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Difficulty: MediumPediatric Hematology and Oncology

An adolescent girl, aged 1010, is evaluated in the outpatient hematology clinic due to recurrent epistaxis and progressive fatigue over the past three months. Her adoptive parents report she has always been significantly smaller than her peers. Vital signs are within normal limits for her age. Physical examination reveals short stature (below the 33 rd percentile), microcephaly, an absent right thumb, and several flat, hyperpigmented macules across her abdomen and back. Laboratory testing shows a hemoglobin of 7.2 g/dL7.2 \text{ g/dL}, a mean corpuscular volume of 112 fL112 \text{ fL}, a leukocyte count of 1,800/mm31,800/\text{mm}^3, and a platelet count of 22,000/mm322,000/\text{mm}^3. Which of the following is the most likely underlying mechanism for this patient's clinical and laboratory findings?

  1. Inherited defect in cellular DNA cross-link repair mechanismsAnswer
  2. B
    Bone marrow aplasia triggered by inappropriate administration of a live-attenuated vaccine
  3. C
    Severe nutritional deficiency misidentified as delayed acquisition of normal developmental milestones
  4. D
    Drug-induced pancytopenia following inappropriate utilization of broad-spectrum antibiotics
  5. E
    Congenital viral syndrome characterized by a rash incorrectly managed as a benign neonatal dermatosis

Answer

Inherited defect in cellular DNA cross-link repair mechanisms
The correct answer accurately identifies the pathophysiology of Fanconi anemia. This patient's presentation of macrocytic anemia, thrombocytopenia, and leukopenia (pancytopenia) combined with classic congenital anomalies (short stature, absent thumb/radial hypoplasia, microcephaly, and café-au-lait spots) is highly characteristic of Fanconi anemia. This condition is an autosomal recessive disorder caused by mutations in genes responsible for the repair of DNA interstrand cross-links. Patients typically present with bone marrow failure in the first decade of life and are at a significantly increased risk of developing acute myeloid leukemia (AML) and solid tumors later in life.

Step-by-Step Solution

1
Analyze the patient's laboratory findings.
The patient has macrocytic anemia, leukopenia, and thrombocytopenia, indicating bone marrow failure (pancytopenia).
Identifying the hematologic disturbance is the first step in formulating a differential diagnosis.
2
Evaluate the physical examination findings.
The patient exhibits short stature, microcephaly, an absent right thumb (radial hypoplasia), and café-au-lait spots.
Correlating lab results with physical anomalies helps differentiate between acquired and inherited causes of bone marrow failure.
3
Synthesize findings to determine the most likely diagnosis.
The combination of pancytopenia and this specific pattern of congenital anomalies is the classic presentation of Fanconi anemia.
Recognizing the pathognomonic physical signs prevents misdiagnosing the condition as an acquired nutritional or infectious aplasia.
4
Identify the underlying pathophysiology of the diagnosed condition.
Fanconi anemia is caused by a genetic defect in the repair of DNA interstrand cross-links.
The question specifically asks for the mechanism causing the patient's presentation.

Key Concept

Fanconi anemia presentation and pathophysiology
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Topics

Pediatric Hematology and Oncology

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