Long-term metabolic, endocrine, and neuropsychological ... - Nature

Bone Marrow Transplantation (2009) 43, 21–27 & 2009 Macmillan Publishers Limited All rights reserved 0268-3369/09 $32.00

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ORIGINAL ARTICLE

Long-term metabolic, endocrine, and neuropsychological outcome of hematopoietic cell transplantation for Wolman disease J Tolar1, A Petryk2, K Khan3, KJ Bjoraker4, J Jessurun5, M Dolan5, T Kivisto1, L Charnas4, EG Shapiro4 and PJ Orchard1 1 Division of Pediatric Hematology-Oncology, Department of Pediatrics, Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA; 2Division of Endocrinology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; 3Division of Gastroenterology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; 4Division of Pediatric Clinical Neuroscience, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA and 5Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA

Wolman disease is the infantile form of autosomal recessive acid lipase deficiency, typically presenting in early infancy with diarrhea, massive hepatosplenomegaly, failure to thrive, and calcification of adrenal glands. Hematopoietic cell transplantation (HCT) is the only therapy reported to prevent hepatic failure and death, which without treatment occurs within the first year of life. We report a single institution’s experience with HCT treatment of four Wolman patients, two of whom are longterm survivors (the longest survival reported to date, (4 and 11 years). Survivors showed resolution of diarrhea within weeks after engraftment, normalized hepatic function, improved hepatosplenomegaly, and in one patient normal adrenal function. The older patient has normal adaptive functions but mild to moderate neurocognitive deficiencies thought to be secondary to treatment and other medical problems. The younger patient has ageappropriate neurodevelopmental and adaptive abilities. We conclude that Wolman disease can be successfully treated with HCT, and that hepatic and cognitive function can be preserved with early diagnosis and timely referral to a transplant center. Bone Marrow Transplantation (2009) 43, 21–27; doi:10.1038/bmt.2008.273; published online 8 September 2008 Keywords: Wolman disease; acid lipase; adrenal insufficiency; hematopoietic cell transplantation; hyperthyroidism; growth hormone deficiency

Correspondence: Dr J Tolar, Division of Pediatric HematologyOncology, Department of Pediatrics, Blood and Marrow Transplantation, University of Minnesota, MMC 366, 420 Delaware Street SE, Minneapolis, MN 55455, USA. E-mail: [email protected] Received 1 July 2008; accepted 25 July 2008; published online 8 September 2008

Introduction Wolman disease, initially described by Abramov et al. in 1956,1 is an autosomal recessive disorder of infancy caused by deficiency of the soluble mannose-6-phosphate-targeted lysosomal enzyme acid lipase (AL).2 Deficiency of this enzyme leads to massive storage of cholesterol and cholesteryl esters. Triglycerides and cholesteryl esters are internalized by the cell through receptor-mediated endocytosis of lipoproteins and metabolized, in part, by AL.3,4 The clinical manifestations of this disorder are caused by both accumulation of cholesteryl esters and triglycerides, and toxicity from lipoprotein oxidation.5 Children affected with Wolman disease appear healthy at birth but shortly thereafter develop hepatosplenomegaly, jaundice, diarrhea, severe vomiting, failure to thrive, and pathognomonic pattern of calcification of the adrenal glands.1,2 Wolman disease is uniformly lethal in early infancy unless treated with hematopoietic cell transplantation (HCT).6–8 Donor cells supply AL to lysosomes of host cells, and restore sufficient enzymatic activity for normal hydrolysis of triglycerides and cholesteryl esters.2,4,9,10 Graft failure and the high mortality rate associated with disease-related pretransplant liver injury and post-transplant liver sinusoidal obstruction syndrome (veno-occlusive disease)6,7 are, however, major barriers to optimal outcomes. Wolman disease is rare (with fewer than 80 cases identified by a PubMed search) and available long-term follow-up data are limited. We report a single institution experience of HCT treatment of four Wolman patients, two of whom are long-term survivors, for 4 and 11 years after HCT.

