Journal of Medical Genetics 1987, 24, 602-608

Epiphyseal dysplasia of the femoral head, mildvertebral abnormality, myopia, and sensorineuraldeafness: report of a pedigree with autosomaldominant inheritanceK D MACDERMOT*, S C ROTHt, C HALLS, AND R M WINTER*From * The Kennedy Galton Centre, Harperbury Hospital, and Clinical Research Centre, Watford Road,Harrow; tGuy's Hospital, London SE] 9RT; and f The Hospitals for Sick Children, Great Ormond Street,London WCJN3JH.

SUMMARY A family is presented with short stature, femoral epiphyseal dysplasia, mild vertebralchanges, and sensorineural deafness inherited as an autosomal dominant trait. Myopia andretinal detachment presenting in adult life were also present in some affected members. Wesuggest that this disorder may be a distinct entity within the spondyloepiphyseal dysplasia groupof disorders.

The group of conditions classified as multipleepiphyseal dysplasia (MED) and spondyloepiphysealdysplasia (SED) present with characteristic radio-logical changes of the epiphyses of the long bonesand vertebrae. Associated features, in particularcleft palate, myopia, retinal abnormality, dys-morphic facies, and deafness, have been describedsingly or in combination in patients with spondylo-epiphyseal dysplasia congenita (SEDC).'3 Wepresent a family with an autosomal dominant condi-tion that clearly falls into this group of disorders, butappears to show a previously undescribed combina-tion of features segregating together with minimalvariability.

Case reports

CASE 1The proband (IV.11, fig 1) was referred because ofundiagnosed familial short stature at the age of twoand a half years. Pregnancy, delivery, and develop-mental milestones were unremarkable. The birthlength is not known. Her height and weight wererecorded as being on the 10th centile at the age ofone year and the hip joint was found to be stable atthat age. At 18 months of age, a waddling gait wasnoticed with hip and knee pain which presented asdiscomfort on movement. An episode was describedwhen the child was unable to get up from kneeling

Received for publication 12 February 1986.Revised version accepted for publication 14 August 1986.

position because of inability to straighten her leg. Inaddition, surgical boots with inserts were needed be-cause of abnormally shaped heels. The height andweight were just below the 3rd centile at 18 monthsof age. Unilateral hearing loss was discovered onroutine testing at two years of age.On examination at the age of two and a

half years she had short stature with a short neckand mild shortening of the spine. Lumbar lordosis,prominent heels, and bilateral clinodactyly werepresent. The face was triangular, with a protrudingforehead and bluish sclerae. There was no apparenthypertelorism, malar hypoplasia (fig 2), or cleftpalate. When she was reviewed at the age of threeand a half years, her symptoms and clinical findings

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FIG 1 Pedigree illustrating autosomal dominanttransmision ofepiphyseal dysplasia of the femoral head,mild vertebral abnormality, myopia, and sensorineuraldeafness.

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Epiphyseal dysplasia of thefemoral head, vertebral abnormality, myopia, and deafness

FIG 2 Family photograph showingthe proband aged three and a halfyears (lower centre), proband'smother (right), maternal grandmother(left), and unaffected sib (centre).Normalfacial appearance with noevidence ofmalar hypoplasia.

were unchanged, except that her sclerae were white.There was no joint laxity or stiffness and no historyof fractures. The hips were stable. Head circum-ference was 50-3 cm (50th centile), weight 12-2 kg(3rd centile), height 84 cm (<3rd centile), uppersegment 50 cm, lower segment 34 cm (US/LS ratio1-47), and arm span 88 cm. Developmental testingshowed normal gross and fine motor function, visualspatial performance, and social behaviour.Language comprehension and picture recognitionwas very good, but pronunciation was poor.

Routine haematological and biochemical para-meters including thyroid function test were normal.Two dimensional electrophoresis of urinary glyco-saminoglycans showed a normal pattern. Hearingtests were compatible with unilateral sensorineuraldeafness up to 50 db. Ophthalmological examina-tion showed no abnormality of the disc, macula, orretinae and the ocular media were clear. It was notpossible to measure visual acuity because of the ageof the child, but after dilatation there was norefractive error.

