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2007-05-09-12 Brain tumor and Fanconi’s anemia © Dalmon
Brain tumor and Fanconi’s anemia

Cécile Dalmon*, MD, Geneviève Brodaty*, MD, Bettina Bessières**, MD, Véronique Mirlesse*, MD, Luc Gourand*, MD.

*   Ex-Service de Médecine Foetale, Fernand Daffos, MD, Institut de Puériculture, Paris
**  Service de foetopathologie, IPP Paris.



Fanconi’s anemia (OMIM #227650) is remarkable by the variability of the clinical phenotype, which includes bone-marrow failure, a variety of congenital malformations, a propensity to develop acute myeloid leukemia and cellular hypersensitivity to DNA cross-linking agents. Fanconi’s anemia is manifested in children by a progressive hematopoietic deficiency. (1,2)


Fanconi anemia, Fanconi pancytopenia.


Its frequency has been estimated to be 0.03:10.000 births. Fanconi’s anemia has been found in all ethnics groups but with a higher frequency in a two ethnic group: Ashkenazi Jews and Afrikaans population of South Africa. (1,3)


Fanconi’s anemia is a rare, autosomal recessive disease associated with chromosomal instability. To date, twelve complementation groups have been reported (Fanconi’s anemia-A, B, C, D1, D2, E, F, G, I, J, L, and M) and eleven associated genes have already identified: FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG/XRCC9, BRIP1/FANCJ, FANCL and FACM/Hef. Biallelic BRCA2 mutations cause Fanconi’s anemia D1, heterozygote BRCA2 mutation carriers are risk of breast and other cancer. (4,5,6)


Fanconi’s anemia is characterized by defective DNA repair disorders and hypersensitivity to DNA cross-linking agents. The identification of 12 different Fanconi’s anemia genes has revealed a complex web of interacting proteins that are involved in the recognition or repair of DNA inter-strand crosslinks and perhaps other forms of DNA damage. The specific function of these genes has not been elucidated; they cooperate in a common pathway involved in the repair of damaged DNA. There appears to be little correlation between specific Fanconi’s anemia subgroups and specific cellular or clinical findings.

Sonographic findings

Prenatal recognition of Fanconi’s anemia is difficult. We found only 5 articles. Association  of limb abnormalities (thumbs, radial abnormalities), renal, gastrointestinal, cardiac, neurological findings can be highly suggestive of Fanconi’s anemia. Hydrocephalus and ventriculomegaly have been reported in two studies. (Giamppietro 1993, Pavlakis 1992) (7,8). Tercanli (2001) (9) described a fetus with increased nuchal translucency at 12 weeks GA and an enlarged cisterna magna, ventricular septal defect and signs of dysmorphism and growth restriction at 20 weeks GA. Merill (2005)(10) described two cases . For the first case, at 19 weeks’ gestation, they found bilateral ventriculomegaly, absent cavum, absent left radius and poorly visualized right kidney. For the second case, they found a large fetal stomach (suggestive of obstruction or duodenal atresia), absent kidneys, mild ventriculomegaly.

Differential diagnosis

Nijmegen breakage syndrome is an autosomal recessive inheritance associated with chromosomal instability. There are microcephaly, micrognathia, retrognathia, short neck, thymic aplasia/hypoplasia, beaked nose. Thrombocytopenia chromosome breakage is an autosomal dominant inheritance associated with chromosome breakage and thrombocytopenia.

Associated anomalies

Giampietro (1993) analyzed clinical data from 370 patients with Fanconi’s anemia and reported that only 220 individuals presented congenital anomalies. Although 60% of affected individuals showed congenital malformations, diagnosis before the onset of hematologic manifestations was made in only 28%.
In addition to the high incidence of congenital abnormalities, Fanconi’s anemia develop bone marrow failure (aplastic anemia) at an early age and have a greatly increased risk of developing myelodysplasia, acute myeloid leukemia, and solid malignancies.
A recent survey of cancer incidence in 144 Fanconi’s anemia patients reported 18 solid tumors (squamous cell carcinomas, vulvar cancer, esophageal cancer, head and neck cancer). The median age at onset of the solid tumors was 28, 9 years (11)
Only a small number of brains tumors cases were the initial presentation of Fanconi’s anemia.
Alter (1994) (12) reported two cousins with the similar multiple congenital abnormalities suggestive of Fanconi’s anemia who both developed brains tumors. The first cousin, aged 4 years developed a brain tumor diagnosed on a computed tomography brain scan (medulloblastoma or astrocytoma). The second cousin, aged 1 year 9 months, was dead and the post mortem examination revealed a right cerebellar astrocytomas.
A report by Chaderevian (13) described  an 18 month old child with Fanconi’s anemia who died following a short history of vomiting; the post-mortem examination revealed a right cerebellar medulloblastoma.
Tisckowitz (14) reported a case of medulloblastoma as a first presentation of Fanconi’s anemia, a boy aged 2 years 11 months with no congenital abnormalities and normal bone marrow who presented a cerebellar medulloblastoma.


