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Diamond Black Fan Syndrome and Its Association with Portal Cavernoma

Kashif Chauhan, Naveed Alizai

St James’s University Hospital, Leeds, England

 

Correspondence:

Kashif Chauhan

18 Mountsorrel Drive

West Bridgford, Nottingham

NG2 6LJ, UK

Phone: +447783235601

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Abstract

Aim

To establish an association between patients diagnosed with Diamond Black Fan syndrome and subsequently developing Portal Cavernoma.

Method

We are treating two patients diagnosed with Diamond-Black Fan Syndrome. Both have multiple oesophago-gastroduodenoscopies (for esophageal varies), ultrasound scan of abdomen, blood transfusions, liver biopsies and subsequently developed portal cavernoma. First patient is 6 years old, had been diagnosed with Diamond-Black Fan anaemia at 3 years of age and portal cavernoma at 4 years of age and the second one is 23 years old, Diamond-Black Fan anaemia was diagnosed at 10 years of age, Portal Cavernoma at 11 years of age

Results

Both patients have repeated blood transfusion leading to iron deposition in the liver with non-cirrhotic liver changes causing portal hypertension with esophageal varices and developed portal cavernoma. They have repeated hospital admission requiring intensive treatment and are managed conservatively. Collateral circulations around porta hepatic are seen on ultrasound and MRI. Medical management is successful so far and no surgical intervention is needed.

Conclusion

It is a rare condition and its association with portal cavernoma has never been reported. Patients who has diagnosed with Diamond-Black Fan anaemia should be monitored closely with repeated ultrasound scan of liver for early detection of portal cavernoma and if there is any suspicious an MRI should be done for the best management and treatment of this condition. Surgical intervention is a major procedure. Proposed intervention will be Porto-systemic shunt or biliary intestinal bypass

Keywords: Diamond Black Fan syndrome, leukaemia, portal cavernoma

 

Introduction

We are reporting two cases of Diamond Blackfan syndrome, which subsequently developed portal cavernoma. This kind of association has never been reported before in the literature. Diamond-Black Fan anaemia (DBA) is a rare, genetically and clinically heterogeneous, inherited red call aplasia characterised by pro-apoptotic haematopoiesis leading to bone marrow failure, congenital anomalies and prediposition to cancer. Classical DBA affects seven per million live births without ethnic predilection with both sexes affected equally [1]. Portal cavernoma is also a rare condition consisting of portosystemic or porto-portal collaterals that substitute for a thrombosed portal vein to overcome the obstructed portal vein, a hepatopetal collateral network develops within the hepatoduodenal and hepatocolic ligaments, around the common bile duct, hepatic ducts, and gallbladder, draining into mid-sized intrahepatic portal veins. This results in formation of paracholedochal varices (portal cavernoma) that may extend into the liver (intrahepatic cavernoma) [2, 3]. The extra hepatic portal vein obstruction results in hepatopetal blood flow, and is an important cause of non-cirrhotic portal hypertension particularly in developing countries [4].

Case 1

First patient is now 5 years and 6 months old male. He was born at 29 weeks of gestation, ventilated for 12 days and was remained on CPAP until day 45 of life. He was oxygen dependant for one year. During his stay in special baby care unit he required multiple blood transfusions and bone marrow examination revealed Blackfan Diamond Syndrome. He improved on prednisolone with regular blood transfusions and had cleft palate, hypospadias, inguinal hernia repaired later at life. He has dysmorphism and at 9 months of age noted to have active CMV infection with feeding problems, gastro-oesophageal reflux and started on anti-reflux treatment. He had an episode of malena when he was 3 years and 4 months of age and upper GI endoscopy showed patchy gastritis with no oesophageal varices.

At the age of 3 years and 10 months he had an episode of hematemesis and oesophago-gastroduodenoscopy (OGD) showed oesophageal varices with no active bleeding and was started on omeprazole. There was no organomegaly on clinical examination. He was on iron supplements and blood tests showed high ferritin level. Liver function tests showed slight elevation of ALT only. He had a liver ultrasound done at the age of 4 years and 2 months which showed liver is normal in size but there appeared to be portal cavernoma with varices at the porta and around left and right branches of portal vein. A repeat OGD done at the same time showed grade 3 oesophageal varices, a contiguous varix and portal enteropathy.

He was treated with sclerotherapy and had a liver biopsy at 4 years and 2 months of age which reveals marked haemosiderosis which may account for elevated ALT an MR was done when he was 4 years and 4 months of age which showed there is extensive iron deposition within liver, pancreas and spleen with portal cavernoma and patent portal venous confluence. He had no further episodes of malena or haematemesis and the portal hypertension appeared to be secondary to portal cavernoma. He had repeated OGD’s and all of them showed oesophageal varices and sclerotherapy were done. Varices were secondary to portal hypertension, which is caused by portal cavernoma. He does not have any fibrosis as a cause of portal hypertension. His case was discussed and it was proposed that he might benefit from meso-portal or mesocaval shunt. He is 5 years and 5 months old now had an OGD and sclerotherapy done recently (5 years 3 months age) which shows grade 2 varices and doing well with no surgical intervention needed. He is going to be seen again in OPD after 3 months of time.