Patients Table 1 summarizes the specifics of the transplant procedure and graft characteristics. The University of Minnesota Institutional Review Board approved all transplantation protocols, and informed consent was

HCT for Wolman disease J Tolar et al

22 Table 1 Patient age at HCT (days)

Patients’ ages transplant and graft characteristics Graft

1

192

BM

2

134

BM

3

579

BM

618

BM

775

BM

72

UCB

4

HLA match

5 of 6 URD 6 of 6 related donor 6 of 6 URD 6 of 6 same donor 6 of 6 different URD 4 of 6 URD

Conditioning

NC (107 cells per kg)

CD34+ (106 cells per kg)

TCD

Follow-up (years)

Donor engraftment

Acid lipase (nmol/h per mg protein)

GVHD

Recovery myeloid days Acute

Chronic

g3 (skin, liver) No

Yes

CY, ATG, TBI CY, TBI

4.1

6.5

Yes

11

100%

5.3 (normal)

18

20

3.76

No

0.2 Died

100%

2.5 (50% of normal)

20

CY, ATG, TBI ATG

13

2.3

Yes

—

0

NA

NA

No

No

3.38

3.83

Yes

—

0

NA

NA

No

No

1.78

No

0.7 Died

100%

4.1 (normal)

19

g3 (skin, liver)

No

4

No

4

100%

5.9 (normal)

12

g3 (skin)

Yes

BU, FLU, TBI BU, CY, ATG

30.2

2.65

No

Abbreviations: ATG ¼ antithymocyte globulin; g ¼ grade; FLU ¼ fludarabine; HLA ¼ human leukocyte antigen; NC ¼ nucleated cells; TCD ¼ T-cell depletion; UCB ¼ umbilical cord blood; URD ¼ unrelated donor.

obtained in all cases before the procedure. Pretransplantation management of diarrhea and poor weight gain included a combination of low-fat, soy, or hydrolyzed oral formula in three patients, and parenteral nutrition in patient 2. Follow up is reported through April 2008.

Patient 1 A 1-month-old girl (whose brother had died from Wolman disease) was admitted to the hospital with diarrhea and vomiting, which had started at 1 week of age. Her diagnosis and initial transplant course, including early posttransplant skin GVHD and hemolytic anemia, have been reported previously.7 Subsequent to that report, we identified and treated her seizures, severe short stature and hyperthyroidism. Patient 2 A 6-week-old son of consanguineous parents (second cousins) of Iranian Jewish heritage developed failure to thrive and coagulopathy. Adrenal calcifications were detected at 2 months of age. Very low leukocyte AL activity (6% of normal) confirmed the diagnosis of Wolman disease. At 19 weeks of age he was transplanted using a 6 of 6 HLA antigen-matched (AL heterozygote), sibling BM graft after conditioning with CY (60 mg/kg i.v. once daily on days 5 and 4, total dose 120 mg/kg) and TBI (dose 1400 cGy). He developed sinusoidal obstruction syndrome on day 19 and died of hepatorenal failure, pulmonary failure, coagulopathy, and sepsis on day 67. His parents declined autopsy. Patient 3 A 1-year-old boy presented with diarrhea and hepatosplenomegaly. Adrenal calcifications were detected on abdominal ultrasound at 17 months of age. Very low leukocyte AL activity (3.8% normal) confirmed the diagnosis of Bone Marrow Transplantation

Wolman disease. He received a 6 of 6 HLA antigenmatched, T-cell-depleted BM infusion from an unrelated donor at 19 months of age after a preparative regimen of CY (60 mg/kg i.v. once daily on days 5 and 4, total dose 120 mg/kg), anti-thymocyte globulin (15 mg/kg per dose i.v. every 12 h on days 3, 2 and 1, total dose 90 mg/kg) and TBI (dose 1400 cGy). He developed primary graft failure and, after 5 days of conditioning with ATG, was infused with stem cells from the same donor (39 days after the original stem cell infusion). Autologous recovery occurred. At 25 months of age, 6 months after the first stem cell infusion, he received a 6 of 6 HLA antigen-matched, unmanipulated BM graft from a different unrelated donor. The preparative regimen included BU (1 mg/kg per dose i.v. every 12 h on days 7 and 6, total dose 4 mg/kg), FLU (40 mg/m2 i.v. once daily on days 5, 4, 3, 2 and 1, total dose 200 mg/m2) and TBI (dose 200 cGy). On day 14 after stem cell infusion, he developed sepsis and liver failure. He died 46 days after the third stem cell infusion, at 27 months of age. Autopsy examination revealed lipid deposition in the anterior mitral valve, right atrial thrombus, diffuse fibrosis of the liver, multiple areas of ulceration in the colon, and hemorrhage and necrosis in the adrenal medulla.

