1 Harris J.C. Leonardo da Vinci’s Mona Lisa. 2 Austen I. New look at ‘Mona Lisa’ yields some new secrets. Figure Mona Lisa (circa 1503-1506). Oil on panel, 77 × 53 cm (30 × 21 in). René-Gabriel Ojéda. Musée Du Louvre, Paris, France (with permission, Art Resource, New York, NY). Note the high forehead, thinned and coarse hair, absent eyebrows, xanthalesma at the left medial canthus, swelling on the dorsum of the right hand, suggesting a lipoma or xanthoma, and overall yellowish hue of the skin. Importantly, note the absence of corneal archus and presence of possible goiter in the region of the thyroid. The iconic portrait of Lisa Gherardini, the enigmatic Mona Lisa, has endured centuries of fascination by artists, scholars, medical professionals, and even thieves.A wealthy silk merchant in Florence, Italy, Francesco del Giocondo commissioned Leonardo da Vinci to produce this masterpiece of his wife following the birth of their child, Andrea, in 1502.Although evidence is fragmentary, general belief is that work on the painting began in 1503. Subsequently, the painting was taken to France in 1516, completed there, and adorned the court of King Francis I until its permanent display in the Louvre in 1797 ( Figure ) .

3 Dequeker J.

Muls E.

Leenders K. Xanthelasma and lipoma in Leonardo da Vinci’s Mona Lisa. 3 Dequeker J.

Muls E.

Leenders K. Xanthelasma and lipoma in Leonardo da Vinci’s Mona Lisa. 4 Hales D. Mona Lisa: A Life Discovered. The Mona Lisa, also referred to as La Gioconda (or La Joconde), attracted medical attention in 2004 when a team of rheumatologists and endocrinologists pointed to the presence of potential cutaneous abnormalities captured in the stunningly detailed portrait that suggested the presence of a lipid disorder. Dequeker et alsuggested that the skin lesions noted on the inner end of the left upper eyelid were highly suggestive of xanthalesma and the swelling depicted on the dorsum of the right hand, resting upon the left, was consistent with a subcutaneous lipoma. These findings led them to postulate the connection between hyperlipidemia and consequent ischemic heart disease, which may have led to Gherardini’s demise. Thus, they defined this observed constellation to consist of a possible familial form of hyperlipidemia leading to premature atherosclerosis. In their excellent work, these authors also point to the possibility that the mysterious smile may have been a residual of a Bell’s palsy. Arguments that reduce compatibility with a familial or genetic cause of the disorder include the absence of corneal arcus or an extensive family history of premature death. Importantly, Lisa Gherardini (1479-1542) lived to be 63 years of age (not 37 years of age as has been erroneously reported), and it would have been unusual, if not impossible, to see her advance to that age in the presence of untreatable premature atherosclerosis from a genetically driven hyperlipidemia.We believe that a more unifying diagnosis, that of clinical hypothyroidism, is evident and more likely in this uncannily detailed portrayal.

5 Goswami U.C.

Choudhury S. The status of retinoids in women suffering from hyper- and hypothyroidism: interrelationship between vitamin A, beta-carotene and thyroid hormones. 6 Heymann W.R. Cutaneous manifestations of thyroid disease. 7 Elta G.H.

Sepersky R.A.

Goldberg M.J.

Connors C.M.

Miller K.B.

Kaplan M.M. Increased incidence of hypothyroidism in primary biliary cirrhosis. 8 Ashrafian H. Leonardo da Vinci’s Mona Lisa: medical differentials and primary biliary cholangitis. The painting suggests a yellowish discoloration of the skin, which is known to occur in hypothyroidism because of impaired hepatic conversion of carotene to vitamin A, resulting in excess deposition of serum carotene in the stratum corneum.The black veil that hangs below what appears to be a large forehead indicates a receding hair line, with hair that appears to be thinned. A complete lack of eyebrows or other hair throughout the pale skin further supports this diagnosis, and cascading hair down the side appears coarse in character.Curiously, a close look at the neck does insinuate the possible presence of a diffuse enlargement such as a goiter. The xanthelasma could certainly represent a secondary hyperlipidemia, and swelling in the dorsum of the right hand may be a xanthoma or a lipoma, further supporting the presence of a systematic metabolic dyslipidemia as often noted in advanced stages of hypothyroidism. In this circumstance, if Lisa Gherardini was indeed suffering from severe hypothyroidism or its consequences, the mysterious smile may at one level be representative of some psychomotor retardation and muscle weakness leading to a less than fully blossomed smile. An even more intriguing diagnosis could suggest the presence of hypothyroidism in concordance with primary biliary cirrhosis.The later diagnosis has been posited by some authors, but association with hypothyroidism was not postulated.However, we believe that the answer may be simpler and epidemiologically supported as a postpartum hypothyroidism.

