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A rare manifestation of Fanconi anemia

Fanconi anaemia is a rare genetically inherited autosomal recessive disorder characterised by congenital malformations, progressive pancytopenia, cellular hypersensitivity to DNA cross linking agent with predisposition to acute myeloid leukaemia (AML) and other malignancies. The incidence of Fanconi anaemia is approximately 1to 5 per million. The commonly associated genetic mutation in Fanconi anaemia are FANC genes. Sixteen distinct FANC genes have been reported among which, mutation in FANC-A are the most frequent. These include microdeletions, large deletions, micro insertions and point mutations. The disease is most commonly seen in children between 5-15 years. Physical abnormalities are seen in 75% of affected individuals which includes short stature, hyperpigmentation of the skin and intertriginous areas, skeletal malformations of the upper and lower limbs, microcephaly along with multisystemic involvement like renal problems, hearing defects, cardiac disease, gastrointestinal problems, ophthalmic and genitourinary tract anomalies like hypogonadism (Table 1). Progressive bone marrow failure with pancytopenia typically present in first decade, often initially with thrombocytopenia or leucopoenia. 20% of patients with Fanconi Anemia can develop cancers like AML, myelodysplastic syndrome, squamous cell carcinomas of the head and neck, oesophageal and tongue carcinoma, tumours of the liver, brain, skin, kidney, stomach and large bowel.


INTRODUCTION
Fanconi anaemia is a rare genetically inherited autosomal recessive disorder characterised by congenital malformations, progressive pancytopenia, cellular hypersensitivity to DNA cross linking agent with predisposition to acute myeloid leukaemia (AML) and other malignancies. 1 The incidence of Fanconi anaemia is approximately 1to 5 per million. 2 The commonly associated genetic mutation in Fanconi anaemia are FANC genes. Sixteen distinct FANC genes have been reported among which, mutation in FANC-A are the most frequent. 3 These include microdeletions, large deletions, micro insertions and point mutations. 4 The disease is most commonly seen in children between 5-15 years. 5 Physical abnormalities are seen in 75% of affected individuals which includes short stature, hyperpigmentation of the skin and intertriginous areas, skeletal malformations of the upper and lower limbs, microcephaly along with multisystemic involvement like renal problems, hearing defects, cardiac disease, gastrointestinal problems, ophthalmic and genitourinary tract anomalies like hypogonadism (Table 1). Progressive bone marrow failure with pancytopenia typically present in first decade, often initially with thrombocytopenia or leucopoenia. 7 20% of patients with Fanconi Anemia can develop cancers like AML, myelodysplastic syndrome, squamous cell carcinomas of the head and neck, oesophageal and tongue carcinoma, tumours of the liver, brain, skin, kidney, stomach and large bowel. 8 Fanconi anaemia can be accurately diagnosed using DEB induced chromosome breakage which is highly specific. The cells of patients with FA are characterised by chromosomal hypersensitivity to cross linking agents and the resulting increase in chromosome breakage provides the basis for a diagnostic test. 9 The only proven long term cure of the bone marrow manifestations is successful allogenic hematopoietic stem cell transplantation (HSCT). 10

CASE REPORT
Two and half years old female child presented with failure to gain adequate weight since birth.     Her anthropometry was suggestive of short stature height-76 cm (<-3SD) with microcephaly head circumference-41 cm (<-3SD). There was no pallor; vital signs were within normal limits. Systemic examinations were normal. Ophthalmic and hearing examination were normal. In view of thumb anomaly and congenital heart disease possibility of Holt Oram and TAR syndrome was considered. On investigation Complete blood count was normal, USG abdomen showed horse shoe kidney ( Table  2). X-ray radius was normal. Genetic opinion was obtained, and cytogenetic report was suggestive of Fanconi anemia (Table 3).
This child was born elsewhere, preterm-33weeks via labour naturalis with birth weight of 1.9kg. Baby was admitted in NICU for 10 days for respiratory distress. Evaluation showed normal haemogram and chest X-ray. ECHO showed large PDA with left to right shunt. Child underwent surgical repair for the same at 1 year of age. Child did not have significant bleeding or pallor requiring blood transfusion.

DISCUSSION
Fanconi anemia (FA) is the most common inherited bone marrow failure syndromes. Approximately 75% of them are between 5-15 years of age at time of diagnosis. In present case child is two and half years of age at diagnosis. Majority of patient will have both physical anomalies and abnormal haematological findings. Unknown percentage will have physical anomalies without haematological findings. Present child belongs to this rare manifestation of only physical anomalies without any haematological findings. Child did not have significant bleeding or pallor requiring any blood transfusion in the past.
Fanconi anaemia closely mimics Holt Oram and TAR syndrome, as all of them are associated with congenital heart disease and limb anomalies. In present child x-ray both hands did not show any radial abnormalities and complete blood count showed no thrombocytopenia hence TAR Syndrome was ruled out. Holt Oram syndrome also called atrio-digital syndrome is an autosomal dominant disorder. This syndrome may include thumb abnormality like triphalangeal thumb, thumb hypoplasia, an absent radial bone in the forearm with atrial septal defect as prominent manifestation in the heart. 11 Though present case had thumb hypoplasia with PDA, other features-short stature, microcephaly, multiple cafe-au-lait spots were more consistent with Fanconi Anemia.

CONCLUSION
To conclude high index of suspicion is required to diagnose Fanconi Anemia as unknown percentage of them presents with physical anomalies without having haematological findings This child is on regular follow up to monitor for progression of bone marrow failure. Genetic counselling has been given to the parents as this is the first child. Successes with HSCT have dramatically improved the outlook. Careful surveillance for known complications, especially cancer and prompt intervention on their detection has also contributed to the improved survival.