Patient 4 Born after a pregnancy complicated by oligohydramnios, a 1-month-old girl of Iranian Jewish ethnicity developed intractable diarrhea. Computer tomography (CT) and abdominal X-ray showed significant adrenal calcifications, and an enlarged liver and spleen. Low leukocyte AL activity (12.5% normal) confirmed the diagnosis of Wolman disease. At 10 weeks of age she received an unrelated cord blood transplant using a graft documented to have normal AL activity (10.2 nmol/h per mg protein). The preparative regimen included BU (1 mg/kg per dose i.v. every 6 h on days 9, 8, 7 and 6; total dose


23

16 mg/kg), CY (50 mg/kg i.v. once daily on days 5, 4, 3 and 2; total dose 200 mg/kg) and ATG (30 mg/kg per dose i.v. once daily on days 3, 2 and 1; total dose 90 mg/kg). She was fully engrafted with donor hematopoiesis. At 6 weeks after HCT she developed grade 3 skin acute GVHD and responded well to prednisone therapy.

Results Gastrointestinal pathology Gastrointestinal tract endoscopy performed as part of the diagnostic evaluation before HCT in patient 3 demonstrated no grossly visible abnormalities in the duodenum, stomach, or esophagus. Upper intestinal mucosa and rectal biopsy contained foamy macrophages. A rectal mucosa biopsy 2 months after HCT from patient 4, performed because of increasing diarrhea, was normal. Liver imaging and pathology Liver images by ultrasound (patient 2) or CT (patients 3 and 4) were consistent with fatty changes. In patient 2, liver biopsy prior to HCT showed typical features of Wolman disease (Figure 1): microvesicular steatosis, foamy histiocytes, hepatocytes with vacuolated cytoplasm and intracytoplasmic cholesterol clefts. Hypertrophied Kupffer cells

were difficult to differentiate from hepatocytes (Figure 1a) on hematoxylin-eosin slides. A periodic acid-Schiff (PAS) stain prior to diastase digestion helped to differentiate glycogen-rich liver cells containing few lipid vacuoles from pale-staining Kupffer cells with abundant vacuolated cytoplasm that obliterated the sinusoids (Figure 1b). A CD68 immunohistochemical reaction further highlighted Kupffer cells with lipid vacuoles and acicular crystals typical of cholesterol (Figure 1c). No autopsy was performed. Postmortem liver sections from patient 3 (day þ 46) showed centrilobular pericellular fibrosis associated with veno-occlusive disease and portal fibrosis (Figure 2a). Numerous vacuolated CD-68-positive Kupffer cells were present (Figure 2b). In patient 1, the longest survivor, hepatosplenomegaly had resolved within 6 months of HCT. Biopsy specimens obtained at 5, 7 and 12 weeks following HCT showed a noticeable decrease in number of hypertrophic Kupffer cells (Figure 3).

Endocrine function Adrenal function. Patient 1 had borderline standard-dose adrenocorticotropin (ACTH) stimulation tests prior to HCT and adrenal insufficiency at 1 and 2 years after HCT during prednisone therapy for GVHD. Prednisone therapy continued for almost 4 years.7 A low-dose ACTH

Figure 1 Liver pathology in Wolman disease before hematopoietic cell transplantation (HCT). (a) Hematoxylin and eosin stained sections showing a mosaic pattern. (b) A periodic acid-Schiff (PAS) stained section prior to diastase digestion shows pale-staining Kupffer cells with abundant vacuolated cytoplasm. (c) CD-68-expressing Kupffer cells show numerous needle-shaped crystals typical of cholesterol.

Bone Marrow Transplantation


24

Figure 2

Liver pathology in Wolman disease after failed hematopoietic cell transplantation (HCT). (a) Liver autopsy specimen stained with trichrome showing centrilobular pericellular fibrosis secondary to venoocclusive disease and portal fibrosis. (b) Same specimen stained for CD68. Numerous immunoreactive Kupffer cells are present.

