Leopard syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]

LEOPARD syndrome is a rare autosomal dominant,^[1] caused by a mutation in the protein tyrosine phosphatase non-receptor type 11 gene. Many systems can be involved, mostly involving the skin, skeletal and cardiovascular systems, but in other cases they are absent. The word LEOPARD is an acronym for the major features of this disorder, including multiple Lentigines, EKG abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth, and sensorineural Deafness

It was first described by Zeisler and Becker with multiple lentigines, hypertelorism, pectus carinatum (protruding breastbone) and prognathism (protrusion of lower jaw) in 1936.^[2] In 1962, cardiac abnormalities and short stature were first associated with the condition.^[2]

LEOPARD syndrome is most commonly caused by missense mutations in the PTPN11 gene. It has also been associated with other gene mutations such as RAF1 and BRAF.

Leopaed syndrome is a rare condition, but the exact birth prevalence is unknown. Approximately 200 patients have been reported.^[3] However, LEOPARD syndrome is likely underdiagnosed or misdiagnosed as many of its features are mild and the correct diagnosis might be missed in the absence of lentiginosis.

In general, males are more affected than females. LEOPARD syndrome is not a life threatening diagnosis, cardiomyopathy and other pathologic findings involving the cardiovascular system may be a cause of death in those whose cardiac deformities are profound.

LEOPARD syndrome affects many areas in the body. The characteristic feature associated with the condition is brown skin spots called lentigines. Patients are showing a wide spectrum of features include multiple lentigines, facial dysmorphisms, cardiac anomalies, electrocardiographic (EKG) conduction abnormalities, retardation of growth, abnormal genitalia and sensorineural deafness.^[4]

Hormonal abnormalities may be revealed in some patients with endocrine system involvement. laboratory studies should include molecular analysis of the PTPN11 and RAF1 genes.^[5]

Different imaging studies like X-rays, CT scanning, and Echocardiography have been used to detect abnormalities of LEOPARD syndrome.

Medical management depend on the symptoms present. Drug therapy for cardiac abnormalities,endocrine, and dermatological issues is recommended.

Different procedures may be necessary in cases with severe outflow tract obstruction^[6], patients with cryptorchidism, genitourinary, or severe skeletal deformity.

Genetic counseling should be offered before deciding to have children, careful examination of all family members as the syndrome usually present with incomplete form.

Once a decision to have children is made and the couple conceives, the fetus is monitored during the pregnancy for cardiac evaluation. If a gross cardiac malformation is found, parents receive counseling on continuing with the pregnancy.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]

LEOPARD syndrome has been described by Zeisler and Becker for the first time in 1936 with multiple lentigines, hypertelorism, pectus carinatum (protruding breastbone) and prognathism (protrusion of lower jaw) .^[1] In 1962, cardiac abnormalities and short stature were first associated with the condition.^[1]

LEOPARD syndrome has been described by Zeisler and Becker for the first time in 1936 with multiple lentigines, hypertelorism, pectus carinatum, and prognathism.^[1] Other different descriptions were added through the years. In 1962, cardiac abnormalities and short stature were first associated with the condition.^[1] In 1966, three familial cases were added, a mother, her son and daughter.^[2] Another case of mother to two separate children, with different paternity of the two children, was added in 1968.^[3] In 1969, Gorlin and his colleagues created the acronym ‘LEOPARD’ that characterized multiple lentigines syndrome.^[4] It was believed as late as 2002^[5] that LEOPARD syndrome was related to neurofibromatosis type I (von Recklinghausen syndrome). In fact, since both ICD9 and ICD10 lack a specific diagnosis code for LEOPARD syndrome, the diagnosis code for NF1 is still sometimes used for diagnostic purposes, although it has been shown that the gene is not linked to the NF1 locus.^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]

Leopard syndrome is most commonly caused by missense mutations in the PTPN11 gene. It has also been associated with other gene mutations such as RAF1 and BRAF.

Although genes PTPN11, RAF1, and BRAF are the genes known to be associated with LEOPARD syndrome, it is most commonly caused by missense mutations in the PTPN11 gene. The mutations cause a loss of catalytic activity of the SHP2 protein (the gene product of the PTPN11 gene located at chromosome 12q22-qter), which is a previously unrecognized behavior for this class of mutations.^[1] This interferes with growth factor and related signalling. While further research confirms this mechanism,^[2][3] Genetic heterogeneity recently confirmed by the identification of RAF1 gene mutations in two out of six PTPN11 mutation negative LEOPARD syndrome patients.^[4] Additional research is needed to determine how this relates to all of the observed effects of LEOPARD syndrome.

