Hypoplastic Anemia in Cartilage-Hair Hypoplasia—Balancing betweenIron Overload and Chelation

Mervi Taskinen, MD, PhD1, Sanna Toiviainen-Salo, MD, PhD2, Jouko Lohi, MD, PhD3, Pentti Vuolukka, MD4,

Michaela Gr€asbeck, MD5, and Outi M€akitie, MD, PhD6,7

Objective To evaluate the severity of iron overload and the success of iron chelation therapy in patients withcartilage-hair hypoplasia (CHH) and hypoplastic anemia, with particular focus on adverse effects of iron chelators.Study design Four of the 23 presently surviving Finnish patients with CHH under 18 years of age are dependenton regular red blood cell transfusions. Their hospital records were reviewed for history of anemia and chelation ther-apy. Cumulative iron load from transfusions was calculated. Efficacy of the chelation therapy was evaluated bio-chemically and by liver iron content assessments.Results At the introduction of iron chelation, the patients had received on average 99 (37-151) transfusions; themean cumulative iron overload was 4640 (800-8200) mg, the annual iron accumulation rate 0.35 (0.25-0.41) mg/kg/d, and themeanplasma ferritinwas2896 (1217-6240)mg/L. Liver iron content, determinedbybiopsy in 3patients,was on average 20.0 (6.6-30.0) mg/g liver dry weight. All patients, except 1 with Hirschsprung disease, tolerateddeferoxamine, deferiprone, and deferasirox therapy well, showing only mild adverse effects typical for the agents.Plasma ferritin levels and liver magnetic resonance imaging T2* of iron overload showed successful chelation.Conclusion Iron chelation is well tolerated in patients with CHH, with possible exception of patients with Hirsch-sprung disease. Successful chelation will prepare for hematopoietic stem cell transplantation in patients with CHHwith persistent transfusion dependency. (J Pediatr 2013;162:844-9).

Cartilage-hair hypoplasia (CHH) OMIM #250250 is a rare autosomal recessive metaphyseal chondrodysplasia mostprevalent in the Finnish and Amish populations.1,2 CHH is caused by mutations in the ribonuclease mitochondrialRNA processing (RMRP) gene, encoding the RNA component of the ribonuclease complex RNase MRP.3,4 The RNase

MRP consists of an RNA molecule bound to several proteins, and this complex is involved in ribosome assembly and cell-cycleregulation.3

Clinically, CHH is characterized by severe short-limbed, short stature (adult height 110-140 cm), hypoplastic hair, and im-mune deficiency.2-7 The prevalence of Hirschpsrung disease is increased.8 Hematological abnormalities, especially lymphope-nia and anemia, are frequently seen.5,9 Over 70% of patients with CHH have mild macrocytic anemia, which is usually presentin early infancy and resolves spontaneously.5 In 6% of the patients, anemia is severe and leads to transfusion-dependency5,9 andconsequent iron overload. Anemia results from impaired erythroid precursor growth in the bone marrow (BM).10

In this study, our aim was to evaluate the severity of iron overload and the success of iron chelation therapy in patients withtransfusion-dependent CHH with particular focus on growth and adverse effects of iron chelators.

ALAT

BM

CHH

GH

Hb

HSCT

LIC

MRI

RBC

RMRP

844

Methods

From the 1Departments of Pediatric Hematology,Oncology, and Stem Cell Transplantation, 2Radiology,Children’s Hospital, Helsinki University Central Hospital;3Department of Pathology, Haartman Institute and

This retrospective study analyzed patients with CHH treated for severetransfusion-dependent anemia at the Children’s Hospital, Helsinki UniversityCentral Hospital. Among the 23 presently known surviving Finnish patientswith CHHunder 18 years of age, 4 patients (2males and 2 females) are dependenton regular red blood cell (RBC) transfusions to maintain their hemoglobin (Hb)

