An 11-year-old girl (UPN1) was referred for evaluation for matched sibling bone marrow transplantation (BMT) for treatment of MDS. She was the youngest of three children born to unrelated parents. The first male born to her parents was small for gestational age, weighing 1.87
kg at term. He had severe chest deformity (babygram shown in Figure
) and died of respiratory distress at four hours of age. A diagnosis of probable ATD was made although no genetic testing could be performed, as causative genes were unknown at that time. The second was a well, unaffected male (who subsequently became the bone marrow donor for UPN1).
Babygram of the affected male sibling with severe respiratory distress. There is mild platyspondyly and generalised shortening of ribs and long bones. The metaphyses of the long bones are slightly irregular and there is some metaphyseal sclerosis.
UPN1 was born at 40
weeks gestation by a normal vaginal delivery. Her Apgar scores were 6 at one minute and 8 at 5 minutes and she required suction and oxygen by mask. Her birth weight was 2.59
kg, length 47
cm and head circumference 33
cm (all approximately on the 3rd
percentile). From 12 to 36 hours of postnatal life she developed tachypnoea, reaching a maximum of 120 breaths per minute. There was no cyanosis. On examination she had an obvious narrow chest, poor chest expansion, hepatomegaly of 2
cm and significant tachypnoea but no other obvious abnormalities. Chest auscultation was clear and cardiac examination was normal. A chest radiograph (not available) showed a narrow chest with no evidence of cardiac disease and the lung fields were consistent with transient tachypnoea of the neonate. UPN1 was admitted to the neonatal unit and was discharged 48-hour later with mild tachypnoea only. A geneticist had reviewed her and a diagnosis of probable ATD was reached. At this time her haemoglobin and platelet counts were normal and her total white cell count was 5.2 x 109
/l (no differential performed). Shortly afterwards her respiratory symptoms resolved completely.
Through the first two years of life head circumference stayed at the third percentile and her length percentile dropped. By two years she was 10
cm below the 3rd
percentile for height and 2
kg below the 3rd
percentile for weight. At 22
months of age she was admitted with sepsis with a short history of vomiting, pyrexia and a rapidly progressive purpuric rash. Meningococcal septicaemia was the presumed diagnosis and she was fully treated for this but meningococcus was not cultured and coliforms were grown subsequently from urine. Haemoglobin on admission was 4.6
g/dl, white cell count was 7.8 x 109
/l (neutrophils 2.34 x 109
/l) and the platelet count was 18 x 109
/l. These abnormalities were presumed to be secondary to severe sepsis and she made a rapid and full response to intravenous antibiotics. Ten days later her neutrophils had dropped to 1.14 x 109
/l but platelets had recovered to 53 x 109
/l. There is no documented full blood examination until 5
years of age when she developed haemolytic uraemic syndrome (HUS) and required several weeks of dialysis; this was followed by intermittent, self-limiting episodes of haematuria with mild renal impairment. At the time of admission with HUS she was noted to have learning difficulties and short stature. Renal imaging at the age of 7
years with ultrasound and DMSA showed no renal scarring, malformation, dilatation or reflux. At this time and for the following 4
years her blood counts were normal (including neutrophils) apart from a platelet count ranging from 43‐161 x 109
/l but mostly in the range 50–100 x 109
Between the ages of 9 and 10
years UPN1 progressed to being consistently pancytopenic (haemoglobin 6.8
g/dl, white cell count 1.8 x 109
/l, neutrophils 0.47 x 109
/l, lymphocytes 1.09 x 109
/l and platelets of 33 x 109
/l). She had no evidence of hepatosplenomegaly or lymphadenopathy. A bone marrow aspirate and trephine showed normal cellularity with trilineage dysplasia and no fibrosis. There was no excess of blasts initially, although repeat examination after referral showed 10% blasts and the marrow had become hypocellular. Cytogenetics revealed a deletion of 7p in a clone on the initial bone marrow aspirate but serial testing eventually revealed three different clones, one with an isochromosome of 7q, an abnormality frequently described in SDS and rarely seen outside this syndrome [8
]. Lymphocytes showed no increase in chromosome breakage compared to control in response to mitomycin C challenge, excluding Fanconi anaemia.
UPN1 became red cell and platelet transfusion dependent in the year leading up to transplant referral. During this time she suffered epiglottitis requiring intensive care, a prolonged episode of fever with a perianal abscess and periorbital cellulitis of one eye. Perianal soreness and infection became a recurring theme.
Specific questioning to exclude well-recognised causes of bone marrow failure revealed that UPN1 had passed 1‐2 stools per day throughout her life, which were yellow, offensive and difficult to flush. Microbiological examination had been consistently negative. Subsequent examination revealed the presence of fat globules and a reduced faecal chymotrypsin (0.7U/g, normal range 6‐99). Fat-soluble vitamin levels were reduced (vitamin A 0.6
μmol/l [reference range 1.1‐3.5] and vitamin E 9.7
μmol/l [reference range 10.2‐39.0]). UPN1 was growing but was still small for age; at eleven years and two months she weighed 22.9
kg below 3rd
percentile) and was 113
cm tall (approximately 20
cm below the 3rd
percentile). Skeletal survey (See Figures
, and ) revealed abnormalities in the metaphyseal regions, most prominent in the upper femoral neck and in the lower femoral and upper tibial metaphyses. These showed areas of lucency and sclerosis and irregularity. Coxa valga was present on the right and some broadening and coxa vara on the left. The ribs were a little shortened.
