Recurrence risks and prognosis severe sporadic osteogenesis … · Recurrence risks and prognosis...

Journal of Medical Genetics 1987, 24, 390-405

Recurrence risks and prognosis in severe sporadicosteogenesis imperfectaE M THOMPSON*, I D YOUNGt, C M HALL:, AND M E PEMBREY*From *the Mothercare Unit of Paediatric Genetics, Institute of Child Health, London; ttheDepartment of Child Health, Leicester Royal Infirmary, Leicester; and #the Department of Radiology,The Hospital for Sick Children, Great Ormond Street, London.

SUMMARY A study was carried out in the United Kingdom of patients with severe osteogenesisimperfecta (01), born with fractures to normal parents, in order to determine recurrence risks. Atotal of 105 cases from 98 families survived the perinatal period and 60 cases from 57 familieswere stillborn or died during the first week of life. The majority of the perinatal survivorscorrespond to the overlapping group of Sillence type III and sporadic type IV 01. In 40 of these,the radiograph at birth was available and in 37 it showed a characteristic appearance similar tothat described previously for type III 01. The other three cases had radiological type IIB 01 atbirth and died before 26 months of age. The patients with perinatally lethal 01 were subdividedon radiological appearance into Sillence type IIA (30 cases, described in the previous paper),type IIB (12 cases from 11 families), and type IIC (three cases from three families), and in fivecases from three families the radiological appearance was the same as that of the 37 perinatalsurvivors described above. Ten cases from 10 families were not classified because theirradiographs were unavailable.To analyse the empirical recurrence risks, patients were grouped according to radiological

appearance at birth. Those with a type III-like pattern numbered 42 cases and they were groupedwith the other cases of severe deforming 01 who survived the perinatal period, for whom no x rayat birth was available, making a total of 107 cases. Taking one affected child per family as theproband, there were 98 probands. They had 146 sibs, of whom 10 were affected, giving anempirical recurrence risk of 6-9%. This is consistent with the disease arising as a new dominantmutation in about three quarters of families and as a recessive in about one quarter in thisheterogeneous group. It is reasonable to give a recurrence risk of up to 25% in cases withparental consanguinity and a risk of 4-4% in cases with unrelated parents. Fifteen patients (14probands) with Sillence type IIB 01 had 13 sibs, one affected, giving an empirical recurrence riskof 7*7%. The parents were consanguineous in three families and the evidence for autosomalrecessive inheritance for the majority in this group is probably stronger. The three patients withtype IIC 01 had three healthy sibs and the 10 unclassifiable perinatally lethal cases had 22 sibs, allnormal.The radiological appearance at birth predicts prognosis to some extent; essentially, the better

the bone morphology and mineralisation, the longer the survival.

There is increasing evidence that osteogenesis no reason to assume that any particular clinicalimperfecta (01) is a group of monogenic disorders subgroup has just one pattern of inheritance.involving the collagen genes. Where there is a family The division of 01 into four main types by Sillencehistory, the type of inheritance and recurrence risk et all in 1979 highlighted the diversity of 01 andis usually self-evident. Single cases in a family are provided a useful classification which has beenlikely to represent either new dominant mutations widely used by clinicians. Types I and IV werewith no recurrence risk or autosomal recessive autosomal dominantly inherited; sclerae were blueinheritance with a 25% recurrence risk, but there is in type I and normal in type IV. Bone deformity was

Received for publication 22 December 1986. generally mild in type I but in type IV deformity wasRevised version acceptcd for publication 13 February 1987. variable and could be severe. Type II, the 'perinat-

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Recurrence risks and prognosis in severe sporadic osteogenesis imperfecta

ally lethal' form, was later subdivided into threeradiological subgroups by Sillence et at2 in 1984. Theauthors "suggest that most cases of 01 type II

represent autosomal recessive traits".Patients with type III OI developed severe

progressive deformity and had pale blue or normalsclerae. Although all 21 patients in the originalpaper were sporadic, the authors suggested thatautosomal recessive inheritance was likely, based onconsanguinity of parents in two families and on

previous reports of affected sib pairs. While recog-nising that some cases may be due to autosomaldominant new mutation, type III 01 was shown asautosomal recessive in their table 7,1 and this hasbecome widely quoted.3 4Subsequently, the authorssaw five families with either multiple affected sibs or

parental consanguinity.5 6 More recently, Sillence etal7 have described eight sibships in seven familieswith multiple affected sibs (seven sibships) or

consanguineous parents (one sibship); two werebeing re-reported. Having originally classified typeIII 01 on clinical grounds of severe progressivelydeforming OI, they now use the criterion of beingrecessive to redefine the range of severity in type III01, so that "the 01 type III phenotype does notnecessarily equate with progressively deforming 01,

and probably only a proportion of cases with severedeformity and normal sclerae have 01 type III".For purposes of genetic counselling, the Sillence

classification has some limitations. Because ofoverlapping features between types, single cases can

be difficult to classify. This is particularly true ofsingle cases of types III and IV which cannot bedistinguished with certainty. There is increasingevidence for genetic heterogeneity within types,particularly in type III 01. There are instances ofprobable autosomal recessive severe deforming 01,

with reports of affected sibs7-14 and of single casesin a sibshi or affected cousins with parental consan-guinity.7 17 It is noteworthy, however, thatseveral studies record a paucity of affected sibs"'20or note that the majority of severe 01 are sporadic.2'Genetic counselling is difficult in severe 'sporadic'

01 because single cases of type III and IV cannot bedistinguished reliably and there are no clinical or

radiological features which allow identification of an

isolated case of recessive type III 01. To resolve thisgenetic counselling dilemma we determined recur-rence risks and assessed prognosis in this severe

'sporadic' group of patients.

