LEOPARD syndrome is a complex dysmorphogenetic disorder of variable penetrance and expressivity. Gorlin et al introduced the acronym LEOPARD as the name of the syndrome in 1969 to recall the main features of the disorder, as follows:
Not all of the findings are present in any given patient. Zeisler and Becker first described the syndrome in 1936 in a 24-year-old woman with progressive generalized lentigines, hypertelorism, pectus carinatum, and prognathism. The first familial cases were reported in twins by Rosen and subsequently in 8 persons from a large 3-generation pedigree reported by Pipkin. Subsequent communications added new findings in isolated patients or families. Moynahan first documented the association of the syndrome with cardiac abnormalities and short stature in 1962.
Molecular studies have proven that LEOPARD syndrome and Noonan syndrome are allelic disorders caused by different missense mutations in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located at band 12q24.1.
In 2005, Ogata and Yoshida documented that PTPN11 mutations can be identified in approximately 40% of Noonan syndrome patients and in greater than 80% of LEOPARD syndrome patients. Because the vast majority of mutations reside in and around the broad intramolecular interaction surface between the N-SH2 and PTP domains of the PTPN11 protein, they have been suggested to affect the intramolecular N-SH2/PTP binding in the absence of a phosphopeptide, leading to excessive phosphatase activities.
In 2006, Hanna et al found that Noonan syndrome mutations enhance SHP-2 catalytic activity, whereas the activity of representative LS mutants is undetectable when assayed using a standard PTP substrate. The results are also supported by studies by Kontaridis et al. They revealed that whereas Noonan syndrome is caused by gain-of-function PTPN11 mutations, LEOPARD syndrome mutants are catalytically defective and act as dominant negative mutations that interfere with growth factor/Erk-mitogen-activated protein kinase–mediated signaling. LEOPARD syndrome may be caused by heterozygous missense mutation of Tyr 279 Cys in the PTPN11 gene. In one Bosnian family, five patients had the same recurrent mutation Y279C in the PTPN11 gene, but had different phenotypes and a variable expression of multiple lentigines.
In 2006, Tartaglia et al reported that germline mutations in the PTPN11 gene cause LEOPARD and Noonan syndromes, whereas somatic mutations in the same gene contribute to leukemogenesis. To date, 2 patients with LEOPARD syndrome and myelomonocytic or acute lymphoblastic leukemias have been reported.[8, 9]
Importantly, however, not all patients with LEOPARD syndrome demonstrate linkage to 12q24.1.
Reported in 2005, Kalidas et al performed mutation screening and linkage analysis of PTPN11 in 3 families, each of which had a history of LEOPARD syndrome for 3 generations. One family was found to carry a novel mutation (Q510P; 176876.0022). No variations in sequence were observed in the other 2 families, and negative lod scores excluded linkage to the PTPN11 locus, showing that LEOPARD syndrome is genetically heterogeneous.
Writzl et al reported a family with molecularly proven (p.Thr468Met in PTPN11) LEOPARD syndrome in a father and his adult son. The father had multiple lentigines equally dispersed over his body as depicted below, whereas his son was devoid of lentigines on the left part of the thorax, back, and left arm. In addition, the son was found to have a mosaic karyotype in lymphocytes (47, XXY/46XY). On skin biopsy, mainly 47,XXY karyotype was present in the pigmented skin and 46,XY karyotype in the unpigmented areas. The authors considered various pathogenetic mechanisms: revertant mosaicism, silencing of a second PTPN11 mutation, genes located on a sex chromosome influencing the phenotype, and epigenetic influences.
Multiple, small lentigines evenly distributed over the trunk of an adult female with LEOPARD syndrome.
No epidemiologic data are available. The syndrome seems to be rare both in the United States and internationally.
Most patients with LEOPARD syndrome lead a normal life. Cardiac pathologic findings (eg, obstructive cardiomyopathy, cardiac dysrhythmias) may be a cause of death in selected patients. A 19-year-old woman who died as a result of respiratory insufficiency secondary to thoracic deformities and a congenital heart defect has been reported.