Figure 2 Chest radiograph of UPN1 at referral for BMT aged 11years. There is mild metaphyseal sclerosis and irregularity of the proximal humeri (black arrows). The posterior ribs are bowed (white arrows) and there is the impression of cardiomegaly due (more ...)
Figure 3 Pelvis radiograph of UPN1 at referral for BMT. There is prominent sclerosis and lucency in both proximal femoral metaphyses (black arrow) and femoral necks (white arrow). These changes extend into the subtrochanteric regions. The acetabular roofs are (more ...)
Knee radiograph of UPN1. There is sclerosis and lucency in the distal femoral and proximal tibial metaphyses (white arrows) with pseudofragmentation of the medial part of the distal femoral metaphysis (black arrow).
The radiographic changes on skeletal survey in combination with the evidence of pancreatic insufficiency, confirmed a clinical diagnosis of SDS as a cause of her chondroplasia and bone marrow failure. A DNA sample from UPN1 was later tested for conversion mutations of the SBDS gene. The restriction endonuclease digest assay confirmed mutations c.183_184TA>CT and c.258+2T>C. These account for 74% of SBDS mutations [9
]. Testing of parental DNA also confirmed that one mutated allele was inherited from each parent.
UPN1 had significant learning difficulties and was in a special school. MRI brain was unremarkable. She was commenced on fat-soluble vitamins and pancreatic enzyme replacement with rapid improvement in stool frequency and consistency. An MRI scan of the abdomen showed that the pancreas was bulky and infiltrated with fat. At referral she was receiving packed cell transfusions every three weeks and platelets approximately weekly, but blood counts improved rapidly following pancreatic and vitamin supplementation. During the following 16
months, she required only one further packed cell transfusion and became platelet independent, although she did require G-CSF in order to increase her neutrophil count. She had minimal infectious complications. Due to this improvement, plans for transplantation were postponed.
When UPN1 was 12.5
years old, her blood count fell further, she developed pyrexia of unknown origin (PUO) lasting four weeks and was admitted for intravenous antibiotics. During this time her spleen enlarged to 14
cm below the costal margin, causing significant abdominal discomfort. The PUO settled and she was discharged but returned 4
months later with recurrence of fever and further progression of splenomegaly. Extensive imaging was performed during these two admissions. Chest radiographs and CT scans initially showed no focus of infection. There was hepatosplenomegaly and, of note, the pancreas was enlarged with markedly reduced attenuation consistent with being almost completely replaced by fat (See Figure
). There was also mural thickening of the sigmoid colon and rectum, suggesting neutropenic colitis/proctitis as the cause of PUO (See Figure
). Lung function studies revealed both FVC and FEV1 in the low normal range.
Figure 5 Contrast enhanced computed tomography (CT) of abdomen. The spleen is enlarged and contains a well-defined wedge shaped peripheral zone of low attenuation which does not enhance consistent with infarction (arrows). There is enlargement and tortuosity of (more ...)
Contrast enhanced computed tomography (CT) of abdomen. There is wall thickening of the sigmoid colon with stranding of adjacent mesenteric fat (arrow). The appearances are of colitis.
Progressive splenomegaly was thought to be related to progression of MDS and chronic G-CSF exposure as imaging showed no evidence of portal hypertension. UPN1 continued to have fevers resistant to intravenous antibiotics with no evidence of invasive fungal disease. Splenectomy was performed due to concerns that splenic sequestration was contributing to decreasing blood counts. Pathology revealed a large spleen (737 grams compared with mean weight for age being 89 grams) with several areas of infarction. The white pulp was atrophic and the red pulp congested. Microscopy showed areas of infarction with diffuse expansion of the red pulp, resulting from extensive infiltration of left shifted myeloid cells and clusters of atypical blasts. These features were thought to be attributable to MDS. Rectal biopsy was also performed, revealing features consistent with neutropenic colitis.
Persistent neutropenia, abdominal pain and recurrent fevers necessitated matched sibling BMT after conditioning therapy comprising fludarabine (125
), melphalan (140
) and alemtuzumab (0.9
mg/kg). This procedure was complicated by primary graft rejection, necessitating re-transplantation following administration of fludarabine (100
), high dose methylprednisolone (10
mg/kg twice daily for four doses, then 2
mg/kg twice daily for four doses followed by slow weaning) and OKT3 (0.2
mg/kg for eight doses). This was followed by rapid and uncomplicated donor engraftment. Mixed T-cell chimerism led to donor lymphocyte infusions to reduce the risk of relapse of MDS. UPN1 is now over 5
years post-transplant and is well with normal blood counts. Whole blood and T-cell chimerism levels are 98% and 89% donor respectively. Hepatomegaly resolved rapidly following successful engraftment.