Down syndrome differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview

The diagnosis of Down syndrome should be suspected in pre-natal assessment of fetuses on ultrasound examination. Second quad screen showing decreased alfa-fetoprotein (AFP) should raise the suspicion of fetal chromosomal abnormlaity. Pre-natal differentials of low AFP include Down syndrome, Edwards syndrome and Patau syndrome. In the newborn, Down syndrome should be differentiated from other congenital conditions presenting with hypotonia, poor feeding, poor growth and dysmorphic facial features. The differentials include isolated hypotonia, congenital hypothyroidism and Zellweger syndrome.

Differential Diagnosis

Pre-natal differentials

The diagnosis of Down syndrome should be suspected in pre-natal assessment of fetuses on ultrasound examination during first trimester of pregnancy. Second trimester quad screen showing decreased alfa-fetoprotein (AFP) should raise the suspicion of fetal chromosomal abnormlaity. The following are the differential diagnosis of decreased AFP levels during a first trimester quad screen:

Fetal chromosomal abnormality	Quad screen results				Pregnancy associated protein-A (PAPP-A)
	Alfa-fetoprotein (AFP)	Beta human chorionic gonadotrpin (B-hCG)	Estriol	Inhibin A
Down syndrome (trisomy 21)	↓	↑	↓	↑	↓
Edwards syndrome (trisomy 18)	↓	↓	↓	↓ or normal	↓
Patau syndrome (trisomy 13)	↓	↓	↓	↓	↓

Differentials in newborns and children

In the newborns and children, Down syndrome should be differentiated from other congenital conditions presenting with hypotonia, poor feeding, poor growth and dysmorphic facial features. The differentials include the following:

Congenital condition	Physical examination																Karyotype examination	Echocardiography
	Hypotonia	Poor feeding	Poor growth	Dysmorphic features (simian crease)	Single palmar crease	Epicanthal folds	Flat occiput and face	Seizures	Dry skin	Ophtalmologic examination	Abundant neck skin	Gap between first and second fingers (sandal gap)	Protruding tongue	Downward turned mouth	Almond eyes	Round face
Down syndrome	+	+	+	+	+	+	+	+	-	Brushfield spots Amblyopia Corneal ectasis Presenile cataracts Glaucoma Retinovascular abnormalities Strabismus Refractive errors Corneal hydrops	+	Increased	+	+	+	+	Meiotic error: 47,XX, +21 or 47, XY, +21 (meiotic I error leads to heterodisomy whereas meiotic II error leads to isodisomy) Robertsonian translocation: 46, XX, -14, +t(14q;21q) etc.
Congenital hypothroidism	+	+	+	+	-	-	-	+	+	Refractive errors Strabismus	-	-	+	-	-	-	46, XX or 46, XY
Zellwegger syndrome	+	+	+	+	+	+	+	+	-	Brushfield spots Cataracts	-	-	-	-	-	-	46, XX or 46, XY
Isolated hypotonia	+	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	46, XX or 46, XY

Down syndrome must be differentiated from other similar conditions which lead to multiple endocrine disorders such as autoimmune polyendocrine syndrome, POEMS syndrome, Hirata syndrome, Kearns–Sayre syndrome and Wolfram syndromes.

Disease	Addison's disease	Type 1 diabetes mellitus	Hypothyroidism	Other disorders present
APS type 1	+	Less common	Less common	Hypoparathyroidism Candidiasis Hypogonadism
APS type 2	+	+	+	Hypogonadism Malabsorption
APS type 3	-	+	+	Malabsorption
Thymoma	+	-	+	Myasthenia gravis Cushing syndrome
Chromosomal abnormalities (Turner syndrome, Down's syndrome)	-	+	+	Cardiac dysfunction
Kearns–Sayre syndrome	-	+	-	Myopathy Hypoparathyroidism Hypogonadism
Wolfram syndrome	-	+	-	Diabetes insipidus Optic atrophy Deafness
POEMS syndrome	-	+	-	Polyneuropathy Hypogonadism Plasma cell dyscrasias