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Autopsy findings in an adult with Down syndrome.

What two additional co-morbid conditions can be diagnosed from these images?

Answers: Vitiligo and Hashimoto thyroiditis

Down syndrome (DS) is the most common chromosome abnormality among liveborn neonates, occurring in 1 out of nearly every 700 live births. (1) Individuals with DS have a specific combination of phenotypic features that universally includes mental retardation. In 95% of cases, the cause of DS is chromosomal aneuploidy, Trisomy 21, but rare cases of DS can arise from either chromosomal translocation or from mosaicism. (2) DS is characterized by a wide variety of well-recognized dysmorphic features and many, well-known, congenital malformations including congenital heart defects in 40%-50% of cases. Though life expectancy in DS is shorter than that in the general population, survival has improved substantially, with a median age at death nearly doubling over the past 20 years to 56.8 years. (3) As such, awareness of adult-onset conditions and provision of medical services for adults with DS are becoming increasingly important. The patient reported here and the documented findings at autopsy further substantiate the need for a review of the more common pathologic features potentially seen in the adult DS population. A listing of medical problems, and their estimated prevalence, found more frequently in the adult DS population is shown in Table 1.

A wide array of immunologic abnormalities have been associated with DS, including thymic atrophy, susceptibility to infections, and a higher incidence of autoimmune diseases that affect both endocrine (thyroid, pancreas, adrenal) and nonendocrine (stomach, small bowel) organs, including thyroiditis, diabetes, Addison disease, autoimmune hepatitis, primary sclerosing cholangitis, and alopecia areata (occasionally in combination with vitiligo). (12-14)

The link between DS and thyroid dysfunction is well established as the most common endocrine disorder in the DS population. (6) Studies suggest a lifetime prevalence of thyroid disorders on the order of 25%-30%, compared to a prevalence in the general population of less than 2%. (7) The variety of disorders ranges from congenital hypothyroidism to autoimmune thyroiditis, including both Graves and Hashimoto disease. (7,15) Hashimoto thyroiditis, or chronic lymphocytic thyroiditis, as seen in the current case, however, is by the far the most common acquired thyroid disorder in DS and typically causes hypothyroidism with or without detectable serum anti-thyroid antibodies at a median age of onset of 12.3 years and with an equal distribution in both male and female DS individuals. (16)

The link between DS and vitiligo is less well-defined and appears to be tied not only to the concomitant presence of cutaneous alopecia areata (AA) but also to thyroiditis. The milder AA is reported in nearly 9% of DS individuals, while the more severe form of alopecia universalis, as was seen in the current case, is relatively rare at only 2% of DS patients. (12)

The mechanism behind the autoimmune predisposition in the DS population has yet to be determined; however, there are two proposed mechanisms that implicate the additional copy of chromosome 21. (15) There is a strong association between autoimmune hypothyroidism and the coding genes for the major histocompatibility complex (MHC) antigens expressed on B cells. While the MHC gene family region occurs on chromosome 6, it is postulated that genes on chromosome 21 participate in the upregulation of the MHC gene complex. (15) The second proposed mechanism involves the autoimmune regulatory gene (AIRE) located on chromosome 21. This gene is selectively expressed in the thymic medulla and is hypothesized to be a protector against organ specific autoimmune disease. Inactivating mutations in the AIRE gene cause the rare autosomal recessive disease autoimmune polyendocrine syndrome type 1, a condition with a similar autoimmune profile to Down syndrome. Despite the additional AIRE gene copy in the DS, AIRE expression has recently been found to be paradoxically reduced in DS. (13,17)

The current case illustrates many of the comorbid conditions known to challenge the adult DS community, which is expanding due to an improved life expectancy and a community more vigilant health surveillance. The cause of death in the current case is a large pulmonary thromboembolus (PTE). A single case report of a fatal PTE in a postoperative DS adolescent is described in the literature, making the premise of inherent hypercoagulability unlikely. (18) As such, the role that the ostium secundum atrial septal defect played, along with the finding of right ventricular cardiac dilatation and pulmonary hypertension, is unclear but leaves open the possibility for the development of a right-to-left cardiac shunt and subsequent pulmonary arterial thrombus formation. (19) Continued awareness of comorbid conditions in the adult down syndrome poplulation is critical to continuing efforts at establishing practice guidelines and improving care.


The authors would like to gratefully acknowledge the support of the Orleans Parish Coroner's Office for providing the case material for this report.


(1.) Parker SE, Mai CT, Canfield MA, et al. Updated National birth prevalence estimates for selected birth defects in the Unites States, 2004-2006. Birth Defects Res A. 2010;88:1008-1016.

