History
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. [20]
Multiple lentigines must be present.
Features of at least two of the following other categories must be present:
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Other cutaneous abnormalities
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Cardiac structural or electrocardiographic abnormalities
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Genitourinary abnormalities
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Endocrine abnormalities
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Neurologic defects
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Cephalofacial dysmorphism
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Shortness of stature
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Skeletal abnormalities
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%). [22] The hypertrophic cardiomyopathy can be clinically silent, evident only by a murmur over the precordium on routine examination. [23]
Physical Examination
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. [24]
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 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, [25] 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:
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Axillary freckling
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Café au lait spots
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Localized hypopigmentation
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Onychodystrophy (see the image below)
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Interdigital webs
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Hyperelastic skin
Multiple granular cell tumors have been observed with LEOPARD syndrome. [26]
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. [27] 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. [28] Accelerated cardiomyocyte proliferation in the heart of a neonate with this syndrome has been described associated with a fatal cardiomyopathy. [29]
In 2004, Yagubyan et al reported a patient with recurrent upper extremity aneurysms that required multiple operations. [30] This patient also had multiple other peripheral aneurysms, thus far asymptomatic. Abnormal, extremely elongated vertebral and basilar arteries have also been reported. [31]
About 35% of the patients demonstrate various cephalofacial findings. Ocular hypertelorism was the most frequently reported (25%). Other findings include the following:
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Mandibular prognathism
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Broad nasal root
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Dysmorphic skull
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Low-set ears
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Dental abnormalities
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High palate arch
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Epicanthal folds
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Ptosis
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Corneal tumors
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. [32]
LEOPARD syndrome may be associated with hypertrophic plexuses, possibly leading to neuropathic pain. [33]
Complications
Complications may arise due to associated abnormalities.
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Multiple lentigines on the face of a child with LEOPARD syndrome.
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Lentigines on the sclerae in a child with LEOPARD syndrome.
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Area of disordered pigmentation on the trunk of a patient with LEOPARD syndrome.
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Onychodystrophy in a child with LEOPARD syndrome.
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Multiple, small lentigines evenly distributed over the trunk of an adult female with LEOPARD syndrome.
