Leopard Syndrome

What is LEOPARD Syndrome?

LEOPARD Syndrome is a multifaceted  genetic disorder. The acronyms of this rare syndrome itself provide the detail expression  of the associated complexity.

L:  Lentigines, means numerous visible blackish or dark brownish spots on the skin;

E: Electrocardiographic conduction defects means irregularity of the electrical impulse generation and transmission of the heart;

O: Ocular hypertelorism means wide- spaced eyes;

P: Pulmonary stenosis means obstructed blood outflow from the lower right chamber (right ventricle) of the heart;

A: Abnormalities of the genitals;

R: Retarded growth, which leads to short physic;

D: Deafness means sensorineural hearing loss due to faulty functioning of the inner ear. ^(1,3)

Image 1 – LEOPARD Syndrome Definition

Clinical presentation

The symptoms related contract is common in LEOPARD Syndrome. Some patients have partial symptom development, while others may develop a complete list of symptoms. Severity is also depends upon the affected organ system.

Facial characteristics

The facial abnormalities are not distinct at the time of birth in LEOPARD Syndrome. The child has developed multiple distinct Dysmorphic features with increasing of age, which include:

• Hypertelorism: orbits are distantly apart from each other
• Flat nasal bridge
• Dysmorphic ears
• Low-set ears
• Thick lips
• Drooping or falling of the upper eyelid (palpebral ptosis)
• Wrinkled skin

Anomalies of Cardiovascular system

The heart related problems with LEOPARD Syndrome are individual specific and that can be observed in abnormal electrocardiogram findings. The most common cardiac  and associated problems are as follows:

• Hypertrophic cardiomyopathy is most common features and mainly affect left ventricle. This leads to significant obstructive left ventricular outflow.
• Prolonged QTc
• Conduction defects
• Pulmonary valve stenosis
• Mitral valve prolapse

Following  are the less commonly heart related problems also observed:

• Coronary artery abnormalities,
• Atrial and atrioventricular septal defects,
• Apical aneurysm and non compaction of the left ventricle,
• Isolated left ventricular enlargement
• Multiple ventricular septal defects
• Endocardial fibroelastosis

Skin

The specific clinical presentation of LEOPARD Syndrome is  Lentigines. The lentigines are looks like not elevated, blackish or brownish macules, distinctly appear on the face, neck, and trunk, but limited in the mucosa.

Usually lentigines are visible at the age of 4 to 5 years old and rapidly spread. The number of these distinct spots becomes more than a thousand within adolescent age. The rate of progression does not depend on direct sun exposure. The color of the lentigines is not specific, but it has been observed that the color is darker in dark skinned individual. In rare cases, hypo-pigmented skin is also noticeable.

Physical development

The birth weight is normal in LEOPARD Syndrome, but gradually growth becomes retarded with increasing of age.

Bone abnormality

The following bone or skeletal system abnormalities are observed in LEOPARD Syndrome;

• Wide chest
• Pectus carinatum (protrusion of the sternum and ribs)
• Excavatum (sunken sternum)
• Mandibular prognathism or protruding jaw
• Winging of the scapulae
• Scoliosis (spine curvature towards the side)
• Hyperflexibile joint

Genitourinary and renal anomalies

The following genital and urological abnormalities are associated with LEOPARD Syndrome:

• Bilateral cryptorchidism  (nonexistence of both testes)in affected male
• Hypospadia (opening of the urethra does not located at the tip of the penis, present in underside) in men
• Genital hypoplasia in male
• Reduced male fertility.
• Delayed puberty and hypo-plastic
• Horseshoe kidney is present with renal abnormality.

Hearing problem

Sensorineural hearing loss (deafness) is common in  LEOPARD Syndrome. This problem may diagnose at the time of birth, but can arise with increasing age.

Neurological abnormalities

Some neurological abnormalities such as hypotonia , delayed psychomotor development, mild learning difficulties are common. In rare cases, mental retardation occurs.

Tumors

Malignant cell development related to hematological complications, including myelodysplasia, acute myelogenous leukaemia, malignant melanoma, neuroblastoma and bilateral choristomas are rare findings. ^(2,3)

Causes

LEOPARD syndrome is usually developed due to  abnormal genetic mutations in the protein-tyrosine phosphatase, nonreceptor type 11 (PTPN11) gene or RAF1. The pattern of transmission of disease can explain that LEOPARD syndrome is an inherited autosomal dominant disease. The abnormal genetic transmission from one parent to each child is 50%; though there is a chance of new mutations can cause  sporadic development of the LEOPARD syndrome.  ⁽⁴⁾

Diagnosis

Molecular genetic testing for the PTPN11 gene and the RAF1 gene is accessible to validate the diagnosis and for prenatal diagnosis.

The graphical representation of ECG with X-ray imaging technique, apply to  confirm hypertrophic obstructive cardiomyopathy and other cardiac problems.

The newborn with LEOPARD syndrome may immediately not identified; but the gradual clinical presentation confirms the presence of disease.

The heart and lung sound assessment with a stethoscope is distinct with physical examination and abnormality of findings may due to  pulmonary stenosis.

A light microscopy or an electron beam substantially measure multiple lentigines at the pigmented areas of skin. A skin biopsy is also conducted.

Echographic and radiological techniques can be conducted for detection or confirmation of the genital abnormalities

X-ray assessment assists to detect certain skeletal abnormalities ^(2,3)

What treatments are available?

The multifaceted expert team is required to treat . The disease is non curable, but the aim of the provided treatment is to improvement of the quality of life of the patient. The treatment approach is usually supportive. The medical team to manage the  includes cardiologist, endocrinologist, dermatologist, orthopedist, geneticists, and social support networks.

• A beta-blockade or calcium channel blockers therapy  can be prescribed to manage a considerable gradient between the left ventricle and the aorta.
• Surgical removal of the left ventricular outflow obstruction is required if medical does not provide effective outcome
• Growth hormone (GH) therapy may recommend for treat the retarded growth
• Application of topical retinoids and hydroquinone cream can provide improved outcome on skin symptoms. But most frequently applied treatment approaches are chemical peels, laser treatments, cryotherapy,  or surgical excision to treat skin symptoms.
• Hearing aids can recommend to get benefits. ^(2,3,4)

Pictures

Image 2 – Lentigines over hands

Image 3 – Hypertelorism in leopard syndrome

Image 4 – Few Lentigine over trunk (chest)

References

1. Robert A Schwartz (2016), Leopard syndrome; Retrieve from: http://emedicine.medscape.com/article/1096445-overview
2. Anna Sarkozy,Maria Cristina Digilio, Bruno Dallapiccola; Leopard syndrome; Orphanet Journal of Rare Diseases20083:13; DOI: 10.1186/1750-1172-3-13; Retrieve from: https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-3-13
3. LEOPARD Syndrome; National Organization for Rare Disorders; Retrieve from: http://rarediseases.org/rare-diseases/leopard-syndrome/
4. LEOPARD syndrome; DermNet NZ; Retrieve from:  http://www.dermnetnz.org/systemic/leopard.html