LEOPARD Syndrome Clinical Presentation
- Author: Robert A Schwartz, MD, MPH; Chief Editor: William D James, MD more...
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.
Multiple lentigines must be present.
Features of at least two of the following other categories must be present:
Other cutaneous abnormalities
Cardiac structural or electrocardiographic abnormalities
Shortness of stature
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%).
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.
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, 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:
Café au lait spots
Multiple granular cell tumors have been observed with LEOPARD syndrome.
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. 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.
In 2004, Yagubyan et al reported a patient with recurrent upper extremity aneurysms that required multiple operations. This patient also had multiple other peripheral aneurysms, thus far asymptomatic. Abnormal, extremely elongated vertebral and basilar arteries have also been reported.
About 35% of the patients demonstrate various cephalofacial findings. Ocular hypertelorism was the most frequently reported (25%). Other findings include the following:
Broad nasal root
High palate arch
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.
LEOPARD syndrome may be associated with hypertrophic plexuses, possibly leading to neuropathic pain.
Familial cases suggest an autosomal dominant mode of inheritance with variable expressivity. Speculation exists on the more severe course of the disease in males, which may partially explain the slight preponderance of men in the large collected series of Voron et al in 1976.
Complications may arise due to associated abnormalities.
Motegi SI, Yokoyama Y, Ogino S, Yamada K, Uchiyama A, Takeuchi Y, et al. Pathogenesis of Multiple Lentigines in LEOPARD Syndrome with PTPN11 Gene Mutation. Acta Derm Venereol. 2015 Apr 28. [Medline].
Noda S, Takahashi A, Hayashi T, Tanuma S, Hatakeyama M. Determination of the catalytic activity of LEOPARD syndrome-associated SHP2 mutants toward parafibromin, a bona fide SHP2 substrate involved in Wnt signaling. Biochem Biophys Res Commun. 2016 Jan 22. 469 (4):1133-9. [Medline].
Ogata T, Yoshida R. PTPN11 mutations and genotype-phenotype correlations in Noonan and LEOPARD syndromes. Pediatr Endocrinol Rev. 2005 Jun. 2(4):669-74. [Medline].
Hanna N, Montagner A, Lee WH, Miteva M, Vidal M, Vidaud M, et al. Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1. FEBS Lett. 2006 May 1. 580(10):2477-82. [Medline].
Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG. PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem. 2006 Mar 10. 281(10):6785-92. [Medline].
Wang Y, Chen C, Wang DW. Leopard syndrome caused by heterozygous missense mutation of Tyr 279 Cys in the PTPN11 gene in a sporadic case of Chinese Han. Int J Cardiol. 2014 Jul 1. 174(3):e101-4. [Medline].
Begic F, Tahirovic H, Kardaševic M, Kalev I, Muru K. Leopard syndrome: a report of five cases from one family in two generations. Eur J Pediatr. 2014 Jun. 173(6):819-22. [Medline].
Tartaglia M, Martinelli S, Stella L, Bocchinfuso G, Flex E, Cordeddu V, et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 Feb. 78(2):279-90. [Medline].
Ucar C, Calyskan U, Martini S, Heinritz W. Acute myelomonocytic leukemia in a boy with LEOPARD syndrome (PTPN11 gene mutation positive). J Pediatr Hematol Oncol. 2006 Mar. 28(3):123-5. [Medline].
Laux D, Kratz C, Sauerbrey A. Common acute lymphoblastic leukemia in a girl with genetically confirmed LEOPARD syndrome. J Pediatr Hematol Oncol. 2008 Aug. 30(8):602-4. [Medline].
Kalidas K, Shaw AC, Crosby AH, Newbury-Ecob R, Greenhalgh L, Temple IK, et al. Genetic heterogeneity in LEOPARD syndrome: two families with no mutations in PTPN11. J Hum Genet. 2005. 50(1):21-5. [Medline].
