Too short stature, too many stigmata

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Too short stature, too many stigmata
  Rare disease Too short stature, too many stigmata Lydia Kossiva, 1 George Vartzelis, 1 Marieta Harisi, 2 Ioanna Logotheti, 1 Anastasia Garoufi 1 1 Second Department of Pediatrics,  ‘ P&A Kyriakou ’  Children ’ s Hospital, Athens University, Athens, Greece 2 Laboratory of Hematology,  ‘ P&A Kyriakou ’  Children ’ s Hospital, Athens University, Athens, Greece Correspondence to  Lydia Kossiva; Summary Dyskeratosis congenita (DC) is a rare disease characterised by bone marrow failure and skin manifestations. Patients with DC may exhibit shortstature that is not usually related to growth hormone (GH) deficiency. Replacement treatment with GH should be done cautiously as it can pre-dispose to haematological malignancy. We present a 10-year-old boy with DC and GH deficiency. BACKGROUND Dyskeratosis congenita (DC) is a very rare bone marrowfailure syndrome with special characteristics and predispo-sition to malignancies. Due to its rarity, DC often remainsundiagnosed during childhood with patients suffering a lotof ‘medical abuse’. Short stature in these patients is consid-ered idiopathic. In our patient, short stature was attributedto primary growth hormone (GH) deficiency and hereceived replacement treatment. This treatment is off-labelin cases of DC and might lead to evolution of haematologi-cal malignancy. All these considerations are presented anddiscussed in our case in order to increase the degree of sus-picion among paediatricians when facing a patient withmorphological stigmata, short stature and abnormal hae-matological findings CASE PRESENTATION Short stature is a common paediatric problem affectingapproximately 2% of children. Some of these children mayhave a GH deficiency while others do not meet the criteriaforreplacementtreatment.Itisveryimportantwhenevalu-ating a child with short stature to take into account signifi-cant findings from the clinical examination such asonychodystrophy, leucoplakia and abnormal skin pigmen-tationoftheskin.Alltheaboveincombinationwithabnor-mal haematological findings may indicate the presence of DC. In these cases, replacement treatment with GH, evenwhen meeting the relevant criteria, should be done verycautiously because of the potential risk of developing hae-matological malignancy. The aim of this presentation is toheighten the degree of suspicion among all paediatric spe-cialties when facing a child with short stature.We report on a 10-year-old boy who attended the emer-gency department because of an acute gastroenteritis withbloody stools lasting for 3 days.Routine laboratory investigation: complete blood count(white blood cell count 4×10 3 /μl, Neutrophils (N) 51%,Lymphocytes (LY) 33%, Monocytes (Mo) 15%, haemoglo-bin 11 g/dl, haematocrit 32.3%, mean corpuscular volume94.9 fl, mean corpuscular haemoglobin 32.4 pg, mean cor-puscular haemoglobin concentration 34.1 g/dl, platelets88×10 3 /μl), biochemistry and coagulation screening werenormal. Detailed physical examination revealed short stat-ure (126 cm, below 3rd percentile), low weight (24 kg,below 3 percentile), head circumference (50 cm, below 3rdpercentile), leucoplakia of the tongue and the buccalmucosa, bilateral blepharitis, abnormal skin pigmentationoftheupperhalfofthetrunkandonychodystrophyofbothupper and lower extremities.The patient is the first child of non-consanguineoushealthyparentsofGreekorigin.Hewasbornfulltermwitha relatively low birth weight (2500 g). The perinatal periodwas uneventful. At the age of 2 years he exhibited leuco-plakia of the tongue and onychodystrophy. Biopsy of orallesions revealed traumatic ulcer and no further evaluationwas suggested. Abnormal skin pigmentation of the upperhalfofthetrunkwasaddedattheageof6years.Atthatage,because of short stature, the boy underwent detailed endo-crinologicalevaluationandGHdeficiencywasrevealed.Hewas placed