CASE 2 (III.7)The mother of the proband is aged 36 years and hasshort stature, deafness, and myopia. The hearingdeficit was noted at the age of two years. Her speechis indistinct with a nasal quality. Waddling gait withintoeing was present from an early age, when shealso experienced pain in the hips and knees.Subsequently, in her second and third decades,referred pain from the hip joint and cervical spine

was her major symptom. Myopia was present fromearly teens. Her general health is good and she is ofaverage intelligence.On examination she had a short neck and mild

shortening of the spine, disproportionate to thelimbs. Her face showed no dysmorphic features andthe hands and feet were unremarkable. Mild lumbarlordosis was present. The height was 133 cm (<<3rd centile), weight 46-7 kg, lower segment 64 cm,upper segment 69 cm, US/LS ratio 1-07, arm span145 cm, and head circumference 54 cm (50thcentile). A prominent bony protrusion at the occiputwas present. She also had bilateral pes planuswithout a prominent heel and no clinodactyly.On ophthalmological examination the vision was

6/6 in each eye corrected. The anterior chamberswere normal. Following dilatation, negligibleperipheral cortical lens opacities were seen in theright eye but they were not thought to represent anearly cataract. The retina and vitreous of each eyewas normal. Chromosome analysis showed a normalfemale karyotype.

CASE 3 (II.3)The maternal grandmother of the proband, aged 65years, has short stature, deafness, a history of retinaldetachment, and has had bilateral hip joint replace-ment. She has had a waddling, intoeing gait fromchildhood, but deafness was only noticed in the thirddecade. Hip and knee pain was present for manyyears and bilateral hip replacement was indicated inthe fourth decade. She is blind in her right eye. The

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K D MacDerinot, S C Roth, C Hall, and R M Winter

blindness is attributed to a childhood injury, whichshe does not recall. At the age of 40 she had multipleretinal detachments and subsequently developed acataract in her left eye.On examination she was short and obese with a

very short neck and trunk. Her facial features wereunremarkable. A palpable occipital protrusion waspresent, resembling that of her daughter. The handsshowed marked osteoarthritic interphalangeal andmetacarpophalangeal enlargements and elbow andfinger extension was reduced. Her height was 137cm (<< 3rd centile), upper segment 70 cm, lowersegment 67 cm, US/LS ratio=104, arm span 146cm, and head circumference 54-5 cm (50th centile).Audiometry showed bilateral reduction in bothbone and air conduction. She has worn a hearing aidfor the last 20 years.

OTHER FAMILY MEMBERSThe proband's brother (IV.10), aged 12 years, isasymptomatic and of normal stature (fig 2). Hisheight is 141 cm (25th centile), lower segment 64cm, upper segment 77 cm, US/LS ratio 1-2, armspan 138 cm, and head circumference 55-5 cm (50thto 90th centile). His hearing is normal and radiolo-gical appearance of his hip joint is normal. Familymembers 111.1, 2, 3, 4, 5, and 6 were reported to beasymptomatic, with adult heights of 150 to 160 cm.All their offspring are normal. Subjects 11.1 and 2are still alive, with no evidence of the disorder. 1.2was reported as being short with waddling gait, withperhaps mild deafness, but no history of eyeproblems.

Radiological features

CASE 1

Pelvis (fig 3)At the age of 20 months, the configuration of iliacwings was abnormal with lack of normal flaring andhorizontal acetabulae. The pubic rami were ossified.The capital femoral epiphyses were small, irregular,and fragmented corresponding to a skeletal matura-tion of about six months. The femoral necks showedsome medial beaking.

Spine (fig 4)At the age of 20 months, some vertebral bodies were'pear shaped' and others biconvex (this oval orbiconvex configuration is a normal finding onlyunder the age of about one year). The odontoidprocess was partially ossified.

SkullThe base of the skull appeared abnormally steepwith relative deepening of the middle cranial fossa,giving rise to an increase in the angle between thefloor of the anterior fossa and posterior clivus. Nowormian bones were present.