Case 2

Second patient is now 23 years old male. He was born full term and was diagnosed as Diamond Blackfan Syndrome at 4 months of age. He had repeated blood transfusions, and at 26 months of age operated for bilateral bifid thumb. During the course of years he was transfused regularly and marginally improved on steroid therapy. He had operations for inguinal, umbilical and a circumcision for phimosis at age 3. At 5 years of age he was prescribed glasses for poor vision. He had bone marrow transplant for Diamond Blackfan Syndrome at 11 years of age. Two years later he developed joint pains, pneumothoraces, significant gastro-oesophageal reflux and an endoscopy showed oesophageal varices.

Ultrasound scan of abdomen showed coarse echo texture of liver with portal hypertension and spleeno-mesocolon collaterals. All the blood tests related to liver were normal. The coarse echotexture of liver seems to be related to his previous transfusions, bone marrow transplant and iron overload. At the same time he was diagnosed as hypothyroidism, hypoadrenalism and hypopituitarism and treated by endocrinologist. He had bilateral stapling of apical bullae’s done at the age of 16 years and had a repeat liver ultrasound done which showed portal hypertension and portal cavernoma. Clinically there was mild spleenomegaly only.

A repeat endoscopy at 18 years of age showed oesophageal varices but no active bleeding and ultrasound showed abnormal liver. Liver biopsy showed changes consistent of non-cirrhotic portal hypertension. At 19 years of age an MRI scan was done which showed hepatic and portal veins are patent with marked varices and splenorenal shunt. He was managed conservatively. Last OGD was done about 18 months back, which shows grade 2 oesophageal varices. He was diagnosed with severe osteoporosis and had urethral stricture for which an urethroplasty was done. At present he is doing well with no surgical intervention needed.

Discussion

Diamond-Black Fan anaemia (DBA) is a rare, genetically and clinically heterogeneous, inherited red call aplasia characterised by pro-apoptotic haematopoiesis leading to bone marrow failure, congenital anomalies and predisposition to cancer. It was first reported by Josephs in 1936 and refined as a distinct clinical entity by Diamond and Black fan in 1938 [5]. The first DBA was identified as RPS19 and is mutated in approximately 25% of patients. RPS19 codes for a ribosomal protein located at chromosome 19 [5, 7]. Further mutations have been identified in ribosomal proteins coded by RPS24 at chromosome 10 and RPS17 at chromosome 15 [6]. DBA usually presents in the first year of life.

Diagnostic and supporting criteria for the diagnosis of DBA are described in Table 1. DBA is associated with other congenital abnormalities in approximately 30% of cases particularly affecting the upper limb, craniofacial regions, heart and urogenital tract [7]. These are summarised in Table 2.

Table 1. Diagnostic and supporting criteria for the diagnosis of DBA. (DBA - Diamond-Black Fan anaemia)

DIAGNOSTIC CRITERIA

Age < 1 year

Macrocytic anaemia with no other significant cytopenias

Reticulocytopenia

Normal marrow cellularity with a paucity of erythroid precursors

SUPPORTING  CRITERIA

Major

Gene mutation desribed in “classical” DBA

Positive family history

Minor

Elevated erythrocyte adenosine deaminase activity

Congenital anomalies described in “classical” DBA

Elevated HbF

No evidence of another inherited bone marrow failure

syndrome


Table 2: Congenital abnormalities observed in DBA. From ‘Diagnosing and treating Diamond Black Fan anaemia: results of an international clinical consensus conference [5]. (DBA - Diamond-Black Fan anaemia)

 

 

Craniofacial


Hypertelorism,broad,flat nasal bridge,cleft palate,high arched palate,microcephaly, micrognathia,  microtia,low set ears,low hair line,epicanthus,ptosis

Ophthalmological

Congenitalglaucoma,strabismus,congenital cataract

Neck

Short neck,webbed neck,sprengel deformity,Klippel-Feildeformity

 

Thumbs

 

Triphalyngeal,duplex orbifid,hypoplastic,flat thenareminence,absent radial artery

 

Urogenital

 

Absent kidney,horse shoe kidney,hypospadias

Cardiac

 

  Ventricular septal defect,atrial septal defect,coarctation of the aorta,complecardiac anomalies

 

Other musculoskeletal

 

Growth retardation,syndactyly

 

Neuromotor

 

Learning difficulties

Patients are predisposed to malignancies including acute leukaemias, myelodysplastic syndrome, sarcomas and lymphomas (Table 3). Survival of DBA patients with cancer appears to be less than patients with similar cancers in the general populations.


