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History of Medicine |

Akhenaten and the Strange Physiques of Egypt's 18th Dynasty

Irwin M. Braverman, MD; Donald B. Redford, PhD; and Philip A. Mackowiak, MD, MBA
[+] Article and Author Information

From Yale University School of Medicine, New Haven, Connecticut; The Pennsylvania State University, State College, Pennsylvania; the Akhenaten Temple Project, Amarna, Egypt, and the Veterans Affairs Maryland Health Care System and University of Maryland School of Medicine, Baltimore, Maryland.


Note: This discussion was presented originally in an open forum sponsored by the Veterans Affairs Maryland Health Care System and the University of Maryland School of Medicine as part of an ongoing series of historical clinicopathologic conferences.

Acknowledgment: The authors thank Mr. Larry Pitrof and Mr. Wayne Millan for assistance in organizing the conference on which this article is based and Professor Bette Sue Masters, Department of Biochemistry, University of Texas Health Science Center at San Antonio, Texas, for alerting us to the Antley–Bixler syndrome.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Philip A. Mackowiak, MD, MBA, Medical Service-111, Veterans Affairs Medical Center, 10 North Greene Street, Baltimore, MD 21201; e-mail, Philip.Mackowiak@va.gov.

Current Author Addresses: Dr. Braverman: Yale University School of Medicine, Department of Dermatology, 333 Cedar Street, Box 208059, New Haven, CT 06520-8059.

Dr. Redford: 1292 Chestnut Ridge Drive, State College, PA 16803.

Dr. Mackowiak: Medical Service-111, Veterans Affairs Medical Center, 10 North Greene Street, Baltimore, MD 21201.


Ann Intern Med. 2009;150(8):556-560. doi:10.7326/0003-4819-150-8-200904210-00010
Text Size: A A A

Akhenaten was one of Egypt's most controversial pharaohs, in part because of his strange appearance in images produced after he had declared Aten, the Sun-disc, his one-and-only god. Whether these were symbolic representations or realistic ones that indicate a deforming genetic disorder is the subject of continuing debate. The authors present evidence that the bizarre physical features portrayed in these images are not only realistic but were shared by many members of Egypt's 18th Dynasty. The features are best explained by either 2 different familial disorders—the aromatase excess syndrome and the sagittal craniosynostosis syndrome—or a variant of the Antley–Bixler syndrome caused by a novel mutation in one of the genes controlling the P450 enzymes, which regulate steroidogenesis and cranial bone formation.

Figures

Grahic Jump Location
Figure 1.
Alabaster statuette of Akhenaten.

Reproduced with permission from Bildarchiv Preussischer Kulturbesitz/Art Resource, NY Aegyptische Museum, Staatliche Museen zu Berlin, Berlin, Germany.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Relief of Akhenaten, Nefertiti, and their 3 eldest daughters.

The second daughter, Meketaten, sitting on Nefertiti's lap, is 5 to 7 years old and has prominent breasts and wide hips. Reproduced with permission from Vanni/Art Resource, NY Aegyptisches Museum, Staatliche Museen zu Berlin, Berlin, Germany.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Images of members of Egypt's 18th Dynasty.

A. Statue of Amenophis II (Akhenaten's great-grandfather), showing gynecomastia, making an offering from the Temple of Amun at Thebes. Reproduced from reference 16 with permission. B. Votive figure of Amenophis III (Akhenaten's father), showing gynecomastia. Reproduced from reference 13 with permission. C. Fragment of a statue of Akhenaten, showing gynecomastia. Reproduced from reference 17 with permission. D. Tutankhamun (Akhenaten's brother), as the King of Upper and Lower Egypt, showing gynecomastia. Reproduced from reference 13 with permission. E. Alabaster statuette of a daughter of Akhenaten, showing elongated head, cranial (parietal bone) widening, breast development, and widened hips and buttocks. On the basis of facial development, she is 3 to 5 years of age. Reproduced from reference 24 with permission. F. Daughter of Akhenaten as a teenager or young adult, showing elongated and widened cranium. Reproduced from reference 17 with permission. G. Forensic reconstruction of Tutankhamun from computed tomography scan data of his skull. Reproduced from reference 13 with permission. H. Elongated head of the mummy of Thutmose III. Reproduced from reference 10 (public domain).

Grahic Jump Location

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Akhenaten and the strange physiques of Egypt's 18th dynasty
Posted on May 12, 2009
Walter L. Miller
University of California, San Francisco
Conflict of Interest: None Declared

In their "History of Medicine" article "Akhenaten and the strange physiques of Egypt's 18th dynasty" (Ann Int Med 150:556, 2009), Braverman et al. present the intriguing hypothesis that Akhenaten (Amenophis IV) had gynecomastia and brachycephaly attributable to the form of the Antley- Bixler syndrome (ABS) caused by mutations in P450 oxidoreductase (POR). Having reviewed the clinical findings and/or identified the genetic defects in most reported cases of POR deficiency (1-3), I find this unlikely. ABS, first described in 1975, is a rare skeletal dysplasia syndrome characterized by craniosynostosis, radio-ulnar or radio-humeral synostosis, brachycephaly, femoral bowing, femoral fractures, midface hypoplasia, proptosis, a "pear-shaped" nose, choanal atresia and other bony findings (4, 5). The ABS phenotype can result from either of two distinct genetic disorders: autosomal dominant, gain-of-function mutations of FGFR2 and autosomal recessive, loss-of-function mutations of POR (2). The multi-generational history of brachycephaly described in Akhenaten's family could be consistent with an autosomal dominant disorder, possibly in FGFR2. However, there is nothing in Akhenaten's kindred to suggest the femoral bowing or decreased range-of-motion that would accompany the elbow synostosis typical of ABS.

