A 2-month-old infant with trisomy 21 is undergoing routine screening investigations. Which of the following is NOT a recognized metabolic or hematologic abnormality in Down syndrome?

Explanation

## Down Syndrome: Metabolic and Hematologic Complications ### Hematologic Malignancies in Trisomy 21 **Key Point:** Down syndrome carries a dramatically elevated risk of leukemia: | Leukemia Type | Risk in DS | Risk in General Population | Relative Risk | | --- | --- | --- | --- | | Acute Lymphoblastic Leukemia (ALL) | 1 in 100–150 | 1 in 2,000–3,000 | 10–20× higher | | Acute Myeloid Leukemia (AML) | 1 in 150–200 | 1 in 3,000–5,000 | 10–15× higher | | Transient Myeloproliferative Disorder (TMD) | 3–10% of newborns | Rare | 100–1000× higher | **High-Yield:** Transient myeloproliferative disorder (TMD, also called transient abnormal myelopoiesis or TAM) is a unique neonatal complication: - Occurs in 3–10% of Down syndrome newborns - Presents with hepatosplenomegaly, jaundice, and elevated WBC (often >100,000) - Usually self-resolves within 3 months - ~20–30% of TMD cases progress to AML within 2–5 years - Caused by GATA1 mutations in megakaryoblasts **Clinical Pearl:** All infants with Down syndrome should have a complete blood count and liver function tests in the first week of life to screen for TMD. ### Endocrine Abnormalities in Down Syndrome **Key Point:** Hypothyroidism is the most common endocrine disorder: - Occurs in 15–30% of Down syndrome individuals - Can be congenital (primary hypothyroidism) or acquired (autoimmune thyroiditis) - Screening is mandatory at birth and periodically thereafter - TSH and free T4 should be checked **Mnemonic: "ENDO-DS"** — Endocrine disorders (Hypothyroidism, Growth hormone deficiency, Diabetes) are common in Down syndrome. ### Metabolic Screening in Down Syndrome **Key Point:** Down syndrome itself does NOT cause elevated serum phenylalanine levels. Phenylketonuria (PKU) is an **independent autosomal recessive disorder** caused by phenylalanine hydroxylase deficiency: - PKU and Down syndrome are separate genetic conditions - Both require newborn screening, but PKU is not more common in Down syndrome - Elevated phenylalanine is diagnostic of PKU, not trisomy 21 - Down syndrome does not alter phenylalanine metabolism **Warning:** Do not confuse Down syndrome with metabolic disorders. While Down syndrome increases the risk of certain conditions (leukemia, hypothyroidism, diabetes), it does not cause primary metabolic defects like PKU, galactosemia, or maple syrup urine disease. These are screened separately on newborn screening panels. ### Down Syndrome Screening Markers (Prenatal & Neonatal) **Prenatal (Second Trimester):** - ↓ Maternal serum alpha-fetoprotein (AFP) - ↓ Unconjugated estriol (uE3) - ↑ Human chorionic gonadotropin (hCG) **Neonatal (Newborn Screening):** - ↑ TSH (hypothyroidism) - Complete blood count (for TMD) - No specific metabolic marker for Down syndrome itself **High-Yield:** Down syndrome is a chromosomal disorder (trisomy 21), not a metabolic disorder. While individuals with Down syndrome may have metabolic complications (hypothyroidism, increased leukemia risk), they do not have primary metabolic enzyme deficiencies.