The hematological disorders resulting from bone marrow dysfunction (thrombocytopenia, progressive pancytopenia) usually appear around a mean age 7 years, but they can arise very early, at birth, or, even more rarely, very late around 40 years. The prognosis of this genetically heterogeneous disorder is poor, with 35% of patients dying at a median age of 13 years due to the frequent respiratory infections caused by leukopenia. Some children have been successfully treated with bone marrow transplantation. (15)

Recurrence risk

Fanconi anemia is an autosomal recessive disorder. A preimplantation genetic diagnosis is possible when the parents have been already a child affected (Bielorai) (16)


Prenatal diagnosis of Fanconi’s anemia is rare by ultrasonography. Amniocentesis and karyotyping with chromosomal breakage testing should be proposed. The option of pregnancy termination must be discussed if the diagnosis of Fanconi’s anemia is made.

Case report

This to our knowledge is the first prenatal report of a brain tumor in a fetus with Fanconi’s Anemia.

The patient is a 30-year-old G4P3. The parents are consanguineous (the grand-parents are first cousin). There is no known family history of Fanconi’s Anemia.

Patient’s obstetrical history:

1996: normal healthy baby boy, birth weight 3770 g.

2001: female child, birth weight 2700 g, diagnosis of incontinentia pigmenti (café-au lait spots). Died at 6 months, nephroblastoma.

2003: male fetus, pregnancy was terminated at 27 weeks due to associated anomalies including hydrops, club foot and chromosomal instability. Post abortive appearance of the fetus showed: diffuse increased skin pigmentation, epicanthic folds, upslanted palpebral fissures, facial structural asymmetry, low set ears, talipes varus, and thumb anomaly. Autopsy was denied. The diagnosis of Fanconi’s Anemia was proposed.

2006: new pregnancy. A chromosomal analysis was performed at 20 weeks after fetal blood sampling had revealed increased spontaneous chromosomal breakages. Ultrasound scans performed at 12, 20, 23 weeks were normal. At 28 weeks a hydrocephalus associated with a brain vascular tumor (3x3 cm), located in the right parieto-occipital area, were discovered. The parents were informed about the fetal prognosis and decided to terminate the pregnancy at 29 weeks.


Postnatal appearance showed macrocephaly, right bifid thumb, talipes varus, increased skin pigmentation spot (3x4 cm). A skeletal x-ray was performed, right thumb with two terminal phalanx, macrocephaly, twelve ribs plus one cervical rib. Brain pathology showed a tumor which invaded the thalami, the temporal and occipital lobe. Immunohistochemistry was performed: vimentin was observed in many cells of the tumors, GFAP, NFP and MAP2 were observed in many cells. EMA and olog2 were observed in few cells. The glioneuronal malignant tumor showed positivity for astrocytoma, oligodendrocytoma, ependymal markers.

Image 1 and 2. 2D gray scale ultrasonography. Image 1 - 19th week of pregnancy - normal intracranial architecture of the fetal head. Image 2 - 22nd week of pregnancy - normal appearance of intracranial structures.


Image 3 and 4. 2D gray scale ultrasonography. 21st week - normal intracranial architecture of the fetal head.


Image 5 and 6. 27th - 28th week of pregnancy. Image 5 - power Doppler axial ultrasound scan of the fetal head showing vascularized tumor of the right parietooccipital region. Image 6 - the same scan as in the image 5 using color Doppler.


Image 7 and 8. 27th - 28th week of pregnancy gray scale ultrasound scans showing tumor of the right parietooccipital region.


Image 9 and 10. Postnatal appearance of the bifid thumb.


Image 11 and 12. Image 11 - postnatal appearance of the baby’s macrocephalic head (image 11) and cafe-au-lait spots (image 12).


Image 13: Chromosomal breakage.                                   Image 12: Cafe-au-lait spots.

Image 14 and 15: Pathological specimens showing tumoral mass of the brain.




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