From endocrine phenotype to hematological diagnosis of Fanconi anemia – apropos of 2 cases

Nicolescu Corina Ramona; Lucie Bazus; Jean-Louis Stephan

Introduction: Fanconi anemia (FA) is a hereditary genomic instability syndrome characterized by congenital abnormalities, bone marrow failure, and cancer predisposition. At the molecular level, FA is caused by pathogenic variants in the FA/BRCA DNA pathway, responsible for DNA repair. FA phenotype include heterogeneous physical abnormalities, with two main associations: VACTERL-H (vertebral abnormalities, anal atresia, cardiac abnormalities, tracheo-esophageal fistula, esophageal/duodenal atresia, renal abnormalities, upper limb abnormalities and hydrocephalus) and PHENOS (skin pigmentation abnormalities, small head, small eyes, central nervous system abnormalities, otologic abnormalities and short stature). Structural and functional endocrine abnormalities are common in FA patients, and may develop in utero, evolve over time or may be influenced by FA treatment.

Case reports: We report 2 male patients followed for endocrine problems who developed persistent thrombocytopenia and macrocytosis (Table 1). The clinical suspicion of FA was genetically confirmed.

Table 1 – Patients’ main clinical and biological characteristics
	Medical history	Phenotype	Biological abnormalities	Diagnosis
Patient 1: 5-year-old boy weight 15 kg (5^th P) height 100 cm (< 5^th P) head circumference 47 cm (5^th P)	8 months diagnosis of anterior pituitary insufficiency substitutive treatment	PHENOS microcephaly (< 5^th P) micrognathia skin discoloration CNS abnormalities - ectopic posterior pituitary, complete interruption of the pituitary stalk no cardiac abnormalities no skeletal/extremities abnormalities no gastrointestinal abnormalities no renal abnormalities no external genitalia abnormalities	persistent thrombocytopenia (50000 – 100000/mm³) macrocytosis MCV 93 fl, without anemia bone marrow biopsy – hypo cellularity	Fanconi anemia positive chromosomal breakage/stress cytogenetics test (mitomycin C) positive immunoblotting FANCD2 test
Patient 2: 3-year-old boy weight 10 kg (< 5^th P) height 87 cm (< 5^th P) head circumference 46 cm (< 5^th P)	congenital cardiac malformation bilateral transmission deafness	VACTERL-H and PHENOS microcephaly short stature thumb abnormalities CNS abnormalities - ectopic posterior pituitary no gastrointestinal abnormalities no renal abnormalities no external genitalia abnormalities	persistent thrombocytopenia (50000 – 70000/mm³) macrocytosis MCV 95 fl, without anemia bone marrow biopsy – normo cellularity	Fanconi anemia positive chromosomal breakage/stress cytogenetics test (mitomycin C) positive immunoblotting FANCD2 test

Conclusion: VACTERL-H and PHENOS phenotypes (alone or in association) are highly suggestive of FA. Endocrine phenotype (growth retardation) and CNS abnormalities (pituitary) are common in children with FA. The heterogeneous clinical phenotype of our patients contrasts with their constant cellular and cytogenetic phenotype.

ESPE Abstracts

P3-185