Gene 555 (2015) 14–22
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Genetics in the art and art in genetics Nenad Bukvic a,⁎, John W. Elling b a b
University Hospital Bari-Policlinics, Medical Genetics Unit, Piazza Giulio Cesare, 11, Bari 70125, Italy Concierge Genomics, Inc., 590 Monte Alto, Santa Fe, NM 87501-6172, USA
a r t i c l e
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Article history: Received 27 May 2014 Received in revised form 23 July 2014 Accepted 24 July 2014 Available online 1 August 2014 Keywords: Genetics and painting masterpieces Down syndrome Angelman syndrome Prader–Willi syndrome Noonan syndrome dwarfism Akhenaten
a b s t r a c t “Healing is best accomplished when art and science are conjoined, when body and spirit are probed together”, says Bernard Lown, in his book “The Lost Art of Healing”. Art has long been a witness to disease either through diseases which affected artists or diseases afflicting objects of their art. In particular, artists have often portrayed genetic disorders and malformations in their work. Sometimes genetic disorders have mystical significance; other times simply have intrinsic interest. Recognizing genetic disorders is also an art form. From the very beginning of my work as a Medical Geneticist I have composed personal “algorithms” to piece together evidence of genetics syndromes and diseases from the observable signs and symptoms. In this paper we apply some ‘gestalt’ Genetic Syndrome Diagnostic algorithms to virtual patients found in some art masterpieces. In some the diagnosis is clear and in others the artists' depiction only supports a speculative differential diagnosis. © 2014 Elsevier B.V. All rights reserved.
1. Introduction The surge of genetic discoveries that result from modern sequencing technology is avidly reported in the scientific and popular press, inspiring scientists, non-scientists and patients alike. The spectacular progress in understanding the genetic nature of disease has profoundly changed the daily practice of Medical Genetics, Clinical Genetics, and Genetic Counseling. However, much has remained unchanged. The problems and questions that confront families are largely the same as they have been, as are the main approaches used in genetic counseling to try to help them. Professor Harper, author of the book “Practical Genetic Counseling” (2010), confirms that: “It is now 30 years since I wrote the first edition of book and more than 40 years since I began to practice Medical Genetics. During this time it Abbreviations: AS, Angelman syndrome; DS, Down syndrome; UBE3A, E3 ubiquitin– protein ligase; PWS, Prader–Willi syndrome; NS, Noonan syndrome; RAS–MAPK, Ras/ mitogen activated protein kinase; PTPN11, Protein Tyrosine Phosphatase, Non-receptor type 11; SOS1, Son of Sevenless Homolog 1; RAF1, v-raf-1 murine leukemia viral oncogene homolog 1; KRAS, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; NRAS, neuroblastoma RAS viral (v-ras) oncogene homolog; BRAF, v-raf murine sarcoma viral oncogene homolog B; SHOCK2, soc-2 suppressor of clear homolog (C. elegans); MEK1, mitogenactivated protein kinase kinase 1; CBL, Cbl Proto-Oncogene, E3 Ubiquitin Protein Ligase; FGFR3, Fibroblasts Growing Factor Receptor 3; Gly, Glycine; Arg, Arginine; COMP, Cartilage Oligomeric Matrix Protein. ⁎ Corresponding author. E-mail address: [email protected] (N. Bukvic).
http://dx.doi.org/10.1016/j.gene.2014.07.073 0378-1119/© 2014 Elsevier B.V. All rights reserved.
has been truly amazing to see what has altered in terms of what we are able to do.”
“At another level, though, much has remained unchanged. The problems and questions that families bring to us are largely the same and so are the main approaches used in genetic counseling to try to help them. New laboratory advances have greatly extended what we are able to do, but have not removed the need for the practice of genetic counseling and of clinical genetics generally, to rest on these long established foundations and on sound psychological principles for the way in which we interact with those we see.” As each new genetic test is made available in the clinic, developing the appropriate counseling for each new diagnosis is necessarily a multidisciplinary endeavor that includes involvement of a Medical Geneticist who must help its patients understand a genetic diagnosis and assist them in making and coping with decisions relating to the diagnosis (Bukvic and Margaglione, 2013) based on these long established technical, scientific/medical, ethical and psychological principles. Even with today's knowledge of a greater number of genetic pathologies and the recent understanding of the molecular basis of many of these illnesses, diagnosis starts with the recognition of a clinical situation based on observation of symptoms and signs. Here these unchanged, fundamental clinical skills are applied to Masterpieces of Art using only the painter's record.
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Fig. 1. The Adoration of the Christ Child, ca. 1515, by a follower of Jan Joest of Kalkar. Oil on wood. The Jack and Belle Linsky Collection, Metropolitan Museum of Art, New York, NY, USA. Oil on wood, 104.1 × 71.8 cm.
2. Down syndrome Levitas and Reid (2003) suggested that an angel in The Adoration of the Christ Child by a follower of Jan Joest of Kalkar (Fig. 1) is depicted with Down syndrome. At first glance this painting is one of many contemporary depictions of the Nativity. Our attention as Medical Geneticists is drawn to two subjects of this painting, one of the angels and one of the earthly admirers whom have a similar and distinctive facial appearance. The angel next to Mary, whose single visible wing is behind the head, seems to have features consistent with Down syndrome: a flattened midface, epicanthal folds, upslanted palpebral fissures, small and upturned nasal tip, and downward curving of the mouth corners. (The curly hair of this angel is not characteristic of Down syndrome but is conventional for paintings of angels.) This angel stands out especially as its facial appearance differs from that of the central angel in the triad, whose aquiline appearance resembles Mary's and the other angels' features. Further symptomatic are the short fingers, especially on the left hand (partially covered by Mary's hair). Again this contrasts with the hands of Mary and the other foreground angels who have long and tapering fingers. The shepherd with a ram's horn in this painting (in the center behind the angels) also has an unusual appearance that is indicative of Down syndrome. The shepherd's hair is straight and he has increased length and an up slant of the palpebral fissures with some degree of ptosis. In addition, the eyes are widely spaced but this apparent hypertelorism may be an artistic interpretation of flattened nasal bridge. The Shepherd's gloves prevent interpretation of the configuration of the hand. Whether this figure was intended to resemble the unusual angel is uncertain (Levitas and Reid, 2003), but these features could be suggestive for Down syndrome, as well as for hypothyroidism which was frequent in this historical period. Levitas and Reid (2003) suggest that the angelic depiction of an individual with Down syndrome was symbolic and may denote that the artist had an affinity for individuals with disabilities. 2.1. Mantegna paintings Ruhrah (1935) argued that a child in Mantegna's painting Virgin and Child (Fig. 2) displays Down syndrome-like characteristics. The child in this painting exhibits oblique eyes, possible epicanthic folds, a small nose, an open mouth, an adenoidal expression, a prominent tongue, square hands, an incurving little finger, wide spacing between the first and second toes of the foot, and a short and broad neck (Ruhrah, 1935; Stratford, 1982), features consistent with Down syndrome (Cone, 1964; Volpe, 1986; Ward, 2004). In 1982, Stratford (1982), suggested that the Italian Renaissance painter Andrea Mantegna used
Fig. 2. Virgin and Child painting by Andrea Mantegna (1431–1506) (or follower) dated to around 1460 A.D. Image A depicts a woman holding a child with suspected Down syndrome-like facial characteristics (Cone, 1964; Ruhrah, 1935; Ward, 2004). Museum of Fine Arts, Boston, USA. Tempera on panel, 48.5 × 34.6 cm.
a little boy with Down syndrome as the model for his Christ child and a woman with goiter as the model for the Virgin (Fig. 2). Stratford's “diagnosis” was based on the child's distinctive facial features and the shape of his hands and toes. Cone also argued that a child in another of Mantegna's painting titled Madonna and Child (Fig. 3), had Down syndrome (Cone, 1964, 1968; Pueschel, 2000), pointing out the oblique eyes, possible epicanthic folds, a small nose, an open mouth, and an adenoidal expression. A third painting attributed to Mantegna, Virgin and Child with Saints Jerome and Louis of Toulouse, Fig. 4, also seems to depict a child with Down syndrome. The child in this painting is portrayed with Down syndrome-like features including widely spaced eyes, upslanted palpebral fissures, an open mouth expression, square-shaped hands with an incurving little finger, and a prominent tongue. This child looks very similar to the child depicted in both above-mentioned Mantegna paintings. Overall, the qualitative evidence that Down syndrome may be depicted in the three paintings is strong (Starbuck, 2011). As Levitas and Reid discussed in their 2003 paper, the benign depiction of disabled individuals in 16th-century culture is unusual. At that time children with obvious mental retardation were typically abandoned to death or servitude. Culturally individuals with recognized disabilities tended to be depicted in paintings as symbols of comedy or evil, the latter being consistent with the attitude expressed by Martin Luther in his religious writings. The depiction in these three works by Mantegna in light of the prevailing culture further suggests that the artist had warm feelings toward the model.
