Diagnosis of Fanconi Anemia: Chromosomal Breakage Analysis

Table 1

General features and symptoms associated with Fanconi anemia.

Birth prevalence	0.5–2.5 per 10^5 newborns; varies with ethnic background.
Mode of inheritance	Autosomal recessive (>98%) and X-linked (~1-2%).
Carrier frequency	Traditional overall estimate: “1/300 worldwide.” Needs reassessment according to subtype and ethnic background.
Congenital abnormalities*	Radial ray abnormalities (aplastic or hypoplastic radii and absent or extra thumbs) and other skeletal abnormalities; small head circumference; abnormal shape of the ears; microphthalmia; ectopic or horse-shoe kidney; hypogonadism; heart abnormalities; intestinal or anal atresia.
Other somatic abnormalities*	Short stature/retarded growth; reduced fertility; skin pigmentation abnormalities (hyperpigmentation, café-au-lait spots); deafness. Endocrinopathy affecting the pancreas (diabetes mellitus), growth hormone deficiency, and hypothyroidism; early menopause.
Hematological symptoms	Bone marrow failure or aplastic anemia typically starting at 5–10 years with thrombocytopenia. Exception: D1 and N patients may die before that age from AML or other childhood solid tumors (such as medullo- or nephroblastoma).
Cancer risk	800-fold increased risk of AML, mostly occurring at age 5–15 years, typically after the onset of marrow failure. At older ages there is a similarly increased risk of solid tumors, mainly carcinomas of the head and neck or oesophagus, as well as, in females, the vulva and vagina. D1 and N patients typically develop malignancies during early childhood (<5 years).
Overlapping syndromes**	Inherited bone marrow failure syndromes: Dyskeratosis congenita, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, severe congenital neutropenia, thrombocytopenia absent radii (TAR) syndrome, amegakaryocytic thrombocytopenia.Other overlapping syndromes: Baller-Gerold syndrome, Nijmegen breakage syndrome, Rothmund-Thomson syndrome, Roberts syndrome, Warsaw Breakage syndrome, DK-phocomelia, VACTERL hydrocephalus syndrome, Wiskott-Aldrich syndrome.

∗Many symptoms show highly variable penetrance. In a sizable proportion of patients (ca. 30%), congenital abnormalities may be absent altogether. Features in bold are most consistently associated with the FA phenotype.
∗∗For an overview of the overlapping inherited bone marrow failure syndromes, see [5, 25]. For the other overlapping syndromes, the reader is referred to the OMIM database. Three overlapping syndromes may score positive in a chromosomal breakage test (italic): Nijmegen breakage syndrome [7–9], Roberts syndrome, and Warsaw Breakage Syndrome [10].