While the skeletal findings in ABS secondary to FGFR2 or POR mutations are indistinguishable, these two genetic disorders are readily distinguished by the absence of a steroidogenic disorder in patients with FGFR2 mutations, but the presence of disordered steroidogenesis, often associated with genital ambiguity in patients with POR mutations (2). The clinical spectrum of steroid POR deficiency is quite broad: minimal POR activity causes severe ABS and a severe disorder of steroidogenesis resulting in ambiguous genitalia in both sexes, whereas individuals having mild POR defects have infertility associated with normal external genitalia and a normal skeleton. However, even in very mild cases devoid of a skeletal phenotype, infertility is typical (1, 2). Thus, if Akhenaten truly fathered six children, his POR function would have to have been sufficiently robust so as to have precluded the skeletal disorder. Thus it seems unlikely that Akhenaten had either ABS or POR deficiency.

References

1. Flück CE, Tajima T, Pandey AV, Arlt W, Okuhara K, Verge CF, et al. Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nat Genet. 2004;36:228-230.

2. Huang N, Pandey AV, Agrawal V, Reardon W, Lapunzina PD, Mowat D, et al. Diversity and function of mutations in P450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis. Am J Hum Genet. 2005;76:729-749.

3. Scott RR, Miller WL. Genetic and clinical features of P450 oxidoreductase deficiency. Hormone Res. 2008;69:266-275.

4. Antley R, Bixler D. Trapezoidocephaly, midfacial hypoplasia and cartilege abnormalities with multiple synostoses and skeletal fractures. Birth Defects Orig Artic Ser. 1975;11:397-401.

5. Crisponi G, Porcu C, Piu ME. Antley-Bixler syndrome: case report and review of the literature. Clin Dysmorphol. 1997;6:61-68.

Conflict of Interest:

None declared

Akhenaten's Strange Physique
Posted on June 4, 2009
philip a. mackowiak
va maryland health care system
Conflict of Interest: None Declared

IN RESPONSE: Our analysis of Akhenaten's kindred revealed two abnormalities: craniosynostosis and gynecomastia (1). These were best explained by two genetic disorders: sagittal craniosynostosis and aromatase syndrome producing excessive estrogen. The Antley-Bixler syndrome (2) was brought to our attention as a possible explanation for our findings. However the type of cranial deformity in ABS is very different from that found in Akhenaten's kindred, and infertility was not a problem for Akhenaten. However the gene for the aromatase syndrome regulates a portion of the P450 enzyme system, and the gene for POR deficiency also regulates a portion of the P450 enzyme system. Since the ABS syndrome with cranial abnormalities and deficient steroidogenesis is caused by a single gene related to the P450 system, we are postulating the possibility of a novel gene, yet to be discovered, that would produce both sagittal craniosynostosis and excessive estrogen formation. A starting point to look for this gene in DNA obtained from appropriate members of the 18th Dynasty would be in the genomic neighborhood of the aromatase gene and POR gene.

References

1. Braverman IM, Redford DB, Mackowiak PA. Akhenaten and the strange physiques of Egypt's 18th dynasty. Ann Intern Med. 2009; 150: 556-60

2. Flück CE, Tajima T, Pandey AV, Arlt W, Okuhara K, Verge CF, et al. Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nat Benet. 2004:36:228-30.

Conflict of Interest:

None declared

Further links from Pharaoh Akhenaten to medicine
Posted on June 17, 2009
Timo E. Strandberg
Institute of Health Sciences/Geriatrics, Univ of Oulu, and Oulu Univ Hosp, Unit of General Practice
Conflict of Interest: None Declared

While scholarly analyzing and discussing the features of a familial disorder (possibly sagittal craniosynostosis syndrome) of Pharaoh Akhenaten (1) the authors leave the cause of his death unknown. The circumstances of death have, however, been described fictionally, which offer further links from Akhenaten to the medical profession..

Pharaoh Akhenaten is an important figure in the Finnish author Mika Waltari's (1908-1979) novel Sinuhe, the Egyptian, which topped international best-seller lists in 1949-1950, for example, unusually long in the U.S. The central idea of this fascinating book is universal: Seen through the eyes of Sinuhe, the novel's teller-doctor, it reflects the pessimistic feelings of the post-war era and warns about selfish and destructive ideologies.

In the novel, Akhenaten was murdered and the deadly poison was given to him by Sinuhe, Pharaoh's personal physician and clandestine half- brother. Akhenaten's death was deemed necessary to rescue the nation which was ailing because of the ruler's eccentricities. But as it frequently goes, also personal intrigues by courties "“ especially by subsequent pharaoh Horemheb - were involved.

Initially, Sinuhe was ordered to kill Akhenaten by trepanning "“ an ancient method of physicians for various ailments as well as a way of euthanasia. Sinuhe, however, considers this to be against his doctor's ethics, but opportunistically yields to giving the Pharaoh poison disguised as a medicine. Afterwards Sinuhe briefly tries to analyze his personal motives.

Although a frequently speculated Nobel Prize winner, Mika Waltari never got one, possibly due to his "best-selling" reputation. Although Mr. Waltari did not visit Egypt during his lifetime, his description of the everyday life during the pharaohs were deemed very accurate by egyptologians. Except epileptic seizures, I could not find other references to Akhenaten's diseases in Waltari's novel. But might craniosynostosis provoke epilepsy, too? (2).

References

1. Braverman, IM, Redford DB, Mackowiak PA. Akhenaten and the strange physiques of Egypt's 18th Dynasty. Ann Int Med 2009;150:556-560

2. Fehlow P. Craniosynostosis as a risk factor. Childs Nerv Syst 1993;9:325-7

Conflict of Interest:

None declared

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