HUSLAB, University of Helsinki and Helsinki UniversityCentral Hospital, Helsinki, Finland; 4Department ofPediatrics, L€ansi-Pohja Central Hospital, Kemi, Finland;5Department of Pediatrics, Kymenlaakso CentralHospital, Kotka, Finland; 6Department of Endocrinology,Children’s Hospital, Helsinki University Central Hospitaland University of Helsinki, and 7Folkh€alsan ResearchCenter, Helsinki, Finland

Supported by the Foundation for Pediatric Research (toO.M.), the Sigrid Juselius Foundation (to O.M.), theAcademy of Finland (to O.M.), the Helsinki UniversityCentral Hospital Research Funds (to M.T. and O.M.),Folkh€alsan Research Center, and the Nona and KullervoV€are Foundation (to M.T.). The authors declare no con-flicts of interest.

0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc.

All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2012.09.050

Alanine aminotransferase

Bone marrow

Cartilage-hair hypoplasia

Growth hormone

Hemoglobin

Hematopoietic stem cell transplantation

Liver iron content

Magnetic resonance imaging

Red blood cell

Ribonuclease mitochondrial RNA processing

Vol. 162, No. 4 � April 2013

level above 80 g/L. Patient characteristics are presented belowand summarized in Table I. In all 4 patients, the diagnosis ofCHH was confirmed with RMRP mutation analysis (allhomozygous for 70A > G). Data were collected fromhospital records, and the Research Ethics Committee of theChildren’s Hospital, Helsinki University Central Hospitalapproved the use of data for the present study.

Patient 1 was born at term with severe short-limbed, shortstature; her birth length was 39.0 cm (�6.3 SDS). She hadcombined cellular and humoral immune deficiency and im-munoglobulin replacement from age of 6 months; clinical in-fections have been infrequent. Shewas severely anemic at birth(Hb 34 g/L) and required transfusions at 2-week intervals dur-ing the first 6 months. After a stable period of 7 months, sheagain became transfusion-dependent. BM showed pure ery-throid hypoplasia with no myelodysplastic features or clonalchromosomal aberrations in repeated sampling; BM stemcell culture showed very poor erythroid lineage growth. He-molysis or hemorrhage did not occur, vitamin B12 and folatelevelswere normal, and erythropoietin level supranormal, as inall the study patients. The life-span of erythrocytes was short-ened and splenectomywasperformedat 8.8 years.Now, at 15.2years, first signs of pubertal development are developing.

Patient 2 is now 11.9 years old. He was born at 32 weeks’gestational age with short stature and short limbs; birthlength was 32.0 cm (�8.0 SDS). Despite confirmed cellularimmune deficiency with abnormal mitogen responses indi-cating impairment in T-cell function and in T/B -cell coop-eration, he had no major problems with infections prior tosplenectomy. At birth, he was anemic with Hb of 86 g/L,and he has remained transfusion-dependent since birth.BM showed erythroid hypoplasia with features of dyserythro-poiesis in the remaining erythroid cells but no signs of clonalaberrations. Poor erythroid growth was observed in BM stemcell culture. The life-span of erythrocytes was found to beshortened, and splenectomy was performed at age 5.5 years.

Patient 3 is a 5-year-old female who was born at term withrespiratory distress and high pulmonary blood pressure need-ing respiratory support for the first week of life. Short stature

Table I. Clinical characteristics of the transfusion-dependent

Patient GenotypeLength atbirth (SDS)

Duration of GH therapy(starting in relationto chelation), y

Immune deficien(IvIgG infusions

1 70A > G(homozygous)

�6.3 13 y;6.5 y before chelation

Combined (+)

2 70A > G(homozygous)

�8.0 7 y;1 y after chelation

Cellular (�)

3 70A > G(homozygous)

�6.0 - Mild decrease inCD8 lymphocytcount (�)

4 70A > G(homozygous)

�6.2 2.2 y;8.7 y before chelation

Cellular (�)

BPD, bronchopulmonary dysplasia; IvIgG, intravenous immunoglobulin.