MethodsASCERTAINMENT OF CASESThere is no single criterion which will include allpatients with severe OI. Nevertheless, the majorityof patients with severe 01 will have fractures at

birth,22 making this the best inclusion criterion forthis group of patients. Ascertainment of cases of 01with fractures at birth requires different sources forpatients who died perinatally (defined as stillbornbabies or those who died within one week of birth)and for those who survived the perinatal period.(a) Patients who survived the perinatal periodThese were ascertained largely through the BrittleBone Society (BBS), a support group in the UnitedKingdom for patients with 01 and their families,founded in 1968. Patients known to the BBS includethe majority of those with severe 01 for tworeasons. First, such patients and their familiesrequire much support in terms of physical aids andadvice on management of daily activities. The BBShas a reputation for providing generously for theseneeds. Secondly, the BBS has developed an infor-mal network of communication, so that new casesare rapidly brought to their attention and offeredtheir services. On joining the BBS (which does notrequire payment), patients or their families com-plete a short questionnaire on certain clinical data,including whether or not fractures were present atbirth. The ascertainment of these cases is summa-rised in table 1. The initial sample of patientsincludes all patients known to the BBS to the end ofJuly 1984, who had fractures at birth. Thesenumbered 185 cases from 179 families. Two patientswere excluded as no information about their pedi-gree was available. Fifty-two cases with provenautosomal dominant 01, that is, with an affectedparent, were excluded. The remaining families wereapproached by the committee of the BBS. Familiesof 25 patients (all single cases) did not wish toparticipate and so had to be excluded as there wasno other avenue of access to information aboutthem. The 100 families of 106 cases who agreed toparticipate in the study were contacted by one of theauthors (EMT). During the course of the study, toJune 1985, a further 23 cases (from 22 families)came to light and were studied. These were referredby clinical geneticists who knew of our interest in 01and 10 of the cases were born during the time of thestudy. Thus, the group studied who were born withfractures, whose parents were unaffected, number129 cases from 122 families (table 1).

(b) Patients with perinatally lethal 01Ascertainment of perinatally lethal cases wasthrough clinical geneticists in the UK, as describedby Young et al (see preceding paper). A total of 60cases from 57 families was ascertained. Only two ofthese families were known to the BBS, whichemphasises the need for separate ascertainment ofperinatally lethal cases and cases surviving theperinatal period.

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E M Thompson, I D Young, C M Hall, and M E Pembrey

TABLE 1 Ascertainment of perinatal survivors.

*Cases (families)

COLLECTION OF DATA

(a) Patients who survived the perinatal period (table2)The group studied numbered 129 patients from 122families. A total of 98 cases from 92 families wasstudied personally (by EMT) mostly during a homevisit. During the interview, the patient and familyanswered a standardised questionnaire and the

affected subject was examined and photographedwhere possible. The colour of sclerae was measuredusing a paint chart and the darkest colour of thesclerae was scored as either white or one of threeshades of blue (pale, moderate, or deep blue). Theparents and sibs were examined where possible.A detailed pedigree was constructed which includedrelevant information on first, second, and third

Initial sample 185 (179)*Fractures at birthknown to BBS at end of July 1984

1 1~A//\Include 106 (100) Exclude

No information available 2 (2)Affected parent 52 (52)Family not wishing to 25 (25)

participate79 (79)

Additional cases referredduring the study 23 (22)

Sample studiedFractures at birthUnaffected parents 129 (122)

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TABLE 2 Collection of data on perinatal survivors, who had fractures at birth and normal parents, and exclusion of casesof probable type I new mutation, to arrive at sample analysed for recurrence risks.

.Cases (families)

degree relatives where possible. Further informa-tion was obtained from hospital records wherenecessary. Twenty-six families who were relativelyinaccessible were sent a postal questionnaire and 13provided useful returns including a photograph ofthe affected subject. The 13 who either did notreturn the questionnaire or gave inadequate infor-mation are excluded. The information on five casesfrom four families was provided by a consultant

clinical geneticist. In all cases, exhaustive attemptswere made to obtain all the radiographs of eachaffected subject. Radiographs were available in 97cases and in 40 cases radiographs taken in the firstweek of life were also available.

(b) Patients with perinatally lethal OICollection of data was described in the precedingpaper.

Sample studied 129 (122)*

IncludeSeen personally 98 (92)Useful questionnaire

returns 13 (13)Information given by

clinical geneticist 5 (4)

116 (109)

1 1~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

ExcludeInadequate questionnairereturns 13 (13)

ExcludeCases of probable type I01 new mutation 11 (11)

Final sample for analysis Patients with severe 01 with fractures at birth,of recurrence risks unaffected parents

105 (98)

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Results

The purpose of this report is to present data relatingto recurrences in sibships and to show radio-graphical appearances in the neonatal period whichhelp in prediction of immediate prognosis. Furtherclinical analyses are in preparation.

