Should the children of patients with hemochrotnatosis be screened for the disease ?

Idiopathic hemochromatosis is an underdiagnosed treatable condition 
inherited in an autosomal recessive pattern. Since early treatment is of demonstrated 
value, screening of high risk groups of individuals in a valuable exercise in 
preventive medicine. Although examination of siblings is always recommended, the 
frequency of the hemochromatosis gene makes the screening of children of patients 
with hemochromatosis an important undertaking, as illustrated by the families 
described in this report.

of id iopathic prima ry hemochromatosis can p reven t the iron overload which results in life th reaten ing complications in chis u nderdiagnosed d isorder (! ).[nheritancc of hemoch romatosis is autosornal recessive; it h as b een estimated that approx imate ly 10°-'o of the population in North America and Europe are heterozygous for the hemochromatosis gene, fo rmally design a rcd HFE 12.3).These two observations h ave important implications, in terms of screen ing relatives of patients to determine whether they arc homozygous fo r HFE and.therefore, have the hemoch romatosis genotype.
Screening itself is inexpensive and simple; measurement of transfcrrin saturation will accu rately identify ac least90°{, o f persons homozygous for H FE (4)(5)(6).T he aurosomal recessive in he ritance of the con dition implies that siblings of patients are at 25'1o risk of being homozygotes themselves a nd should be screent:d.H owever, because of the h igh frequency of the HFE gene in th e general populatio n , offspring of affected individuals arc also at a considerably elevated risk of homozygosity a nd clin ical disease.Two Newfound land families which ill ustrate the value of screening offspring, as well as siblings, of hemoch romatosis patien ts are presented.

PATIENTS AND M ETHODS D iagnosis: A provisional diagnosis o(
hemochromatosis was maJ c with a transferrin saturauon (seru m iron/total iron bindingcapacity x !OO)greaterthan 55°., and a serum fcrr itin level greater than the 90th percentile (6).Percutaneous liver biopsic~ were performed on these individuals and h istological demonstration of pare n c h ymal iron depos ition wa s taken as confi r ming the diagn osis of h emochromatosis.H LA typ ing of affected and unaffected family members allowed the cotransmission of the H FE gene and particular HLA hap lotypcs to be followed in forni lies ( 1.7).Patie nts: The index case of fami ly I (Fig-  In his sibship of eight, one brother was affected and o f this brother's offspring, seven were tested and three were found to have hemochrommosis. In both families, liver biopsies of rho.e individuals provisionally diagno ed using iron metabolism studies revealed moderate to heavy parenchymal iron deposition in every case.In no case was any alteration of liver architecture found, nor was any excess fibrous tissue depo• sition found.Because 10% of the spouses of hcmo chromatosb paricn rs will be HFE heterozygorcs, simply by chance , it is not sur• prising chat families, such as rhose reported here , are observed in which hemochrommosis occurs in the offspring of patients.In a mating between an affected (homozygous) and a carrier (het• erozygous) individual.all offspring will necessarily receive the HFE gene from the affected (homozygous) parent and each has a 50°;, chance of receiving the HFE gene from the unaffected, hctero• zygous parent.On average, one-half of the offspring of such matings are expected to be homozygous for HFE, likely to develop clinical hemochromarosis even• tually This is illustrated by the familie~ reported here: three of six children in family I and three of seven children in family 2 are affected.

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As indicated, 10":, of matings of pati• cnts a re expected to be of chis type; families showing vertical transmission of hcmochromatosis arc probably not observed more frequently s imply because the onset of hemochromatosis 1s relatively late in life.Such pseudodominant transmission of the clinical disease con fused early attempts 10 elucidate its mode of inhe ritance.C lear appreciation of recessive inheritance required the discovery chat the HFE locus is closely linked co the HLA A locus on chromosome 6 and the use of measurements of iron load to identify family members with pre symptomatic disease (9-ll ).Families such as those reported here would have CY caped notice because some family members with hcmochromatosi~ arc asymp• tomatic and because affected younger members showed mini mal cl inical signs lifhemochromatosis.T he e cwo fami lies high light the signi ficance of anh ropathy " an early manifestation of this dbease and as a useful clue in differential diagnc",s ( 1.12). If . N iederau and co-workers ( I) demonstrated a significant reduction of life expect:mcy 111 patients whose hemochromato:,is had resulted in cirrhosis or di.1bctes and that patients treated prior to the onset of cirrhosis had an expectation of survival indentical to that of the general population.Of particular note, hcpacocellular carcinoma, a recognized complication of hemochromacos1s, has neve r been reported in no ncirr hotic patients with hemochromatosis (I).
The pattern of association of the HFE gene with certain HLA haplocypes suggests that a small number of mutations, or perhaps a single mutation event, is responsible for this gene ( 14).This raises the possibility that tests using oligonucleotide DNA probes could be developed, which would allow homozygotes and hetcrozygotes to be identified accurately, simply and cheaply Developing such prohcs would not be easy; this Hemochromotosis in poftents' children would requ ire that the HFE gene actually he found and ,cquenced At present, although the linkage of HFE to HLA on chromosome 6 1s cerum.its actual position , w1th111 at least a million base pairs.1s not known and the gene wou ld have to he found before It could be sequenced The fn:quency of the HI-E gene would make devclopmg oligonuclconde pmhcs worthwhile.However, even assuming the clinical impactof the H FE gene becomes hetter appreciated.as it should.the treatability ofhemochromacosis may place its molecular genetics at a lower priority than that of numerous disorders less susceptible to clinical management Abo.population screening for iron overload rather than the HFE allele has the additional hencfit of 1denufying persons with iron overload due to ocher causes, who also require diagnosis and therapy The authors conclude that members of the families of hemochromamsis panents should be screened for iron overload.that this screenmg should mclude the child ren as well as the siblings of affected 111div1duals and that screening should be early.with the aim of preventmg iron overload and its well documented complications.L'hcmochromato,e est une cond1t1on curable sous diagnostiqucc qui se transmet sur le mode aumsomique rccessif.L',mportancc de traiter le suJet attemt le plus tc'H possible ecant ccrtaine, le dcp istage des groupes ,1.h aut risque est une mesure de mcJecine preventive imperative .Bien quc ['examen des freres Ct soeurs SOit tOUJOUr\ recommandc, la frcquence du gene porteur de l'h cmochromose accencue la nccessite de dcpister lcs enfants des patients attcmts d'hemoch romatosc.ams, que le dcmontrc lcs fami lies dont fan ctat cc rapport.

Figu re 2 )
Figu re 2) Family 2. Sec Figure I for key w symhoLI 144 Les enfants d es patients atte ints d'he moc hromatose :D evraient-ils etre soumis a un exame n d e d e pistage ?