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Indeed it is quite possible that all three of Mantegna's paintings, which were painted around the same time, may depict the same child with Down syndrome (Starbuck, 2011). Stratford (1996) speculates that Mantegna was painting his own child or a child of the rich and powerful Gonzaga family of Mantua, Italy (Stratford, 1982). Stratford claims that one of Mantegna's 14 children had Down syndrome and that the Gonzaga family hired him because one of their children also had the same condition — and in fact this could have been a factor in Ludovico Gonzaga's choice of Andrea Mantegna as his court painter. If a child with Down syndrome was born to the Gonzaga family, it may have lived a better life because of the prestige and wealth of this family during this period however, Stratford notes that the Gonzaga child in question reportedly died at the age of 4. 2.2. Clinical and genetics
Fig. 3. Madonna and Child painting by Andrea Mantegna (1431–1506) dated to around 1460. Image depicts a woman holding a child with Down syndrome-like facial characteristics.
Fig. 4. Virgin and Child with Saints Jerome and Louis of Toulouse painting by Andrea Mantegna (1431–1506) dated to around 1455 A.D. Image depicts a woman holding a child with suspected Down syndrome-like facial characteristics.
Children with Down syndrome have multiple malformations, medical conditions, and cognitive impairment caused by the presence of extragenetic material from chromosome 21 (Bull and the Committee on Genetics, 2011). Although the phenotype is variable, there typically are multiple features (Pavarino Bertelli et al., 2009) that enable the experienced clinician to suspect the diagnosis. Like the art subjects discussed here, the more common physical findings are hypotonia, small brachycephalic head, epicanthal folds, flat nasal bridge, upwardslanting palpebral fissures, Brushfield spots, small mouth, small ears, excessive skin at the nape of the neck, single transverse palmar crease, and short fifth finger with clinodactyly and wide spacing, often with a deep plantar groove between the first and second toes. Down syndrome is associated with cognitive impairment and sufferers also have a significant risk of hearing loss (75%); obstructive sleep apnea (50%–79%); otitis media (50%–70%); eye disease (60%), including cataracts (15%) and severe refractive errors (50%); congenital heart defects (50%); neurologic dysfunction (1%–13%); gastrointestinal atresias (12%); hip dislocation
Fig. 5. Portrait of a Child with a Drawing by Giovanni Francesco Caroto (1480–1555/1558), an Italian Renaissance painter active mainly in his native city of Verona. Castelvecchio Museum, Verona, Italy. Oil on canvas 37 × 29 cm.
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(6%); thyroid disease (4%–18%); and, less commonly, transient myeloproliferative disorder (4%–10%) and later leukemia (1%) and Hirschsprung disease (1%). In approximately 95% of children with Down syndrome, the condition is due to trisomy 21, in which there are 47 chromosomes and a free extra chromosome 21. In 3% to 4% of persons with the Down syndrome phenotype, the extra chromosomal material is the result of an unbalanced translocation between chromosome 21 and another acrocentric chromosome. Approximately three-quarters of these unbalanced translocations are de novo, and the remainder result from familial translocations. Finally, in 1% to 2% of persons with the Down syndrome phenotype, two cell lines are present: one normal and the other with trisomy 21. This condition is called mosaicism. Persons with mosaicism may be more mildly affected than persons with complete trisomy 21 or translocation chromosome 21, but this is not always the case, and their condition may include any of the associated medical problems and be indistinguishable from trisomy 21. Recurrence risks for families with an affected child depend on many factors and families benefit from counseling by a clinical genetic professional. 3. Angelman syndrome (AS) Dr. Harry Angelman, a pediatrician first reported three children with this condition in 1965 (Angelman, 1965). Angelman later described his choice of the title “Puppet Children” to describe these cases as being related to an oil painting he had seen while vacationing in Italy (Fig. 5). Dr. Angelman relates that (Angelman, 1991): “The history of medicine is full of interesting stories about the discovery of illnesses. The saga of Angelman's syndrome is one such story. It was purely by chance that nearly thirty years ago (~ 1964) three handicapped children were admitted at various times to my children's ward in England. They had a variety of disabilities and although at first sight they seemed to be suffering from different conditions I felt that there was a common cause for their illness. The diagnosis was purely a clinical one because in spite of technical investigations which today are more refined I was unable to establish scientific proof that the three children all had the same handicap. In view of this I hesitated to write
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about them in the medical journals. However, when on holiday in Italy I happened to see an oil painting in the Castelvecchio museum in Verona a Boy with a Puppet. The boy's laughing face and the fact that my patients exhibited jerky movements gave me the idea of writing an article about the three children with a title of Puppet Children. It was not a name that pleased all parents but it served as a means of combining the three little patients into a single group. Later the name was changed to Angelman syndrome. This article was published in 1965 and after some initial interest lay almost forgotten until the early eighties.” In the case of the painting, the subject appears to have a very happy demeanor with a rictus smile. An unusually happy demeanor with frequent laughter and smiling is one of the notable characteristics of AS, which occurs along with intellectual and developmental disabilities, sleep disturbance, seizures, and jerky movements. Consensus clinical and genetic aspects of AS have only recently been reported (Williams et al., 2006). Newborns typically have a normal phenotype with developmental delays first noted at around age six months. Nothing is known about the subject of this painting, making a diagnosis based on the smile and puppet drawing alone very weak. 3.1. Clinical and genetics Consensus clinical and genetic aspects of AS (Williams et al., 2006) reported different clinical characteristics the most frequent of which are: delayed attainment of developmental milestones without loss of skills, speech impairment (minimal to no use of words; receptive language skills and nonverbal communication skills higher than expressive language skills), behavioral uniqueness, including any combination of frequent laughter/smiling; apparent happy demeanor; excitability, often with handflapping movements; hypermotoric behavior; short attention span, movement or balance disorder (usually ataxia of gait and/ or tremulous movement of the limbs), seizures with abnormal EEG, protruding tongue, hypotonia, prognathia, wide mouth, wide-spaced teeth, and hypopigmented skin with lighter hair and eye color (compared to the family).
Fig. 6. Doña Eugenia Martínez Vallejo, “La Monstrua” (1680) “desnuda” (oil on canvas 165 × 108 cm) and “vestida” (oil on canvas 165 × 107 cm). Juan Carreno de Miranda (1614–1685) was an important Spanish Court Painter. Museo Nacional del Prado, Spain.
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Angelman syndrome features are caused by deficient expression or function of the maternally inherited UBE3A allele (Chamberlain and Lalande, 2010; Dagli and Williams, 2014; Van Buggenhout and Fryns, 2009; Williams et al., 2006, 2010). Different genetic mechanisms may lead to AS, such as: deletion of the 15q11.2–q13 critical region (60–75%), paternal uniparental disomy (2–5%), imprinting defect (2–5%), and mutation in the UBE3A gene (10%).
4. Prader–Willi syndrome (PWS) The Spanish baroque court painter Juan Carreño de Miranda (1616–1685) depicted Doña Eugenia Martinez Vallejo in the painting “La Monstrua” (Fig. 6). When she was brought to the court of Charles II of Spain as “object” to be seen she was approximately 6 years old and weighed ~ 55 kg with excessive central obesity, a small triangular mouth, and small hands and feet and almond-shaped eyes. While there are competing diagnoses for this girl, the strong argument for PWS comes from by Dr. Andrea Prader whom, upon viewing
these paintings in the Museo del Prado, Madrid, immediately recognized features consistent with Prader–Willi syndrome (Butler et al., 2006). In addition in the “vestida” portrait this young lady holds an apple in one hand and a piece of bread in the other — perhaps a sign for the food related behavioral problems and hyperphagia that are important characteristics of PWS. Although we may never know if this child did in fact have PWS, the paintings and contemporaneous 17th century descriptions of her condition strongly support this supposition. In fact this painting appears in the preface of book on management of Prader–Willi syndrome (Butler et al., 2006). 4.1. Clinical and genetics Prader–Willi syndrome is a highly variable genetic disorder whose most consistent major manifestations include hypotonia with poor suck and poor weight gain in infancy, mild mental retardation, hypogonadism, growth hormone insufficiency resulting in short stature, early childhood-onset hyperphagia and obesity, characteristic appearance, and a wide range of behavioral and sometimes psychiatric disturbances that range from food related behavioral problems alluded in the painting all the way to an unusual skill with jigsaw puzzles. However a wide range of other clinical diagnostic criteria are reported by McCandless and The Committee on Genetics (2011). Three major genetic causes of PWS exist: a 5–7 Mb deletion of the paternally inherited chromosomal 15q11.2–q13 region, a maternal uniparental disomy 15, and a defect in the imprinting process in the 15q11.2–q13 region on the paternally inherited chromosome. Occasionally, deletion results from chromosomal translocation (Cassidy and Driscoll, 2009). A number of imprinted genes have been mapped to the PWS region of 15q11.2–q13, but their role in most aspects of the phenotype is not well understood. While the genetic causes are complex, over 99% of PWS cases can be diagnosed with a simple DNA methylation analysis. 5. Noonan syndrome (NS) Ivan Le Lorraine Albright's 1929 painting “Among Those Left”, Fig. 7, depicts a blacksmith — a man of short stature whose widely spaced eyes angle downward under drooping eyelids with eyes turning outward to his low, prominent ears. His shirt is open to reveal the hollow of his sternum. This may be the most famous portrait of someone with NS (Emery, 1996). This painting also illustrates the difficulties faced in
Fig. 7. Ivan Le Lorraine Albright (1897–1983) painting “Among Those Left” 1929, Museum of Art, Carnegie Institute, Pittsburgh, USA. Oil on canvas 185.4 × 91.4 cm.