A. CLASSIFICATION OF PATIENTS

1. Patients who survived the perinatal period (firstweek of life)Information on 116 cases from 109 families wasobtained.

(a) Exclusion of probable cases of type I 0I newmutationsIt is well known that patients with the milder type I01 may present with fractures at birth. ' Eleven suchcases could be identified on the basis that they hadlittle or no bony deformity associated with mildradiological changes, minimal handicap (they wereall able to walk well unaided), and moderately ordeep blue sclerae. Their heights were belowaverage, but were all greater than -6-0 SD belowthe mean, with an average SD of -4-0 (range -2-8to -6-0 SD). All but one of these were seenpersonally. In nine cases the mother reported that atbirth the number of fractures present was one (twocases), two (four cases), three (one case), four (onecase), 14 (one case). In two cases the number offractures at birth was unknown. Neonatal radio-graphs of two of these patients were available; theyconfirmed the presence of two and four fractures,respectively, and showed good length and modellingof long bones, and mild bowing only of the femoraand tibiae in one (fig 1). These 11 cases withprobable type I 01 are excluded from the analysis ofrecurrence risks, on the basis that they representknown new dominant mutations of type I 01 andtheir inclusion would falsely lower the recurrencerisks. This left 105 cases from 98 families with severe01, who were born with fractures to normal parentsand who survived the first week of life (table 2).

(b) Ages of patients and severity of 01The ages of the 105 cases ranged from 16 days to 54years, with a mean of about 12 years. Four-fifthswere under 20 years. Twenty-six of the 105 had died(25%), all before 20 years. Of these, 18 (69%) haddied before 26 months and 24 (92%) by 10 years.There was progressive bone deformity and handicapwas generally severe: of the 70 cases over five yearsof age, 70% had never been able to walk and onlythree could walk well unaided. Sclerae were white insix, pale blue in 46, moderately blue in 13, deep bluein 26, and unknown in 14. The heights measured in

FIG I Radiograph taken on day I ofa case ofprobabletype 101 who represents a new mutation. Note good lengthand modelling oflong bones and only mild bowing.

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. 't. /R' Sjjj:9. >:,"t'. , t E,s;Stijj S w} .,,,. .. ,, , *e ;> ,>*0}st 'ta | | - .. .-:,=.g_ - ^.i :;# A, f. , ' " . ' .': .. ':

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* ;g.' ;$ 2.' 4 b2 S < . , ' " .. , .: . ... .. -:5*+ 'd S) S. .

FIG 2 A 14 year old girl with severe, progressivelydeforming 01 (type lllIIV).

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Recurrence risks and prognosis in severe sporadic osteogenesis imnperfecta 395

80 cases were less than -6 SD below the mean in allbut eight cases. Apart from three with radiologicaltype IIB 01 [see section (c)(ii)] these patientsrepresent a heterogeneous group and correspond ingeneral to the overlapping group of Sillence type IIIand sporadic type IV. Fig 2 shows a patient in thisgroup.

(c) Radiographical appearance in the first week of lifeRadiographs taken in the first week of life wereavailable in 40 cases and comprised a complete'babygram' in 34 and incomplete radiographs in six.These revealed one of two main patterns.

(i) Type IIIIV 01 patternMost cases (37/40) had the following pattern, shownin fig 3. The femora were shortened with flaredmetaphyses probably due to multiple small frac-tures. The diaphyses were thin and showed amoderate degree of modelling and often mid-shaftangulation. The overall appearance of the femurwas like an apple core and was seen in 36/37 cases.In nine of these, the length of the femora was a littlegreater than in the rest, but overall the changes weremore severe than in type I 01. After about onemonth, the femur developed an unmodelledrectangular appearance, presumably due to callusformation around the mid-shaft (fig 4).The ribs were generally slender with or without

FIG 3 Radiograph taken on day 1 after birth at term ofa acute fractures. In 2/32 there were multiple discon-child with severe, progressive/y deforming 01 (type IIIIIV) tinuous 'beads' on the ribs, presumably due towho is now agedfouryears. Note moderate shorteningof fractures with callus formation. Both children arelong bones. Femora show some modelling with thin alive at 10 and 30 months respectively.angulated diaphyses andflared metaphyses. The ribs are The humeri 3() usualypell ell.slender, the humeri are well modelled, and the skull shows The humeri were usually well modelled.good mineralisation. The skull was usually well mineralised, revealing

multiple wormian bones.The vertebral bodies were usually of normal

height but showed platyspondyly in 4/32 cases.

FIG 4 Radiograph offiemnora of'a child with III/IIV 01 taken atone month. Note that the femorahave become thick and unmodelled,whereas on dav 2 they were as in fig 3.



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The tibiae were usually angulated at the junctionof the upper 2/3 and lower 1/3, except in one childwho was a breech presentation with extended legs;his tibiae were straight.The number of discrete fractures was often very

difficult to count accurately, but ranged in numberfrom four to 30, with a mean of about nine. Seven of40 of these patients died; five died under six monthsand the other two at 14 months and 46 months.Neonatal x rays were available for only one pair ofsibs (family 7, fig 5) and both showed the sameradiological pattern as described above. The radio-logical picture described is similar to that describedby Sillence for type III O0,1 7 but we believe thesepatients represent a heterogeneous type III/sporadicIV group.

