An infant weighing 2300 g was born at 39 weeks gestation to a 40-year-old gravid 4, para 4 mother. The three other children were reportedly healthy and normal. This pregnancy was complicated by sonographic evidence of intrauterine growth retardation and a two-vessel cord. At the time of delivery, the patient was noted to have a hypoplastic pedunculated right thumb and right microtia. Apgar scores were 8 at 1 min and 9 at 5 min. In the neonatal nursery, a nasogastric tube was placed and a skeletal survey (Figures 1 and 2), abdominal sonogram (Figure 3), voiding cystourethrogram (Figure 4) and a cranial computed tomography were obtained (Figure 5). The infant underwent a successful repair of the esophageal atresia with distal tracheoesophageal fistula on the fourth day of life. The initial hemoglobin and hematocrit levels were normal, and the mean corpuscular erythrocyte volume was slightly elevated. The platelets and white blood cell counts were normal. A test for hypersensitivity to the effect of the DNA cross-linking agent diepoxybutane (DEB) was ordered.
Denouement and discussion
This infant has anomalies of the VACTERL association (esophageal atresia, thumb hypoplasia, vesicoureteral reflux), as well as a first branchial cleft anomaly and atresia of the external auditory canal. The presence of branchial anomalies, hydrocephalus, ophthalmologic anomalies and facial dysmorphism are rare in the VACTERL association, which is a nonhereditary condition with <1% recurrence rate. However, these head and neck abnormalities are more common in genetic conditions associated with esophageal atresia.1 These genetic conditions include Feingold's syndrome (n-MYC gene mutation), CHARGE syndrome (CHD7 mutation), anopthalmia–esophageal–genital syndrome (SOX2 mutation), X-linked VACTERL-H syndrome and Fanconi's anemia (FA).1, 2
The DEB test that was conducted in this infant showed increased chromosomal breakage with DEB, consistent with FA. A genetic analysis of the FANC A gene showed a compound heterozygote for FANC A mutations. In FA, maternal mutation is a classically described mutation and paternal mutation is a novel mutation. At 14 months, the infant received a bone marrow transplantation.
Fanconi's anemia was first described in 1927 by Guido Fanconi in three siblings with aplastic anemia.3 This is a relatively common condition with a carrier rate of the gene mutation of 1 in 200–300 in the general population.4 It is an autosomal recessive, rarely X-linked condition that is associated with progressive bone marrow failure, congenital anomalies, growth retardation, hyperpigmentation of the skin, café au lait spots and a predisposition to malignancies, especially acute myelocytic leukemia and squamous cell carcinoma. The red blood cells in FA show spontaneous chromosomal breakage and are hypersensitive to cross-linking agents, such as mitomycin C, DEB and cisplatin. FA is one among a group of several diseases caused by the defected handling of damaged DNA, including ataxia telangiectasia, xeroderma pigmentosa and dyskeratosis congenita.3
There are 13 gene loci described in FA, listed below with their gene and gene frequency:
The exact proteins encoded at these 13 loci and their molecular functions are not known, but there is significant interaction among the encoded proteins, particularly proteins A, C, F and G. Their function is assumed to be to carry out a process that maintains genomic integrity.
Approximately 70% of patients with FA have congenital anomalies, including 10% who have at least three features of the VACTERL association.4, 5 Radial ray anomalies occur in 63–79% of patients, especially anomalies of the thumb (49–66%). Other congenital abnormalities include congenital hip dislocation, scoliosis with vertebral anomalies, café au lait spots (63–79%), low birth weight, microphthalmia, microcephal, renal anomalies (30%) (especially renal agenesis and renal ectopia), microcephaly, hypogenitalia (51%) with hypoplastic gonads, small uterus in females and hypospadias in males, gastrointestinal anomalies (including esophageal atresia, duodenal atresia and imperforate anus), congenital heart disease (especially patent ductus arteriosus), ventricular septal defect, pulmonic valvar stenosis and coarctation.6, 7 The concurrence of VACTERL features has been described in FANC A, C, D1, F and G.4 VACTERL-H syndrome, which is an X-linked condition with hydrocephalus, usually aqueductal stenosis, has been associated with FANC B.8 FA with features of the VACTERL association or the VACTERL-H syndrome can be confirmed by the DEB chromosomal breakage test.
The risk of bone marrow abnormality is quite high. Pancytopenia usually develops at a mean patient age of 7 years, presenting as bleeding, pallor, or recurrent or serious infections. The risk of pancytopenia by the age of 20 years is 84%, and the risk of acute myelogenous leukemia by age 40 is 52%. For individuals who survive beyond the age of 40 years, there is an increased risk of hepatocellular tumors (probably related to androgen therapy for anemia) and squamous cell carcinoma of the head/neck and genitourinary system.6
The differential diagnosis of FA also includes hereditary bone marrow disorders with radial ray defects, such as thrombocytopenia-absent-radius syndrome, Diamond–Blackfan anemia, conditions with increased chromosomal breakage, such as Nijmegen breakage syndrome, and conditions associated with aplastic anemia, such as dyskeratosis congenita and Shwachman–Diamond syndrome. The thrombocytopenia-absent-radius syndrome is an autosomal recessive condition, in which characteristic radial absence with preserved thumbs is associated with infantile thrombocytopenia. Diamond–Blackfan anemia is associated with defective or absent erythroid progenitors and may have radial ray anomalies. It is heterogeneous with both autosomal dominant, recessive and sporadic cases described. The Nijmegen breakage syndrome is an autosomal recessive condition found particularly among patients of Slavic descent characterized by microcephaly, immune deficiency and hypersensitivity to ionizing radiation. Dyskeratosis congenita is an autosomal dominant or occasional X-linked disorder, with reticular skin pigmentation with frequent development of aplastic anemia and acute myelocytic leukemia. The Shwachman–Diamond syndrome is an autosomal recessive condition associated with exocrine pancreatic insufficiency, metaphyseal chondrodysplasia and variable bone marrow failure, including aplastic anemia.6
Treatment of FA includes androgens, especially oxymethalone to increase bone marrow cellularity. The latter drug is associated with increased risk of acne, hyperactivity, premature physeal closure and hepatic tumors.6
The current therapy in use is hematopoietic stem cell transplantation before the development of pancytopenia. In general bone marrow transplantation performed at a young patient age, before the use of androgens and with normal platelet levels at the initiation of the transplant, has been associated with a good survival.9 However, even with bone marrow transplantation, there is a 42% risk of malignancy by 20 years after transplantation.6
Conflict of interest
The authors declare no conflict of interest.
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Herman, T., Siegel, M. Fanconi's anemia, type A presenting as VACTERL association with atresia right external auditory canal. J Perinatol 30, 73–76 (2010). https://doi.org/10.1038/jp.2009.105