Fig. 8. A) This limestone relief found in the Royal Tomb at Amarna depicts Akhenaten, Nefertiti, and two of their daughters making an offering to the sun-disk Aten. Akhenaten and Nefertiti carry flowers to be laid on the table beneath the “life-giving” rays of the Aten. B) A statue of Akhenaten now in the Cairo Museum.
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making a differential diagnosis: “Looking at this picture is puzzling because some of the man's features are individual or familial, some are imposed by the artist and some may be syndromic.” (Editorial, Nature Genetics Vol 38, Number 3, 2006). Noonan syndrome is an autosomal dominant congenital disorder that is diagnosed primarily on clinical features — the range and severity of which vary greatly in patients. In addition to the features we see in the blacksmith in the painting, common features also include scoliosis, cervical spine fusion and excess skin at the neck and nystagmus. 5.1. Clinical and genetics The syndrome is caused, in about 75% of the cases, by an autosomal dominant genetic defect in the Ras/mitogen activated protein kinase (RAS–MAPK) signaling pathway genes (PTPN11, SOS1, RAF1, KRAS, NRAS, BRAF, SHOC2, MEK1, CBL) (Lee et al., 2011; Tartaglia et al., 2011). It occurs in between 1:1000 and 1:2500 live births and is heterogeneous with similar conditions (all grouped as “RASopathies” because they share similar pathogenic mechanisms and clinical features). The clinical diagnosis in conjunction with appropriate molecular tests allows Counselors to offer appropriate guidance about risks, genotype–phenotype correlations, follow-up procedures, etc. Clinical features of NS (modified from Tartaglia et al., 2011) include characteristic facial appearance (epicanthal folds, ptosis, down-slanting palpebral fissures, triangular facies, low set and/or posteriorly rotated ears), webbed neck with low posterior hairline, small stature, different cardiovascular problems (congenital heart defects, pulmonic stenosis, atrioventricular septal defects, aortic coarctation, mitral valve defects etc.), developmental delay with attention deficit/hyperactivity disorder, and different skeletal signs (pectus excavatum and/or carinatum, cubitus valgus, scoliosis, vertebral anomalies, etc.). 6. The many possible syndromes of Akhenaten Akhenaten was a pharaoh of the eighteenth dynasty of Egypt who ruled for 17 years and died in 1336 or 1334 BC. He initiated a major socio-religious revolution with important consequences for his country (François and Cilliers, 2011). In addition to his historical importance, his particular physiognomy and appearance are fascinating. Statues and reliefs of Akhenaten consistently show him with narrow chest with gynecomastia, wide hips with prominent fatty deposits, elongated spindly limbs and an elongated neck and skull. Compared to the normal athletic appearance, in Egyptian art he is the only individual portrayed with a short torso, long head, arms and feet, pronounced collarbones, a pot belly and apparently poor muscle tone (Figs. 8 and 9). When
Fig. 9. Akhenaten and His Family (with his wife Nefertiti and their three daughters under the rays of Aton). Painted limestone relief from Akhenaten (Tell-el-Amarna), 32.5 × 39 cm. Egypt, 18th dynasty, ca. 1345 BCE. Aegyptisches Museum, Staatliche Museen zu Berlin, Berlin, Germany.
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researchers first encountered pictures and statues of this figure they wondered about any underlying medical condition that caused him to be portrayed in such way. A variety of diagnoses have been suggested to explain Akhenaten's characteristics, reported as well by Hawass et al. (2010), including: Marfan syndrome, Wilson–Turner X linked mental retardation syndrome, Fröhlich (adiposogenital dystrophy) syndrome, Klinefelter syndrome, androgen insensitivity syndrome, aromatase excess syndrome in conjunction with sagittal craniosynostosis syndrome, or Antley–Bixler syndrome or a variant form of that syndrome or others (Braverman et al., 2009; Farag and Iskandar, 1998; François and Cilliers, 2011; Paulshock, 1980; Walshe, 1973). Furthermore, Akhenaten's appearance could result from classical homocystinuria due to deficit of cystathionine beta-synthase characterized by the involvement of the eyes, skeleton, nervous system, and vascular system suggested by Cavka et al. (2010). Another interesting observation for Akhenaten's family is the relief in Fig. 9, “Akhenaten and His Family”, representing Akhenaten, his wife Nefertiti, and their daughters. All the daughters seem to have a head shape associated with dolichocephaly. This feature could be due to some kind of heredity craniosynostosis (Hawass et al., 2010), but, of course this head shape could also be a “phenocopy”, secondarily caused after birth. 6.1. Considerations Most of the diseases hypothetically diagnosed from ancient depictions cannot be supported (Hawass et al., 2010), even though some signs undoubtedly fit with clinical suppositions. For example, while there is little doubt of Akhenaten's fertility, many hypothetical diagnoses are for conditions associated with infertility. Although some of his at least 6 children with at least 5 wives might perhaps have had extraconnubial parentage, it is most unlikely (but not impossible of course) that all of them did (François and Cilliers, 2011). For further reading see also: Bearn (1975), Burridge (1995), London (1987), Nelson and Thron (1966), Nunn (1996), and Strachan and Walker (2010).
Fig. 10. Las Meninas (1656) painting by Diego Velázquez, Museo del Prado, Madrid, Spain. Oil on canvas 318 × 276 cm.
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Fig. 11. The Bronzino's double painting, “Portrait of Dwarf Morgante”, Uffizi, Florence, Italy. Agnolo di Cosimo (called Bronzino) 1503–1572, was the leading painter of mid-16th-century. Oil on canvas 149 × 98 cm.
Finally we arrived on Las Meninas (1656), a painting by Diego Velázquez, the leading artist of the Spanish Golden Age. The importance and complexity of this work - its composition which create relationship between the viewer and figures depicted – are summarized by the
description of the work as the "theology of painting" made by Baroque painter Luca Giordano and description of Sir Thomas Lawrence as "the true philosophy of the art" (Lord Sutherland Gower F.S.A., R. 1900). Dwarfs were often kept as curiosities in royal courts and so frequently were the subject of court painters. Las Meninas (Fig. 10) shows a large room in the Royal Alcazar of Madrid during the reign of King Philip IV of
Fig. 12. Prince Baltasar Carlos with a Dwarf 1631. Museum of Fine Arts, Boston, USA. Oil on canvas, 136 × 104 cm.
Fig. 13. The Dwarf Francisco Lezcano, Called El Nino de Vallecas 1642–45. Museo del Prado, Madrid, Spain. Oil on canvas, 107 × 83 cm.
7. Dwarfs
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Spain. In it the young infanta Margaret Theresa is surrounded by her entourage of maids of honor, chaperone, bodyguard, two dwarfs and a dog. The two dwarfs are the achondroplastic German, Maribarbola (Maria Barbola), and the Italian, Nicolas Pertusato, who playfully tries to rouse a sleepy mastiff with his foot (for further reading see also: Alpers, 2005; Carr, 2006; Janson, 1977; Gaggi, 1989; Honour and Fleming, 1982; Kahr, 1975; Leppanen, 2000; López-Rey, 1999; Snyder, 1985; Stone, 1996; White, 1969). Another example of a dwarf subject is Braccio di Bartolo, who became the predilected dwarf of Cosimo I de Medici with name the Morgante (the name of the giant in Luigi Pulci's poema). A detailed anatomical study was painted by Agnolo di Cosimo, Fig. 11. Maribarbola and Braccio di Bartolo both exhibit the common characteristics of achondroplasia. Other well known example of subjects with achondroplasia, depicted by Diego Velázquez, include Prince Baltasar Carlos with a Dwarf 1631 (Fig. 12), The Dwarf Francisco Lezcano (Fig. 13), and The Dwarf Sebastian de Morra, (Fig. 14).