Noonan syndrome and neurofibromatosis 1 have a great similarity in presentations with LEOPARD, which make the diagnosis difficult and mostly based on genetic testing. Laboratory studies should include molecular analysis of the PTPN11 and RAF1 genes. In a study of 10 infants with clinical indications of LEOPARD syndrome prior to their first birthday, 8 (80%) patients were confirmed to have the suspected mutation. An additional patient, with the suspected mutation was subsequently found to have NF1, following evaluation of the mother.^[5] There are 5 identified allelic variants responsible for LEOPARD syndrome. Which seems to be a unique familial mutation, in that all other variants are caused by transition errors, rather than transversion.

On histological examination of the lentigines there is pigment accumulation in the dermis as well as the deeper layers of epidermis. There is an increase in melanocytic density owing to corrugation of the dermoepidermal junction. There are no naevus cells and the rete ridges are prominent.^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]

Cutaneous manifestations of LEOPARD syndrome may be similar to several other conditions including McCune-Albright syndrome, Carney syndrome, and neurofibromatosis. LEOPARD syndrome should also be distinguished from other syndromes with developmental delay, short stature, congenital heart defects, and distinctive facies, especially Williams syndrome.

• McCune-Albright syndrome

The hallmark symptom of McCune-Albright syndrome is precocious puberty. Other symptoms include bone fractures, deformities of the bones in the face, gigantism, and irregular, large patchy café-au-lait spots, especially on the back.

• Carney syndrome

Coexistence of several neoplasms, including gastric epithelioid leiomyosarcoma, pulmonary chondroma, and extra-adrenal paraganglioma. Other symptoms may be involved like Cushing syndrome symptoms, Symptoms of a prolactin-secreting tumor include hypogonadism (eg, amenorrhea, impotence) associated with symptoms of increased prolactin levels (eg, galactorrhea) in female patients.

• Lentigo

A lentigo is a small pigmented spot on the skin with a clearly-defined edge, surrounded by normal-appearing skin. It is a harmless (benign) hyperplasia of melanocytes which is linear in its spread.

• Neurofibromatosis

Neurofibromatosis is a genetically-inherited disease in which nerve tissue grows tumors (e.g. neurofibromas), it may be may be harmless or may cause serious damage by compressing nerves and other tissues.

• Williams syndrome (also Williams-Beuren syndrome)

A rare genetic disorder characterized by a distinctive, “elfin” facial appearance, along with a low nasal bridge, an unusually cheerful demeanor and ease with strangers, coupled with unpredictably occurring negative outbursts. Mental retardation coupled with unusual (for persons who are diagnosed as mentally retarded) language skills, a love for music, and cardiovascular problems, such as supravalvular aortic stenosis and transient hypercalcaemia.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]

LEOPARD syndrome is a rare condition, but the exact birth prevalence is unknown. Not less than 200 patients have been reported and two reviews published.^[1] However, LEOPARD syndrome is likely underdiagnosed or misdiagnosed as many of its features are mild and the correct diagnosis might be missed in the absence of lentiginosis.

Various literature describes it as being rare.^[2] There is no epidemiologic data available regarding how many in the world population suffer from the syndrome, however there are slightly over 200 cases described in medical literature. Within the group of the so called ‘neuro-cardio-facial-cutaneous’ syndromes, LEOPARD syndrome is probably the second most common disorder after Noonan syndrome.^[3]

Lentigines may be present at birth or develop during childhood, they become more numerous and darker with age.

Slightly increased prevalence in men has been documented.

LEOPARD syndrome has no clear racial predilection.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]

In general, males are more affected than females. LEOPARD syndrome is not a life threatening diagnosis, cardiomyopathy and other pathologic findings involving the cardiovascular system may be a cause of death in those whose cardiac deformities are profound.

Males are more likely than females to be affected with LEOPARD syndrome.^[1] LEOPARD syndrome is not a life threatening diagnosis, but Obstructive cardiomyopathy and other pathologic findings involving the cardiovascular system may be a cause of death in those whose cardiac deformities are profound. It is suggested that, once diagnosed, individuals be routinely followed by a cardiologist, endocrinologist, dermatologist, and other appropriate specialties as symptoms present.

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