LEOPARD Syndrome (Lentigines, EKG abnormalities, Ocular Hypertelorism, Pulmonary stenosis, Abnormal Genitalia, Retarded Growth, Deafness; Also known as Multiple lentigines syndrome and Cardiocutaneous syndrome, Gorlin syndrome II, Cardio-Cutaneous syndrome, Lentiginosis profusa, Moynahan syndrome, or Progressive Cardiomyopathic Lentiginosis)

Are You Confident of the Diagnosis?

Observed expression of the characteristic phenotypes of LEOPARD syndrome (LS) is extraordinarily variable, making an accurate diagnosis difficult. The minimal criteria that must be met for a diagnosis of LS includes multiple lentigines (Figure 1) and 2 or more of the following: cutaneous abnormalities not including lentigines (cafe noir spots, cafe au lait spots); structural or ECG cardiac conduction abnormalities; pulmonic stenosis; obstructive cardiomyopathy; genitourinary abnormalities (hypospadiasis,cryptorchidism); endocrine abnormalities; neurologic defects (sensorineural deafness, mild learning disabilities); cephalofacial dysmorphism; short stature below the 25th percentile; or skeletal abnormalities (pectus excavatum/carinatum).

Figure 1.

In the absence of lentigines, 3 of the previously mentioned areas must be afflicted as well as a first degree relative with a confirmed diagnosis.

What to be alert for in the history

Characteristic findings on physical examination

Children that are suspected of LS have 3 principal traits: characteristic facial features (ocular hypertelorism, broad nasal root, prognathism, or low-set potentially rotated ears), hypertrophic cardiomyopathy (HCM), and café au lait spots (CLS), which occur in 100%, 87%, and 75% of cases, respectively. The most common (90% of LS cases) and noticeable finding on physical examination are lentigines that cover vast areas of skin and are small (between 2mm to 1cm), dark brown, polygonal, and irregularly shaped macules. They can often be seen in the mouth or on the sclerae.

Other cutaneous malformations include onychodystrophy, axillary freckling, localized hypopigmentation, café au lait spots, café noir spots, interdigital webs, and hyperelastic skin. Other systemic abnormalities include mild mental retardation (30%); short stature with 20% of cases below the third percentile after the newborn period; and cephalofacial abnormalities (reported in 35%) with ocular hypertelorism being the most documented (25%).

Further cephalofacial deformities include mandibular prognathism, broad nasal root, dysmorphic skull, low set ears, dental abnormalities, high arched palate, epicanthal folds, ptosis, and corneal tumors. Congenital genitourinary system problems are seen in 26% of patients, primarily males, as well as abnormalities such as cryptorchidism or hypospadias. Various musculoskeletal findings such as pectus excavatum, pectus carinatum, kyphoscoliosis, scapula alata (winged scapula), rib anomalies, and syndactyly are also seen. Dental deformities that are sometimes seen in LS patients include agenesis of adult teeth or hyperdontia.

Expected results of diagnostic studies

Histologic findings indicate that lentigo biopsy specimens have an elevated melanocyte count per unit skin area with prominent rete ridges. Langerhans cells under electron microscopy reveal bulky clusters of melanosomes. Additionally, skin samples in areas lacking pigmentation as well as those pigmented areas contain an increased buildup of melanosomes in LS patients.

Those patients presenting with endocrine dysfunction occasionally show low levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyrotropin and elevated levels of 17-hydroxy- and 17-ketosteroids. Genitourinary system evaluation may be facilitated using abdominal ultrasonography or urographic imaging.

To check for pulmonic valve stenosis (PVS), obstructive cardiomyopathy, myxomas, and other structural heart defects, it may be beneficial to perform a transthoracic echocardiogram and an electrocardiogram (ECG), which also may reveal conduction abnormalities such as left axis deviation, prolonged PR intervals, and right bundle branch block. Cranial computed tomography (CT) or magnetic resonance imaging (MRI) may show brain atrophy. To determine the presence of skeletal defects or a bone age assessment, skeletal radiography can be preformed. Sensorineural deafness can be diagnostically confirmed using audiography or auditory evoked potentials.

Noonan syndrome (NS) and Noonan-like/multiple giant cell lesions syndrome present with germinal mutations of the same PTPN11 gene mutated in LS in approximately 40% to 50% of patients. Clinically similar disorders, LS and NS are differentiated molecularly by the disease-causing mutation.