7.1. Clinical and Genetics Achondroplasia is inherited in an autosomal dominant manner and 80% of individuals with achondroplasia are the result of a de novo gene mutation. FGFR3 is the only gene in which mutations (c.1138GNA (p.Gly 380Arg) ~ 98%; c.1138GNC (p.Gly 380Arg) ~ 1%) are known to cause achondroplasia (Pauli, 2014). Clinical features of achondroplasia published by Langer et al. (1967) (reported in Pauli 2012) include different characteristics such as: small stature with hizomelic shortening of the arms and legs with redundant skin folds on limbs, limitation of elbow extension, short fingers, trident configuration of the hands, bow legs, exaggerated lumbar lordosis, large
Fig. 15. “Retrato de enano”, Juan Van Der Hamen, 1596–1631, Museo del Prado, Madrid, Spain. Oil on canvas, 122 × 87 cm.
head with frontal bossing, midfacial retrusion and depressed nasal bridge. In addition to achondroplasia, painters have captured subjects with short stature but without that disorder's characteristic physical and facial features. In the subject of “Retratto de enano”, Fig. 15 is probably an example of pseudoachondroplasia. 7.2. Clinical and genetics Pseudoachondroplasia is inherited in an autosomal dominant manner. This condition is characterized by normal length at birth and normal faces. Often the presenting feature is a waddling gait, recognized at the onset of walking. Typically, by approximately two years of age, the growth rate falls below the standard growth curve, leading to a moderately severe form of disproportionate short-limb short stature. Joint pain during childhood, particularly in the large joints of the lower extremities, is common. Degenerative joint disease is progressive and approximately 50% of individuals with pseudoachondroplasia eventually require hip replacement surgery. COMP, encoding cartilage oligomeric matrix protein, is the only gene in which mutations are known to cause pseudoachondroplasia (Briggs and Chapman, 2002; Briggs et al., 1995; Hecht et al., 1995). 8. Conclusions
Fig. 14. The Dwarf Sebastian de Morra 1645. Museo del Prado, Madrid, Spain. Oil on canvas 106.5 × 81.5 cm.
As concluding remarks for this manuscript I join A. Guerra (2007) in echoing Friedrich Nietzsche: “Art is given to us to prevent us from dying of truth.”
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Acknowledgment The author acknowledges Prof. Emery, whose book Elements of Medical Genetics together with his works regarding Art and Medicine/ Genetics led to the choice of genetics as my professional interest. It is also a particular pleasure to gratefully acknowledge my colleague Dr. Della Monica (Benevento/Italy) who gave me the inspiration for this work many years ago when I assisted in a lecture given by him during the Italian Clinical Genetics Conference. Finally, I would like to thank all patients and their families. To F.V. References A. Guerra on Sierra Valenti X, 2007. Medicine and Disease in Baroque Art. Alpers, S., 2005. The Vexations of Art: Velázquez and Others. Yale University Press, New Haven, New Haven. Angelman, H., 1965. ‘Puppet’ children: a report of three cases. Dev. Med. Child Neurol. 7 (6), 681–688. Angelman, H., 1991. Personal Communication (Letter) to Dr. Charles Williams. Bearn, A.E., 1975. Marfan's syndrome. In: Beeson, P.B., McDermott, W. (Eds.), Textbook of Medicine. WB Saunders, Philadelphia, pp. 1869–1870. Braverman, I.M., Redford, D.B., Mackowiak, P.A., 2009. Akhenaten and the strange physiques of Egypt's 18th dynasty. Ann. Intern. Med. 150 (8), 556–560. Briggs, M.D.,Chapman, K.L., 2002. Pseudoachondroplasia and multiple epiphyseal dysplasia: mutation review, molecular interactions, and genotype to phenotype correlations. Hum. Mutat. 19, 465–478. Briggs, M.D., Hoffman, S.M., King, L.M., Olsen, A.S., Mohrenweiser, H., Leroy, J.G., Mortier, G.R., Rimoin, D.L., Lachman, R.S., Gaines, E.S., Cekleniak, J.A., Knowlton, R.G., Cohn, D.H., 1995. Pseudoachondroplasia and multiple epiphy seal dy splasia due to mutations in the cartilage e oligomeric matrix protein gene. Nat. Genet. 10, 330–336. Bukvic, N.,Margaglione, M., 2013. Genetic counselling in post-genomic era — to be or not to be. World J. Med. Genet. 3 (3), 9–13. Bull, J.M., the Committee on Genetics, 2011. Health supervision for children with Down syndrome. Pediatrics 128, 393. Burridge, A., 1995. Did Akhenaten suffer from Marfan's Syndrome? Temple Project Newsletter, Akhenaten (No. 3). Butler, G.M., Lee, D.K.P., Whitman, Y.B., 2006. Management of Prader–Willi Syndrome. Prader–Willi Syndrome Association (USA) Springer Science + Business Media, Inc., 233 Spring Street, New York. Carr, D.W., 2006. Painting and reality: the art and life of Velázquez. In: Carr, W.D., Bray, X. (Eds.), Velázquez. National Gallery, London. Cassidy, B.S., Driscoll, J.D., 2009. Prader–Willi syndrome. Eur. J. Hum. Genet. 17, 3–13. Cavka, M., Kelava, T., Cavka, V., Busic, Z., Olujic, B., Brkljacic, B., 2010. Homocystinuria, a possible solution of the Akhenaten's mystery. Coll. Antropol. 34 (Suppl. 1), 255–258. Chamberlain, S.J., Lalande, M., 2010. Angelman syndrome, a genomic imprinting disorder of the brain. J. Neurosci. 30, 9958–9963. Cone, T.E., 1964. An infant with some facial features of Mongolism. Am. J. Dis. Child. 106, 333–334. Cone, T.E., 1968. Is Down's syndrome a modern disease? Lancet 829. Dagli, I.A.,Williams, A.C., 2014. Angelman syndrome. In: Pagon, R.A., Adam, M.P., Bird, T.D., et al. (Eds.), GeneReviews® [http://www.ncbi.nlm.nih.gov/books/NBK1144/?report = printable]. University of Washington, Seattle, Seattle (WA) (1993–2014 (last update 2011)). Editorial, 2006. Syndromes run together in the RAS pathway. Nat. Genet. 38 (3). Emery, A.E.H., 1996. Genetic disorders in portraits. Am. J. Med. Genet. 66, 33–39. Farag, T.I., Iskandar, A., 1998. Tutankhamun's paternity. J. R. Soc. Med. 91 (5), 291–292. François, P., Cilliers, L., 2011. Akhenaten, a unique pharaoh. S.A.M.J. 101 (9), 628–630. Gaggi, S., 1989. Modern/Postmodern: A Study in Twentieth-Century Arts and Ideas. University of Pennsylvania Press, Philadelphia. Harper, P.S., 2010. Practical genetic counselling, 2010 Hoddered Arnold, An Imprint of Hodder Education, An Hachette UK Company, 338 Euston Road, London NW1 3BH7th edition. (first published in Great Britain in 1981 by John Wright Ltd. and the 7th edition published 2010 by Hoddered Arnold).
Hawass, Z.,Gad, Z.Y.,Ismail, S., Khairat, R., Fathalla, D., et al., 2010. Ancestry and pathology in King Tutankhamun's family. JAMA 303 (7). Hecht, J.T., Nelson, L.D., Crowder, E., Wang, Y., Elder, F.F., Harrison, W.R., Francomano, C.A., Prange, C.K., Lennon, G.G., Deere, M., Lawler, J., 1995. Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondroplasia. Nat. Genet. 10, 325–329. Honour, H., Fleming, J., 1982. A World History of Art. Macmillan, London. Janson, H.W., 1977. History of Art: A Survey of the Major Visual Arts from the Dawn of History to the Present Day, 2nd ed. Prentice-Hall, New Jersey, Englewood Cliffs. Kahr, M.M., 1975. Velazquez and Las Meninas. Art Bull. 57 (2), 225–246. Langer, L.O., Baumann, P.A., Gorlin, R.J., 1967. Achondroplasia. Am. J. Roentgenol. Radium Ther. Nucl. Med. 100, 12–26. Lee, B.H., Kim, J.M., Jin, H.Y., et al., 2011. Spectrum of mutations in Noonan syndrome and their correlation with phenotype. J. Pediatr. 159, 1029–1035. Leppanen, A., 2000. Into the house of mirrors: the carnivalesque in Las Meninas. Aurora 1. Levitas, S.A., Reid, S.C., 2003. An angel with Down syndrome in a sixteenth century Flemish Nativity painting. Am. J. Med. Genet. 116A, 399–405. London, D.R., 1987. Kallmann's syndrome. In: Weatherall, D.J., Ledingham, J.G.G., Warrell, D.A. (Eds.), Oxford Textbook of Medicine, 10. Oxford Med. Publ., pp. 87–88. López-Rey, J., 1999. Velázquez: Catalogue Raisonné. Taschen. Lord Sutherland Gower, F.S.A.R., 1990. Sir Thomas Lawrence. Goupil & Co., London, Paris & New York, p. 83. McCandless, E.S.,The Committee on Genetics, 2011. Clinical report—health supervision for children with Prader–Willi syndrome. Pediatrics 127, 195. Nelson, D.H., Thron, G.W., 1966. Fröhlich's syndrome. In: Harrison, T.R., Adams, R.D., Bennett, S.L. (Eds.), Harrison's Principles of Internal Medicine. McGraw Hill, New York, p. 411. Nunn, J.F., 1996. Ancient Egyptian Medicine. University of Oklahoma Press, Norman, p. 84. Pauli, M.R., 2014. Achondroplasia. In: Pagon, R.A., Adam, M.P., Bird, T.D., et al. (Eds.), GeneReviews® [http://www.ncbi.nlm.nih.gov/books/NBK1152/]. University of Washington, Seattle, Seattle (WA) (1993–2014 (last update 2012)). Paulshock, B.Z., 1980. Tutankhamun and his brothers: familial gynecomastia in the Eighteenth Dynasty. JAMA 244 (2), 160–164. Pavarino Bertelli, E.C.,Biselli, J.M.,Bonfim, D.,Goloni-Bertollo, E.M., 2009. Clinical profile of children with Down syndrome treated in a genetics outpatient service in the Southeast of Brazil. Rev. Assoc. Med. Bras. 55 (5), 547–552. Pueschel, S.M., 2000. A Parent's Guide to Down Syndrome: Towards a Brighter Future, 2nd edition. Paul H Brookes Pub Co., New York. Ruhrah, J., 1935. Cretin or Mongol or both together? Am. J. Dis. Child. 49, 477–478. Snyder, J., 1985. Las Meninas and the mirror of prices. Crit. Inq. 11, 539–572. Starbuck, J.M., 2011. On the antiquity of trisomy 21: moving towards a quantitative diagnosis of Down syndrome in historic material culture. J. Contemp. Anthropol. II (I), 62–89. Stone, H., 1996. The Classical Model: Literature and Knowledge in Seventeenth-Century France. Cornell University Press, Ithaca. Strachan, M.M.J., Walker, B.R., 2010. Endocrine disease. In: Colledge, N.R., Walker, B.R., Ralston, S.H. (Eds.), Davidson's Principles and Practice of Medicine. Churchill Livingstone, Edinburgh, p. 763. Stratford, B., 1982. Down's syndrome at the court of Mantua. Matern. Child Health 7, 250–254. Stratford, B., 1996. In the Beginning. New Approaches to Down Syndrome. Cassell Publishers, London, pp. 3–11. Tartaglia, M., Gelb, B.D., Zenker, M., 2011. Noonan syndrome and clinically related disorders. Best Pract. Res. Clin. Endocrinol. Metab. 25, 161–179. Van Buggenhout, G., Fryns, J.P., 2009. Angelman syndrome. Eur. J. Hum. Genet. 17, 1367–1373. Volpe, E.P., 1986. Is Down syndrome a modern disease? Perspect. Biol. Med. 29, 423–436. Walshe, J.M., 1973. Tutankhamun: Klinefelter's or Wilson's? Lancet 1 (7794), 109–110. Ward, O.C., 2004. Further early historical evidence of Down syndrome. Am. J. Med. Genet. A 126A (2), 220. White, J.M., 1969. Diego Velázquez: Painter and Courtier. Hamish Hamilton Ltd., London. Williams, C.A., Beaudet, A.L., Clayton-Smith, J., et al., 2006. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am. J. Med. Genet. A 140, 413–418. Williams, C.A., Driscoll, D.J., Dagli, A.I., 2010. Clinical and genetic aspects of Angelman syndrome. Genet. Med. 12, 385–395.