Writzl K, Hoovers J, Sistermans EA, Hennekam RC. LEOPARD syndrome with partly normal skin and sex chromosome mosaicism. Am J Med Genet A. 2007 Nov 1. 143A(21):2612-5. [Medline].
Voron DA, Hatfield HH, Kalkhoff RK. Multiple lentigines syndrome. Case report and review of the literature. Am J Med. 1976 Mar. 60(3):447-56. [Medline].
Digilio MC, Sarkozy A, de Zorzi A, Pacileo G, Limongelli G, Mingarelli R, et al. LEOPARD syndrome: clinical diagnosis in the first year of life. Am J Med Genet A. 2006 Apr 1. 140(7):740-6. [Medline].
Bujaldon AR. LEOPARD syndrome: what are café noir spots?. Pediatr Dermatol. 2008 Jul-Aug. 25(4):444-8. [Medline].
Xing Q, Chen X, Wang M, Bai W, Peng X, Gao R, et al. A locus for familial generalized lentiginosis without systemic involvement maps to chromosome 4q21.1-q22.3. Hum Genet. 2005 Jul. 117(2-3):154-9. [Medline].
Aragüés IH, Domínguez MC, Blanco VP, Zubicaray BE, Fernández RS. LEOPARD syndrome and multiple granular cell tumors: An underreported association?. Indian J Dermatol Venereol Leprol. 2016 Jan-Feb. 82 (1):77-9. [Medline].
Limongelli G, Sarkozy A, Pacileo G, Calabro P, Digilio MC, Maddaloni V, et al. Genotype-phenotype analysis and natural history of left ventricular hypertrophy in LEOPARD syndrome. Am J Med Genet A. 2008 Mar 1. 146A(5):620-8. [Medline].
Limongelli G, Pacileo G, Marino B, Digilio MC, Sarkozy A, Elliott P, et al. Prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD syndrome. Am J Cardiol. 2007 Aug 15. 100(4):736-41. [Medline].
Yagubyan M, Panneton JM, Lindor NM, Conti E, Sarkozy A, Pizzuti A. LEOPARD syndrome: a new polyaneurysm association and an update on the molecular genetics of the disease. J Vasc Surg. 2004 Apr. 39(4):897-900. [Medline].
Porciello R, Divona L, Strano S, Carbone A, Calvieri C, Giustini S. Leopard syndrome. Dermatol Online J. 2008 Mar 15. 14(3):7. [Medline].
Rudolph G, Haritoglou C, Kalpadakis P, Boergen KP, Meitinger T. [LEOPARD syndrome with iris-retina-choroid coloboma. Discordant findings in monozygotic twins (MIM # 151 100)]. Ophthalmologe. 2001 Nov. 98(11):1101-3. [Medline].
Spatola M, Wider C, Kuntzer T, Croquelois A. PTPN11 mutation manifesting as LEOPARD syndrome associated with hypertrophic plexi and neuropathic pain. BMC Neurol. 2015 Apr 16. 15:55. [Medline]. [Full Text].
Lodish MB, Stratakis CA. The differential diagnosis of familial lentiginosis syndromes. Fam Cancer. 2011 Sep. 10(3):481-90. [Medline].
Cheng YP, Chiu HY, Hsiao TL, Hsiao CH, Lin CC, Liao YH. Scalp melanoma in a woman with LEOPARD syndrome: possible implication of PTPN11 signaling in melanoma pathogenesis. J Am Acad Dermatol. 2013 Oct. 69(4):e186-7. [Medline].
Jozwiak S, Schwartz RA, Janniger CK. LEOPARD syndrome (cardiocutaneous lentiginosis syndrome). Cutis. 1996 Apr. 57(4):208-14. [Medline].
Jozwiak S, Schwartz RA, Janniger CK, Zaremba J. Familial occurrence of the LEOPARD syndrome. Int J Dermatol. 1998 Jan. 37(1):48-51. [Medline].