(ii) Type lIB OI patternThree cases showed the radiographical pattern of OItype IIB with broad, rectangular, unmodelled,crumpled femora, thin ribs with multiple discon-tinuous beads, some modelling of humeri, platy-spondyly (in one out of the three), and angulatedtibiae (fig 6). These three patients died at fourweeks, six weeks, and 26 months respectively. These

FIG 6 Radiograph taken on day 5 ofa girl who died atfourmonths. Note that thefemora are short and unmodelled, theribs are thin with occasional beads, the humeri are shortwith some modelling, the skull shows some mineralisation,and there is platyspondyly ofsome vertebral bodies. Thisappearance is that of IIB (see fig 7) rather than IIIIIV (fig3).

LI@

1aA(e

Termination of pregnancy of affected fetus(sex female or unknown, respectively)

(c ) Consanguineous parentsFIG 5 Sibships of cases with severe deforming OI withaffected sibs. In families I to 7, the affected subjects survivedthe perinatal period. In family 8, the proband diedperinatally and these three sibs had the 'type IIIIIV'radiological pattern (see fig 11).

results are summarised in tables 3 and 4. It isnoteworthy that no perinatal survivor had theappearance of type IIA 01.

2. Patients with perinatally lethal 01 (stillborn or diedwithin one week of birth)The 60 cases from 57 families were classifiedaccording to radiological appearance where possible(tables 3 and 4).

(a) Type IIA 01

Thirty cases had type IIA OI with 38 sibs, allhealthy, as described in the previous paper.

(b) Type lIB OISeventeen cases were initially classified as typeIIB.23 Subsequently we recognised that only 12 ofthese (from 11 families) conformed to the radio-logical description for IIB of Sillence et al.2 Thisconsists of short, broad, crumpled, unmodelledfemora and thin ribs with multiple discontinuous

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TABLE 3 Radiological features at birth.

Type of 01 Femora Ribs Humneri Skiill Heiglot of Tibiaetinteralisatiot *rertebral

bodies

IIA Very short. Broad. Like Absent Flat Angulattedbroad, continuous femoraunmodelled beads

IIB Very short. Thin± Some Near normal Near normal Angulatedbroad. diseontinuous modellingunmodelled beads

IIC* Short. pooriv Thin. Like femora Poor Near normal Angulatedmodelled. irregularlymultiple shapedangulations

III/IV Moderately Thin, Well modelled Normail Usually normal Angulatedshort, rarely withdiaphvses discontinuousthin and beadsangulated withsome modelling.metaphyses flared.Overall. femurlooks like anapple core

'Hallmarks: irregularity of bone shape, speckled calcificattion. aind long, downward pointing ischia.

TABLE 4 Classification of cases of severe 01, born with fractures to unaffected parents, based on radiographicalappearance within the first week of life.

Cases No of perinatal survirlors No of perinatal lethal cases Total(lired bervond first reek) (stillborn or died in first week)

Total 15)5 60IRadiographical appearance

at birthType IIA' (0 311 311Type IIB (fig 7) 3- 12 15Type IIC (fig 12) () 3 3Type III/IV (fig 3) 37 Severe. progressively :5 1()7-,-Original x ray at birth h5 J deforming 01 I(0now unavailable

*See previous paper by Young et al."The patients died at four wecks. six wecks, and 26 months, but haid the typical IIB x ray pattern at birth.-Total No of type III/IV is 37+5+65 (see text).

beads (11/12 cases) (fig 7) or without beads (onecase, an 18 week terminated fetus). This contrastswith the thick, continuously beaded ribs in type IIA01 shown in the previous paper. In addition, wenoted that these patients with IIB 01 have bettermodelled humeri, better skull mineralisation, andmore normal height of vertebral bodies than thosewith type IIA. All had angulated tibiae. In twosingle cases (delivered at 23 and 36 weeks) thethickness of the ribs was intermediate between IIBand IIA 01; since the other features were moretypical of IIB, they were classified as such. Anothersingle case (born at 34 weeks) had longer femorathan the others, but these were completely un-modelled and the other features were consistentwith IIB. There was one affected sib pair and the

others were single cases. The affected sibs had thesame radiological appearance (figs 7 and 8).Nine of the 12 babies were liveborn, at a mean

gestational age of 37-6 weeks (range 34 to 41weeks), two were terminations at 18 and 23 weeksafter detection of bone shortening and deformity atultrasound scan, and in one these details wereunavailable. The mean duration of survival of thenine liveborn babies was about 14 hours, range oneto 48 hours. There were six females and six males.Fig 9 shows a baby with IIB 01.The other five babies (from three families) who

died perinatally, and who were originally classifiedas IIB,23 in fact had radiological appearances similarto those described in (c) (i), that is, with the typeIII/IV appearance (fig 10). One index case was

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stillborn at 30 weeks and two were liveborn at38 weeks and lived 24 and 10 hours respectively. Thefirst two babies were single cases in their family, butthe third had two affected sibs in whom the diseasewas detected prenatally by ultrasound scan andconfirmed radiologically after termination ofpregnancy. These three sibs had the same radio-logical appearance (fig 11 a-d).

(c) Type IIC OlThree cases were classified as type IIC 01 on thebasis of broad, irregular femora, thin, irregular,discontinuously beaded ribs, irregularly shapedhumeri, poor skull mineralisation, near normalheight of vertebral bodies, and angulated tibiae (fig12). The pelvis showed flared ilia and long ischiawhich pointed downwards. The hallmarks of thistype of 01 appear to be irregularity of bone shape,including of the scapulae, and speckled calcification.Two of the three cases were stillborn at 28 and 30weeks. In the other case, the pregnancy wasterminated at 19 weeks' gestation after detection of

skeletal abnormalities during routine ultrasoundscanning.