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Gene journal homepage: www.elsevier.com/locate/gene
Genetics in the art and art in genetics Nenad Bukvic a,⁎, John W. Elling b a b
University Hospital Bari-Policlinics, Medical Genetics Unit, Piazza Giulio Cesare, 11, Bari 70125, Italy Concierge Genomics, Inc., 590 Monte Alto, Santa Fe, NM 87501-6172, USA
a r t i c l e
i n f o
Article history: Received 27 May 2014 Received in revised form 23 July 2014 Accepted 24 July 2014 Available online 1 August 2014 Keywords: Genetics and painting masterpieces Down syndrome Angelman syndrome Prader–Willi syndrome Noonan syndrome dwarfism Akhenaten
a b s t r a c t “Healing is best accomplished when art and science are conjoined, when body and spirit are probed together”, says Bernard Lown, in his book “The Lost Art of Healing”. Art has long been a witness to disease either through diseases which affected artists or diseases afflicting objects of their art. In particular, artists have often portrayed genetic disorders and malformations in their work. Sometimes genetic disorders have mystical significance; other times simply have intrinsic interest. Recognizing genetic disorders is also an art form. From the very beginning of my work as a Medical Geneticist I have composed personal “algorithms” to piece together evidence of genetics syndromes and diseases from the observable signs and symptoms. In this paper we apply some ‘gestalt’ Genetic Syndrome Diagnostic algorithms to virtual patients found in some art masterpieces. In some the diagnosis is clear and in others the artists' depiction only supports a speculative differential diagnosis. © 2014 Elsevier B.V. All rights reserved.
1. Introduction The surge of genetic discoveries that result from modern sequencing technology is avidly reported in the scientific and popular press, inspiring scientists, non-scientists and patients alike. The spectacular progress in understanding the genetic nature of disease has profoundly changed the daily practice of Medical Genetics, Clinical Genetics, and Genetic Counseling. However, much has remained unchanged. The problems and questions that confront families are largely the same as they have been, as are the main approaches used in genetic counseling to try to help them. Professor Harper, author of the book “Practical Genetic Counseling” (2010), confirms that: “It is now 30 years since I wrote the first edition of book and more than 40 years since I began to practice Medical Genetics. During this time it Abbreviations: AS, Angelman syndrome; DS, Down syndrome; UBE3A, E3 ubiquitin– protein ligase; PWS, Prader–Willi syndrome; NS, Noonan syndrome; RAS–MAPK, Ras/ mitogen activated protein kinase; PTPN11, Protein Tyrosine Phosphatase, Non-receptor type 11; SOS1, Son of Sevenless Homolog 1; RAF1, v-raf-1 murine leukemia viral oncogene homolog 1; KRAS, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; NRAS, neuroblastoma RAS viral (v-ras) oncogene homolog; BRAF, v-raf murine sarcoma viral oncogene homolog B; SHOCK2, soc-2 suppressor of clear homolog (C. elegans); MEK1, mitogenactivated protein kinase kinase 1; CBL, Cbl Proto-Oncogene, E3 Ubiquitin Protein Ligase; FGFR3, Fibroblasts Growing Factor Receptor 3; Gly, Glycine; Arg, Arginine; COMP, Cartilage Oligomeric Matrix Protein. ⁎ Corresponding author. E-mail address: [email protected] (N. Bukvic).
http://dx.doi.org/10.1016/j.gene.2014.07.073 0378-1119/© 2014 Elsevier B.V. All rights reserved.
has been truly amazing to see what has altered in terms of what we are able to do.”
“At another level, though, much has remained unchanged. The problems and questions that families bring to us are largely the same and so are the main approaches used in genetic counseling to try to help them. New laboratory advances have greatly extended what we are able to do, but have not removed the need for the practice of genetic counseling and of clinical genetics generally, to rest on these long established foundations and on sound psychological principles for the way in which we interact with those we see.” As each new genetic test is made available in the clinic, developing the appropriate counseling for each new diagnosis is necessarily a multidisciplinary endeavor that includes involvement of a Medical Geneticist who must help its patients understand a genetic diagnosis and assist them in making and coping with decisions relating to the diagnosis (Bukvic and Margaglione, 2013) based on these long established technical, scientific/medical, ethical and psychological principles. Even with today's knowledge of a greater number of genetic pathologies and the recent understanding of the molecular basis of many of these illnesses, diagnosis starts with the recognition of a clinical situation based on observation of symptoms and signs. Here these unchanged, fundamental clinical skills are applied to Masterpieces of Art using only the painter's record.
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Fig. 1. The Adoration of the Christ Child, ca. 1515, by a follower of Jan Joest of Kalkar. Oil on wood. The Jack and Belle Linsky Collection, Metropolitan Museum of Art, New York, NY, USA. Oil on wood, 104.1 × 71.8 cm.
2. Down syndrome Levitas and Reid (2003) suggested that an angel in The Adoration of the Christ Child by a follower of Jan Joest of Kalkar (Fig. 1) is depicted with Down syndrome. At first glance this painting is one of many contemporary depictions of the Nativity. Our attention as Medical Geneticists is drawn to two subjects of this painting, one of the angels and one of the earthly admirers whom have a similar and distinctive facial appearance. The angel next to Mary, whose single visible wing is behind the head, seems to have features consistent with Down syndrome: a flattened midface, epicanthal folds, upslanted palpebral fissures, small and upturned nasal tip, and downward curving of the mouth corners. (The curly hair of this angel is not characteristic of Down syndrome but is conventional for paintings of angels.) This angel stands out especially as its facial appearance differs from that of the central angel in the triad, whose aquiline appearance resembles Mary's and the other angels' features. Further symptomatic are the short fingers, especially on the left hand (partially covered by Mary's hair). Again this contrasts with the hands of Mary and the other foreground angels who have long and tapering fingers. The shepherd with a ram's horn in this painting (in the center behind the angels) also has an unusual appearance that is indicative of Down syndrome. The shepherd's hair is straight and he has increased length and an up slant of the palpebral fissures with some degree of ptosis. In addition, the eyes are widely spaced but this apparent hypertelorism may be an artistic interpretation of flattened nasal bridge. The Shepherd's gloves prevent interpretation of the configuration of the hand. Whether this figure was intended to resemble the unusual angel is uncertain (Levitas and Reid, 2003), but these features could be suggestive for Down syndrome, as well as for hypothyroidism which was frequent in this historical period. Levitas and Reid (2003) suggest that the angelic depiction of an individual with Down syndrome was symbolic and may denote that the artist had an affinity for individuals with disabilities. 2.1. Mantegna paintings Ruhrah (1935) argued that a child in Mantegna's painting Virgin and Child (Fig. 2) displays Down syndrome-like characteristics. The child in this painting exhibits oblique eyes, possible epicanthic folds, a small nose, an open mouth, an adenoidal expression, a prominent tongue, square hands, an incurving little finger, wide spacing between the first and second toes of the foot, and a short and broad neck (Ruhrah, 1935; Stratford, 1982), features consistent with Down syndrome (Cone, 1964; Volpe, 1986; Ward, 2004). In 1982, Stratford (1982), suggested that the Italian Renaissance painter Andrea Mantegna used
Fig. 2. Virgin and Child painting by Andrea Mantegna (1431–1506) (or follower) dated to around 1460 A.D. Image A depicts a woman holding a child with suspected Down syndrome-like facial characteristics (Cone, 1964; Ruhrah, 1935; Ward, 2004). Museum of Fine Arts, Boston, USA. Tempera on panel, 48.5 × 34.6 cm.