LEOPARD syndrome has no clear racial predilection.
In a large collected series of 77 patients, a slight preponderance of men has been documented (47 men, 30 women).
Lentigines may be present at birth or develop during childhood. They become more numerous and darker with age. Other skin lesions, such as nevocellular nevi and malignant melanomas, reported sporadically in the LEOPARD syndrome, may undergo depigmentation.
Highly variable expressivity of the syndrome makes the diagnosis difficult, especially in sporadic patients. Seventy percent of reported cases are familial. Based on clinical analysis of a large series of patients collected from the literature, in 1976 Voron et al proposed minimum criteria for the diagnosis.
Multiple lentigines must be present.
Features of at least 2 of the following other categories must be present:
If lentigines are absent, a diagnosis of LEOPARD syndrome may be established if the patient has features in at least 3 above-mentioned categories and has an immediate relative with the defined diagnosis.
Diagnosis of LEOPARD syndrome is very difficult in small children. According to Digilio et al, the diagnosis can be clinically suspected in the first months of life in patients who have 3 main features: characteristic facial features (100%), hypertrophic cardiomyopathy (87%), and café au lait spots (75%).
Lentigines are small, dark brown, polygonal, irregularly shaped macules, usually 2-5 mm in diameter, but sometimes larger, even up to 1-1.5 cm. These large and darkly pigmented lesions are called by some authors café noir spots, by analogy to café au lait spots observed in neurofibromatosis type 1.
They are often present on the face, neck, and upper part of the trunk but also on the palms, soles, and the sclerae as shown in the images below.
Lentigines on the sclerae in a child with LEOPARD syndrome.
Area of disordered pigmentation on the trunk of a patient with LEOPARD syndrome.
Lentigines are the most prominent manifestation of the LEOPARD syndrome and are present in more than 90% of the patients; however, an absence of the feature does not exclude the diagnosis of the syndrome. Speculation about generalized lentiginosis always being a part of the spectrum of LEOPARD syndrome have been recently weakened by a study from Xing et al, who mapped familial generalized lentiginosis without systemic involvement to band 4q21.1-q22.3.
On careful skin examination, other cutaneous abnormalities may be detected, such as the following:
Mental retardation, usually of mild degree, is observed in about 30% of the affected persons.
About 25% of patients have sensorineural hearing loss.
Seizures, nystagmus, or hyposmia have been documented in a few patients.
One third of the patients demonstrate short stature (in 20% of the cases below third percentile), which seems to become evident soon after birth (most newborns are of normal birth weight).
Despite frequent cardiac involvement, most patients are asymptomatic, and findings upon routine physical examinations may be negative. Interestingly, a higher frequency of family history of sudden death and atrial fibrillation has been reported in patients with left ventricular hypertrophy without PTPN11 mutations. A comprehensive review of 26 patients with LEOPARD syndrome documented left ventricular hypertrophy in 19 patients (73%) and right ventricular hypertrophy in 8 patients (30%). Long-term prognosis was overall benign, but the occurrence of 4 fatal events in patients with left ventricular hypertrophy indicates that such patients require careful risk assessment.
In 2004, Yagubyan et al reported a patient with recurrent upper extremity aneurysms that required multiple operations. This patient also had multiple other peripheral aneurysms, thus far asymptomatic. Abnormal, extremely elongated vertebral and basilar arteries have also been reported.
About 35% of the patients demonstrate various cephalofacial findings. Ocular hypertelorism was the most frequently reported (25%). Other findings include the following:
Developmental anomalies of the genitourinary system are described in 26% of patients, predominantly in men. Abnormalities of the external genitals, such as cryptorchidism or hypospadias, may be observed on physical examination.
Different types of skeletal anomalies have been documented in affected patients, including chest deformity (pectus excavatum, pectus carinatum), kyphoscoliosis, winging of the scapulae, rib anomalies, syndactyly, delayed development or agenesis of permanent teeth, or supernumerary teeth.