Figure 3

stimulation test, performed at 9 years 1 month of age during treatment with hydrocortisone at 2.5 mg twice a day (6.8 mg/m2 per day) demonstrated baseline cortisol 11.2 mg per 100 ml with minimal increase to 12.3 mg per 100 ml at 30 min. This was interpreted to reflect possible adrenal suppression from prior GVHD therapy. Hydrocortisone was discontinued at 9 years 11 months of age. A repeat lowdose ACTH stimulation test at 10 years 7 months of age showed improved adrenal function with baseline serum cortisol of 6.5 mg per 100 ml and peak of 18.6 mg per 100 ml at 60 min. Adrenal recovery was confirmed by a standard-dose ACTH stimulation test performed 4 months later. At that time, the cortisol level was 11.2 mg per 100 ml at baseline and 23.4 mg per 100 ml at 60 min. Dense calcifications of the adrenal glands persist 11 years after transplant. Hydrocortisone replacement has been discontinued for the last 2 years. Fludrocortisone was never prescribed. Patient 2 had two normal standard-dose ACTH stimulation tests, at 2 months and again at 3 months of age. Hydrocortisone replacement was not used before or during transplant at 19 weeks of age. Patient 3 had a normal standard-dose ACTH stimulation test 2 months prior to his first HCT at 18 months. A repeat standard-dose ACTH stimulation test at 21 months of age remained normal (peak cortisol 26 mg per 100 ml). GVHD treatment with prednisone precluded testing after the third transplant. Patient 4 had a normal standard-dose ACTH stimulation test 1 month prior to HCT (peak cortisol 32.1 mg per 100 ml). She received hydrocortisone and fludrocortisone treatment during HCT as a precaution. Adrenal suppression developed from prednisone treatment for skin GVHD. Prednisone treatment stopped at 5 months of age. At 2 years 10 months, she continued to receive hydrocortisone 2.5 mg twice a day (9 mg/m2 per day) and fludrocortisone 0.1 mg daily. A low-dose ACTH stimulation test demon-

Liver pathology in Wolman disease after successful hematopoietic cell transplantation (HCT). Progressive decrease of CD68-positive Kupffer cells (a) 5 weeks, (b) 7 weeks, and (c) 12 weeks after HCT.



25

strated almost no endogenous cortisol production (o0.5 mg per 100 ml at baseline, peak 0.7 mg per 100 ml). Nearly identical results occurred with repeat testing at 4 years of age (baseline 0.6 mg per 100 ml, peak 0.7 mg per 100 ml). She continues on hydrocortisone and fludrocortisone replacement. Thyroid function Patient 1. A short stature evaluation at 4 years 4 months of age identified autoimmune hyperthyroidism: T3 474 ng per 100 ml (nl 119–218); T4 21.1 mg per 100 ml (nl 5.5–12.8) and suppressed TSH 0.09 mU/l (nl 0.4–5.0) with elevated thyroidstimulating immunoglobulin (313%, nl o130%), thyroglobulin antibody (111 IU/ml, nl o40) and thyroid peroxidase antibody (3496 IU/ml, NL o35 IU/ml). A homogenous increased iodine-123 uptake within the thyroid gland confirmed autoimmune hyperthyroidism. In retrospect, the patient had had clinically recognized proptosis that was interpreted as combination of familial traits and HCT complication. Propylthiouracil treatment produced leukopenia after 1 month, leading to methimazole treatment for 4 years with long-term remission of Graves’ disease. Patient 2.

Thyroid function was normal before HCT.

Patient 3. Thyroid function was normal prior to his first HCT at 18 months. Thyroxine therapy for hypothyroidism, identified during the second transplant evaluation, began at 25 months of age. Patient 4.

All thyroid testing has been normal.

Linear growth Patient 1. At 4 years 4 months, she underwent growth hormone (GH) stimulation testing (L-DOPA clonidine) due to severe short stature (height at 5.9 s.d.). Peak GH level

Patient 4. Her initial length was 2.9 s.d. before HCT. She showed slow but progressive improvement in growth velocity after HCT. At 4 years of age, height was –1.6 s.d.