a little boy with Down syndrome as the model for his Christ child and a woman with goiter as the model for the Virgin (Fig. 2). Stratford's “diagnosis” was based on the child's distinctive facial features and the shape of his hands and toes. Cone also argued that a child in another of Mantegna's painting titled Madonna and Child (Fig. 3), had Down syndrome (Cone, 1964, 1968; Pueschel, 2000), pointing out the oblique eyes, possible epicanthic folds, a small nose, an open mouth, and an adenoidal expression. A third painting attributed to Mantegna, Virgin and Child with Saints Jerome and Louis of Toulouse, Fig. 4, also seems to depict a child with Down syndrome. The child in this painting is portrayed with Down syndrome-like features including widely spaced eyes, upslanted palpebral fissures, an open mouth expression, square-shaped hands with an incurving little finger, and a prominent tongue. This child looks very similar to the child depicted in both above-mentioned Mantegna paintings. Overall, the qualitative evidence that Down syndrome may be depicted in the three paintings is strong (Starbuck, 2011). As Levitas and Reid discussed in their 2003 paper, the benign depiction of disabled individuals in 16th-century culture is unusual. At that time children with obvious mental retardation were typically abandoned to death or servitude. Culturally individuals with recognized disabilities tended to be depicted in paintings as symbols of comedy or evil, the latter being consistent with the attitude expressed by Martin Luther in his religious writings. The depiction in these three works by Mantegna in light of the prevailing culture further suggests that the artist had warm feelings toward the model.
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Indeed it is quite possible that all three of Mantegna's paintings, which were painted around the same time, may depict the same child with Down syndrome (Starbuck, 2011). Stratford (1996) speculates that Mantegna was painting his own child or a child of the rich and powerful Gonzaga family of Mantua, Italy (Stratford, 1982). Stratford claims that one of Mantegna's 14 children had Down syndrome and that the Gonzaga family hired him because one of their children also had the same condition — and in fact this could have been a factor in Ludovico Gonzaga's choice of Andrea Mantegna as his court painter. If a child with Down syndrome was born to the Gonzaga family, it may have lived a better life because of the prestige and wealth of this family during this period however, Stratford notes that the Gonzaga child in question reportedly died at the age of 4. 2.2. Clinical and genetics
Fig. 3. Madonna and Child painting by Andrea Mantegna (1431–1506) dated to around 1460. Image depicts a woman holding a child with Down syndrome-like facial characteristics.
Fig. 4. Virgin and Child with Saints Jerome and Louis of Toulouse painting by Andrea Mantegna (1431–1506) dated to around 1455 A.D. Image depicts a woman holding a child with suspected Down syndrome-like facial characteristics.
Children with Down syndrome have multiple malformations, medical conditions, and cognitive impairment caused by the presence of extragenetic material from chromosome 21 (Bull and the Committee on Genetics, 2011). Although the phenotype is variable, there typically are multiple features (Pavarino Bertelli et al., 2009) that enable the experienced clinician to suspect the diagnosis. Like the art subjects discussed here, the more common physical findings are hypotonia, small brachycephalic head, epicanthal folds, flat nasal bridge, upwardslanting palpebral fissures, Brushfield spots, small mouth, small ears, excessive skin at the nape of the neck, single transverse palmar crease, and short fifth finger with clinodactyly and wide spacing, often with a deep plantar groove between the first and second toes. Down syndrome is associated with cognitive impairment and sufferers also have a significant risk of hearing loss (75%); obstructive sleep apnea (50%–79%); otitis media (50%–70%); eye disease (60%), including cataracts (15%) and severe refractive errors (50%); congenital heart defects (50%); neurologic dysfunction (1%–13%); gastrointestinal atresias (12%); hip dislocation
Fig. 5. Portrait of a Child with a Drawing by Giovanni Francesco Caroto (1480–1555/1558), an Italian Renaissance painter active mainly in his native city of Verona. Castelvecchio Museum, Verona, Italy. Oil on canvas 37 × 29 cm.
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(6%); thyroid disease (4%–18%); and, less commonly, transient myeloproliferative disorder (4%–10%) and later leukemia (1%) and Hirschsprung disease (1%). In approximately 95% of children with Down syndrome, the condition is due to trisomy 21, in which there are 47 chromosomes and a free extra chromosome 21. In 3% to 4% of persons with the Down syndrome phenotype, the extra chromosomal material is the result of an unbalanced translocation between chromosome 21 and another acrocentric chromosome. Approximately three-quarters of these unbalanced translocations are de novo, and the remainder result from familial translocations. Finally, in 1% to 2% of persons with the Down syndrome phenotype, two cell lines are present: one normal and the other with trisomy 21. This condition is called mosaicism. Persons with mosaicism may be more mildly affected than persons with complete trisomy 21 or translocation chromosome 21, but this is not always the case, and their condition may include any of the associated medical problems and be indistinguishable from trisomy 21. Recurrence risks for families with an affected child depend on many factors and families benefit from counseling by a clinical genetic professional. 3. Angelman syndrome (AS) Dr. Harry Angelman, a pediatrician first reported three children with this condition in 1965 (Angelman, 1965). Angelman later described his choice of the title “Puppet Children” to describe these cases as being related to an oil painting he had seen while vacationing in Italy (Fig. 5). Dr. Angelman relates that (Angelman, 1991): “The history of medicine is full of interesting stories about the discovery of illnesses. The saga of Angelman's syndrome is one such story. It was purely by chance that nearly thirty years ago (~ 1964) three handicapped children were admitted at various times to my children's ward in England. They had a variety of disabilities and although at first sight they seemed to be suffering from different conditions I felt that there was a common cause for their illness. The diagnosis was purely a clinical one because in spite of technical investigations which today are more refined I was unable to establish scientific proof that the three children all had the same handicap. In view of this I hesitated to write
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about them in the medical journals. However, when on holiday in Italy I happened to see an oil painting in the Castelvecchio museum in Verona a Boy with a Puppet. The boy's laughing face and the fact that my patients exhibited jerky movements gave me the idea of writing an article about the three children with a title of Puppet Children. It was not a name that pleased all parents but it served as a means of combining the three little patients into a single group. Later the name was changed to Angelman syndrome. This article was published in 1965 and after some initial interest lay almost forgotten until the early eighties.” In the case of the painting, the subject appears to have a very happy demeanor with a rictus smile. An unusually happy demeanor with frequent laughter and smiling is one of the notable characteristics of AS, which occurs along with intellectual and developmental disabilities, sleep disturbance, seizures, and jerky movements. Consensus clinical and genetic aspects of AS have only recently been reported (Williams et al., 2006). Newborns typically have a normal phenotype with developmental delays first noted at around age six months. Nothing is known about the subject of this painting, making a diagnosis based on the smile and puppet drawing alone very weak. 3.1. Clinical and genetics Consensus clinical and genetic aspects of AS (Williams et al., 2006) reported different clinical characteristics the most frequent of which are: delayed attainment of developmental milestones without loss of skills, speech impairment (minimal to no use of words; receptive language skills and nonverbal communication skills higher than expressive language skills), behavioral uniqueness, including any combination of frequent laughter/smiling; apparent happy demeanor; excitability, often with handflapping movements; hypermotoric behavior; short attention span, movement or balance disorder (usually ataxia of gait and/ or tremulous movement of the limbs), seizures with abnormal EEG, protruding tongue, hypotonia, prognathia, wide mouth, wide-spaced teeth, and hypopigmented skin with lighter hair and eye color (compared to the family).
Fig. 6. Doña Eugenia Martínez Vallejo, “La Monstrua” (1680) “desnuda” (oil on canvas 165 × 108 cm) and “vestida” (oil on canvas 165 × 107 cm). Juan Carreno de Miranda (1614–1685) was an important Spanish Court Painter. Museo Nacional del Prado, Spain.