(birth length 39.5 cm, �6.0 SDS) and short limbs wereobserved at birth. She has no clinical symptoms of immune de-ficiency, but only amild decrease inCD8 lymphocyte count. Atbirth, herHbwas 79 g/L. Since then, she has neededRBC trans-fusions at 2- to4-week intervals. BMshowedpure erythroidhy-poplasia andpoor erythroid lineage growth in stem cell culture.Patient 4 was born at term; his birth length was 39.0 cm

(�6.2 SDS) and limbs were short. He was diagnosed with to-tal colon Hirschsprung disease at 2 weeks. After operativetreatment, he has functional short bowel syndrome and hasremained on almost total parenteral nutrition. He has cellu-lar but not humoral immune deficiency and has had severallife-threatening septicemias. He was born with normal Hb.Anemia was detected at 3 weeks and he needed regularRBC transfusions until age 4 years. After a remission of 5years, the transfusion dependency reoccurred and is continu-ing at his present age, 14.2 years. In infancy, erythropoiesiswas megaloplastic but almost normal in number; at recur-rence of anemia, the erythroid production was decreasedand stem cell culture showed poor erythroid growth.

Estimation of Iron OverloadWe collected transfusion history for each patient from birth tothe present. An estimated iron content of 0.65 mg per trans-fused mL of RBC was used in calculations, in line with theproduct manual of the Finnish Red Cross Blood Service. Cu-mulative iron load (mg/kg/d) was calculated. Plasma ferritin(photometric immunochemicalmethod), alanine aminotrans-ferase (ALAT) (photometricmethod), and erythropoietin (im-munochemiluminometric method) levels were recorded.Liver biopsy was performed in patients 1, 2, and 4. Biopsies

were taken under general anesthesia as a wedge biopsy in 2patients and as a Tru-cut needle biopsy in 1 patient. The sam-ples were stained with hematoxylin-eosin. Histologically,fibrosis was estimated on a 4-step METAVIR scale.11 Liverhemosiderosis was graded 0-4, grade 0 corresponding to nohemosiderin and grade 4, heavy hemosiderosis.12 Liver ironcontent (LIC) was evaluated by a flame photometric methodand expressed as mg Fe/g of liver dry weight.

CHH patients

cy)

Othercomplications

Hb atbirth BM

ErythropoietinU/L (reference

5.4-21.8)

- 34 Severe pure erythroidhypoplasia, megaloblastic

Poor erythroid growth andgeneral stem cell growth

1468

BPD 86 Severe pure erythroidhypoplasia, megaloblastic

Poor erythroid growth

1200

e- 79 Severe pure erythroid

hypoplasiaPoor erythroid growth

1405

Severe Hirschsprung,parental nutrition,colectomy

153 Mild to severe pureerythroid hypoplasia

Poor erythroid growth

2820

845

THE JOURNAL OF PEDIATRICS � www.jpeds.com Vol. 162, No. 4

Since 2008, magnetic resonance imaging (MRI) T2* relax-ation time measurement of LIC has been available in our in-stitution. TheMRI examinations were performed with a 1.5TMRI (Philips Achieva, Best, Holland).13 Themethod includesscanning of a single 10mm-thick liver slice at several differentecho times (1.083-27.680 ms) with a gradient-echo sequence.T2* relaxation time is then calculated from the exponentialdecay curve derived from these measurements in differentecho times. MRI T2* relaxation times <6.3 ms and <1.4 msrepresent iron content of 2 mg/g and >10 mg/g liver dryweight, respectively.13

A real-time B-mode ultrasound imager (Vivid 7; GEVingmed AS, Horten, Norway) was used to quantify the ejec-tion fraction as a measure of cardiac contractility.

Iron ChelationDue to compliance issues, perioral chelator was the firstchoice in 3 patients. Deferiprone was used in 2 patientswith a target dose of 75 mg/kg, and deferasirox in 1 patientat 20 mg/kg. Desferrioxamine at 20 mg/kg as an 8- to 12-hour subcutaneous infusion 5-7 nights per week wasprescribed for 3 patients to intensify chelation. Vitamin Csubstitution was used during desferrioxamine therapy. Afterplasma ferritin decreased to less than 500 mg/L, iron chelationwas continued with deferasirox.