(d) Unclassifiable perinatally lethal O0In 10 cases, the diagnosis of 01 had originally beenmade on x ray appearance, but as the radiographwas no, longer available, classification was notpossible. Seven were liveborn, mean gestational agein six was 35-7 weeks (range 34 to 40 weeks), and nobaby survived longer than one hour. Three babieswere stillborn at 31 and 32 weeks; gestational agewas unknown in the other.

B. RECURRENCES IN SIBS1. Survivors of the perinatal period with severe 01A total of 105 cases from 98 families was studied(tables 2 and 4). There were seven families withrecurrences (fig 5). Since each family was ascer-tained only once, one child (usually the older) wastaken as the proband and affecte.d sibs were countedonly once. In this group overall, there were 142 sibs,eight of whom were affected (including the fetus in

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FIG 8 Radiograplis of the legs (a) and chest (b) of thefemale sib of lthe patient shown in fig 7. She was born at39 weeks, died at 48 holurs, and has the samne radiographicalappearance as hier brother.

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Fl(i 9 A babv with the type IIB radiographiical appearancewho died at 24 houirs. He was delivered at 41 weeks.

FIG 10. Radiograph ofa stillborn female delivered at 30weeks' gestation. Note that the length and modelling of thelong bones are much better than in IIB. (This is notnecessarily attributable to gestational age, since the IIBappearance can be recognised in fetuses-see discussion.)The ribs are thin and discontinuously beaded. Theappearance is more like that of IIIIIV OI (fig 3) than IIB(figs 7and 8).

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Recurrence risks and prognosis in severe sporadic osteogenesis imnperfecta~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.FIG 12 Radiograph ofa baby stillborn at 28 weeks with JICOI. Note the shortening oflong bones, especially thefemorawhich show multiple angulations, the thin, irregular ribs,the absence ofskull mineralisation, the fairly normalvertebral body height, and the long, downward pointingischia. The bone shape is generally irregular with speckledcalcification.

family 7, fig 5), giving an empirical recurrence riskof 5-6%.However, in this analysis, it is more logical to

exclude the three (single) perinatal survivors withradiological type IIB 01 [see section A1(c)(ii)], andto include the five cases (from three families) withperinatally lethal disease but with the type III/IVradiological appearance [see section A2(b) andtable 4], since consistency in radiological appear-ance is more likely to indicate a true subgroup thanis age of death. The latter five cases included asibship of three affected babies ascertained onlyonce. This group therefore consisted of 107 cases(plus the fetus in family 7). Again .taking one childper family as the proband, there were 98 probandswho had 146 sibs of whom 10 were affected, givingan empirical recurrence risk of 6-9%. It could beargued that since neonatal x rays were available inonly 40 cases, it is invalid to include in the analysisthose with no neonatal x rays. However, themaximum age at death of a child with IIB 01 was26 months, and of the perinatal survivors with no

neonatal x rays, only nine had died under 26 months.Extrapolating from the fact that three of 40 withneonatal x rays were found to be IIB, then about oneother (3/40x9=0.675) could in fact be expected tohave IIB 01.

Sixty of the 146 sibs (41%) were post-born. Of themothers of single cases, 16 gave a history of one earlyspontaneous miscarriage, two of two, and one of fivemiscarriages. Of the mothers of affected sibs, tworeported one miscarriage each and one motherreported two.The eight families with affected sibs are shown in fig

5. In families 5, 6, and 7 the parents are first cousins; allcome from ethnic groups in which consanguinity iscommon. The parents in family 5 were Jordanian, infamily 6 they were Pakistani, and in family 7 they wereWelsh gypsies. The parents of the mother in the latterfamily were also consanguineous and she was said tohave had affected sibs. In the other five families theparents were unrelated and British, except for thefather in family 3 who is German. Consanguinity waspresent in one other family in which the parents of asingle case were first cousin Pakistanis (fig 13). Themother's two sibs (III.6, 111.7) were born in Pakistanand were said to have 'brittle bones'. They died at oneweek and one year respectively. One of the singlecases who died at four months was said to have a greataunt with 01 and another single case was said to have acousin who had had several fractures. In both, the twointervening relatives were normal.There were no clinical or radiological features

which distinguished cases with affected sibs fromsporadic cases.

Parental agesMean parental ages at the birth of the sporadic cases(excluding the presumed recessive single case shownin fig 13) were raised above that of a control popu-

I

II -3~~~~~~~~~~~~~~~~__IV 'rE

FIG 13 Pedigree ofa proband (IV. 1) with severe deforming01 whose parents were first cousins. 11.6 and 1I. 7 werereported to have 01. It is assumed that the disease isrecessively inherited in this family and that 1. 1, 11.2, 11.3,III. 1, and 111.2 were heterozygotes.

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lation, but this was not statistically significant (table5). The control means were calculated from dataobtained from the Office of Population Censuses andStatistics Series FMI (HV).24 Since the study group

were born between 1930 and 1985, an average of thepopulation means (when available) was calculated,and it was weighted according to the number of studycases born in each year. Figures for "legitimate birthsfor all birth orders" were used, since 88 out of 89 cases

were legitimate births.

