gonz â ílez é áF. Leopard syndrome: clinical features and gene mutations. Mol Syndromol. 2012;3(4):145 " ô157.
ADDITIONAL READING
Porciello é áR, Divona é áL, Strano é áS, et al. LEOPARD syndrome. Dermatol Online J. 2008;14(3):7. é á
CODES
ICD10
Q87.1 Congenital malform syndromes predom assoc w short stature é á
ICD9
759.89 Other specified congenital anomalies é á
SNOMED
- Noonan 's syndrome (disorder)
- Multiple lentigines syndrome
CLINICAL PEARLS
- NSML is an autosomal dominant genetic disorder; typically, the diagnosis is made either on clinical grounds or by identification of a pathogenic variant in PTPN11, RAF1, BRAF, or MAP2K1 by molecular genetic testing.
- Clinical diagnosis requires a high degree of clinical suspicion.
- Clinical diagnostic criteria
- Lentigines plus two cardinal features
- In the absence of lentigines, three cardinal features (plus one first-degree relative diagnosed with NSML)
- Typically, not all features will be present in each patient.
- Management of individuals with NSML syndrome is based on the phenotype.