LEOPARD Syndrome

Clinical Definition, Features, Gene Defect, and Therapeutics

LEOPARD syndrome is a complex dysmorphogenetic disorder transmitted as an autosomal dominant trait with variable penetrance and expressivity. LEOPARD represent an acronym coined by Gorlin et al. in 1969 as a mnemonic Opens in new window to recall the main features of the disorder:

  • Lentigines (multiple)
  • Electrocardiographic conduction defects
  • Ocular hypertelorism
  • Pulmonary stenosis
  • Abnormalities of genitalia
  • Retardation of growth
  • Deafness (sensory neural Deafness)

Lentiginosis Opens in new window is a hallmark of this familial syndrome, which is regarded as a neuroectodermal defect.

Affected individuals typically show an elongated, marfanoid facies, and several café-au-lait macules Opens in new window admixed within the myriad of lentigines Opens in new window.

Variable expressivity is seen within families, so that some affected individuals show only the multiple lentigines whereas others show a variety of the visceral manifestations.

In recent years this multifaceted syndrome has attracted the interest of dermatologists, pediatricians, neurologists, cardiologists, endocrinologists, orthopedists, and radiologists.

Other than the name LEOPARD syndrome, the syndrome is known by a number of names:

  • Cardiocutaneous lentiginosis syndrome
  • Multiple lentigines syndrome
  • Generalized lentiginosis
  • Centrofacial lentiginosis
  • lentiginosis profuse syndrome
  • lentiginosis-deafness-cardiopathy syndrome
  • cardiocutaneous syndrome
  • progressive cardiomyopathic lentiginosis
  • Moynahan syndrome

However the most widely accepted term is LEOPARD syndrome.

Clinical Manifestations

  1. Lentigines

Lentigines Opens in new window are the most common clinical feature of LEOPARD syndrome, seen in 86% of cases. They can be present at birth and the number increases into thousands until puberty.

Lentigines are often small, dark brown, irregular shaped, usually from pinpoint to 5 mm in diameter, but sometimes larger, even up to 1–1.5cm.

leopard syndrom associated symptoms Figure X-1: Skin features of LEOPARD syndrome individual at different ages | Photo courtesy of Orphanet Journal of Rare Diseases Opens in new window
A: Numerous lentigines in the upper part of the trunk in a 2 year old child with a PTPN11 gene mutation. B: Lentigines and a large cafè-au-lait spot (28 year-old female patient). C: A 28 year old female patient with thousands of lentigines scattered all over the neck and back. Note the pterigium colli. D: Multiple lentigines on the lower leg (37 year-old male patient).

Lentigines are usually located on the upper part of the trunk and neck, but also often present on the face, palms, soles, genitals, and even on the sclearae. With age they become darker and more numerous.

On careful skin examination, other cutaneous abnormalities may be detected: axillary freckling, café-au-lait spots Opens in new window, hypopigmentations Opens in new window, onychodystrophy or hyperelastic skin.

In some cases, patches of hair loss on the scalp can be observed.

Some isolated lentigines may be successfully treated with intense pulsed light and cryosurgery. However, such treatment modalities are less effective in respect to multiple lentigines. For some patients, treatment with tretinoin cream and hydroquinone cream may be helpful.

  1. Cardiac and vascular abnormalities

In 1976, Voron et al. reported that about 40% of patients with LEOPARD syndrome have pulmonary stenosis Opens in new window, either valvular or infundibular type.

Frequently, an obstruction of left or right ventricular outflow tracts was related to obstructive hypertrophic cardiomyopathy with clinical manifestations even in infancy.

Several other types of cardiac or vascular structural defects were revealed, including atrial myxomas, atrial insufficiency or aneurysms of large vessels.

Yagubyan et al. (2004) reported a patient with recurrent upper extremity aneurysms requiring multiple operations. Another unusual vascular finding in LEOPARD syndrome was congenital intrahepatic portosystemic venous shunt Opens in new window.

Despite frequent cardiac involvement, most patients are asymptomatic, and routine physical examination may be negative.

Normal electrocardiogram does not exclude a risk of sudden death. The conduction impairment tends to occur gradually and progressively.

In patients with cardiac structural abnormalities beta-adrenergic receptor or calcium channel blocking agents are applied to reduce outflow tract obstruction and adrenergic responsiveness.

Antiarrhythmic treatment may be given in selected patients with ventricular rhythm abnormalities.

  1. Neurologic abnormalities

Mental retardation Opens in new window, the most frequent neurologic abnormality among patients with the LEOPARD syndrome, was documented in 30% of subjects reviewed by Voron et al. (1976), and 27% those reported by Sarkozy et al. (2004). Mental retardation is usually of mild degree.

Sensorineural hearing loss Opens in new window appears in 20–25% of affected persons. As melanocyte participates in the formation of the inner ear, some postulate, that this kind of deafness may be due to a primary abnormality in neural crest development.

Other uncommon neurological manifestations of LEOPARD syndrome include nystagmus Opens in new window, hyposmia Opens in new window, seizures Opens in new window and abnormalities in electroencephalograms.

In few patients, mild cerebral atrophy Opens in new window can be found in neuroimaging examinations.

There is no specific treatment for neurological abnormalities in LEOPARD syndrome. If seizures occur, EEG and antiepileptic therapy is recommended.

  1. Genitourinary abnormalities

The most common abnormalities of genitourinary system Opens in new window in LEOPARD syndrome comprise cryptorchidism Opens in new window, either unilateral or, more likely, bilateral, hypospadias Opens in new window and delayed puberty.

