Symptom-Based Diagnosis in Pediatrics (CHOP Morning Report) 1st Ed.

CASE 9-1

Eight-Year-Old Girl



The patient is an 8-year-old girl who presented to her primary care physician with several months history of bruising of the chest, groin, arms, and legs without any obvious source of trauma. During the months of bruising the patient also complained of mild leg pain, which the family had attributed to excessive exercise. A relative noted that she was increasingly pale. She had no history of fever, weight loss, or night sweats.


Three years prior to this visit the patient had been neutropenic and thrombocytopenic following a viral illness, but the hematologic abnormalities resolved. The child has congenital conductive hearing loss for which she wears a hearing aid in the left ear and had surgical repair of the right ear. A maternal grandfather has anemia but details were not available. Birth history is otherwise unremarkable.


T 37.3°C; RR 24/min; HR 96 bpm; BP 107/46 mmHg

Height 5-10th percentile; Weight 5-10th percentile

Physical examination was remarkable for mucous membrane pallor. Scattered petechiae were noted on the posterior pharynx and upper chest. There were 1-2 cm areas of ecchymoses on the forehead, left hip, left arm, posterior right heel, and right knee. Lung examination revealed decreased breath sounds at the bases. Cardiac examination revealed no murmurs, rubs, or gallops. There was no hepatosplenomegaly and no prominent adenopathy.


Laboratory analysis revealed 2300 WBCs/mm3 with 1% band forms, 14% segmented neutrophils, 84% lymphocytes, 8% eosinophils, and 1% monocytes. The hemoglobin was 6.2 g/dL and there were 16 000 platelets/mm3. The peripheral blood smear revealed anisocytosis, poikilocytosis, and hypochromia. Electrolytes, blood urea nitrogen, and creatinine were normal. Alkaline phosphatase was 159 mU/mL. Lactate dehydrogenase was 1062 IU/L. Serum transaminases, albumin, and bilirubin were normal. Uric acid was normal. Antibodies to Epstein-Barr virus were consistent with past infection. Serologic tests for hepatitis B and C infection were negative.


The patient was admitted to the hospital where bone marrow biopsy (Figure 9-1) and a hemato-logic test were diagnostic for the patient’s condition.


FIGURE 9-1. Bone marrow biopsy. (Photo courtesy of Marybeth Helfrich, MT, ASCP.)



Bruising and petechiae are types of vascular rashes. Because of the location of the lesions in areas where accidental trauma was unlikely, first on the differential in this age child would be coagulation disorders such as leukemia or immune thrombocytopenic purpura (ITP). Leukemia is possible given the bone complaints and pancytopenia. ITP is an acute and self-limited illness presenting with bruising and petechiae 2-4 weeks after a minor illness. The timing of this patient’s symptoms and the effect on all three cell lines rather than on the platelets alone makes ITP unlikely. Because of the slow evolution of her illness and the lack of other systemic symptoms, acute illness causing vasculitis would also be less likely. It is the fact that all three cell lines were affected which caused clinicians to suspect a congenital or acquired aplastic anemia.


Bone marrow biopsy revealed a markedly hypo-cellular marrow with only rare hematopoietic cells (Figure 9-1). There was also stromal edema and focal hemosiderosis. Peripheral blood lymphocytes were cultured in the presence of diepoxybutane (DEB), an alkylating agent. The DEB test was considered positive by the presence of consistent chromosomal abnormalities. This indicated the diagnosis of Fanconi anemia, or congenital aplastic anemia.


Fanconi anemia is transmitted in an autosomal recessive inheritance pattern. More than 600 cases have been reported in many ethnic groups since the disorder was first described by Professor Fanconi in Switzerland in 1927, but is seen in higher frequency among Ashkenazi Jews. Scientists have identified 15 Fanconi anemia or Fanconi anemialike genes. Although usually transmitted as an autosomal recessive fashion, there is one gene that is X-linked. It is estimated that approximately 1000 persons worldwide are living with Fanconi anemia, and genetic counseling and testing is recommended for families that may be carriers.


There are three features of Fanconi anemia: chromosome breakage, pancytopenia, and congenital anomalies (Table 9-2). Although chromosomal breakage and pancytopenia are universal features of the disease, congenital anomalies and resultant dysmorphic features are not. Over one-half of patients with Fanconi anemia have skeletal abnormalities including thumb abnormalities or absence of the radii, and one-third have renal abnormalities. Other findings in some include short stature and hyperpigmentation. In this case, the absence of obvious congenital anomalies led to delays and difficulties in the diagnosis.

TABLE 9-2. Congenital abnormalities of Fanconi anemia.

Developmental delay



Ear malformations, hearing loss

Cardiac murmur

Skin hyperpigmentation

Renal malformations

Hypospodias, cryptorchidism

Scoliosis, thumb abnormalities (supernumery thumb, absent thumb), absent radius, congenital hip dislocation, short stature

Although genetically determined, pancytopenia does not usually present until after 5 years of age. The onset of progressive bone marrow failure is initially manifested by petechiae and ecchymosis secondary to thrombocytopenia between ages 2 and 22 (mean age 7 years). Anemia and neutropenia develop later. In addition to the cytopenias, recent studies have also identified specific immune dysfunctions with patients with Fanconi anemia, including deficits in natural killer cell function.


Complete blood count. Disordered erythropoesis is demonstrated by macrocytosis and elevated levels of fetal hemoglobin before marrow failure. Thrombocytopenia is usually noted at presentation with pancytopenia ultimately developing.

Bone marrow biopsy. Serial bone marrow aspirates show progressive hypocellularity and finally frank aplasia.

Chromosomal breakage test. The laboratory diagnosis is made by finding an increased incidence of chromosome breakage induced by alkylating agents, such as nitrogen mustards, mitomycin C, and diepoxybutane (DEB), as in this case. Fanconi anemia cells are characteristically hypersensitive to these DNA cross-linking agents, with new testing developments allowing for testing on fetal blood, chorionic villus, and amniotic cells, offering prenatal diagnosis. An increased incidence of spontaneous chromosome breakage is seen in these patients.


Supportive therapy including transfusions of erythrocytes and platelets are only of temporary benefit. In the past, 75% of these patients died within 2 years of diagnosis. Therapy administered with pharmacologic doses of androgenic hormones give hematologic benefit in more than two-thirds of the patients and may be maintained for several years. However, complications of androgenic therapy are common and most patients eventually become refractory to therapy. Bone marrow transplantation has been successful and curative in patients who find a successful donor match.


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