on treatment with GH (4 mg subcutaneouslyweekly) until the time he came to our attention.Withtheworkingdiagnosisofaninheritedbonemarrowfailure syndrome he was admitted to our clinic for furtherevaluation. INVESTIGATIONSExtended laboratory investigation Immunoglobulins, subclasses and C3, C4 were within nor-mal values for his age. Bone marrow aspirate and trephinebiopsy revealed decreased cellularity with increased lipoidinfiltration. Bone marrow karyotypic analysis was normal(46, XY). Anaemia Fanconi study was negative. Immu-nophenotype of peripheral blood revealed a decrease in Blymphocytes and T helper lymphocytes and a decreasedCD4/CD8 ratio. The above findings were frequentlyreported in cases of DC. Imaging studies Ultrasound of the abdomen, brain MRI, chest x-ray andendoscopicevaluationofthedigestivesystemwerenormal.The diagnosis of DC was confirmed by molecular study.Ourpatientwasfoundtobeheterozygousofthec.1058C/T 1 of 3  BMJ Case Reports  2010; doi:10.1136/bcr.06.2010.3087  mutation on the exon 11 of the  DKC1 gene. A new stoma-tological examination did not reveal any signs of malig-nancy at the oral lesions. The treatment with GH wasdiscontinued.Theyoungpatientrecoveredcompletelyfromthegastro-enteritis2daysafterhisadmissionwithnopathogenfoundinthestoolcultures.Hewasplacedonregularhaematologi-cal follow-up every 3 months and bone marrow aspirationevery year. His condition, 1 year after the diagnosis of DC,is stable. The optimal treatment for the bone marrow fail-ure is bone marrow transplantation. We examined hisyounger brother who was human leucocyte antigen (HLA)matched and his molecular analysis did not reveal the  DKC1  mutation. He was considered to be the ideal bonemarrow donor. TREATMENT Our patient underwent a successful transplantation 1 yearafter diagnosis. OUTCOME AND FOLLOW-UP Three months after transplantation, the patient is in goodclinical condition under treatment with cyclosporine andtrimethoprime-sulfamethoxazole. DISCUSSION Theinheritedbonemarrowfailuresyndromesmustbecon-sidered in the investigation of patients with aplasticanaemiaorcytopenia,withorwithoutphysicalstigmata,aswellasinpatientswithyoungonsetofspecifictypesofcan-cers. More than 25% of paediatric patients who presentwith aplastic anaemia have an inherited cause. 1 Diagnosticmolecular tests for inherited bone marrow failure syn-dromes are available.DC is a rare bone marrow failure syndrome with a fre-quency of 1:10 6  people. It is a form of ectodermal dysplasiain which 50% of the patients develop aplastic anaemia.Mostofthephysicalfindingsappearwithageandthisisthereason why DC is under-recognised by paediatricians. Thediagnostic triad includes skin reticulated hyperpigmenta-tion, dystrophic nails, which appear during the first decadeof life, and mucous membrane leucoplakia in the seconddecade. A variety of other (gastrointestinal, ophthalmic,pulmonary, skeletal and dental) abnormalities have alsobeen reported. Among them, short stature is referred as afinding in DC patients and is considered to be idiopathic.Our patient had primary GH deficiency, which was con-firmed by two endocrinological tests (clonidine and glu-cagone). Despite the replacement treatment he gained only22.4 cm over 4 years and he was still under the 3rd percen-tile for his age.DC is principally a disease of defective telomere mainte-nance. All patients with DC have very short telomeres.Mutations have been found in genes that encode compo-nents of the telomerase complex (DKC1, TERC, TERT,NOP10, NHP2) and telomere shelterin complex (TNF2). 2 Telomerase and shelterin protect and process the telom-eres. 3 Genetically, DC is heterogeneous with three formsidentified: X-linked recessive, autosomal dominant andautosomal recessive. Most of the reported cases are maleandthereislinkagetoXq28.DKC1encodesdyskerinandisthemaingeneresponsiblefortheX-linkedrecessiveformof the disease. Autosomal dominant DC is attributed to het-erozygous mutations in the core components of telomerase—namely TERC (the RNA component) andTERT (the enzymatic component). 4 5 The autosomal reces-sive form of DC is caused by biallelic NOP10, NHP2 andTERTmutations.NOP10andNHP2arefoundtobecompo-nents of the small nucleolar ribonucleoprotein particle.Mortality in DC arises from either bone marrow failure orspecificcancersinrelativelyyoungage.Bonemarrowtrans-plantation is the treatment of choice when HLA-matchedsibling donor is available. Some patients may respond toandrogens alone or in combination with granulocytecolony-stimulatingfactor. 1 Beingamonogenicdisorder,DCcould be a suitable candidate for gene therapy in the future.Despite the fact that our patient had the classical triad of DC, the diagnosis was delayed even though he had visitedmany different paediatric subspecialists. The presentationof the above rare bone marrow failure syndrome focusesnotonlyonthepathologicalentityitselfbutalsoonthehighdegreeofsuspicionneededamongallthepaediatriciansandsubspecialists when facing a child with short stature, oralleucoplakia and onychodystrophy. Additionally, currentbibliographic research did not reveal similar case of DCwithshortstatureduetoprimaryGHdeficiency.Theuseof GH in these patients is off-label and could increase the riskof developing leukaemia or myelodysplasic syndromebecauseofthepresenceofGHreceptorsonmyeloidprecur-sors and should be avoided or be very cautious. Learning points ▲ Short stature may be a part of a more complex entitysuch as a bone marrow failure syndrome. ▲ Oral leucoplakia, onychodystrophy andhyperpigmentation should raise suspicion of DC. ▲ Be very cautious when treating a child with GH as theunderlying cause of short stature may not beidiopathic. Competing interests  None. Patient consent  Obtained. REFERENCES 1.  Alter PB.  Diagnosis, genetics, and management of inherited bone marrowfailure syndromes.  Hematology Am Soc Hematol Educ Program  2007:29 – 39.2.  Kirwan M,  Beswick R, Vulliamy T,  et al  . Exogenous TERC alone can enhanceproliferative potential, telomerase activity and telomere length in lymphocytesfrom dyskeratosis congenita patients.  Br J Haematol   2009; 144 :771 – 81.3.  Walne AJ,  Vulliamy T, Beswick R,  et al  . TINF2 mutations result in very shorttelomeres: analysis of a large cohort of patients with dyskeratosis congenitaand related bone marrow failure syndromes.  Blood   2008; 112 :3594 – 600.4.  Vulliamy T,  Marrone A, Goldman F,  et al  . The RNA component of telomeraseis mutated in autosomal dominant dyskeratosis congenita.  Nature 2001; 413 :432 – 5.5.  Armanios M,  Chen JL, Chang YP,  et al  . Haploinsufficiency of telomerasereverse transcriptase leads to anticipation in autosomal dominantdyskeratosis congenita.  Proc Natl Acad Sci USA  2005; 102 :15960 – 4. 2 of 3  BMJ Case Reports  2010; doi:10.1136/bcr.06.2010.3087  This pdf has been created automatically from the final edited text and images.Copyright 2010 BMJ Publishing Group. All rights reserved. For permission to reuse any of this content visit Case Report Fellows may re-use this article for personal use and teaching without any further permission.Please cite this article as follows (you will need to access the article online to obtain the date of publication).Kossiva L, Vartzelis G, Harisi M, Logotheti I, Garoufi A. Too short stature, too many stigmata.  BMJ Case Reports  2010;10.1136/bcr.06.2010.3087, date ofpublicationBecome a Fellow of BMJ Case Reports today and you can: ▲  Submit as many cases as you like ▲  Enjoy fast sympathetic peer review and rapid publication of accepted articles ▲  Access all the published articles ▲  Re-use any of the published material for personal use and teaching without further permissionFor information on Institutional Fellowships contact consortiasales@bmjgroup.comVisit for more articles like this and to become a Fellow3 of 3  BMJ Case Reports  2010; doi:10.1136/bcr.06.2010.3087
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