(2.) Tyler C, Edman JC. Down syndrome, Turner syndrome, and Klinefelter syndrome: primary care throughout the life span. Prim Care. 2004; 31:627-648.

(3.) Englund A, Jonsson B, Zander CS, et al. Changes in mortality and causes of deafir in the Swedish Down syndrome population. Am J Med Genet A. 2013;161:642-649.

(4.) Smith DS. Health care management of adults with Down syndrome. Am Fam Physician. 2001;64:1031-108.

(5.) McVicker RW, Shanks OE, McClelland RJ. Prevalence and associated feahrres of epilepsy in adults with Down's syndrome. Br J Psychiatry. 1994;164:528-532.

(6.) Hawli Y, Nasrallah M, El-Hajj Fuleihan G. Endocrine and musculoskeletal abnormalities in patients with Down syndrome. Nat Rev Endocrinology. 2009;5:327-334.

(7.) Prasher VP. Down syndrome and thyroid disorders: a review. Downs Syndr Res Pract. 1999;6:25-42.

(8.) Head E, Powell D, Gold BT, et al. Alzheimer's disease in in Down syndrome. Eur J Neurodegener Dis. 2012;1:353-364.

(9.) Goldhaber SZ, Brown WD, Robertson N, et al. Aortic regurgitation and mitral valve prolapse with Down's syndrome: a case-control shrdy. J Ment Defic Res. 1988;32:333-336.

(10.) Cohen WI. Health care guidelines for individuals with Down syndrome. Down Syndrome Quarterly. 1999;4:1-15.

(11.) Berk AT, Saatci AO, Ercal MD, et al. Occular findings in 55 patients with Down's syndrome. Opthalmic Genet. 1996;

(12.) Madan V, Williams J, Lear JT. Dermatological manifestations of Down's syndrome. Clin Exper Dermatol. 2006;31:623-629.

(13.) Gimenez-Barcons M, Casteras A, del Pilar Armengol M, et al. Autoimmune predisposition in Down syndrome may result from a partial central tolerance failure due to insufficient intrathymic expression of AIRE and peripheral antigens. J Immunol. 2014;193:3872-3879.

(14.) Goldacre MJ, Wotton CJ, Seagroatt V, et al. Cancers and immune related diseases associated with Down's syndrome: a record linkage shrdy. Arch Dis Child. 2004;89:1014-1017.

(15.) Graber E, Chacko E, Regelmann MO. Down syndrome and thyroid function. Endocrinol Metab Clin N Amer. 2012;41:735-745.

(16.) Popova G, Paterson WF, Brown A, et al. Hashimoto's thyroiditis in Down's syndrome: clinical presentation and evolution. Horm Res. 2008;70:278-284.

(17.) Lima FA, Moreira-Filho CA, Ramos PL, et al. Decreased AIRE expression and global thymic hypofunction in Down syndrome. j Immunol. 2011;187:3422-3430.

(18.) Mohan UR, Mangat JS, Sutaria N, et al. Saddle arterial embolus in a patient with Down syndrome. Pediatr Cardiol. 2006;27:117-121.

(19.) Silversides CK, Granton JT, Konen E, et al. Pulmonary thrombosis in adults with Eisenmenger syndrome. J Amer Coll Cardiol. 2003;42:1982-1987.

In the Department of Pathology at Louisiana State University's School of Medicine in New Orleans, Dr. Connor is a second-year Pathology Resident; Ms. Darga is a third-year Medical Student; and Dr. McGoey is an Associate Professor of Pathology and Residency Program Director.

Ellen E. Connor, MD, PhD; Ally Darga; Robin R. McGoey, MD

Table 1: Reported prevalence of medical complications in adults
with DS

Medical Complication               Prevalence in Adult
                                      DS Population

Hearing loss                 [less than or equal to] 70% (4)
Obstructive sleep apnea                  50% (4)
Congenital Heart Defects                  40-50%
Seizures                          46% over 50 years (5)
Thyroid dishrnction                   10%-40% (6,7)
Alzheimer's disease        10% by 40 years (8) 75% by 70 years
Mitral valve prolapse                    57% (9)
Celiac disease                           10% (10)
Cataract                               8%-13% (11)
Alopecia                                 3% (12)
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Title Annotation:Pathology Image of the Month
Author:Connor, Ellen E.; Darga, Ally; McGoey, Robin R.
Publication:The Journal of the Louisiana State Medical Society
Date:Nov 1, 2014
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