Statistical AnalysesSPSS software (IBM, New York, New York) was used for sta-tistical analyses. The biomarkers of iron overload are ex-pressed as mean values. The change in plasma ferritin,ALAT, and daily iron accumulation during iron chelationtherapy was tested by paired t test.

Results

Iron Overload at the Onset of Chelation TherapyPatients 1, 2, and 4 were splenectomized to decrease RBCtransfusion dependency; the median number of transfusionsper patient during the preceding and following year was 19

Table II. Clinical characteristics of the CHH patients on iron

PatientRBC

transfusionsxIron overload/total (mg)

Iron accumulation(mg Fe/kg/d)

Ferritinmg/L

LIC mg/dry weig

1 151 8200 0.38 6240 30

2 83 1400 0,41 2445 24

3 37 800 0.37 1217 -

4 123 8160 0.25 1401 6.6

*Chelators in order of introduction.**Deferiprone partly combined with desferrioxamine.+Continuing.++At start of chelation.xTotal number of RBC transfusions at the start of chelation.

846

and 17 (non-significant). Patient 2 had 3 septicemias aftersplenectomy. All the patients had severe iron overload(Table II). At the introduction of iron chelation, thenumber of transfusions was on average 99, the cumulativeiron overload 4640 mg, and the annual iron accumulation0.35 mg/kg/d; the mean plasma ferritin was 2896 mg/L(Table II). Three patients underwent liver biopsy; themean LIC was 20.0 mg/g liver dry weight. Histologically,the estimated median iron overload was grade 4 (2-4) andthe median grade of fibrosis 2 (0-2). In 1 patient, ironoverload was estimated with T2* MRI; her T2* relaxationwas <2 ms, corresponding to severe iron overload.

Efficacy of Iron ChelationDesferrioxamine and peroral deferiprone chelation, partlycombined, were used in 3 patients and perioral deferasiroxin all 4 patients (Table II). The median age at onset was5.8 years (range 2.3-10.4) and the median total duration5.1 years (0.8-7.7). The patient with Hirschsprung diseaseand daily parenteral nutrition did not tolerate any of thechelators and his chelation therapy was fragmented,totaling 0.8 yrs. In patients with continuous chelation thedaily accumulation of excess iron decreased on average by0.11 mg Fe/kg/d (P = .055) (Figure 1). The mean decreasein plasma ferritin and amino transferase were 3070 mg/L(P = .182) and 128 U/L (P = .084) (Figure 1). The ejectionfraction in 2 patients with continuous chelation showeda mean improvement of 10% (P = .20). In addition, therelaxation time in the T2* MRI increased as a sign ofdecreased iron overload despite continuous transfusiondependency. The median relaxation time in the threepatients with successful chelation increased from 2 (range2-4) ms to 10 (range 4-12) ms over a median time of 2.3years (P = .075).

Adverse Effects and Associated EndocrinopathiesPatient 3 had a transient increase in serum creatinine whendeferasirox therapy started. Patient 1 had painful arthropathywhile on deferiprone at the beginning of iron chelation, but

chelation and details of the iron chelation therapy

ght

T2* relaxationtime (ms)++ Chelator*

Dosage(mg/kg) Duration

Adverseeffect

1. Deferiprone** 30 1.5 y Arthritis2.Desferrioxamine 30 5.0 y None3. Deferasirox 20 7 mo+ None1. Deferiprone** 70 2.8 y None2. Desferrioxamine 20 2.9 y None3. Deferasirox 20 2.9 y+ None

<2 1. Deferasirox 20 2.6 y+ Elevated creatinine

1. Desferrioxamine 20 2 mo Severecholestasis

2. Deferasirox 7 2 mo Diarrhea3. Deferiprone 20 6 mo Diarrhea

Taskinen et al

Figure 1. Plasma ALAT, serum ferritin, and cumulative iron overload per day in the 3 patients with CHH with continuous ironchelation. The start of chelation therapy is indicated by time point 0 and the vertical dashed line; the negative values indicate timepreceding the therapy and the positive values indicate time after onset of the therapy. Fe, iron.