Table 3: Summary of literature reports of malignancies in DBA patients. From ‘Diagnosing and treating Diamond Black Fan anaemia: results of an international clinical consensus conference [5] (DBA -  Diamond-Black Fan anaemia)

 

Type of Malignancy

 

Number of Reported Cases

 

Acutemyeloid  leukaemia  (AML)

 

10

 

Acutelymphoid  leukaemia (ALL)

 

1

 

Myelodysplastic syndrome(did not develop AML)

 

3

 

Sarcoma

 

6

 

Hodgkinslymphoma

 

3

 

Non-Hodgkinslymphoma

 

1

 

Breast

 

2

 

Hepatocellularcarcinoma

 

2

 

Melanoma

 

1

 

Fibrohistiocytoma

 

1

 

Gastric

 

1

 

Colon

 

1

Corticosteroids are the mainstay of treatment in DBA. After an initial period of blood transfusions at diagnosis a trial of steroids should be initiated. Approximately 80% of patients respond to an initial course of steroids. The maintenance dose is highly variable; however, some patients become refractory to steroids despite an initial response whilst others may experience unacceptable steroid side effects. If a patient fails to respond to steroid medication then chronic transfusions with packed red cells are required. However, regular blood transfusions are associated with iron overload and patients may require chelation therapy. Over 20% of DBA patients attain ‘treatment independence’ from steroids or red cell transfusions [5]. The main curative option for DBA is bone marrow transplantation. This is usually reserved for patients who do not respond to steroids or blood transfusions.

Haematopoietic stem cell transplantation (HSCT) has been shown to be curative but is controversial due to insufficient data for meaningful analysis, an association with malignancy and lack of long term follow up. Overall approximately 40% of patients with DBA are steroid dependent, 40% are transfusion- dependent and 20% are transfusion independent and on no medication. The overall survival rate is 75% above 40 years of age. Approximately 70% of deaths are treatment related including: infections, complications of iron-overload and hematopoietic stem cell transplantation complications. The remaining 30% of deaths are disease related like severe aplastic anaemia or malignancy.

Both of our patients had Diamond Blackfan syndrome and at that time there was no evidence of portal cavernoma. With repeated blood transfusion and iron supplements they developed increase serum ferritin levels with deposition of iron and an abnormal appearance of liver, which was picked up by the ultrasound. We think due to iron deposition in the liver they developed non-cirrhotic liver changes with leads to portal hypertension with oesophageal varices and eventually developed portal cavernoma. We did a detailed literature search to find any case with this kind of association but there is not a single case reported and we are reporting two cases of this nature. Still there is some major research work needs to be done in this aspect of Diamond Blackfan syndrome and portal cavernoma.

Portal vein cavernous transformation in children is commonly a congenital deformation of the portal vein system it can also occur secondary to infection, surgical intervention, or abdominal malignancy (e.g., pancreatic or hepatocellular carcinoma) or as a result of liver dysfunction [8]. Balfour and Stewart first described portal cavernoma in 1869 as thrombosis and varicose dilatation of the portal vein leading to splenomegaly and ascites. The pathogenesis of this condition remains elusive. The results of several autopsies and imaging studies [9] favour a mechanical obstructive hypothesis in the formation of portal cavernoma over the congenital (malformation that replaces a non developed portal vein) or neoplastic hemangioma hypothesis. It can be caused by a variety of different conditions that result in portal vein occlusion; these can be both intra-hepatic and extra-hepatic. Acute cases often present with abdominal pain, whereas chronic cases often present with the sequelae, such as portal hypertension, oesophageal varices, hypersplenism, and growth retardation in children.

Congenital malformations such as portal vein atresia, agenesis and stenosis are rare. About 70% of patients suffering acute extra-hepatic portal venous obstruction have a prothrombotic risk factor and clotting disorder, with myeloproliferative diseases representing about 30% of causative blood disorders , clotting disorders include antiphospholipid syndrome, polycythaemia rubra vera, antithrombin III deficiency, protein C and protein S deficiency, factor V Leiden mutation, paroxysmal nocturnal haemoglobinuria, and prothrombin gene G 20210A mutations [4] . In the acute phase of portal vein thrombosis, immediate vasodilatation of the hepatic arterial bed and a patent mesenteric collateral circulation compensate for the portal flow obstruction.

Within few days, even with partial recanalization of the thrombus, a hepatoportal collateral venous system (portal cavernoma) will develop as a second compensatory mechanism. Common clinical manifestations of the portal hypertension are oesophageal or gastric varices and splenomegaly with normal liver function tests [10]. With long-standing portal cavernoma, the venous collateral network may compress or encase the biliary tree, resulting in extra hepatic and intra hepatic bile duct damage. The first line of surgical treatment includes endoscopic dilatation of the biliary tree strictures with or without stent insertion. As the second line, a porto systemic shunt is recommended. Biliary intestinal bypass may be considered as the third line of therapy.

 

 

References

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2. Gallrgo C, Valesco M, Marcuello P, Tejedor D, De Campo, L. Friera A. Congenital and acquired anomalies of the portal venous system. Radiographics 2002;22:141-159

3. Sarin SK, Agarwal SR. Extrahepatic portal vein obstruction. Semin Liver Dis 2002;22:43- 58.

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6. Gazda, H.T., Grabowska, A., Merida-Long, L.B., et al. Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia. Am J Hum Genet 2006:79, 1110–1118

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