Down's Syndrome (Trisomy 21)

Background

This is the most common serious disorder of the autosomal chromosomes. The overall incidence in the United States is 1 in 700 live births. Most cases result from an extra copy of the long arm region of q22.1 to q22.3 on chromosome 21, resulting in a trisomy 21. In 95% of cases of Trisomy 21, the extra chromosome is of maternal origin. It results from meiotic nondisjunction but the reason for this is still unknown. In a smaller percentage, there are a normal number of chromosomes (46) but extra chromosomal material is present as a translocation, such as a Robertsonian translocation. In these cases, the translocated chromosome is inherited from one of the parents, usually the mother. The fertilized egg has two copies of chromosome 21 and the extra translocated material acts as a triple gene dosage. Mosaics result form mitotic nondisjunction of chromosome 21 during an early stage.

EPIDEMIOLOGIC ASSOCIATIONS CHARACTERIZATION

Maternal Age Maternal age is a well-known risk factor for DS. It must be remembered that this risk is for cases of trisomy 21 and not for mosaics or translocations

Risk

<20 yrs
1/1550

35 yrs
1/385

40 yrs
1/105

>45 yrs
1/25

PATHOGENESIS CHARACTERIZATION

Chromosomal Abnormality Percentage of Cases

Trisomy 21
47, XX, +21 (female)
94%

Translocations
46, XX,der(14;21)(q10;q10),+21 (female)
5%

Mosaics
46,XX/47,XX,+21

1%

Intraneuronal A-Amyloid Precedes Development of Amyloid Plaques in Down Syndrome

Kymberly A. Gyure, etal.

Arch Pathol Lab Med 2001;125:489�492 Abstract quote

Context.�Down syndrome patients who live to middle age invariably develop the neuropathologic features of Alzheimer disease, providing a unique situation in which to study the early and sequential development of these changes.

Objective.�To study the development of amyloid deposits, senile plaques, astrocytic and microglial reactions, and neurofibrillary tangles in the brains of young individuals (<30 years of age) with Down syndrome.

Methods.�Histologic and immunocytochemical study of a series of autopsy brains (n = 14, from subjects aged 11 months to 56 years, with 9 subjects <30 years) examined at the Office of the Chief Medical Examiner of the State of Maryland and The Johns Hopkins Hospital.

Results.�The principal observations included the presence of intraneuronal A immunostaining in the hippocampus and cerebral cortex of very young Down syndrome patients (preceding the extracellular deposition of A) and the formation of senile plaques and neurofibrillary tangles.

Conclusions.�We propose the following sequence of events in the development of neuropathologic changes of Alzheimer disease in Down syndrome: (1) intracellular accumulation of A in neurons and astrocytes, (2) deposition of extracellular A and formation of diffuse plaques, and (3) development of neuritic plaques and neurofibrillary tangles with activation of microglial cells.

LABORATORY/RADIOLOGIC/OTHER TESTS CHARACTERIZATION

Radiographs

CT scan and MRI

Laboratory Markers
Laboratory tests which have been used to screen for Down's syndrome include a low serum alpha-fetoprotein. If maternal serum AFP is used alone, it detects about 60% of cases. When this value is combined with measurements of total human chorionic gonadotropin (THCG) and unconjugated estriol (UE3), the initial screen is strengthened.

When this triple screening is used, about 80% of the infants with Down's syndrome may be detected. These results must be utilized with the gestational age, maternal weight, presence of multiple gestation, and other variables. If the risk of DS is 1:190 or greater, amniocentesis and chromosomal analysis may be offered.

Test
Value

Maternal serum AFP
Decreased

THCG
Increased

UE3
Decreased

GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION

General

VARIANTS

Organ System or Site Abnormality

Nervous System Mental retardation
Hypotonia
Alzheimer-like changes in brain>40 yrs

Cardiovascular Congenital heart defects (endocardial cushion defects consisting of ostium primum, atrial septal defect, atrioventricular valve malformations, and ventricular septal defects

Facies Flat facies
Epicanthal folds
Abundant neck skin

Musculoskeletal Simian crease
Gap between first and second toe

Gastrointestinal Intestinal stenosis
Umbilical hernia
Atresia of the esophagus

Hematopoietic Predisposition to leukemia

Immune system Predisposition to serious infections, usually T cell disturbances

HISTOLOGICAL TYPES CHARACTERIZATION

General

VARIANTS

Transient Myeloproliferative Disorder and Acute Myeloid Leukemia in Down Syndrome An Immunophenotypic Analysis

Nitin J. Karandikar, MD, PhD, Deborah B. Aquino, MD, Robert W. McKenna, MD, and Steven H. Kroft, MD

Am J Clin Pathol 2001;116:204-210 Abstract quote

Immunophenotypic analysis of transient myeloproliferative disorder (TMD) and acute myeloid leukemia (AML) using multiparameter flow cytometry might provide insight into their relationship.

We retrospectively analyzed the expression of multiple lymphoid, myelomonocytic, and megakaryocytic antigens on blast proliferations in 18 patients with Down syndrome (DS; AML, 9; TMD, 9). The AMLs and TMDs shared several immunophenotypic characteristics. Blasts in all expressed CD45, CD38, and CD33; most AMLs and all TMDs were CD36+; and the majority expressed CD41 and CD61, suggesting megakaryocytic differentiation. The majority of cases were CD34+, CD14�, and CD64�. There was aberrant expression of the T-cell�associated antigen CD7 in most AMLs and TMDs. CD56 was expressed aberrantly in 5 AMLs and 7 TMDs.