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Angelman syndrome features are caused by deficient expression or function of the maternally inherited UBE3A allele (Chamberlain and Lalande, 2010; Dagli and Williams, 2014; Van Buggenhout and Fryns, 2009; Williams et al., 2006, 2010). Different genetic mechanisms may lead to AS, such as: deletion of the 15q11.2–q13 critical region (60–75%), paternal uniparental disomy (2–5%), imprinting defect (2–5%), and mutation in the UBE3A gene (10%).
4. Prader–Willi syndrome (PWS) The Spanish baroque court painter Juan Carreño de Miranda (1616–1685) depicted Doña Eugenia Martinez Vallejo in the painting “La Monstrua” (Fig. 6). When she was brought to the court of Charles II of Spain as “object” to be seen she was approximately 6 years old and weighed ~ 55 kg with excessive central obesity, a small triangular mouth, and small hands and feet and almond-shaped eyes. While there are competing diagnoses for this girl, the strong argument for PWS comes from by Dr. Andrea Prader whom, upon viewing
these paintings in the Museo del Prado, Madrid, immediately recognized features consistent with Prader–Willi syndrome (Butler et al., 2006). In addition in the “vestida” portrait this young lady holds an apple in one hand and a piece of bread in the other — perhaps a sign for the food related behavioral problems and hyperphagia that are important characteristics of PWS. Although we may never know if this child did in fact have PWS, the paintings and contemporaneous 17th century descriptions of her condition strongly support this supposition. In fact this painting appears in the preface of book on management of Prader–Willi syndrome (Butler et al., 2006). 4.1. Clinical and genetics Prader–Willi syndrome is a highly variable genetic disorder whose most consistent major manifestations include hypotonia with poor suck and poor weight gain in infancy, mild mental retardation, hypogonadism, growth hormone insufficiency resulting in short stature, early childhood-onset hyperphagia and obesity, characteristic appearance, and a wide range of behavioral and sometimes psychiatric disturbances that range from food related behavioral problems alluded in the painting all the way to an unusual skill with jigsaw puzzles. However a wide range of other clinical diagnostic criteria are reported by McCandless and The Committee on Genetics (2011). Three major genetic causes of PWS exist: a 5–7 Mb deletion of the paternally inherited chromosomal 15q11.2–q13 region, a maternal uniparental disomy 15, and a defect in the imprinting process in the 15q11.2–q13 region on the paternally inherited chromosome. Occasionally, deletion results from chromosomal translocation (Cassidy and Driscoll, 2009). A number of imprinted genes have been mapped to the PWS region of 15q11.2–q13, but their role in most aspects of the phenotype is not well understood. While the genetic causes are complex, over 99% of PWS cases can be diagnosed with a simple DNA methylation analysis. 5. Noonan syndrome (NS) Ivan Le Lorraine Albright's 1929 painting “Among Those Left”, Fig. 7, depicts a blacksmith — a man of short stature whose widely spaced eyes angle downward under drooping eyelids with eyes turning outward to his low, prominent ears. His shirt is open to reveal the hollow of his sternum. This may be the most famous portrait of someone with NS (Emery, 1996). This painting also illustrates the difficulties faced in
Fig. 7. Ivan Le Lorraine Albright (1897–1983) painting “Among Those Left” 1929, Museum of Art, Carnegie Institute, Pittsburgh, USA. Oil on canvas 185.4 × 91.4 cm.
Fig. 8. A) This limestone relief found in the Royal Tomb at Amarna depicts Akhenaten, Nefertiti, and two of their daughters making an offering to the sun-disk Aten. Akhenaten and Nefertiti carry flowers to be laid on the table beneath the “life-giving” rays of the Aten. B) A statue of Akhenaten now in the Cairo Museum.
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making a differential diagnosis: “Looking at this picture is puzzling because some of the man's features are individual or familial, some are imposed by the artist and some may be syndromic.” (Editorial, Nature Genetics Vol 38, Number 3, 2006). Noonan syndrome is an autosomal dominant congenital disorder that is diagnosed primarily on clinical features — the range and severity of which vary greatly in patients. In addition to the features we see in the blacksmith in the painting, common features also include scoliosis, cervical spine fusion and excess skin at the neck and nystagmus. 5.1. Clinical and genetics The syndrome is caused, in about 75% of the cases, by an autosomal dominant genetic defect in the Ras/mitogen activated protein kinase (RAS–MAPK) signaling pathway genes (PTPN11, SOS1, RAF1, KRAS, NRAS, BRAF, SHOC2, MEK1, CBL) (Lee et al., 2011; Tartaglia et al., 2011). It occurs in between 1:1000 and 1:2500 live births and is heterogeneous with similar conditions (all grouped as “RASopathies” because they share similar pathogenic mechanisms and clinical features). The clinical diagnosis in conjunction with appropriate molecular tests allows Counselors to offer appropriate guidance about risks, genotype–phenotype correlations, follow-up procedures, etc. Clinical features of NS (modified from Tartaglia et al., 2011) include characteristic facial appearance (epicanthal folds, ptosis, down-slanting palpebral fissures, triangular facies, low set and/or posteriorly rotated ears), webbed neck with low posterior hairline, small stature, different cardiovascular problems (congenital heart defects, pulmonic stenosis, atrioventricular septal defects, aortic coarctation, mitral valve defects etc.), developmental delay with attention deficit/hyperactivity disorder, and different skeletal signs (pectus excavatum and/or carinatum, cubitus valgus, scoliosis, vertebral anomalies, etc.). 6. The many possible syndromes of Akhenaten Akhenaten was a pharaoh of the eighteenth dynasty of Egypt who ruled for 17 years and died in 1336 or 1334 BC. He initiated a major socio-religious revolution with important consequences for his country (François and Cilliers, 2011). In addition to his historical importance, his particular physiognomy and appearance are fascinating. Statues and reliefs of Akhenaten consistently show him with narrow chest with gynecomastia, wide hips with prominent fatty deposits, elongated spindly limbs and an elongated neck and skull. Compared to the normal athletic appearance, in Egyptian art he is the only individual portrayed with a short torso, long head, arms and feet, pronounced collarbones, a pot belly and apparently poor muscle tone (Figs. 8 and 9). When
Fig. 9. Akhenaten and His Family (with his wife Nefertiti and their three daughters under the rays of Aton). Painted limestone relief from Akhenaten (Tell-el-Amarna), 32.5 × 39 cm. Egypt, 18th dynasty, ca. 1345 BCE. Aegyptisches Museum, Staatliche Museen zu Berlin, Berlin, Germany.
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researchers first encountered pictures and statues of this figure they wondered about any underlying medical condition that caused him to be portrayed in such way. A variety of diagnoses have been suggested to explain Akhenaten's characteristics, reported as well by Hawass et al. (2010), including: Marfan syndrome, Wilson–Turner X linked mental retardation syndrome, Fröhlich (adiposogenital dystrophy) syndrome, Klinefelter syndrome, androgen insensitivity syndrome, aromatase excess syndrome in conjunction with sagittal craniosynostosis syndrome, or Antley–Bixler syndrome or a variant form of that syndrome or others (Braverman et al., 2009; Farag and Iskandar, 1998; François and Cilliers, 2011; Paulshock, 1980; Walshe, 1973). Furthermore, Akhenaten's appearance could result from classical homocystinuria due to deficit of cystathionine beta-synthase characterized by the involvement of the eyes, skeleton, nervous system, and vascular system suggested by Cavka et al. (2010). Another interesting observation for Akhenaten's family is the relief in Fig. 9, “Akhenaten and His Family”, representing Akhenaten, his wife Nefertiti, and their daughters. All the daughters seem to have a head shape associated with dolichocephaly. This feature could be due to some kind of heredity craniosynostosis (Hawass et al., 2010), but, of course this head shape could also be a “phenocopy”, secondarily caused after birth. 6.1. Considerations Most of the diseases hypothetically diagnosed from ancient depictions cannot be supported (Hawass et al., 2010), even though some signs undoubtedly fit with clinical suppositions. For example, while there is little doubt of Akhenaten's fertility, many hypothetical diagnoses are for conditions associated with infertility. Although some of his at least 6 children with at least 5 wives might perhaps have had extraconnubial parentage, it is most unlikely (but not impossible of course) that all of them did (François and Cilliers, 2011). For further reading see also: Bearn (1975), Burridge (1995), London (1987), Nelson and Thron (1966), Nunn (1996), and Strachan and Walker (2010).
Fig. 10. Las Meninas (1656) painting by Diego Velázquez, Museo del Prado, Madrid, Spain. Oil on canvas 318 × 276 cm.
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Fig. 11. The Bronzino's double painting, “Portrait of Dwarf Morgante”, Uffizi, Florence, Italy. Agnolo di Cosimo (called Bronzino) 1503–1572, was the leading painter of mid-16th-century. Oil on canvas 149 × 98 cm.