April 2013 ORIGINAL ARTICLES

later deferiprone could be reintroduced during desferriox-amine chelation. The patient with severe Hirschsprungdisease did not tolerate any of the chelators. He had severecholestatic episode while on desferrioxamine therapy, anduncontrollable diarrhea during deferiprone on deferasiroxtherapy. None of the patients developed decreasing neutro-phil counts, autoantibodies, or zinc deficiency. The patientswere significantly shorter at birth than the general CHHpopulation (median birth length �6.6 vs �3.0 SDS,P = .029).14 During chelation, 2 patients showed stablegrowth but the patient with the heaviest iron overload hadprogressive deterioration of growth, compared with the gen-eral CHH population (Figure 2). Growth hormone (GH)deficiency was diagnosed and GH therapy started in patient2. In patients 1 and 4, GH deficiency was excluded, but GHtherapy was introduced to stimulate erythropoiesis, asprevious observations have suggested that in CHH, anemia

Figure 2. Growth curves (open circles) of the 3 patients with CHindicate the median height (in SD units) in the general CHH popuduration of the therapy is indicated above the growth curves. Thevertical dashed line; the negative values indicate time preceding tthe therapy.

Hypoplastic Anemia in Cartilage-Hair Hypoplasia—Balancing bet

is related to the insulin growth factor-I system.15 However,the number of RBC transfusions remained unaltered andno marked improvement in growth occurred. None of thepatients has developed diabetes or hypoparathyroidism;patient 4 is treated for hypothyroidism. Patients 1 and 4have delayed puberty and subnormal gonadotropinresponse in gonadotrophin-releasing hormone testing,confirming hypogonadotropic hypogonadism. Patient 2 hascommenced estrogen therapy to induce puberty.

Discussion

Anemia in CHH may be associated with an intensivetransfusion-dependency requiring iron chelation at an earlyage. However, in rare diseases such as CHH, the experienceon the use of new drugs and even drug groups is accumulat-ing painfully slowly. In our patients, iron overload had

H with continuous iron chelation. The lines with black circleslation at each age.13 GH therapy was used in 2 patients andstart of chelation therapy is indicated by time point 0 and thehe therapy and the positive values indicate time after onset of

ween Iron Overload and Chelation 847

THE JOURNAL OF PEDIATRICS � www.jpeds.com Vol. 162, No. 4

reached a substantially high level before the introduction ofiron chelation. The multiplicity of comorbidities has led tocautious introduction and low dosing of chelating agents.In fact, our patients had more severe growth failure sincebirth than the average CHH population and infrequentcomorbidities, including combined immune deficiency andtotal colon Hirschsprung disease, but all were homozygousfor the major 70A > G mutation in RMRP and otherwisehad no features predicting the development of severe ane-mia.2,8,14 The findings of the present study show that ironchelation can be performed successfully and safely in patientswith CHH. However, patients with Hirschsprung diseasemay be more prone to complications.

Iron excess may be caused by repeated blood transfusionsor increased gastrointestinal iron absorption. Severe transfu-sion dependency in our patients led to an extensive ironaccumulation comparable to thalassemia major patients.16

The activity of gastrointestinal iron absorption in patientswith CHH and anemia is not known. Ineffective erythropoi-esis, anemia, and hypoxia increase gastrointestinal ironabsorption, as is seen in thalassemia syndromes.17 Erythro-poietin has recently been shown to participate in the processby directly promoting enterocytic iron absorption.18 Our pa-tients’ erythropoietin levels were supranormal (Table I) and,thus, the gastrointestinal route may also be involved in ironaccumulation.