Upper and lower limbsThe long bones were of normal proportions andnormally modelled. Apart from the capital femoralepiphyses, the configuration of epiphyses andmetaphyses was normal. Inferior calcaneal spurswere present bilaterally (fig 5). The bone matura-tion at the carpal bones appeared normal at the age

FIG 3 Case I. A P pelvis at the ageof 20 months showing abnormalconfiguration of iliac wings andhorizontal acetabulae. The capitalfemoral epiphyses are small andirregular with delayed bonematuration.

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Epiphyseal dysplasia of the femoral head, vertebral abnormality, myopia, and deafness

of 20 months. Clinodactyly and short middle phal-anges of the index fingers were present bilaterally(fig 6).

CASE 2

PelvisThe radiological appearance at the age of 27 yearsshowed symmetrical changes with abnormal iliacwing flaring and reduced cephalocaudal height withconstriction inferiorly and sloping acetabular roofs.The heads of the femora were flattened and incom-pletely covered, with subarticular cyst formationand loss of joint space indicating premature osteoar-thritis (fig 7). A radiograph of the left hip taken atthe age of 12 years showed a small, flat, irregularcapital femoral epiphysis with a normal femoralneck (fig 8).

SpineMild flattening with some irregularity of vertebralend plates was present. The pedicles were short witha reduction in the AP diameter of the spinal canal(fig 9).

Upper and lower limbsF: These showed no apparent shortening, normal bone

modelling, and no evidence of epiphyseal dysplasia,apart from the capital femoral ephiphyses.

SkullThe skull and odontoid peg appeared normal.

CASE 3

Pelvis (fig 10)FIG 4 Case 1. Lateral spine at the age of20 months. The radiological appearance before surgery showedBiconvex vertebrae are present in the dorsal region and pear reduced cephalocaudal height of the iliac wings withshaped vertebrae in the lumbar region. some constriction inferiorly above the acetabular

FIG 5 Case 1. Lateral left ankle.Calcaneal spur.

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FIG 7 Case 2. AP right hip aged 27years. Abnormal iliac

wing flaring and sloping acetabular roofs. The head of thefemur is flattened and incompletely covered, with subartic-

ular cystformation indicating premature osteoarthritis.

FIG 6 Case 1. Hands at the age of20months. Normal carpal bonematuration, bilateral clinodactvly, andshort middle phalanges of the indexfingers bilaterally.

FIG 8 Case 2. A P left hip aged 12 years. There is flattening,fragmentation, and sclerosis of the capital femoralepiphysis.Normal bone modelling.

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Epiphyseal dysplasia ofthefemoral head, vertebral abnormality, myopia, and deafness

roofs. The acetabula were sloping, with scleroticchanges secondary to osteoarthritis. The femoralheads were flattened and incompletely covered andthe femoral necks were short. There was complete

FIG 9 Case 2. Lateral spine. Vertebral end plate irregularityand short pedicles.

loss of joint spaces. Recent radiographs showedbilateral hip prostheses.

SpineSome platyspondyly and reduced intervertebralspaces were present. Thoracic scoliosis and wide-spread spondylotic changes were apparent.

Upper and lower limbsThere was no apparent shortening of long bones andno evidence of epiphyseal dysplasia.

Discussion

The differential diagnoses in this family includedconditions where skeletal abnormalities are associ-ated with deafness and ocular abnormality. Theskeletal abnormalities in our family consisted mainlyof severe capital femoral epiphyseal dysplasia andmild flattening of vertebral bodies. The pattern offemoral head dysplasia with some vertebral involve-ment and extraskeletal features resembles spondylo-epiphyseal dysplasia congenita (SEDC).3 In theirsurvey of 29 patients Spranger and Langer3 reportedvariability of epiphyseal and metaphyseal involve-ment between different persons and different sitesof the skeleton in the same person. The appearanceof a short neck, unusual configuration of the pelvis,and dysplasia of the capital femoral epiphysespresent in our family have been reported in surveysof cases with SEDC. 1-3 However, the epiphysealdysplasia in our family is mainly limited to the hipjoint, vertebral changes are mild, and the disorder'breeds true', suggesting a distinct entity within the

FIG 10 Case 3. APpelvis. Reducedcephalocaudal height ofiliac wings.The acetabula are sloping withsclerotic changes secondary toosteoarthritis. The femoral heads areflattened and incompletely covered.Thefemoral necks are short.