Neurologic outcomes Patient 1 experienced two episodes of partial complex status epilepticus of unknown etiology. The first cranial MRI was normal. She remains seizure free 5 years after a 2-year treatment course with lamotrigine. Patient 4 experienced two episodes of eye deviation with arm jerking 4 months after HCT. She received phenobarbital treatment for 2 months. She has had no seizure recurrence in over 3 years. Neuropsychological functions Patients 1 and 4 (Table 2) were given serial neuropsychological evaluations prior to, and yearly following, transplant to measure central nervous system function at baseline and after treatment. For brevity, data are only reported for every other year. Patients 2 and 3 were assessed at baseline and found to be normally developing and mildly impaired, respectively.

Neuropsychological results

Table 2

Measure 1

was 6.3 ng/ml, confirming GH deficiency. At the start of GH treatment, her height was 79.2 cm (6.4 s.d.) and baseline growth velocity calculated over the preceding 5 months was 0.8 cm per year (5.6 s.d.). During the first year of treatment with GH at a dose of 0.3 mg/kg per week, growth velocity increased to 8.1 cm per year (1.4 s.d.). Depot leuprolide treatment was initiated at pubertal onset because of poor final height prediction. Bone age was normal at 11 years. At 12 years of age, her height was 118.3 cm (4.3 s.d.) after 7 1/2 years of treatment with GH (2.1 s.d. above pretreatment height).

2

Developmental quotient/verbal IQ Nonverbal IQ Receptive vocabulary Expressive fluency Visual-motor skills Adaptive behavior —

3

—

4

—

Baseline

2 years post-HCT

4 years post-HCT

6 years post-HCT

8 years post-HCT

10 years post-HCT

78a — — — — 96g 97h 78g 63a 86g 79h 102g

NA — — — — NA — — — — 89h 98g

66b 76b — — — 53g — — — — — —

68b 78b 63d 79e 65f 62g — — — — — —

77b 84b 60d 90e 63f 58g — — — — — —

54c,* 66c,* 63d 90e 72f 86g — — — — — —

Abbreviations: HCT ¼ hematopoietic cell transplantation; IQ ¼ intelligence quotient; NA ¼ not administered. Average range for all measures 100±15. *Outlier; see text. a Bayley Scales of Infant Development II. b Stanford Binet IV. c Stanford Binet V. d Peabody Picture Vocabulary. e McCarthy/NEPSY verbal fluency. f Beery Test of Visual Motor Integration. g Vineland Adaptive Behavior Scale. h Mullen Scales of Early Learning. Bone Marrow Transplantation


26

Patient 1 has had overall mildly impaired cognitive abilities (Table 2) that have been stable since baseline. However, scores on her most recent cognitive evaluation at age 10 years 3 months indicated a decline in both verbal and nonverbal cognition that results from a revision in the test administered (which emphasizes areas of her deficit rather than a true decline). When compared to other test results, these results are outliers. Sustained visual attention was significantly impaired. Reading was stronger than mathematics skills that recently have slowed in development. Verbal fluency has been average. Visual-spatial skills, verbal and visual memory, and visual-motor skills were mild to moderately impaired. She recently demonstrated improved adaptive functions (ability to perform daily activities, Table 2) and she has had no behavioral, social, or emotional difficulties. She has been homeschooled and has received intermittent private occupational, physical and speech/language therapies throughout the years. Patient 4 has average cognition that has improved from baseline (Table 2). Her receptive and expressive language was in the high-average range. Her visual-spatial problemsolving skills have improved since her baseline evaluation and are now average. Her fine motor skills have been just below average, and her gross motor skills consistently average. Adaptive skills (Table 2) as well as emotional and social behavior have been average. She attends an early childhood special education preschool and speaks three languages.

Discussion This is the first report of long-term outcomes after successful HCT in patients with Wolman disease. We demonstrate that a progressive decrease in number of Kupffer cells, a lasting correction of hepatic dysfunction, and normal adrenal function, and a normal neurologic outcome are possible after treatment with either BM or umbilical cord blood HCT. These data show that Wolman disease, despite management challenges, is a condition successfully treatable with HCT to correct AL deficiency. We believe that efforts should be focused on improvements in early disease management to improve HCT outcome. Gross and microscopic changes in the adrenal gland with increased weight, cholesteryl esters and triglycerides accumulation, and bilateral adrenal calcifications are well described.2,11,12 In vivo evaluation of adrenal function is less well studied, most likely due to early lethality. The incidence and timing of glucocorticoid deficiency, as well as the status of mineralocorticoid production, is also not well characterized.7,13 The adrenocorticotropin stimulation test is used to evaluate adrenal cortisol production. The standard-dose ACTH stimulation test (250 mg cosyntropin) is typically used to diagnose primary adrenal insufficiency, while the low-dose ACTH stimulation test (1 mg cosyntropin) is more sensitive than the standard-dose test14–17 and thus may be more appropriate for diagnosis of subtle adrenal insufficiency, including secondary adrenal insufficiency or adrenal suppression, to test for adrenal recovery. A peak cortisol response 420 mg per 100 ml is generally considered normal, Bone Marrow Transplantation