2. Type 101(a) Type IIAThere were no recurrences in 38 sibs (see previouspaper).

(b) Type IIBThere were 12 cases from 11 families ascertainedthrough the perinatally lethal survey, and three cases

from three families ascertained through the BBS whodied beyond the perinatal period [see Al (c)].These 15 cases had 13 sibs, one ofwhom was affected,giving an empirical recurrence risk of 7-7%. Nine sibswere post-born and four pre-born. Parents were

consanguineous in three families; in family 1 they werefirst cousin Pakistanis, in family 11, a West Indianfamily, the child was born of an incestuous union, andin family 12 the parents were first cousin Sri LankanChristians. The latter two families come from racialgroups in which consanguinity is uncommon. Parentsin the other 11 families were unrelated; 10 coupleswere Caucasian and one was Negro. None of themothers reported having any early spontaneousmiscarriages. Mean parental ages at the birth of the(first) affected child were: paternal 25-44 years (n=11, range 15-9 to 34-58 years); maternal 22-28 years(n= 14, range 13-25 to 27-5 years). If the three familieswith consanguineous parents are excluded, the meanparental age at the birth of the affected child are

paternal 24-36 years (n=9, range 15-9 to 32-92 years)and maternal 22-51 years (n=11, range 16-4 to 27-2

years), which are not raised above the parental ages inthe general population.

(c) Type IICThere were three cases, with three sibs, all of whomwere healthy. The parents were all unrelated; twopairs were Caucasians and one was Negro. Themothers reported no early miscarriages. Parental ages

at the birth of the affected child were paternal 29 0,28-5, and 25-8 years (mean 27-77 years) and maternal27-67, 27-0, and 25-2 years (mean 26-62 years).

(d) Unclassifiable perinatally lethal 01Ten cases had 22 sibs, all normal. The parents were allunrelated Caucasians. One mother reported one earlymiscarriage. Mean parental ages at the birth of theaffected child were: paternal 32-72 years (n=9, range

22-33 to 49-7 years) and maternal 27-98 years (n= 10,range 18-5 to 39-75 years).

Discussion

We studied a large group of patients with severe

deforming 01, born with fractures to normal parents,in order to determine recurrence risks. Patients whodied in the perinatal period were ascertained differ-ently from those who survived it. The majority ofthe latter (for whom x rays were available) had a

characteristic radiographical appearance in the firstweek of life, which corresponds to that described bySillence et al1 7 for type III 01. These patientsrepresent a heterogeneous group of 'type III' and,sporadic type IV'. The patients who died within oneweek of life mostly had type IIA 01, some had typeIIB, a minority IIC, and some were not classifiable.In addition, five patients with perinatally lethaldisease from three families had the 'type III'radiographical appearance. This draws attention tosome important points regarding classification andprognosis.

TABLE 5 Mean parental ages at the birth of the sporadic type IIIIIV cases.

Paternal age

Mean age of Mean age ofstudy eases in years control population(n=89) in years (see text)

30-51 2943 t=1643, p<O-l

Maternal age

Mean age of Mean age ofstudy cases in years control population(n=89) in years (see text)

27-82 27-16 t= 1-313, p<0lI

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CLASSIFICATIONThe use of the term 'perinatally lethal' to describetype II 01 is a potential source of confusion,implying that time of death determines type. It isprobably more useful to separate patients intoradiological groups at birth where possible and thiswas recently emphasised by Sillence et al.7 It mustbe stressed that the x ray taken during the first weekof life determines type IIB or III/IV. Even at onemonth callus formation can make a well modelledfemur look thick (fig 4). These bones later becomeprogressively thinner. Suggestions that type IIB andIII 01 overlap may relate to emphasis on time ofdeath and failure to compare the first week x rays ofsibs. For example, Spranger et a125 suggested thatthe two sibs described by Glanzmann8 show type III(the girl) and type IIB (the boy). The girl was aliveat nine years and her first week x rays were notpresented; her brother died at five months. Hisradiograph revealed thick long bones, but was takenat four weeks of age, so that it is not possible toclassify him as IIB or ITT. Although it is possible thatthe type IIB appearance at birth is only a more

severe form of type III, support for the separateidentities of the radiological appearance at birth ofthe two types is the fact that it was shown to 'breedtrue' in three sets of sibs (one set of IIB and two setsof 'III' OI) in our study. It has to be said that somecases are difficult to classify even on radiologicalappearance, so that two (single) cases had inter-mediate rib thickness making differentiationbetween IIA and IIB difficult, and one baby withvery poor modelling (like IIB) had surprisingly goodfemoral length, as in the type III appearance [seesection A2 (b)].

PREDICTION OF PROGNOSIS BY

RADIOGRAPHICAL APPEARANCE AT BIRTHThe radiological appearance at birth can be used topredict prognosis to a certain extent. Prognosis isworst in type IIC Ol in which six of seven cases (thisreport and Sillence et af2) were stillborn; the otherwas a second trimester termination. Prognosis is alsovery bad in type IIA: none of our patients who livedbeyond one week of life had the tye IIA 01

appearance, although Sillence et al reportedmaximum survival to six weeks in type IIA 01.