Finally we arrived on Las Meninas (1656), a painting by Diego Velázquez, the leading artist of the Spanish Golden Age. The importance and complexity of this work - its composition which create relationship between the viewer and figures depicted – are summarized by the
description of the work as the "theology of painting" made by Baroque painter Luca Giordano and description of Sir Thomas Lawrence as "the true philosophy of the art" (Lord Sutherland Gower F.S.A., R. 1900). Dwarfs were often kept as curiosities in royal courts and so frequently were the subject of court painters. Las Meninas (Fig. 10) shows a large room in the Royal Alcazar of Madrid during the reign of King Philip IV of
Fig. 12. Prince Baltasar Carlos with a Dwarf 1631. Museum of Fine Arts, Boston, USA. Oil on canvas, 136 × 104 cm.
Fig. 13. The Dwarf Francisco Lezcano, Called El Nino de Vallecas 1642–45. Museo del Prado, Madrid, Spain. Oil on canvas, 107 × 83 cm.
7. Dwarfs
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Spain. In it the young infanta Margaret Theresa is surrounded by her entourage of maids of honor, chaperone, bodyguard, two dwarfs and a dog. The two dwarfs are the achondroplastic German, Maribarbola (Maria Barbola), and the Italian, Nicolas Pertusato, who playfully tries to rouse a sleepy mastiff with his foot (for further reading see also: Alpers, 2005; Carr, 2006; Janson, 1977; Gaggi, 1989; Honour and Fleming, 1982; Kahr, 1975; Leppanen, 2000; López-Rey, 1999; Snyder, 1985; Stone, 1996; White, 1969). Another example of a dwarf subject is Braccio di Bartolo, who became the predilected dwarf of Cosimo I de Medici with name the Morgante (the name of the giant in Luigi Pulci's poema). A detailed anatomical study was painted by Agnolo di Cosimo, Fig. 11. Maribarbola and Braccio di Bartolo both exhibit the common characteristics of achondroplasia. Other well known example of subjects with achondroplasia, depicted by Diego Velázquez, include Prince Baltasar Carlos with a Dwarf 1631 (Fig. 12), The Dwarf Francisco Lezcano (Fig. 13), and The Dwarf Sebastian de Morra, (Fig. 14).
7.1. Clinical and Genetics Achondroplasia is inherited in an autosomal dominant manner and 80% of individuals with achondroplasia are the result of a de novo gene mutation. FGFR3 is the only gene in which mutations (c.1138GNA (p.Gly 380Arg) ~ 98%; c.1138GNC (p.Gly 380Arg) ~ 1%) are known to cause achondroplasia (Pauli, 2014). Clinical features of achondroplasia published by Langer et al. (1967) (reported in Pauli 2012) include different characteristics such as: small stature with hizomelic shortening of the arms and legs with redundant skin folds on limbs, limitation of elbow extension, short fingers, trident configuration of the hands, bow legs, exaggerated lumbar lordosis, large
Fig. 15. “Retrato de enano”, Juan Van Der Hamen, 1596–1631, Museo del Prado, Madrid, Spain. Oil on canvas, 122 × 87 cm.
head with frontal bossing, midfacial retrusion and depressed nasal bridge. In addition to achondroplasia, painters have captured subjects with short stature but without that disorder's characteristic physical and facial features. In the subject of “Retratto de enano”, Fig. 15 is probably an example of pseudoachondroplasia. 7.2. Clinical and genetics Pseudoachondroplasia is inherited in an autosomal dominant manner. This condition is characterized by normal length at birth and normal faces. Often the presenting feature is a waddling gait, recognized at the onset of walking. Typically, by approximately two years of age, the growth rate falls below the standard growth curve, leading to a moderately severe form of disproportionate short-limb short stature. Joint pain during childhood, particularly in the large joints of the lower extremities, is common. Degenerative joint disease is progressive and approximately 50% of individuals with pseudoachondroplasia eventually require hip replacement surgery. COMP, encoding cartilage oligomeric matrix protein, is the only gene in which mutations are known to cause pseudoachondroplasia (Briggs and Chapman, 2002; Briggs et al., 1995; Hecht et al., 1995). 8. Conclusions
Fig. 14. The Dwarf Sebastian de Morra 1645. Museo del Prado, Madrid, Spain. Oil on canvas 106.5 × 81.5 cm.
As concluding remarks for this manuscript I join A. Guerra (2007) in echoing Friedrich Nietzsche: “Art is given to us to prevent us from dying of truth.”
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Acknowledgment The author acknowledges Prof. Emery, whose book Elements of Medical Genetics together with his works regarding Art and Medicine/ Genetics led to the choice of genetics as my professional interest. It is also a particular pleasure to gratefully acknowledge my colleague Dr. Della Monica (Benevento/Italy) who gave me the inspiration for this work many years ago when I assisted in a lecture given by him during the Italian Clinical Genetics Conference. Finally, I would like to thank all patients and their families. To F.V. References A. Guerra on Sierra Valenti X, 2007. Medicine and Disease in Baroque Art. Alpers, S., 2005. The Vexations of Art: Velázquez and Others. Yale University Press, New Haven, New Haven. Angelman, H., 1965. ‘Puppet’ children: a report of three cases. Dev. Med. Child Neurol. 7 (6), 681–688. Angelman, H., 1991. Personal Communication (Letter) to Dr. Charles Williams. Bearn, A.E., 1975. Marfan's syndrome. In: Beeson, P.B., McDermott, W. (Eds.), Textbook of Medicine. WB Saunders, Philadelphia, pp. 1869–1870. Braverman, I.M., Redford, D.B., Mackowiak, P.A., 2009. Akhenaten and the strange physiques of Egypt's 18th dynasty. Ann. Intern. Med. 150 (8), 556–560. Briggs, M.D.,Chapman, K.L., 2002. Pseudoachondroplasia and multiple epiphyseal dysplasia: mutation review, molecular interactions, and genotype to phenotype correlations. Hum. Mutat. 19, 465–478. Briggs, M.D., Hoffman, S.M., King, L.M., Olsen, A.S., Mohrenweiser, H., Leroy, J.G., Mortier, G.R., Rimoin, D.L., Lachman, R.S., Gaines, E.S., Cekleniak, J.A., Knowlton, R.G., Cohn, D.H., 1995. Pseudoachondroplasia and multiple epiphy seal dy splasia due to mutations in the cartilage e oligomeric matrix protein gene. Nat. Genet. 10, 330–336. Bukvic, N.,Margaglione, M., 2013. Genetic counselling in post-genomic era — to be or not to be. World J. Med. Genet. 3 (3), 9–13. Bull, J.M., the Committee on Genetics, 2011. Health supervision for children with Down syndrome. Pediatrics 128, 393. Burridge, A., 1995. Did Akhenaten suffer from Marfan's Syndrome? Temple Project Newsletter, Akhenaten (No. 3). Butler, G.M., Lee, D.K.P., Whitman, Y.B., 2006. Management of Prader–Willi Syndrome. Prader–Willi Syndrome Association (USA) Springer Science + Business Media, Inc., 233 Spring Street, New York. Carr, D.W., 2006. Painting and reality: the art and life of Velázquez. In: Carr, W.D., Bray, X. (Eds.), Velázquez. National Gallery, London. Cassidy, B.S., Driscoll, J.D., 2009. Prader–Willi syndrome. Eur. J. Hum. Genet. 17, 3–13. Cavka, M., Kelava, T., Cavka, V., Busic, Z., Olujic, B., Brkljacic, B., 2010. Homocystinuria, a possible solution of the Akhenaten's mystery. Coll. Antropol. 34 (Suppl. 1), 255–258. Chamberlain, S.J., Lalande, M., 2010. Angelman syndrome, a genomic imprinting disorder of the brain. J. Neurosci. 30, 9958–9963. Cone, T.E., 1964. An infant with some facial features of Mongolism. Am. J. Dis. Child. 106, 333–334. Cone, T.E., 1968. Is Down's syndrome a modern disease? Lancet 829. Dagli, I.A.,Williams, A.C., 2014. Angelman syndrome. In: Pagon, R.A., Adam, M.P., Bird, T.D., et al. (Eds.), GeneReviews® [http://www.ncbi.nlm.nih.gov/books/NBK1144/?report = printable]. University of Washington, Seattle, Seattle (WA) (1993–2014 (last update 2011)). Editorial, 2006. Syndromes run together in the RAS pathway. Nat. Genet. 38 (3). Emery, A.E.H., 1996. Genetic disorders in portraits. Am. J. Med. Genet. 66, 33–39. Farag, T.I., Iskandar, A., 1998. Tutankhamun's paternity. J. R. Soc. Med. 91 (5), 291–292. François, P., Cilliers, L., 2011. Akhenaten, a unique pharaoh. S.A.M.J. 101 (9), 628–630. Gaggi, S., 1989. Modern/Postmodern: A Study in Twentieth-Century Arts and Ideas. University of Pennsylvania Press, Philadelphia. Harper, P.S., 2010. Practical genetic counselling, 2010 Hoddered Arnold, An Imprint of Hodder Education, An Hachette UK Company, 338 Euston Road, London NW1 3BH7th edition. (first published in Great Britain in 1981 by John Wright Ltd. and the 7th edition published 2010 by Hoddered Arnold).
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