and 18–20 mg per 100 ml is considered borderline.16,17 The interpretation of the ACTH stimulation test, and therefore adrenal recovery, may be confounded by prolonged steroid use after transplant. Adrenal function preservation or recovery of function after transplantation in Wolman disease might be anticipated, with adrenal hypertrophy with preservation of adrenal cortical cells.2 The calcifications present likely represent a reaction to oxidative stress of lipoproteins due to aberrant metabolism in the absence of AL.5 This situation is quite unlike that in adrenoleukodystrophy, another metabolic disease treated successfully with HCT and associated with adrenal failure. In that disorder, the toxicity of very long-chain fatty acids usually produces a progressive and permanent atrophy of the adrenal cortex zona fascicularis18 that antedates neurologic symptoms and treatment with HCT. In our study, three patients (ages 1–16 months) had a normal standard-dose ACTH stimulation test prior to HCT. Patient 1 had borderline-normal adrenal response to a standard-dose ACTH stimulation test before HCT and a normal response 10 years after HCT. Patient 1 also developed Graves’ disease and GH deficiency, which are more likely related to HCT and the preparatory conditioning regimen than to Wolman disease. Patient 4 failed a lowdose ACTH stimulation test 4 years after HCT and continues to take hydrocortisone and fludrocortisone. Our study shows that adrenal insufficiency is not uniformly present in all patients with Wolman disease during infancy, and that function may recover after HCT even after a period of transient suppression; for example, due to steroid treatment of GVHD. However, as adrenal insufficiency, whether documented or presumed, can be life-threatening, it is prudent to use glucocorticoid replacement at times of stress. As there is a potential for recovery of adrenal function, we recommend that adrenal function be evaluated before HCT and annually after HCT. Linear growth is typically impaired in patients with Wolman disease due to malabsorption. Although HCT ameliorates metabolic manifestations of the disease, its effect on growth may be compounded by GH deficiency and other endocrinopathies that frequently develop after HCT.19,20 Patient 1 had GH deficiency and was treated with GH with some improvement in growth velocity, although height s.d. score at the recent visit was still very low at 4.3. Patient 4, however, showed significant improvement in growth after HCT with height s.d. being within the normal range at 1.6. Patient 1 has mild to moderate cognitive limitations. Possible contributing factors include brain dysfunction associated with status epilepticus, and high-dose steroid treatment. She has a pattern of nonverbal deficits usually associated with white-matter dysfunction. Any one of the contributing factors previously mentioned, as well as the transplant regimen, could be associated with this cognitive profile. She has improving adaptive functions and normal behavior. Patient 4 has normal neurologic function, cognition, adaptive skills and behavior. Normal neurologic outcomes following HCT should not be surprising. Normal cranial MRI at 1.5 year after HCT and apparently normal educational function have been


27

reported in a 4-year-old Israeli child.8 The neuropathologic findings in Wolman disease are primarily lipid-laden macrophages in the meninges and perivascular spaces with ‘occasional’ neuronal accumulation of lipid in retinal ganglion cells, brain stem nuclei, and Purkine cells of the cerebellum.11 Only one report of a ‘peculiar’ sudanophilic leukodystrophy with fibrillary gliosis exists.21 In addition, although xanthomatous changes in neurons of the myenteric plexus have been reported by some,21–23 -no myenteric plexus or central nervous system involvement has been reported by others.24,25 In summary, the long-term outcomes of patients with Wolman disease treated with HCT are very encouraging, but early diagnosis and rapid evaluation at a transplant center are prerequisites for cure.

Acknowledgements

11

12

13

14 15

We thank Eileen Hanson for her dedication and persistence in obtaining the necessary data. 16

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