Patients with the radiographical appearance of typeIIB also have a poor prognosis in terms of survival,but survival may be a little longer than in IIA. Ofour 15 cases, 12 were liveborn and nine died before48 hours. The other three died at four and six weeksand 26 months. Maximum survival reported bySillence et af2 was to six weeks. Goldfarb and Ford26reported two sibs with probable IIB 01 who died atfive months and five and a half months and Hein27

described a daughter of first cousin parents withprobable IIB 01 who died at five months. Chawla28reported four sibs with severe congenital 01. Thex ray of one taken on day 3 was consistent withIIB 01. He died at nine months and his affectedsibs died at three years, 24 hours, and four monthsof age. Patients with the type III/IV appearanceat birth may be stillborn (one case) or liveborn,but die within 24 hours (two cases). The vastmajority (103 cases) survived the perinatal periodbut one quarter died in childhood, more thanhalf of these before two years, and the majorityof deaths had occurred by 10 years. Sporadiccases with only mild bowing at birth will usuallyhave mild disease (fig 1) and probably representnew dominant mutations.

Essentially, the better the bone morphology atbirth, the longer the survival. This is similar to theresults of the scoring system devised by Spranger etal.29 Similarly, Shapiro,"1 in a review of 85 patientswith 01, found that poor bone morphology at birthor at the time of initial fracture predicted a worseprognosis for survival and ambulation.

RECURRENCE RISKS (TABLE 6)Type IIlV groupThe empirical recurrence risk of 6-9% is likely to bea maximum, because if any bias in ascertainmentwere present it would be towards finding affected sibpairs whose families are more likely to join the BBSor to be known to clinical geneticists. The recur-rence risk could have been underestimated ifparents had been deterred from further reproductionafter the birth of one affected child. This does notappear to have been the case, since, of the 146 sibs,41% were born after the proband.The recurrence risk of 6-9% in this study is

consistent with the disease arising as a new auto-somal dominant mutation in 72*4% of these familiesand as an autosomal recessive in only 27-6%,assuming that these are the two genetic mechanismsoperating. It would be expected that the autosomalrecessive cases would be overrepresented in familiesin which the parents are consanguineous and thisappears to be the case. If the four families withconsanguineous parents are excluded (figs 5 and 13)then the empirical recurrence risk in families withunrelated parents is 4-4% (six affected sibs out of135 sibs of 104 cases).The current study has specifically addressed the

problem of recurrence risk in sporadic cases of 01born with fractures. We recognise that there are'late onset' autosomal recessive forms, as reportedby Sillence et al,7 Lievre,ll Awwaad and Reda(family 2),12 and Horan and Beighton,'3 but theseare probably rare.

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TABLE 6 Recurrences.

Tvpe of 01 Cases Total sibs Affected sibs Recurrence Conintentrisk (%)

IIA 3(0 38 ( ( Rare reports of affectedsibs suggests a smallrecurrence riskshould be quoted (seeprevious paper)

IIB 15 13 1 7-7 Overall evidence suggestshigher recurrence riskin these rare forms

IIC 3 3 () () (see text)

III/IV All cases 1(07 146 1() 6-9Parents non-consanguineous 11)4 135 6 4-4

All perinatally lethal cases 611 8(1 3 3-8 This provides a recurrencerisk figure if aperinatally lethal caseis unclassifiable

Recurrence risk in IIB 01The recurrence risk of 7-7% (one in 13) is similar tothat in the type III/IV cases, but the numbers areconsiderably smaller. In addition, consanguinity waspresent in three families. Two of these come fromracial groups where consanguinity is uncommon.Other examples of probable type IIB OI in sibs havebeen reported.2 26 28 31 32 The parents of the singlecase of probable type IIB 01 described by Hein27were consanguineous, as were those in the pedigreeof Zeitoun et al. Several fetuses with probable typeIIB 01 were detected as early as 16 weeks ofpregnancy by ultrasonography.3336 After termina-tion of pregnancy, the x rays of the fetuses wereconsistent with IIB 01. Even in the second trimester,the femora were short and broad and the ribs werethin. Each case had one or more affected sibs,whose x ray was presented in only one instance33and was consistent with IIB OI. An additionalfeature in one affected baby was polydactyly and hisaffected sib had amniotic bands leading to fingeramputations.35 One of the two affected sibs of thefetus described by Patel et al34 had cleft lip andpalate and anencephaly. The parents in the family ofGhosh et al36 were consanguineous. Overall, theevidence is probably in favour of autosomal reces-sive inheritance in this group. Prenatal diagnosis ofpregnancies at risk of type IIB (and IIC) 01 can beoffered using careful serial ultrasonography in thesecond trimester. Occasionally, cases will bedetected on routine scans, as happened in two of ourpatients.

Recurrence risk in IIC OIThe numbers in our study are too few to drawconclusions regarding mode of inheritance. Sillenceet a12 described four cases in two families, three of

whom were from one sibship, suggesting autosomalrecessive inheritance.

Unclassifiable perinatally lethal 01If genetic counselling were requested after the birthof a child with radiologically proven perinatallylethal OI, but the x ray was lost so that classificationwas not possible, empirical recurrence risk figuresof 3-8% could be given (table 6), derived from thenumber of affected sibs (n=3) out of total sibs(n=80) of all cases of perinatally lethal OI (n=60).Again, prenatal diagnosis by ultrasound scanningcould be offered for future pregnancies.

