A number sign (#) is used with this entry because Fanconi anemia of complementation group N (FANCN) is caused by homozygous or compound heterozygous mutation in the PALB2 gene (610355) on chromosome 16p12.

Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by Deakyne and Mazin, 2011).

For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see 227650.

Xia et al. (2007) described a female patient with a severe and unclassified form of Fanconi anemia. She was born after an uneventful pregnancy of 40 weeks, with low birth weight. Congenital abnormalities included microcephaly, hypertelorism, short neck, heart defect, long boneless thumb on the right hand, hypoplastic thumb on the left hand, imperforate anus, ectopic right kidney, cafe-au-lait spots, and epicanthus. The patient developed aplastic anemia at age 2 and died at 2 years and 4 months of age from a kaposiform hemangioendothelioma of the left retroocular cavity that had invaded the brain. Cytogenetic studies showed spontaneous chromatid breaks in approximately 50% of cells. Breakage was increased by adding diepoxybutane or mitomycin C (MMC). Several members of the patient's family developed tumors.

Reid et al. (2007) identified individuals with Fanconi anemia and childhood embryonal tumors, a phenotype similar to FANCD1 (605724), attributable to biallelic mutations in BRCA2 (600185), but who lacked such mutations. The phenotype of patients with Fanconi anemia of complementation group N (FANCN) was in many ways typical of Fanconi anemia and included growth retardation and variable congenital malformations. One of the patients, from a British family, showed growth retardation, microcephaly, and hypoplastic thumb, and developed medulloblastoma at the age of 2.3 years. Another, from a North American family, had growth retardation, microcephaly, ventricular septal defect, atrial septal defect, thumb and radial anomalies, and skin hyperpigmentation. Neuroblastoma developed at the age of 0.7 years and acute myeloblastic leukemia at the age of 2 years. All 7 individuals with FANCN reported by Reid et al. (2007) developed cancers in early childhood, including 3 Wilms tumors, 5 medulloblastomas, 2 cases of AML, and 1 of neuroblastoma. One individual developed 3 malignancies within the first year of life, and 3 individuals had 2 cancers. The cellular phenotype was similar to that of BRCA2 deficiency and more severe than other Fanconi anemia subtypes, with elevated spontaneous chromosome breakage rates, markedly reduced lymphocyte survival, and increased chromosome breakage on exposure to MMC. There was also no formation of nuclear RAD51 (179617) foci in fibroblasts after ionizing radiation. Again, this was similar to cells with biallelic BRCA2 mutations and differed from other Fanconi anemia subtypes.

Abdulkareem et al. (2024) described a female patient born at 32 weeks' gestation with dysmorphic features, nonimmune hydrops fetalis, right-sided pleural effusion, mild pulmonary valve stenosis, and lymphangiectasis. Fanconi anemia was diagnosed at 2 months of age. Abdulkareem et al. (2024) noted that nonimmune hydrops, pleural effusion, and lymphangiectasis had not previously been reported as features of Fanconi anemia. Family history was significant for 3 generations of consanguineous marriages. No history of the disease was reported in other family members.

Xia et al. (2007) and Reid et al. (2007) identified pathogenic mutations in the PALB2 gene (610355) in patients with FANCN. The patient described by Xia et al. (2007) showed normal monoubiquitination of FANCD2 (227646) and no detected pathogenic alterations in BRCA2 or FANCJ (609054). Lack of full-length PALB2 protein and the reduced amount of BRCA2 suggested the existence of sequence alterations in the gene encoding PALB2, since PALB2 interacts with BRCA2 and is important in determining the localization and stability of BRCA2 in the nucleus. In a phenotypically reverted (MMC-resistant) subline of patient lymphoblasts, a normal amount of BRCA2 without the reappearance of PALB2 was found. Xia et al. (2007) detected a premature termination mutation (610355.0001) on the maternal allele and an intragenic deletion (610355.0002) on the paternal allele. cDNA sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis uncovered a second sequence alteration in revertant cells that restored part of the PALB2 open reading frame that could explain recovery of PALB2 activity.

In 4 affected individuals, Reid et al. (2007) identified biallelic mutations in the PALB2 gene that resulted in premature protein truncation. Analysis of parental DNA demonstrated that all the mutations had been inherited from different parents, consistent with autosomal recessive inheritance. No sample was available from 3 affected individuals, but their parents all carried truncating PALB2 mutations.

Xia et al. (2007) suggested that, similar to Fanconi anemia associated with biallelic mutations in BRCA2 (FANCD1), Fanconi anemia caused by mutations in PALB2 might represent an extreme variant of this disorder with respect to the severity of the clinical phenotype, time of onset of anemia, and susceptibility to cancer. As PALB2 is critical for the function of BRCA2 in DNA repair and tumor suppression, it could, in principle, also be a tumor suppressor protein. Xia et al. (2007) noted that several family members of the patient's family indeed developed tumors, and some of these tumors fell into the BRCA2 tumor spectrum: cancers of the esophagus, breast, prostate, and stomach.

The cancer spectrum and early mortality associated with biallelic PALB2 mutations as reported by Reid et al. (2007) was very similar to that associated with biallelic BRCA2 mutations. The presence of cancers in adult members of the families studied by Reid et al. (2007) suggested that mutational analyses of PALB2 in individuals with adult-onset cancer, particularly familial breast cancer, should be undertaken to clarify the role of monoallelic PALB2 mutations in cancer susceptibility.

In a 6-month-old female infant, born to consanguineous Saudi parents, with Fanconi anemia and atypical features including nonimmune hydrops, pleural effusion, and lymphangiectasis, Abdulkareem et al. (2024) identified a homozygous missense mutation in the PALB2 gene (T1099R; 610355.0014). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents.