Syndromic Immunodeficiencies: Genetic Syndromes Associated with Immune Abnormalities

56 Pages·2003·0.45 MB·English

CLS TJ839-03 October23,2003 12:25
CriticalReviewsinClinicalLaboratorySciences,40(6):587–642(2003)
Copyright(cid:2)C 2003TaylorandFrancisInc.
ISSN:1040-8363
DOI:10.1080/10408360390250630
Syndromic Immunodeficiencies:
1 Genetic Syndromes Associated
1
2/
2
9/ with Immune Abnormalities
0
n
o
M
R Jeffrey E. Ming,1E. Richard Stiehm,2and John M. Graham, Jr.3
E
S
N
y I 1DepartmentofPediatrics,DivisionofHumanGeneticsandMolecular
b
m Biology,TheChildren’sHospitalofPhiladelphiaandtheUniversityof
co PennsylvaniaSchoolofMedicine,Philadelphia,Pennsylvania,USA;2UCLA
e.
ar SchoolofMedicine;DivisionofImmunology/Allergy/Rheumatology,
c
h
alt DepartmentofPediatrics,MattelChildren’sHospitalatUCLA,LosAngeles,
he California,USA;3MedicalGeneticsBirthDefectsCenter,Ahmanson
a
m
or DepartmentofPediatrics,StevenSpielbergPediatricResearchCenter,
m infnly. SHARE’sChildDisabilityCenter,UCLAUniversityAffiliatedProgram,
oo InternationalSkeletalDysplasiaRegistry,UCLASchoolofMedicine,
wnloaded frersonal use RCeefedreaer:sD-Sr.CinhaaiimMMe.RdoicifamlanC,eHenatde,rD,ivLiosisonAonfIgmemluenso,loCgyaalinfodrAnlliearg,yU,HSosApitalforSickChildren,Toronto,
op
s DFor ONMSG1X8,Canada
e
c
n
e
ci
y S ABSTRACT: Insyndromicimmunodeficiencies,clinicalfeaturesnotdirectlyassociatedwiththeim-
or munedefectareprominent.Patientsmaypresentwitheitherinfectiouscomplicationsorextra-immune
at
or medicalissues.Inadditiontotheimmunologicabnormality,awiderangeoforgansystemsmaybeaf-
b
La fected.Patientsmaypresentwithdisturbancesinskeletal,neurologic,dermatologic,orgastrointestinal
al functionordevelopment.Theseconditionscanbecausedbydevelopmentalabnormalities,chromoso-
c
Clini malaberrations,metabolicdisorders,orteratogens.Foranumberoftheseconditions,recentadvances
n haveresultedinanenhancedunderstandingoftheirgeneticbasis.Thefindingofimmunedeficitsina
s i numberofdefinedsyndromeswithcongenitalanomaliessuggeststhatanunderlyinggeneticsyndrome
w
vie shouldbeconsideredinthosepatientsinwhomasignificantnon-immunefeatureispresent.
e
R
cal KEYWORDS: immunodeficiency,geneticsyndromes,congenitalanomalies,multiplecongenital
Criti anomalies.
ABBREVIATIONS: AT, Ataxia-telangeictasia; ATM, Gene mutated in AT; CMV, Cytomega-
lovirus; IKK-γ, Gene mutated in incontinentia pigmenti. Also called NEMO; MIM, Mendelian
AddresscorrespondencetoDr.JeffreyE.Ming,M.D.,Ph.D.,DivisionofHumanGeneticsand
MolecularBiology,TheChildren’sHospitalofPhiladelphia,3615CivicCenterBoulevard,Room
1002,Philadelphia,PA19104,USA.E-mail:[email protected]
587
CLS TJ839-03 October23,2003 12:25
InheritanceinMan;NBS,Nijmegenbreakagesyndrome;NBT,Nitro-bluetetrazolium;NK,Natural
killercells;PHA,Phytohemagglutinin;SCID,Severecombinedimmunedeficiency.
I. INTRODUCTION
In most primary immunodeficiencies, frequent infections and complications arising
fromdefectiveimmunefunctionarethepredominantclinicalmanifestations.Mostindivid-
uals will have no phenotypic abnormalities except for immune deficiency. In contrast, in
11 syndromicimmunodeficiencies,abnormalitiesinotherorgansystems,aswellasimmune
22/ defects,occur.Manyoftheseconditionsarerecognizablegeneticsyndromes.1
9/
n 0 In syndromic immunodeficiencies, the immune abnormalities are often ascertained
o
M only after the underlying syndrome has been diagnosed. The immunodeficiency is often
R not the major clinical problem, and the immune defects may be present in only some
E
S
N affectedpatients.Severalgeneticdisorders,suchasWiskott-Aldrichsyndromeandataxia-
y I telangiectasia,mayfitintobothprimaryandsyndromicimmunodeficiencycategories.Such
b
m conditions have characteristic organ dysfunction and/or dysmorphology unrelated to the
o
c
e. immunesystemaswellasaconsistent,well-definedimmunedeficiency.
ar
hc Syndromic immunodeficiencies may occur in combination with several diverse pro-
ealt cesses,includingdefectiveembryogenesis,metabolicderangements,chromosomalabnor-
h
ma malities,orteratogenicdisorders.Recognitionofsyndromesresultingfromsuchprocesses,
m infornly. wsishiacnhdcmananaaffgeecmtbeontth.Itnheadimdimtiounn,eiannfodromthateiroonrrgeagnasrdyisntegmgse,nmesaycrfiaticcialiltfaoterathcecudreavteeldoipamgneon-t
oo
ownloaded frpersonal use odothvfeefietrhscvpeieieenicwncivfiioeocsflvattehshsdeaotcscalyiiarsnettieecadmaslissmmomcmaianauytinefedebsedtwaegtifitaeohicnnrtessed.ca.onIgdnngitezhnaibestlriecepgaoesnrptee,tcwitcsesoydfneedlairncohemasteyesn.sdyWrnoedmrwoemiallnicdpridomevlmiidnueenaaotne-
s DFor Theinheritancepatternofeachconditionandthechromosomallocationofthedisease-
e
c
n related genes, when known, are indicated in the tables. Mendelian Inheritance in Man
e
Sci (MIM)2numbersareindicatedwithinparenthesesinthetext.
y
or
at
or
b II. SYNDROMES ASSOCIATED WITH GROWTH DEFICIENCY
a
L
al
c
ni Severalimmunodeficiencystatesareassociatedwithgrowthdeficiency(Tables1,2).
n Cli Thismaybeduetoaskeletaldysplasia,inwhichthereisanabnormalityofboneformation.
s i Manyskeletaldysplasiasareassociatedwithdisproportionateshortstature(thelimbsand
w
vie trunkarenotproportionaltoeachother).Formsofshortstaturethatarenotassociatedwith
e
R skeletalabnormalitiesusuallyshowproportionategrowthfailure.Inthiscase,theoverall
cal heightissmall,butthevariousbodypartsarecommensuratewithoneanother.
Criti
A. Syndromes Associated with Skeletal Dysplasia
Thedisproportionateshortstaturethatoccurswithimmunodeficiencyoftenaffectsthe
limbsmorethanthetrunk,resultinginshort-limbskeletaldysplasia;thishasbeenreported
in association with either a combined immunodeficiency, predominantly cellular defects,
orprimarilyahumoraldefect.
588 J. E. Ming et al.
CLS TJ839-03 October23,2003 12:25
y
equencofID ++++ ++++ ++++ 2sibs) ++++ ++++++ ++++ 1case) ++++ 1case)++++ 1case)++++ 1case)
r ( ( ( ( (
F
e h
Immundefect T,B T,B B T BT,Ph B T,B,P T,B T,B %.
5
6
ws in Clinical Laboratory Sciences Downloaded from informahealthcare.com by INSERM on 09/22/11For personal use only. ciatedwithgrowthdeficiency:skeletaldysplasias Inheritance(Chromosome)Associatedfeatures ARMetaphysealdysplasia,bowedfemurs;maybeseenwithadenosinedeaminasedeficiencyorOmennsyndrome ARMcKusicktypemetaphysealdysplasia,mildlegbowing,(9p13)fine/sparsehair;varicellaandotherinfections,increasedriskforlymphoma/basalcellcarcinoma?ARMetaphysealdysplasia,recurrentinfectioninmaleandfemalesiblings ARSpondyloepiphysealdysplasia,progressivenephropathy,2q34-q36episodiclymphopenia,pigmentaryskinchanges?XLSpondyloepiphysealdysplasia,retinaldystrophyAD,ARBonemedullarystenosis,myopia,hypocalcemia(1q42-q43) ?Prenatalgrowthdeficiency,ischiadichypoplasia,renaldysfunction,postaxialpolydactyly,hypospadias,respiratoryinfections?ARShortlimbs,bowedfemora ?Meso/rhizomelia,hypoplasticvertebrae,brachydactyly,severecombinedimmunedeficiency?Rhizomelia,hipdislocation,bowedfemora/humeri,congenitalsubglotticstenosis ncy;T:Tcelldefect;B:Bcelldefect;Ph:Phagocytedefect;NK:NKcelldefect.++=+++=++++=>%ofreportedcaseswithdocumentedID;5%–30%;30%–65%;=autosomaldominant;XLX-linked.
Critical Revie TABLE1.Syndromesasso Name 1.Shortlimbskeletaldysplasiawithcombinedimmunedeficiency2.Cartilage-hairhypoplasia 3.Shortlimbskeletaldysplasiawithhumoralimmunedeficiency4.Schimkeimmunoosseousdysplasia5.Roifmansyndrome6.Kenny-Caffeysyndrome/Sanjad-Sakatisyndrome7.Braeggersyndrome 8.MacDermotsyndrome 9.Spondylo-mesomelic-acrodysplasia10.Ramanansyndrome Abbreviations:ID:immunodeficie+=FrequencyofID:lessthan5==ARautosomalrecessive;AD
Syndromic Immunodeficiencies 589
CLS TJ839-03 October23,2003 12:25
y s) d)
FrequencofID ++++ ++++ + ++ + + ++++ (3sibship++++ (1case)++++ (1kindre++++ (3sibs)++++ (1case)
e
mmundefect B T,B T B Ph T T,BPhT,B B,Ph Ph B %.
I 5
6
1 >
1
ws in Clinical Laboratory Sciences Downloaded from informahealthcare.com by INSERM on 09/22/For personal use only. ciatedwithgrowthdeficiency:proportionateshortstature Inheritance(Chromosome)Associatedfeatures XLHypogammaglobulinemia,isolatedgrowthhormone(Xq21-q22)deficiency;sinopulmonaryinfections ?ADPrenatalgrowthdeficiency,microcephaly,smallface,prematureaging,multiplenevi,mentalretardation?Coloboma,heartdefect,atresiachoanae,retardedgrowthanddevelopment,genitalhypoplasia,earanomalies/deafness?ADLongpalpebralfissures,prominenteyelashes,skeletalanomalies,congenitalheartdisease;increasedriskofidiopathicthrombocytopenicpurpuraandautoimmunediseasesARMicrocephaly,eczema,pre/postnatalgrowthdeficiency,respiratory/gastrointestinalinfectionsADBroadthumbsandhalluces,prominentnasalseptumbelow(16p13)alaenasi,cryptorchidism,mentalretardationARAbsentthumbs,anosmia,icthyosiformdermatosis,congenitalheartdefect;candidiasis,varicella?Hypogonadotropichypogonadism,growthhormonedeficiency ?ARPrenatalgrowthdeficiency,cataracts,microcephaly,enamelhypoplasia,mentalretardation;pneumonias?ARDevelopmentaldelay,facialdysmorphism,congenitalheartdisease;pulmonaryinfections?Postnatalgrowthretardation,triphalangealthumbs,hypoplasticfirstmetatarsals,microcephaly ncy;T:Tcelldefect;B:Bcelldefect;Ph:Phagocytedefect;NK:NKcelldefect.++=+++=++++=%ofreportedcaseswithdocumentedID;5%–30%;30%–65%;=autosomaldominant;XLX-linked.
Critical Revie TABLE2.Syndromesasso Name 1.X-linkedagammaglobulinemiawithgrowthhormonedeficiency2.Mulvihill-Smithsyndrome3.CHARGEassociation 4.Kabukisyndrome 5.Dubowitzsyndrome 6.Rubinstein-Taybisyndrome7.Shokeirsyndrome 8.Sutorsyndrome 9.Toriellosyndrome 10.Stollsyndrome 11.Hoffmansyndrome Abbreviations:ID:immunodeficie+=FrequencyofID:lessthan5==ARautosomalrecessive;AD
590 J. E. Ming et al.
CLS TJ839-03 October23,2003 12:25
1. Short-Limb Skeletal Dysplasia with Combined
Immunodeficiency (MIM 200900)
The conditions in which short-limb skeletal dysplasia is associated with combined
immunodeficiencyareetiologicallyheterogeneous.3 Whilesomepatientshaveadenosine
deaminasedeficiency(seeMetabolicConditionssection),othershavemoreseveremetaphy-
seal changesthan typically foundin adenosine deaminase deficiency. Short-limb skeletal
dysplasia may also be seen in association with Omenn syndrome, a fatal disorder char-
1 acterized by eosinophilia, skin eruptions, and reticuloendotheliosis4–6 (see the section on
1
2/ dermatologicaldisordersforadditionaldiscussionofOmennsyndrome).
2
9/
0
n
o
M 2. Cartilage-Hair Hypoplasia (MIM 250250)
R
E
S
N Cartilage-hair hypoplasia (CHH) was first described in the Amish population7 and
y I
b has subsequently been reported in the Finnish population and other ethnic groups. The
m
o conditionischaracterizedbyshort-limbdwarfism,finesparsehair,andacellularimmune
c
are. defect. Metaphyseal dysplasia (flared, scalloped, and sclerotic metaphyseal ends) most
c
h frequently affects the lower extremities. There is significant variability in the phenotype.
alt
e Someindividualshavenormalhairandmayhavenormalimmunefunction.Anincreased
h
a
m risk for cancer, especially non-Hodgkin’s lymphoma and basal cell carcinoma, has been
or
m infnly. notedC.e8lAlunlaermimiamisuonfitteynisprpersimenatrailnydacffaenctbeedsaenvderies.9characterizedbymildtomoderatelym-
oo
wnloaded frersonal use pewrhaaostipopenrneisiane,nrdteeiscnproe8na8ss%eedtoodfepalhasyyeteroidehsceumotfaaFngiegnolnuuitssinhhinpyap(tePireHsneAtns.s)9.i1tF0iviIiftmtyyp-rsaeiixsrpepodenriscneesvn,ittarhnoaddcdeinlelccurrleeaaarssieemddmrpirusoknliiotfy-f
es DoFor p isnefveecrtailopna,taienndts6.%Hudmieodraolfimprmimunareydienffeecctstihoanvs.eFbaeteanlnvoatreicdeilnla3i5n%fecotfiopnatiheanstsbaenednmnoatyeadlsino
c
en contributetotheincreasedsusceptibilitytoinfection.11
ci
S MutationsinthegeneencodingtheRNAcomponentofmitochondrialRNA-processing
y
or endoribonuclease(RMRP)havebeendetected.12MRPisinvolvedinnucleolarprocessing
at
or ofribosomalRNAandinmitochondrialDNAsynthesis.Mutationswerealsodetectedin
b
a
L patientswithmetaphysealdysplasiasimilartoCHH,butlackinghairanomalies,immun-
cal odeficiency,andothernon-skeletalfeatures.13
ni
Cli
n
s i 3. Short-Limb Skeletal Dysplasia with Humoral Immune Defect
w
e
vi
e
R Thisprimaryimmunodeficiencywasdescribedintwosiblingswithmetaphysealdysos-
al
Critic tsoosmisewanhdatlodwecIrgeGas,eIdg,AT,acneldlInguMmbleevrse,lsr.e1s4pAonltsheotuoghPHT-Ac,elalnpdrodleilfaeyraetdiocnuttoanaelolouasnhtiygpeenrswenas-
sitivitytestswerenormal.
4. Schimke Immunoosseous Dysplasia (MIM 242900)
The principal features of this autosomal recessive syndrome are short stature with
exaggerated lumbar lordosis, spondyloepiphyseal dysplasia, defective cellular immunity,
Syndromic Immunodeficiencies 591
CLS TJ839-03 October23,2003 12:25
and progressive renal failure.15,16 A broad and low nasal bridge with a bulbous nasal tip
ischaracteristic,andhyperpigmentedmaculesarefrequentlypresent.Thevertebralbodies
are usually ovoid, and epiphyseal changes are most frequently present in the proximal
femur.Patientsdevelopproteinuria,usuallyduetofocalsegmentalglomerulosclerosis,and
frequently progress to end-stage renal disease. Approximately 50% have an arteriopathy
withcerebralinfarctsand/orischemia.Elevatedthyroidstimulatinghormonelevelispresent
in approximately one-half of patients, although T3 and T4 levels are generally normal.
Nearlyallpatientshavenormalintellectualandneurologicaldevelopment.Mutationsinthe
geneencodingthechromatinremodelingproteinSMARCAL1(SWI/SNF2-relatedmatrix-
1
1
2/ associated,actin-dependentregulatorofchromatin,subfamilya-like1)havebeendetected
2
9/ inaffectedpatients.17TheproteinparticipatesinDNA-nucleosomerestructuringthatoccurs
0
on duringgeneregulationandDNAreplicationandrecombination.
M
Patients are prone to viral and bacterial infections and all patients demonstrate
R
SE T-celldeficiencywithdecreasedCD4+ number.18,19 Mitogen-inducedT-cellproliferation
N
y I isimpaired,anddelayedcutaneoushypersensitivityresponsesareabsent.Lymphopeniais
m b characteristic,andimmunoglobulinlevelsareabnormalintwo-thirds,althoughtheabsolute
co B-cell(CD19+)countsarenormal.16
e.
ar
c
h
alt 5. Roifman Syndrome (MIM 300258)
e
h
a
m
or Fiveboysfromfourfamilieshadmicrocephaly,growthretardation,spondyloepiphyseal
m infnly. dysplasia,developmentaldelay,andretinaldystrophy.20,21 Theyhadlow/absentantibody
ownloaded fropersonal use o wrtsieptepeorornesrsteeienpdtiorppeShastytpaisoepennhatsylseldohytcaosovpicenlcabfuseeiscaetaniouofmrnet,ahuldesee,ChcXiropew-salisaanennkddAeidl.sooTrnehgcceeemblsolsannigvuegesmluianbtnihendreiravninesta,drntaefcnubednrahcdltaieasocnnbroeewmaesneaerlsedieunsmgo.girBetmosegtaceelad.nu.Tischeeraerle-l
s DFor
e
c
n
e
ci 6. Kenny-Caffey Syndrome (MIM 127000, 244460)/Sanjad-Sakati
S
ory Syndrome (MIM 241410)
at
or
b
La Cortical thickening of long bones with medullary stenosis, growth deficiency, hy-
al poparathyroidism, facial dysmorphism, and ophthalmologic anomalies occur in Kenny-
c
Clini Caffey syndrome. Both autosomal recessive (type 1) and autosomal dominant (type 2)
n forms have been described. Neutropenia, decreased T cell number and function, and im-
ws i pairedneutrophilphagocytosishavebeennoted.22,23Fouraffectedsibsinaconsanguineous
e
vi kindred had a deletion of 22q11.22 However, other affected individuals do not have this
e
R
al deletion. The Sanjad-Sakati syndrome, also termed the hypoparathyroidism-retardation-
c
Criti Kdyesnmnyo-rCphaifsfmey(sHyRndDr)osmyendarnodmSe,ahnajasds-iSgankifiatciasnytncdlirnoimcaeloavreerdlaupe.Btootmhuatuattoiosnosmianlrtehceesgseinvee
encodingtubulin-specificchaperoneE(TBCE).24
7. Other Syndromes with Disproportionate Short Stature
In Braegger syndrome (MIM 243340), intrauterine growth deficiency, ischiadic hy-
poplasia,microcephaly,renaldysfunction,cryptorchidism,andpost-axialpolydactylywere
592 J. E. Ming et al.
CLS TJ839-03 October23,2003 12:25
presentinaboyofconsanguineousparents.25 Hehadmultiplerespiratoryinfections,de-
creasedIgGandIgM,andundetectableIgA,isohemagglutinins,andanti-diphtheriaanti-
bodies. In MacDermot syndrome, a patient with proximal shortening of the extremities,
andbowingofthefemorahadneutropeniaandundetectableIgG2andIgA.26NomatureB
cellsweredetected.CD4+Tcellnumberandproliferativeresponsesweredecreased.Agirl
withspondylo-acrodysplasia,mildshort-limbdwarfism,andjointdislocationshadsevere
combined immunodeficiency.27 A syndrome of short limb rhizomelic skeletal dysplasia,
bowedfemoraandhumeri,andcongenitalsubglotticstenosiswasdescribedinassociation
withcombinedimmunodeficiencyinaboy.28
1
1
2/
2
9/
0
on B. Syndromes Associated with Proportionate Short Stature
M
R
E
S 1. Growth Hormone Deficiency with X-Linked
N
y I Agammaglobulinemia (MIM 307200)
b
m
o
e.c Individuals affected with growth hormone deficiency (GHD) have recurrent sinopul-
ar
c monary infections, short stature, and decreased growth hormone levels without other en-
h
alt docrinologicabnormalities.29 BothBcellnumberandimmunoglobulinlevelsaregreatly
e
h
a decreasedorabsent,consistentwithX-linkedagammaglobulinemia(XLA).Tcellnumber
m
or andfunctionarenormal.Intwopatients,apointmutationleadingtoprematuretermination
m infnly. oftheproteinhasbeendetectedinBTK,thegeneassociatedwithXLA.30,31Anotherpatient
ownloaded fropersonal use o dcdoeidtmenrbAmointdiehdndaietviioefimnaBamTmlKuuinmtiaosmtdigoeuenfinnceienireadntlhecleyfye,ci3cno3tv,sd3o4inlrvgedepsedoecriqrtneueadeXsneLcidnAeo/nGafasHBtsuoTDrcKa.ila.3t2ikoiFnlluerrwthiecthrelsltiuso(dNliaeKtse)wdialGcltbHiveDintye,ie3n5dcelduandtode
s DFor hypogammaglobulinemia.36 However,thevastmajorityofchildrenwithGHDdonotdis-
nce playanincreasedsusceptibilitytoinfection.37,38
e
ci
S
y
or
orat 2. Mulvihill-Smith Syndrome (MIM 176690)
b
a
L
cal Thisdisorderischaracterizedbypre-andpostnatalgrowthretardation,multiplepig-
ni
Cli mentednevi,microcephaly,reducedfacialfat,genitourinaryanomalies,andahigh-pitched
n voice.39,40 Infectiouscomplicationsarecommonandtheimmunedeficiencyisoftenpro-
s i
w gressive.TherecanbeimpairedTcellresponsetomitogen,decreasedCD4count,and/or
e
vi lowimmunoglobulinlevels.40–42
e
R
al
c
Criti
3. CHARGE Association (MIM 214800)
TheabnormalitiesthatcomprisetheCHARGEassociationincludecoloboma,heartde-
fects,atresiaofthechoanae,retardationofgrowthanddevelopment,genitalhypoplasia,and
earanomaliesand/ordeafness.43–45Thisacronymdenotesthatthisclusteringofanomalies
occurs together more frequently than would be expected by chance. The etiology for the
association between these defects is currently unknown and may be heterogeneous. This
Syndromic Immunodeficiencies 593
CLS TJ839-03 October23,2003 12:25
conceptshouldbepreservedsinceawidevarietyofdifferentchromosomalrearrangements
havebeenreportedinanumberofindividualcasereportsofCHARGEassociation.
Incomparison,CHARGEsyndromereferstoamultipleanomalysyndromewithanas
yet undetermined but specific genetic basis.44 In this syndrome, asymmetric facial palsy,
esophageal or laryngeal abnormalities, renal malformations, and facial clefts are present.
Neonatal brainstem dysfunction requiring complex management often necessitates naso-
gastricand/orgastrostomyfeeding,Nissenfundoplication,andtracheostomy.Completeor
partialsemicircularcanalhypoplasiawithdiminishednumbersofcochlearturns(Mondini
defect) have also been noted on temporal bone CT scans, along with specific facial dys-
1
2/1 morphicfeatures.Majordiagnosticcriteriaconsistofthosefindingsthatoccurcommonly
2
9/ inCHARGE,butarerelativelyrareinotherconditions:coloboma,choanalatresia,cranial
0
n nerveinvolvement(particularlyasymmetricfacialpalsyandneurogenicswallowingprob-
o
M lems),andcharacteristicearabnormalities.Minordiagnosticcriteriaoccurlessfrequently
R
E (or are less specific for CHARGE) and include heart defects, genital hypoplasia, orofa-
S
y IN cialclefting,tracheo-esophagealfistula,shortstature,anddevelopmentaldelay.46 Insome
m b families,thereisacleargeneticcomponent,withparent-to-childtransmissionsuggesting
co autosomal dominant inheritance, and recurrences among siblings born to normal parents
are. suggesting possible germ cell line mosaicism.46 There has been concordance in affected
c
alth monozygotictwins,discordanceindizygotictwins,andstatisticallyadvancedpaternalage
he amongsporadiccasesofCHARGE,withpaternalageof34yearsorgreaternotedin43%of
a
m cases.44,46 Nowell-documentedcasesofCHARGEsyndromehavehadadetectablechro-
or
om infonly. mveolosocamrdeiaonfaocmiaallysyonrdarosmubem/DiicGroesocrogpeicseFqIuSeHncdee)l,e7tiqo3n6o(fm2u2tqa1ti1on(sdeinletSioonnsicaHsseodcgiaetheodgwciathn
wnloaded frersonal use b(amreeupctroaetnsisoeinnststeiinnntpwPaAittiXhe2natdsareweveiatlhsospocmhcioeaantnetadallwdaetirftehesctithaienwvrioetlhnvaioln-rgcwocleiotphbhooaumltiachnosyelounprdarrolocsmerenesc)t.e4cp4e,h4l7alslTyc)ho,enotfrreib1au0tutqir2ne5gs
es DoFor p htoadthtehethDiridGaenodrgfeoaunrothmpahlyaraynndgweahloadrcidhenso.4t8haPvaetiaen2t2sqw1i1thdeCleHtiAonRhGaEveabsseoecniadteisocnriwbehdo.4a9lsIon
c
n
e addition,otheraffectedpatientswithDiGeorgesequencebutinwhomthe22q11deletion
ci
y S statuswasnotknownhavebeenreported.43AnotherpatientwithCHARGEassociationhad
ator severecombinedimmunodeficiencyandlackeddetectablethymustissue.50
or
b
a
L
al 4. Kabuki Syndrome (MIM 147920)
c
ni
Cli
n Thissporadicsyndromefeaturesshortstature,congenitalheartdisease,developmental
ws i delay,skeletalanomalies,andcleftpalate.51–53 Thedistinctivefacialfeaturesincludelong
e
vi palpebralfissureswitheversionofthelowerlateraleyelid,prominenteyelashes,andabnor-
e
al R malears.Frequentinfectionsoccurinapproximately60%ofpatients.54 Patientswithhy-
Critic Apougtaomimmmaugnloebhuelimneomlyitaic,ianncelumdiianganddecirdeiaospeadthIgicGthanrodmvberoycylotwopIegnAic,hpauvrepubreaenharevpeoarltseod.b54e–e5n7
reported57–59andmayreflecttheunderlyingimmunedysfunction.
5. Dubowitz Syndrome (MIM 223370)
Thisautosomalrecessiveconditionischaracterizedbypre-andpostnatalgrowthde-
ficiency, mental retardation, microcephaly, sparse hair, eczema, and dysmorphic facies
594 J. E. Ming et al.
CLS TJ839-03 October23,2003 12:25
(ptosis, short palpebral fissures with lateral telecanthus and dysplastic ears). Respiratory
andgastrointestinalinfectionsarecommon.Granulocytopeniaduetobonemarrowfailure
hasbeenreported,60andhyper-IgEsyndromewasreportedinonepatient.61
6. Rubinstein-Taybi Syndrome (MIM 180849)
Rubinstein-Taybisyndromeischaracterizedbybroadthumbsandgreattoes,charac-
teristicfacialfeatures,shortstature,mentalretardation,andcardiacabnormalities,aswell
1 asanincreasedsusceptibilitytoinfection.DecreasedTcellnumber,impaireddelayedcu-
1
22/ taneoushypersensitivityresponse,62lymphopenia,thymichypoplasia,63andpoorresponse
09/ topneumococcalvaccine64havebeenreported.Microdeletionsandtruncatingmutationsin
M on thegeneencodingCREB-bindingprotein(CBP)havebeendetected.65,66
R
E
S
N 7. Shokeir Syndrome (MIM 274190)
y I
b
m
o Nine individuals from three sibships had absent thumbs, proportionate short stature,
c
are. anosmia,andichthyosiformdermatosis.67Onekindredshowedcardiacdefects.Therewas
c
alth an increased susceptibility to infections, especially mucocutaneous candidiasis and vari-
he cella.Someindividualshaddecreasedimmunoglobulinlevels,anddecreasedorabsentIgA
a
m was the most constant feature. Decreased T cell response to PHA and neutropenia were
or
m infnly. plarseeselenvteinlsawlleirnednivoirdmuaall.sstudied.Adenosinedeaminaseandpurinenucleosidephosphory-
oo
wnloaded frersonal use 8. Other Syndromes with Proportionate Short Stature
op
s DFor InSutorsyndrome,awomanwithrecurrentviral,fungal,andbacterialinfectionshad
e
nc hypogonadotropic hypogonadism and growth hormone deficiency.68 T cell number and
e
Sci function were decreased, and hypogammaglobulinemia was present. Toriello syndrome
y
or (MIM 251190) was reported in two sisters with intrauterine growth deficiency, cataracts,
orat microcephaly, mental retardation, and enamel hypoplasia.69 The older girl died of pneu-
b
a moniaatage5years.TheyhaddecreasedIgMandIgGlevelsandneutropeniaduringin-
L
al fections.InStollsyndrome(MIM601347),developmentaldelay,congenitalheartdisease,
c
Clini vesicoureteral reflux, and facial dysmorphism (prominent forehead, short philtrum, mid-
n facehypoplasia),andfrequentseverepulmonaryinfectionsandneutropeniawerepresent
ws i inthreesibsoffirstcousinparents.70InHoffmansyndrome,hypogammaglobulinemiaand
e
vi absent B cells were noted in a girl with microcephaly, triphalangeal thumbs, partial 4–5
e
al R syndactylyofthetoes,andhypoplasticfirstmetatarsals.71
c
Criti
III. SYNDROMES ASSOCIATED WITH GASTROINTESTINAL
DYSFUNCTION
Gastrointestinal abnormalities may lead to malnutrition and secondarily result in an
immunodeficientstate.However,inthesyndromesdescribedherein,theimmunodeficiency
precedesnutritionaldeprivationandthusislikelytobeintrinsictoeachcondition(Table3).
Syndromic Immunodeficiencies 595
CLS TJ839-03 October23,2003 12:25
y
c + + )
equenofID +++++ +++ +++ 1case
r (
F
e
Immundefect T,BB,Ph T,B B %.
5
6
1 y >
nical Laboratory Sciences Downloaded from informahealthcare.com by INSERM on 09/22/1For personal use only. withgastrointestinaldysfunction Inheritance(Chromosome)Associatedfeatures ARMultipleatresiasfrompylorustorectumADFulminantplasma-likestools/diarrhea,edematousjejunalvilli;inMennonites?Diarrhea,villousatrophy,characteristicfacies,abnormalleasilyremovablehair;pnemonia,CMVhepatitis?Malabsorptionoffat,bileacidsandxylose;diarrhea Tcelldefect;B:Bcelldefect;Ph:Phagocytedefect;NK:NKcelldefect.++=+++=++++=ortedcaseswithdocumentedID;5%–30%;30%–65%;=maldominant;XLX-linked.
Critical Reviews in Cli TABLE3.Syndromesassociated Name 1.Familialintestinalpolyatresia2.Enteropathywithvillousedema 3.Giraultsyndrome 4.Dawsonsyndrome Abbreviations:ID:immunodeficiency;T:+=FrequencyofID:lessthan5%ofrep==ARautosomalrecessive;ADautoso
596 J. E. Ming et al.