The most typical adverse effects associated with desferriox-amine are mild local reactions with skin itching and indura-tion; with higher dosing, growth retardation or sensoryneural disturbances, such as tinnitus or retinal toxicity maybe seen.16 Painful swelling of the joints, mild zinc deficiencyand, infrequently, agranulocytosis are the adverse effectsassociated with deferiprone therapy.16 The most commonadverse effects in patients on deferasirox have been gastroin-testinal or transient increase in serum creatinine.19 Patientswith CHH did not differ from the other patient groups in fre-quency or severity of the adverse effects.

In thalassemia major, iron overload is frequently associ-ated with growth delay and endocrinopathies.16 The harmfuleffect of excess iron on growth was also seen in our patientswith transfusion-dependent CHH (Figure 2). Manyiron chelation-induced endocrine complications can beameliorated, but short stature may persist.20,21 Potentialchelation-related growth retardation is a major concern inthis group of patients with anticipated adult heights of 110-140 cm.2 Desferrioxamine therapy is most likely relate togrowth abnormality if chelation starts before age 3 yearsand doses exceed 40 mg/kg/d.22,23 In our series, only thepatient with the highest iron overload had a progressivedeceleration of growth, starting already before introductionof iron chelators, and the 2 other patients continued togrow steadily during 2.6-7.6 y of chelation. It is possiblethat early introduction of chelation could improve growthin patients with CHH and iron overload.

Two patients had hypogonadotropic hypogonadism and 1also had hypothyroidism. These endocrinopathies are notcharacteristic to CHH, but to iron overload, which may also

848

cause diabetes and hypoparathyroidism.16,20,21 Susceptibilityto endocrinopathies varies in different transfusion-dependent anemias.With similar degree of iron accumulation,thalassemiamajor patientsweremore prone than patients withtransfusion-dependent sickle-cell anemia to present withgrowth failure (33% vs 2%), hypogonadism (40% vs 4%), hy-pothyroidism (10% vs 2%), and diabetes (13% vs 2%).20 Theduration of chronic transfusions was the most significant pre-dictor for endocrine dysfunction.20 Our series is small, but itseems that our patients were, with lower serum ferritin levelsand shorter duration of transfusion therapy, as susceptible toendocrinopathies as thalassemia patients.20 Early introductionof chelation is recommended in CHH because chelation ther-apy aims to prevent endocrine effects of iron accumulation.To decrease the intensity of iron accumulation, 3 of our

patients were splenectomized. The need for transfusionsdid not change, and in 1 patient splenectomy led to multiplesepticemias. Furthermore, splenectomy may increase the rateof gastrointestinal iron absorption.24 Thus, we do not recom-mend splenectomy for patients with CHH and anemia.Allogeneic hematopoietic stem cell transplantation

(HSCT) is an effective treatment for the immunodeficiencyin CHH, but severe infections, major organ damage, or ma-lignancies may jeopardize the outcome.25 Five of the 16 pa-tients with CHH transplanted for severe immunodeficiencyalso had BM failure, and in all these patients, HSCT restoredBM function and cellularity.25 Allogeneic HSCT should, thus,be considered in patients with CHH and continuous transfu-sion dependency.10 However, the decision should be delayeduntil after age 2 years, as spontaneous recovery may occur.9,26

We conclude that in CHH, iron chelation is successful andthe adverse effects are similar to those in other transfusion-dependent patient groups. Consequently, iron chelationshould not be delayed in patients with CHH with heavytransfusion dependency. Successful chelation will preparefor HSCT in patients with CHH with persistent transfusiondependency. n

Submitted for publication May 28, 2012; last revision received Aug 21, 2012;

accepted Sep 26, 2012.

Reprint requests: Mervi Taskinen, MD, PhD, Department of Pediatric

Hematology, Oncology, and Stem Cell Transplantation, Children’s Hospital,

Helsinki University Central Hospital, P.O. Box 281, FIN-00029 HUS, Helsinki,

Finland. E-mail: mervi.taskinen@hus.fi

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ween Iron Overload and Chelation 849