All of these features are distinctly more frequently seen in males, but this predominance can reflect the involvement of visible genitalia and resulting easier diagnosis.

In few patients, other disturbances such as, absent ovary, cystic hyperplastic ovary, agenesia of the kidney and ureter with contralateral hydroureter, double ureter or small penis attached to anterior abdominal wall, were reported.

Taken together, genitourinary abnormalities affect 26% of LEOPARD syndrome patients.

There is no established method to treat genitourinary abnormalities in LEOPARD syndrome. In some cases, hormonal therapy to bring testes into scrotum can be effective.

Surgical treatment is required in hypospodias and hormone-resistant cryptorchidism.

  1. Endocrine abnormalities

As retardation of growth and genitourinary disturbances including delayed puberty are pivotal symptoms of LEOPARD syndrome, endocrine abnormalities are apparently very much involved in the pathogenesis of the disease.

Unfortunately, systematic hormonal examinations of LEOPARD syndrome patients are lacking. In some patients, hypopgonadatropic hypogonadism or hypothyroidism were described.

Laboratory studies performed in few patients revealed low level of follicle stimulating hormone (FSH), and luteinizing hormone (LH), low levels of T3 or T4, elevated urinary concentration of 17-hydroxy- and 19-ketosteroids in some cases.

Interesting, despite retardation of growth seen in many patients with LEOPARD syndrome, growth hormone levels were reported to be normal.

  1. Dysmophic features

Retardation of growth is one of key LEOPARD syndrome features. One third of patients demonstrate short stature and 20% of cases are below 3rd percentile.

In majority of patients birth weight is normal, suggesting that postnatal factors are involved in this symptom pathogenesis.

The detailed background of growth retardation in LEOPARD syndrome is not known.

Although in few cases it seemed to be related to puberty delay, there are no reliable data supporting the association of growth retardation with other coexisting features or low level growth hormone. Therefore, defects in skeletal growth center response to physiological levels of various growth factors as well as mesodermal disorder manifestation are taken into consideration.

Ocular hypertelorism Opens in new window is the most common cephalofacial abnormality, seen in 25% of patients with LEOPARD syndrome. Other features include: mandibular prognatism, low-set large auricles, ptosis, high palatal arch, epicanthic fold and broad nasal root.

Different craniofacial dysmorphic features can be noticed in as much as 90% of patients with LEOPARD syndrome.

  1. Skeletal abnormalities

Skeletal anomalies are relatively frequently found in LEOPARD syndrome patients. Most are minor and do not require special treatment.

Chest deformity (either pector excavatum or carinatum) is the most common anomaly.

Others include kyphoscoliosis, retarded bone age, wingin scapulae, rib anomalies, cervical spine fusion, syndactyly and supernumerary teeth. In some cases, surgical treatment can be beneficial.

Pathogenesis/molecular genetics

The LEOPARD syndrome is an autosomal dominant Opens in new window condition that shares several clinical features with Noonan syndrome.

About 40% of patients with Noonan syndrome Opens in new window have missence mutations in the PTPN11 gene, which encodes for the protein tyrosine phosphatase SHP2.

The recent developments in molecular genetics demonstrate that the LEOPARD syndrome is allelic to Noonan syndrome, with two recurrent PTPN11 mutations in exons 7 (Tyr279Cys) and 12 (THr468Met).

These two mutations are detected in about 80% of the patients with LEOPARD syndrome. Other patients have 5 additional mutations.

The revealed mutations suggest that distinct molecular and pathogenetic mechanisms cause the peculiar cutaneous manifestations of the syndromes.

Clinical variability seen in patients with the same mutation Opens in new window likely reflects the effect of modifier genes or environmental factors, or both, which influences the phenotypes Opens in new window associated with PTPN11 mutations.

Differential diagnosis

First distinction should be made between lentigines Opens in new window and freckles Opens in new window. Lentigines occur at an earlier age than freckles and, unlike the latter, do not increase in number upon solar exposure.

There is also a clinical overlap between LEOPARD syndrome and neurofibromatosis 1 Opens in new window. Café-au-lait macules Opens in new window and multiple lentigines are skin lesions common to both disorders.

However a differential diagnosis in children may be difficult, as café-au-lait macules Opens in new window increase in number with age in both conditions, whereas the lentigines Opens in new window characteristic of LEOPARD syndrome are not present at younger age and develop during childhood.

In adolescents and adult patients the lentigines of LEOPARD syndrome are distinguishable from those found in neurofibromatosis 1, being generalized and dark in color.

Patients with Noonan syndrome Opens in new window have café-au-lait macules similar to those found in neurofibromatosis 1 and frequently pulmonary stenosis.

Watson syndrome Opens in new window, an autosomal dominant disorder characterized by pulmonary stenosis, café-au-lait macules, short stature and limited intelligence should also be differentiated with LEOPARD syndrome.


Cryosurgery and laser therapy may be beneficial for isolated lentigines, however, due to the large number of the lesions this type of treatment may last very long. Treatment with tretinoin cream and hydroquinone cream may be helpful in some patients.

To reduce outflow tract obstruction and adrenergic responsiveness, therapeutic regimens including betaadrenergic receptor or calcium channels blocking agents are recommended.

Amiodarone treatment may be applied in cases of life-threatening ventricular ectopy. Surgery may be necessary in cases with severe outflow tract obstruction.

Surgery may also be necessary in patients with cryptorchidism, hypospadias, or severe skeletal deformity. Other supportive measures may be applied for the management of psychomotor retardation and sensorineural deafness.

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