In 2004, Rudolph et al reported colobomas of the iris, the retina, and the choroid in 3 members of one family.
Familial cases suggest an autosomal dominant mode of inheritance with variable expressivity. Speculation exists on the more severe course of the disease in males, which may partially explain the slight preponderance of men in the large collected series of Voron et al in 1976.
In some patients with endocrine abnormalities, low levels of follicle-stimulating hormone, luteinizing hormone, and thyrotropin and elevated levels of 17-hydroxy and 17-ketosteroids have been revealed.
CT scanning or MRI of the head may reveal brain atrophy.
Skeletal radiography is indicated for detection of skeletal malformations or for bone age assessment.
Echocardiography should be done for visualization of structural heart abnormalities (eg, pulmonary valve stenosis, obstructive cardiomyopathy, myxomas).
Assessment of the genitourinary system may require abdominal ultrasonography or urographic examination.
Perform electrocardiography to exclude conduction abnormalities, which are reported in about one third of the patients. The most common electrocardiographic changes are left axis deviation, prolonged PR intervals, and right bundle branch block. Due to possible arrhythmia, ECG is especially mandatory before all planned surgical interventions.
Due to possible arrhythmia, ECG is mandatory before all planned surgical interventions.
EEG is recommended for patients with seizures.
Sensorineural deafness may be detected by audiography or auditory evoked potentials.
Biopsy of a lentigo reveals an increased number of melanocytes per unit skin area and prominent rete ridges. Electron microscopic examination reveals large accumulations of melanosomes within the Langerhans cells and giant melanosomes. The latter were reported both in normal and pigmented skin in patients with the LEOPARD syndrome; they are also found in patients with neurofibromatosis and nevus spilus.
Cryosurgery and laser treatment may be beneficial for isolated lentigines; however, because of the large number of lentigines it may be time consuming. For some patients, treatment with tretinoin cream and hydroquinone cream may be helpful.
Therapeutic regimens include beta-adrenergic receptor or calcium channel blocking agents to reduce outflow tract obstruction and adrenergic responsiveness in patients with structural cardiac anomalies.
Antiarrhythmic treatment may be required in cases with life-threatening ventricular ectopy.
Surgical treatment may be necessary in cases with severe outflow tract obstruction or in patients with cryptorchidism, hypospadias, or severe skeletal deformity.
Genetic counseling should be offered to all patients with LEOPARD syndrome. Frequent presentation of forme fruste requires careful examination of all family members.
Consult a cardiologist, endocrinologist, and orthopedist as dictated by history and physical examination findings.
Advise patients with outflow tract obstruction or significant cardiac dysrhythmias to avoid strenuous physical exercises.
The combination of tretinoin and hydroquinone can be used as a skin lightening agent.
Clinical Context: Tretinoin is a keratolytic agent. It acts by increasing epidermal cell mitosis and turnover while suppressing keratin synthesis. Tretinoin may help lighten lentigines, particularly when used in combination with hydroquinone.
Retinoids decrease the cohesiveness of abnormal hyperproliferative keratinocytes and may reduce the potential for malignant degeneration. They modulate keratinocyte differentiation. Retinoids have been shown to reduce the risk of skin cancer formation in renal transplant patients. In this case, the combination with hydroquinone is good for topical use.
Clinical Context: Hydroquinonelightens hyperpigmented skin by inhibiting enzymatic oxidation of tyrosine and suppressing other melanocyte metabolic processes, thereby further inhibiting melanogenesis. Exposure to the sun reverses effects and causes repigmentation.
Depigmenting agents block melanogenesis and work well in combination with tretinoin.
No further inpatient care is needed except as indicated for complications of associated abnormalities.
All patients with the LEOPARD syndrome should undergo periodic cardiac assessment with echocardiography and electrocardiographic examination because the heart conduction impairment tends to occur gradually but progressively.
Genetic counseling and examination of other family members is indicated.
Complications may arise due to associated abnormalities.
Prognosis is determined mainly by cardiac complications.