Thinking of VACTERL‐H? Rule out Fanconi Anemia according to PHENOS

Abstract

VACTERL-H association includes three of eight features: vertebral anomalies, anal atresia, congenital heart disease, tracheo-esophageal fistula, esophageal atresia, renal, limb anomalies, and hydrocephalus. The VACTERL-H phenotype among cases with FA is considered to be about 5%; the frequency of FA among patients with VACTERL-H is unknown. We examined 54 patients with FA in the National Cancer Institute Inherited Bone Marrow Failure Syndrome Cohort for features of VACTERL-H, including imaging studies (radiology and ultrasound). Eighteen of the fifty-four patients had three or more VACTERL-H features. The presence of VACTERL-H association in 33% of those with FA is much higher than the previous estimate of 5% (P < 0.0001). We created the acronym PHENOS (Pigmentation, small Head, small Eyes, central Nervous system (not hydrocephalus), Otology, and Short stature) which includes all major phenotypic features of FA that are not in VACTERL-H; these findings were more frequent in the patients with FA who had VACTERL-H. Identification of any components of the VACTERL-H association should lead to imaging studies, and to consideration of the diagnosis of FA, particularly if the patient has radial ray and renal anomalies, as well as many features of PHENOS. There was no association of the presence or absence of VACTERL-H with development of cancer, stem cell transplant, or survival. Early diagnosis will lead to genetic counseling and early surveillance and management of complications of FA. © 2016 Wiley Periodicals, Inc.

Clinical severity in Fanconi anemia correlates with residual function of FANCB missense variants

“…Congenital malformations resembling VACTERL-H association were seen in 15/19 (79%) individuals with FANCB variants with the predominant features being renal (R) and limb (L) abnormalities (observed in 13 individuals each) ( Table 1), which is consistent with previous observations. 7,23 In general, developmental defects were multiple and severe for the individuals in our study: termination of pregnancy elected for three IFAR individuals diagnosed prenatally, and for one previously reported in the literature, and survival was limited to 0.033, 0.2 and 0.5 month for three other individuals. Interestingly, the three individuals in our cohort without VACTERL-H malformations did not carry truncation variants, which suggests that the residual function of the FA core complex may protect against the most severe developmental defects ( Table 1) To assess the genotype and phenotype correlation, we grouped variants based on the severity of structural alterations in the FANCB protein (WGD/truncation vs. missense).…”

Fanconi Anaemia in South African Patients with Afrikaner Ancestry

“…Previous reports differed vastly in their reporting of the percentage of patients with FANCA mutations who meet the diagnostic criteria for VACTERL/H association, with figures of between 3% and 20%. [20,24] Although the VACTERL/H phenotype appears to be more often associated with mutations in FANCD1 (33%), E (40%) and F (30%), more recent work by Alter and Giri [20] suggests that the co-occurrence of this phenotype with FA is under-recognised. [24] The present sample size is however small and the results suggest that Afrikaner patients with a VACTERL/H phenotype should always be tested for FA.…”

“…Additionally, a modified pigmentation, small head, small eyes, CNS (not hydrocephalus), otology, and short stature (PHENOS) score was calculated for each patient. The PHENOS score, developed by Alter and Giri, [20] allocates a score of positive 1 for each of: pigmentation anomaly, microcephaly (small head), microphthalmia (small eyes), CNS anomalies (other than hydrocephalus), otologic anomalies (structural ear anomalies or hearing loss) and short stature, with a maximum score of 6. The score is used to identify patients with VACTERL/H association (which includes at least three of the following cardinal abnormalities: vertebral, ano-rectal, cardiac, tracheo-oesophageal, renal, limb defects and hydrocephalus), who should be tested for FA.…”

“…The score is used to identify patients with VACTERL/H association (which includes at least three of the following cardinal abnormalities: vertebral, ano-rectal, cardiac, tracheo-oesophageal, renal, limb defects and hydrocephalus), who should be tested for FA. [20] We used a modified score as we did not have CNS imaging in our patients.…”

How I manage patients with Fanconi anaemia

“…Classical abnormalities include thumb, hand and forearm, kidney and urinary tract malformation, small face with small eyes, short stature, café au lait spots of the skin or other types of abnormal pigmentation (Table ). FA neonates usually have intrauterine growth retardation, low birth weight and may show malformations included in the so‐called VACTERL (vertebral anomalies, anal atresia, cardiac malformations, tracheoesophageal fistula with oesophageal atresia, renal and limb structural abnormalities) or VACTERL‐H (with hydrocephalus) syndrome in up to 1/3 of cases (Alter & Giri, ). The VACTERL phenotype seems to be more frequently associated with BRCA2 mutations (Alter et al , ).…”