Conclusion

We suggest that the radiological appearance at birthin severe 'sporadic' 01 predicts both survival andrecurrence risks to sibs.The most severe abnormalities of bone miner-

alisation and morphology are seen in types IIA andIIC, and these babies rarely survive the perinatalperiod. In type IIA the recurrence risks are verylow. In type IIC, the rarest form of 01, the evidenceis in favour of autosomal recessive inheritance. Intype IIB the bone abnormalities are severe but lessso than in IIA and IIC. The babies usually die in theperinatal period but occasionally survive for severalmonths. On the available information there is notenough evidence to quote a recurrence risk of lessthan 25%.

Sporadic cases with the moderate bone changes of'type III' OI at birth cannot reliably be diagnosed astype III or IV. They usually survive the perinatalperiod but about one quarter die in childhood. Theoverall empirical recurrence risk is 7%. In practice,we would give a risk of up to 25% if the parents are

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consanguineous and a risk of 4-4% in single cases

with unrelated parents.

The authors thank the patients and their families fortheir enthusiastic cooperation, and Dr ColinPaterson, Mrs Margaret Grant, Miss Yvonne Grant,and Ms Alison Wisbeach of the Brittle BoneSociety for their generous help. We are indebted tomany colleagues for their assistance, especially DrsJ Burn, J M Connor, B C C Davison, N R Dennis,D Donnai, M M Honeyman, R H Lindenbaum,G McEnery, M Oo, F M Pope, C M D Ross, D CSiggers, M Super, I W Turnbull, M Vowles, R GWelch, E M Williams, R M Winter, R Wynne-Davies, and Professors P S Harper and D F Roberts.Permission to publish radiographs or photographswas kindly provided by Dr L Jones (fig 4), Dr F MPope (fig 6), Dr M M Honeyman (figs 7 and 8), DrsA H Chalmers and D C Siggers (fig 11), andDr D Donnai (figs 9 and 12). We thank Mrs MelanieBarham for secretarial assistance and Miss ElizabethLord for typing the manuscript. The study was

funded by a Wellcome Trust Training Fellowshipheld by EMT.

References

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3 Smith R. Disorders of the skeleton. Osteogencsis imperfecta.The Brittic Bone syndromc. In: Weatherall DJ, LcdinghamJGG, Warrcll DA, eds. Oxford textbook of'tnedic-ine. Oxford:Oxford Univcrsity Press, 1983: section 17.25.MeKusick VA. Mendeliant inheritance in tnan. 7th cd. Balti-more: Johns Hopkins University Press. 1986: No 25942.

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7 Sillence DO, Barlow KK, Cole WG, Dietrich S, Garbcr AP,Rimoin DL. Osteogenesis imperfccta typc 111. Dclincition ofthe phenotype with referenec to genctic hctcrogencity. Atn JMed Genet 1986:23:821-32.

x Glanzmann E. Familiarc ostcogcncsis impcrfcctat (typus Vrolik)und ihrc Bchandlung mit Vitamin D-Stoss. Bull Sclhveiz AkadMed Wi.s.s 1944:1:180-90.Kaplan M, Baldino C. Dysplasie pcriostale paraissaint familialcet transmise suivant Ic mode Mendelian reccssif. Arc(i 1'r Pediair1953:10:94-3-50.Adatia MD. Ostcogenesis impcrfccta-ai casc rcport. J ItndianMed Profession 1957:4:181 0-2.LiCvrc JA. La fragilitc osscusc constitutioncllc. Etude dc 25families comportant 53 maladcs. Rev Rhutn Mal O.steoartic1959:26:420-32 (obs 23).Awwatad S, Rcda M. Ostcogcnesis impcrtcctat. Rcvicw ollitcrature with a rcport on three cicses. Arch 1'ediatr 196()177:280-90).

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14 Aylsworth AS, Seeds JW. Guilford WB, Burns CB, WashburnDB. Prenatal diagnosis of a severe deforming type of osteo-genesis imperfecta. Am J Med Geniet 1984:19:70)7-14.Rohweder HJ. Ein Bcitrag zur Frage des Erbganges derOsteogenesis imperfecta Vrolik. Arch Kiniderheilkd 1953:147:256-62.Maloney FP. Osteogenesis imperfecta of early onset in threemembers of an inbred group: '?recessive inheritanec. In:Bergsma D, ed. Skeletal dvsplasias: cliniical delinieationt of birth

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24 Office of Population Censuses and Surveys. Series FMI (liV),1986.

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consecutive siblings. J Pediatr 1954;44:264-8.27 Hein BJ. Osteogenesis imperfecta with multiple fractures at

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32 Braga S, Passargc E. Congcnital ostcogcncsis impcrfccta inthrcc sibs. Hum Geniet 1981;58:441-3.

33 Stephens JD, Filly RA, Callcn PW. Golbus MS. Prcnataldiagnosis of ostcogenesis imperfccta typc 11 by rcal-timeultrasound. Hum Genet 1983;64:191-3.

34 Patcl ZM, Shah HL, Madon PF, Ambani LM. Prenataldiagnosis of Icthal ostcogcncsis impcrtccta (01) by ultra-sonography. Pretiatal Diagtiosis 1983;3:261-3.

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3" Ghosh A, Woo JSK, Wan CW, Wong VCM. Simplc ultrasonicdiagnosis of ostcogcncsis impcrfccta typc If in carly sccondtrimestcr. Prentatal Diagtosis 1984:4:235-4(0.

Correspondence and requests for reprints to Dr E MThompson, Mothercare Unit of Paediatric Genetics.Institute of Child Health, 30 Guilford Street,London WCIN lEH.

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