9 Morrison A.S.

Kirshner J.

Molho A. Epidemics in Renaissance Florence. 10 Keele K.D. The genesis of Mona Lisa. 11 Sterpetti A.V.

De Toma G.

De Cesare A. Thyroid swellings in the art of the Italian Renaissance. 12 Aghini-Lombardi F.

Antonangeli L.

Martino E.

et al. The spectrum of thyroid disorders in an iodine-deficient community: the Pescopagano survey. 2 Austen I. New look at ‘Mona Lisa’ yields some new secrets. 13 Pearce E.N. Thyroid disorders during pregnancy and postpartum. Table a a 11 Sterpetti A.V.

De Toma G.

De Cesare A. Thyroid swellings in the art of the Italian Renaissance. Selected data compiled from Am J Surg, Thyroid Swellings Depicted in Italian Renaissance Art Painting Painter Comment Crucifixion of Saint Andrew Caravaggio 1607 A poor old lady with a goiter, on left lower part of painting Judith and her Maidservant Artemisia Gentileschi 1613 The main character depicted with an obvious large thyroid swelling Transfiguration of Christ Raffaello 1516 A boy “possessed” with exophthalmos and neck swelling, possibly representing a toxic goiter, is shown in the right corner Christ after flagellation Diego Velazquez 1626 Young boy with a large goiter, on the right hand of painting The Resurrection Piero della Francesca 1460 A sleeping soldier with a clear thyroid enlargement that could be a thyroglossal cyst There are at least 2 distinct natural history-supporting data that support this diagnosis of hypothyroidism. First, during the Renaissance period, eating habits in Italy were primarily vegetarian, based on cereals, root vegetables, and legumes, and with little meat, as opposed to dietary patterns in Northern Europe where livestock was more developed. Seafood was uncommon inland and famine was common, because harvest was often scarce, with only 16 full harvest seasons from 1375 to 1791 in the Tuscany region.Thus, the diet was one that was often iodine deficient and more importantly, the eating habits promoted the development of goiters. As early as 1959, Keelepostulated that the Mona Lisa had a “puffy neck,” suggesting a goiter. Evidence of this is noted in several works of art during that period wherein figures are often depicted with goiters. Sterpetti et alstudied thyroid swellings in the art of the Italian Renaissance and concluded that such depictions were very common and were the most prevalent pathological condition shown in Byzantine artworks, noting 70 paintings and 10 sculptures with a thyroid swelling (we adapt a few examples from this work in the Table ). As a contemporary example, in 1999, the Pappano population-based study in Italy concluded that in this southern Italian population, the prevalence of a goiter was 59.8% in adults, suggesting that it is still a problem of agricultural rural populations even in modern times.The second important evidence supporting the theory that Lisa Gherardini had hypothyroidism is the fact that she had given birth to her male child, Andrea, recently within months before sitting for the painting.It is possible that she suffered from a subclinical presentation of peripartum thyroiditis, with an early manifestation of hyperthyroidism eventually setting into a chronic phase of hypothyroidism.This, coupled with the living conditions and iodine-deficient diet of this period in the Florentine region, would have characteristically led to the secondary manifestations of underlying hypothyroidism.

14 Fleur-de-Gigi Caterina Sforza the alchemist & her translated recipes. 15 Elias M.

Cotte P. Multispectral camera and radiative transfer equation used to depict Leonardo’s sfumato in Mona Lisa. Although we have attempted to provide a unifying hypothesis for the Mona Lisa, we admit that the truth may lie elsewhere. A possibility for the loss of facial and bodily hair may be in intentional depilation, which was practiced in those times, with techniques catalogued in Gli Experimenti by Caterina Sforza during the Italian Renaissance.The yellowish discoloration may represent age-related changes (perhaps from the use of varnish, which may yellow over time) rather than an original depiction as such. The smile may be due to da Vinci’s experiments with a technique called sfumato, which allows tones and colors to fade into each other without discrete lines like smoke or blurred dimensions.Certainly, we should also admit that our unifying theory may be as plausible as the multiple explanations provided, each open to individual and collective bias. In summary, we believe that the enigma of the Mona Lisa can be resolved by a simple medical diagnosis of a hypothyroidism-related illness that could have been the result of a peripartum thyroiditis accentuated by the living conditions of the Renaissance. In many ways, it is the allure of the imperfections of disease that give this masterpiece its mysterious reality and charm.

Article Info Footnotes See also page 1169 Potential Competing Interests: Dr Mehra reports consulting fees from Abbott, Medtronic, Janssen, Mesoblast, Portola, Bayer, NupulseCV Inc. Ms Campbell reports no competing interests. Identification DOI: https://doi.org/10.1016/j.mayocp.2017.12.029 Copyright © 2018 Mayo Foundation for Medical Education and Research ScienceDirect Access this article on ScienceDirect

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