Whereas the mutation in LS causes reduced protein activity, the NS change exemplifies a gain of function mutation. Prenatal distinction between LS and NS can be done but is astonishingly difficult. In a fetus with HCM but a normal karyotype, the leading candidate is LS and needs to be followed with a physical examination of both parents. If a parent has a confirmed case of LS, then protocol dictates obstetric ultrasound at various timings with a fetal ECG in the 20th week of gestation. Genetic tests for the previously mentioned mutations can be done on chorionic villi or amniotic fluid samples.

Other neuro-cardio-facial-cutaneous (NCFC) conditions, such as LS, include NS, neurofibromatosis type 1, Costello syndrome, and cardiofaciocutaneous syndrome. Patients that fall into this group feature facial anomalies, malformed hearts, and growth and mental impairment, in combination with the integumentary, skeletal, and urogenital defects. Differential diagnosis of the individual conditions in this group can be difficult but aided by distinct clinical presentations.

LS has numerous lentigines, café au lait spots, HCM and deafness while NS cases display more obvious facial characteristics in youth and present with PVS as the most common cardiac defect and lack the typical deafness and HCM seen in LS patients. However, it remains difficult to diagnose LS in children who may not initially present with lentigines but then develop them over time. Genetic testing and repeated examinations through the years are essential in suspected cases.

Neurofibromatosis-Noonan syndrome (NFNS) displays clinical overlap with LS. It has the facial and cardiac defects seen in NS, as well as the characteristics of NF1 such as CLS, neurofibromas, CNS and skeletal anomalies. The most conclusive way to differentiate cases from LS is through mutation-based testing.

Turner syndrome, found only in females, can be eliminated from the differential by looking at the patient’s karyotype. Costello syndrome is represented by loose skin folds, intellectual impairment, heart defects, distinguishing facial features, short stature and flexible joints; it is caused by a defect in the HRAS gene.

Who is at Risk for Developing this Disease?

LEOPARD Syndrome (LS) is an extremely rare disorder with no birth prevalence data available. Approximately 200 cases have been documented worldwide; however, LS is potentially underdiagnosed or misdiagnosed since characteristics may be mild. An inaccurate diagnosis may occur due to the absence of lentiginosis. It is often grouped with a collection of disorders known as Ras/MAPK pathway syndromes, and follows Noonan syndrome as the second most likely common NCFC (neuro-cardio-facial-cutaneous) syndrome. The risk for LS is the same for males and females.

What is the Cause of the Disease?

Sporadic or inherited missense mutations to the PTPN11 gene located on chromosome 12q24.1 are responsible for 85% of LS cases. The mutation has full penetrance and an autosomal dominant inheritance pattern. The gene product of PTPN11 is an SRC homology 2-domain-containing ATPase(SHP2) protein. With special emphasis in the Ras/MAPK pathway, SHP2 is a cytoplasmic signaling transducer downstream of multiple receptors for growth factors, hormones, and cytokines. Currently, 11 mutations in exons 7, 12, and 13 have been found in the PTPN11 gene, two of which are responsible for 65% of the reported cases of LS.

Mutations in exons 7 and 12 correlate with a higher incidence of hypertrophic cardiomyopathy (HCM), while those in exon 8 are associated with pulmonary valve stenosis (PVS). Cases in which patients present with HCM lacking a PTPN11 mutation have an increased family history of adverse arrhythmic and nonarrhythmic events such as sudden death, increased left atrial dimensions, and bradyarrhythmias. In those patients with LS that lack a PTPN11 mutation, there is an unusually high incidence of ECG abnormalities secondary to left ventricular hypertrophy (LVH). Exon 13 mutations in the PTPN11 gene are linked to rapidly progressive severe biventricular obstructive HCM with onset during the prenatal period.

As noted, 85% of LS patients have a PTPN11 mutation, and those that lack a PTPN11 mutation will likely have a RAF1 mutation. Approximately 5% of LS cases lack a mutation in both RAF1 and PTPN11. Continued research is still needed to determine how the mutations noted are related to the phenotypical presentations of LS.

There is genetic heterogeneity within LEOPARD syndrome. This has led to the designation of LEOPARD syndrome 2, caused by genetic mutations in the RAF1 gene, and LEOPARD syndrome 3, caused by genetic mutations in the BRAF gene (Table I).

Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved.

No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.