The major difference between the disorders was the pattern of expression of myeloid markers CD11b and CD13; each was expressed in 8 AMLs but only 2 TMDs. Blasts were HLA-DR�positive in 3 AMLs vs 7 TMDs. Blasts in TMD and AML in DS have a characteristic immunophenotype distinct from AML in other settings. The immunophenotypic similarities suggest a biologic relationship between the disorders; however, distinct immunophenotypic differences also were observed.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.

Commonly Used Terms

Genetic Disorders

Internet Links

Last Updated 8/20/2001

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Copyright � 2001 The Doctor's Doctor

EPIDEMIOLOGIC ASSOCIATIONS	CHARACTERIZATION
Maternal Age	Maternal age is a well-known risk factor for DS. It must be remembered that this risk is for cases of trisomy 21 and not for mosaics or translocations
	Risk
<20 yrs	1/1550
35 yrs	1/385
40 yrs	1/105
>45 yrs	1/25

PATHOGENESIS	CHARACTERIZATION
Chromosomal Abnormality	Percentage of Cases
Trisomy 21 47, XX, +21 (female)	94%
Translocations 46, XX,der(14;21)(q10;q10),+21 (female)	5%
Mosaics 46,XX/47,XX,+21	1%
Intraneuronal A-Amyloid Precedes Development of Amyloid Plaques in Down Syndrome Kymberly A. Gyure, etal.	Arch Pathol Lab Med 2001;125:489�492 Abstract quote Context.�Down syndrome patients who live to middle age invariably develop the neuropathologic features of Alzheimer disease, providing a unique situation in which to study the early and sequential development of these changes. Objective.�To study the development of amyloid deposits, senile plaques, astrocytic and microglial reactions, and neurofibrillary tangles in the brains of young individuals (<30 years of age) with Down syndrome. Methods.�Histologic and immunocytochemical study of a series of autopsy brains (n = 14, from subjects aged 11 months to 56 years, with 9 subjects <30 years) examined at the Office of the Chief Medical Examiner of the State of Maryland and The Johns Hopkins Hospital. Results.�The principal observations included the presence of intraneuronal A immunostaining in the hippocampus and cerebral cortex of very young Down syndrome patients (preceding the extracellular deposition of A) and the formation of senile plaques and neurofibrillary tangles. Conclusions.�We propose the following sequence of events in the development of neuropathologic changes of Alzheimer disease in Down syndrome: (1) intracellular accumulation of A in neurons and astrocytes, (2) deposition of extracellular A and formation of diffuse plaques, and (3) development of neuritic plaques and neurofibrillary tangles with activation of microglial cells.

LABORATORY/RADIOLOGIC/OTHER TESTS	CHARACTERIZATION
Radiographs
CT scan and MRI
Laboratory Markers	Laboratory tests which have been used to screen for Down's syndrome include a low serum alpha-fetoprotein. If maternal serum AFP is used alone, it detects about 60% of cases. When this value is combined with measurements of total human chorionic gonadotropin (THCG) and unconjugated estriol (UE3), the initial screen is strengthened. When this triple screening is used, about 80% of the infants with Down's syndrome may be detected. These results must be utilized with the gestational age, maternal weight, presence of multiple gestation, and other variables. If the risk of DS is 1:190 or greater, amniocentesis and chromosomal analysis may be offered.
Test	Value
Maternal serum AFP	Decreased
THCG	Increased
UE3	Decreased

GROSS APPEARANCE/CLINICAL VARIANTS	CHARACTERIZATION
General
VARIANTS
Organ System or Site	Abnormality
Nervous System	Mental retardation Hypotonia Alzheimer-like changes in brain>40 yrs
Cardiovascular	Congenital heart defects (endocardial cushion defects consisting of ostium primum, atrial septal defect, atrioventricular valve malformations, and ventricular septal defects
Facies	Flat facies Epicanthal folds Abundant neck skin
Musculoskeletal	Simian crease Gap between first and second toe
Gastrointestinal	Intestinal stenosis Umbilical hernia Atresia of the esophagus
Hematopoietic	Predisposition to leukemia
Immune system	Predisposition to serious infections, usually T cell disturbances

HISTOLOGICAL TYPES	CHARACTERIZATION
General
VARIANTS
Transient Myeloproliferative Disorder and Acute Myeloid Leukemia in Down Syndrome An Immunophenotypic Analysis Nitin J. Karandikar, MD, PhD, Deborah B. Aquino, MD, Robert W. McKenna, MD, and Steven H. Kroft, MD	Am J Clin Pathol 2001;116:204-210 Abstract quote Immunophenotypic analysis of transient myeloproliferative disorder (TMD) and acute myeloid leukemia (AML) using multiparameter flow cytometry might provide insight into their relationship. We retrospectively analyzed the expression of multiple lymphoid, myelomonocytic, and megakaryocytic antigens on blast proliferations in 18 patients with Down syndrome (DS; AML, 9; TMD, 9). The AMLs and TMDs shared several immunophenotypic characteristics. Blasts in all expressed CD45, CD38, and CD33; most AMLs and all TMDs were CD36+; and the majority expressed CD41 and CD61, suggesting megakaryocytic differentiation. The majority of cases were CD34+, CD14�, and CD64�. There was aberrant expression of the T-cell�associated antigen CD7 in most AMLs and TMDs. CD56 was expressed aberrantly in 5 AMLs and 7 TMDs. The major difference between the disorders was the pattern of expression of myeloid markers CD11b and CD13; each was expressed in 8 AMLs but only 2 TMDs. Blasts were HLA-DR�positive in 3 AMLs vs 7 TMDs. Blasts in TMD and AML in DS have a characteristic immunophenotype distinct from AML in other settings. The immunophenotypic similarities suggest a biologic relationship between the disorders; however, distinct immunophenotypic differences also were observed.