LEOPARD Syndrome

Acronym for lentigines (multiple), electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and deafness (sensorineural). Complex congenital dysmorphogenetic disorder associating mainly skin lesions (lentigines), severe cardiac anomalies (dysrhythmias, pulmonary valve stenosis), ocular hypertelorism, abnormalities of genitalia, sensorineural deafness, and severe retardation of growth.

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Cardiocutaneous Syndrome; Cardiocutaneous Lentiginosis Syndrome; Cardiomyopathic Lentiginosis; Centrofacial Lentiginosis; Generalized Lentiginosis; Lentiginosis-Deafness-Cardiopathy Syndrome; Lentiginosis Profusa Syndrome; Moynahan Syndrome; Multiple Lentigines Syndrome; Progressive Cardiomyopathic Lentiginosis.

First described by Zeisler and Becker in 1936. It has many similarities to Noonan syndrome, except in the most striking features, from which its name is derived. The mnemonic was first used by Gorlin et al. in 1969.

Rare; slightly more than 80 cases reported. Life expectancy is normal.

Sporadic or autosomal dominant. Single mutant gene with high penetrance and variable expression produces the defects in this syndrome. Slight male predominance.

Mutation in the stem cell pool of the neural crest in embryonic life is regarded as a common cause of cutaneous (producing lentigines), neurologic, cardiac (resulting in cardiomyopathy), and possibly urogenital defects. Metabolism of dihydroxyphenylalanine (DOPA), epinephrine, and norepinephrine is altered, which may result in abnormal skin pigmentation.

Diagnostic criteria included skin lentigines plus two other recognized features or a first-degree relative with lentigines plus three other features in the patient. Histologic examination of the lentigines shows pigment accumulation in the dermis and in the deeper layers of epidermis. There is an increase in melanocytic density owing to corrugation of the dermoepidermal junction.

Lentigines (1-2 mm; flat, dark brown-to-black cutaneous lesions) can be present at birth and increase in number until puberty. They are most numerous on the face, neck, and upper trunk but spare the mucous membranes. Valvular pulmonary stenosis is the most common (40% of cases) cardiovascular abnormality. Hypertrophic obstructive cardiomyopathy is a major concern with onset usually in childhood. Subsequent progression may be mild and slow or severe and florid with rapid decompensation. Conduction abnormalities are common and result from combinations of blocks in the bundle branch system. These abnormalities may be asymptomatic or sufficiently severe to provoke sudden death. The conduction impairment develops gradually and is progressive. Ocular hypertelorism, mandibular prognathism, and short stature are the most common skeletal abnormalities. Pectus excavatum and carinatum are common, as is scoliosis (10% of cases). Sensorineural hearing loss may be severe and may appear late in life.

Echocardiographic examination to look for the presence of cardiomyopathy, pulmonary valve stenosis, and subaortic stenosis (with outflow tract obstruction) is mandatory. Evaluate pulmonary function (when feasible as a function of patient's age) in the presence of thoracic abnormalities (forced vital capacity [FVC], peak expiratory flow rate [PEFR], forced expiratory volume in 1 second [FEV1], FEV1/FVC ratio, arterial blood gas analysis, and chest radiographs).

Of primary importance is the high incidence of associated disorders affecting the cardiovascular system, such as congenital heart diseases, conduction disturbances, and hypertrophic obstructive cardiomyopathy. All children presenting with multiple cutaneous lentigines should be considered to have Leopard syndrome until proven otherwise. Special consideration given to factors that may produce changes in intravascular volume, ventricular contractility, and transmural distending pressure of the outflow tract. Avoid prolonged preoperative fasting that produces volume depletion. Tachycardia and positive inotropic agents may be deleterious because they decrease diastolic filling time and stroke volume and increase turbulent flow across the outflow tract. Elective surgery under general anesthesia is contraindicated when respiratory and/or cardiac functions are severely impaired (ventricular ejection fraction <0.5, FVC <25%, PEFR <30%). Regional anesthesia (central neuraxial) should be used with great caution in children older than 5 years of age.

Avoid anticholinergic premedication but provide adequate anxiolysis. Halothane is preferred by some because it decreases more ventricular contractility and heart rate compared to isoflurane or sevoflurane. The use of total intravenous anesthesia maintaining the patient's preoperative hemodynamic condition is also an alternative.

Neurofibromatosis Generalisata Type I: Café-au-lait spots, freckles, development of benign neurofibromas. Autosomal dominant. Caused by a mutation on chromosome 17.

Central Neurofibromatoses: Development of schwannomas on the eighth cranial nerve and many other nerves, early cataract, and few (inconstant) café-au-lait spots. Autosomal dominant. Caused by a mutation on chromosome 22.

Noonan Syndrome: Unusual facies mimicking Turner syndrome, short stature, chest deformity, and inconstantly mental retardation. Autosomal dominant (gene defect probably located on chromosome 12q). Multiple lentigines are found in 3% of cases (thus mimicking LEOPARD syndrome and neurofibromatosis).

Forney Syndrome: Rare syndrome characterized by familial mitral insufficiency, congenital conductive hearing loss because of stapes footplate fixation, short stature, and bony fusion of carpal and tarsal bones and cervical vertebrae. The latter could lead to difficult airway management.