Fanconi Anaemia – Need to look at the whole picture

Suresh Chelliah¹,*, Vinod G², Naresh Kumar Natarajan¹, Senguttuvan Duraisamy¹

¹Department of Pediatrics, Kauvery Hospital, Trichy, Tamilnadu

²Department of Pediatric Hemato Oncology, Kauvery Hospital, Trichy, Tamilnadu

*Correspondence: Email: [email protected]

Abstract

Background: Fanconi Anemia is a rare inherited disorder, characterized by chromosomal instability, wide clinical presentation and a predisposition to cancers, especially Acute myeloid leukemia.

Case presentation: A 6-years-old boy treated as a ‘Known case of immune thrombocytopenia purpura’ is presented highlighting the clinical features and need for clinical diligence in keeping the mind open to unusual problems.

Conclusion: Any diagnosis made should take into account all the available clinical and laboratory data in addition to its progress since onset.

Keywords: Fanconi Anemia, Renal malformations, Thrombocytopenia, Chromosomal breakage

Background

Fanconi anemia (FA) is a cancer-prone chromosomal instability disorder with diverse clinical symptoms [1]. Diagnosis is often difficult on the basis of clinical features alone, because it is rare [2]. Clinical suspicion of FA is mostly based on growth retardation and congenital defects in combination with life-threatening bone marrow failure (thrombocytopenia and later pancytopenia), which usually starts between 5 and 10 years of age. However, the clinical manifestations are highly variable, while some of the symptoms may overlap with those observed in other syndromes, making a reliable diagnosis on the basis of clinical features virtually impossible [1].

Case Presentation

A 6-years-old boy was admitted with vomiting and diarrhea for three days. Mother gave history of Immune thrombocytopenic purpura (ITP) diagnosed three years earlier. The boy received blood transfusion for anemia earlier but had no easy bruisability or bleeding. An ultrasonogram done earlier following an episode or urinary tract infection showed a single pelvic kidney.

On examination

He was pale. There was no purpura. He had prominent ears, hyperpigmentation over neck and upper limbs and was short ( < 3rd centile), vitals were stable, systemic examination was normal.

2Relevant investigations

Hb	9.8
MCV	98.9
MCH	34.4
Total WBC count	5200
Differential count	8
When watching man and women hugging/kissing in television	N 43%, L 51%, M
	5%
Platelets	92,000
MPV	8.6 (ref 6–1)

Old medical records revealed anaemia, persistent thrombocytopenia and occasional leucopenia.

Bone marrow aspiration was done twice before: reportedly normal. Bone marrow biopsy: not done.

Since the child had anaemia (macrocytic), chronic thrombocytopenia, occasional leukopenia (not feature of ITP), consanguinity in parents, short stature, single pelvic kidney, possibility of inherited bone marrow failure syndrome like FA was considered. Chromosomal Breakage Analysis was conclusive of FA (Figs. 1 and 2).

Fig. 1. Result of Chromosomal Breakage analysis

Fig. 2. Chromosomal breakages.

At present child is on regular follow up and preparation for bone marrow transplantation. CBC is monitored every month, BM cytogenetics and biopsy on next visit. HLA typing of patient and sister for identifying bone marrow donor.

Plan to start androgens – if progression to transfusion dependent state.
Plan to do bone marrow transplantation – if progression to Bone marrow failure.
Myelodysplastic syndrome.
Acute myeloid leukemia

Discussion

Presence of macrocytic anaemia, persistent low-grade thrombocytopenia and physical features, especially in the presence of an abnormal kidney is very suggestive of FA and the usage of the often-repeated known case of’ delayed this diagnosis.

General features and symptoms associated with FA. Prevalence of FA is 0.5–2.5 per 160000 newborns, mode of inheritance is autosomal recessive (>98%) and X-linked (~1–2%).

Associated 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.

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.

Diagnosis: After the discovery of an extreme sensitivity of FA cells to the chromosome-breaking effect of the cross-linking agents mitomycin C (MMC) and diepoxybutane (DEB) this feature has become routinely utilized to diagnose FA by a “chromosomal breakage test” [3]. In this test, T-lymphocytes in a peripheral blood sample are cultured in the presence of a cross-linking agent, after which chromosomal aberrations are quantified in metaphase spreads [1]. These tests can be performed prenatally on cells from chorionic villi or from the amniotic fluid [2]. Molecular genetic testing is available for all 18 genes associated with FA. Complementation testing is usually done first in order to identify which FA gene is mutated [2].

Recommendations for treatment were agreed upon at a consensus conference in 2014:

Androgen (male hormone) administration: Androgens improve the blood counts in approximately 50% of individuals with FA. The earliest response is seen in red cells, with increase in hemoglobin generally occurring within the first month or two of treatment. Responses in the white cell count and platelet count are variable. Platelet responses are generally incomplete and may not be seen before several months of therapy. Improvement is generally greatest for the red cell count. Resistance to therapy may develop over time.

Hematopoietic growth factors: Granulocyte colony-stimulating factor (G-CSF) may improve the neutrophil count in some individuals. It is usually used only for support during intercurrent illnesses.

Hematopoietic stem cell transplantation (HSCT): It is the only curative therapy for the hematologic manifestations of FA.

Cancer treatment: Treatment of malignancies is challenging secondary to the increased toxicity associated with chemotherapy and radiation in FA.

Surgery may be necessary to correct skeletal malformations such as those affecting the thumbs and forearm bones, cardiac defects, and gastrointestinal abnormalities such as tracheoesophageal fistula or esophageal atresia, as well as anal atresia.

Certain chemicals may increase the risk of chromosomal breakage in individuals with FA and should be avoided whenever possible. These chemicals include tobacco smoke, formaldehyde, herbicides, and organic solvents such as gasoline or paint thinner.

Genetic counseling is recommended for affected individuals and their families [2].

Conclusion

A low platelet counts in a child who is not ill is not always ITP. Careful and critical analysis to include and explain all the features leads us to a diagnosis most often. The phrase “Known case of” should be avoided. Instead we can say, child was diagnosed to have a particular disease with the aid of relevant finding and include where and who made the diagnosis.

Acknowledgements

All the authors were involved in the diagnosis and management of the child. Suresh Chelliah drafted the manuscript and will act as guarantor for the same.

Competing interests

Authors state no competing interests.

References

Oostra AB, Nieuwint AWM, Joenje H, de Winter JP. Diagnosis of Fanconianemia: chromosomal breakage analysis. Anemia. 2012.
Giampietro PF, Adler-Brecher B, Verlander PC, Pavlakis SG, Davis JG, Auerbach AD. The need for more accurate and timely diagnosis in Fanconi anemia: a report from the International Fanconi Anemia Registry. Pediatrics. 1993;91(6):1116–1120.
Sasaki MS, Tonomura A. A high susceptibility of Fanconi’s anemia to chromosome breakage by DNA cross linking agents. Cancer Res. 1973;33(8):1829–1836.

Fanconi Anaemia – Need to look at the whole picture

Fanconi Anaemia – Need to look at the whole picture

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