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group of spondyloepiphyseal dysplasias present atbirth.Our family manifests sensorineural deafness,

myopia with retinal detachment, and epiphysealdysplasia of the hip, all of which are characteristi-cally seen in Marshall/Stickler4 syndrome.Dysmorphic facial features, usually present inMarshall/Stickler syndrome, consist mainly of malarhypoplasia, a depressed nasal bridge, and cleftpalate. However, in our family the normal faciesand marked short stature are not consistent with thisdiagnosis. Beighton et at5 reported a family withmultiple epiphyseal dysplasia, myopia, and deaf-ness, also associated with malar hypoplasia. Inaddition, retinal thinning and crenated cataractswere found in affected members in this family.Detailed ophthalmological examination showedabsence of these findings in affected members of ourfamily. The proband's grandmother (case 3) devel-oped unilateral senile cataract at the age of 60 years.

Myopia and retinal detachment were importantadditional clinical findings in eight of 14 patientswith SEDC originally described by Spranger andLanger.3 Deafness was described in association withSEDC in three out of 12 patients studied by Wynne-Davies and Hall,2 and Fraser et all found four out offive patients with deafness in their study of SEDCassociated with severe visual handicap. Deafnesswas not included among the symptoms of SEDC bySpranger and Langer.

Perthes' disease and its variant, dysplasiaepiphysealis capitis femoris,6 also presents withearly childhood hip discomfort, but the evolution ofusually unilateral radiological changes is clearlydifferent and when bilateral it is always asymmetri-cal. Both of these disorders are usually sporadic, butfamilial cases have been reported.7Namaqualand hip dysplasia8 segregates as an

autosomal dominant trait and the skeletal changesof early fragmentation and flattening of the capitalfemoral epiphyses are very similar to those in our

family. Degenerative arthropathy subsequently de-velops, necessitating hip replacement. However, thevertebral changes are not as marked as in our familyand the onset is later in childhood. Deafness and eyepathology are not features of Namaqualand hipdysplasia.Upington disease9 consists of Perthes'-like hip

changes associated with ecchondromata of periph-eral joints, which are not present in our family.

In the syndrome described by Pfeiffer et al,'t1three brothers with epiphyseal dysplasia limited tothe femoral head, normal vertebrae, severe myopia,and perceptive hearing loss were reported. Theparents of these children were related and auto-somal recessive inheritance is therefore likely. Thisfamily most resembles our cases except for the modeof transmission and a normal radiological appear-ance of the spine in the affected males.Thus, it appears that whereas the family pre-

sented here manifests many features of spondy-loepiphyseal dysplasia congenita, the overall patternof abnormalities segregating together represents apreviously undescribed condition. Detailed histo-pathological'1 12 and molecular studies will beneeded for the precise subdivision of this hetero-geneous group of disorders.

References

Fraser GR, Friedmann Al, Maroteaux P, Glen-Bott AM,Mittwoch U. Dysplasia spondiloepiphysaria congenita and re-lated generalised skeletal dysplasias among children with severevisual handicaps. Arch Dis Child 1969;44:490-8.

2 Wynne-Davies R, Hall C. Two clinical variants of spondylo-epiphysial dysplasia congenita. J Bone Joint Surg (Br)1982;64:435-41.

3 Spranger JW, Langer LO. Spondyloepiphyseal dysplasia con-genita. Radiology 1970;94:313-22.

4 Baraitser M. Marshall/Stickler syndrome. J Med Genet1982;19:139-40.Beighton P, Goldberg L, Op't Hof J. Dominant inheritance ofmultiple epiphyseal dysplasia, myopia and deafness. Clin Genet1978;14: 173-7.

6 Meyer J. Dysplasia epiphysealis capitis femoris. Acta OrthopScand 1964;34: 183-97.

7 Wamoscher Z, Farhi A. Hereditary Legg-Calve-Perthes disease.Am J Dis Child 1963;106:131-4.

8 Beighton P, Christy G, Learmonth ID. Namaqualand hipdysplasia: an autosomal dominant entity. Am J Med Genet1984;19: 161-9.

9 Schweitzer G, Jones B, Timme A. Upington disease: a familialdyschondroplasia. S Afr Med J 1971;45:994-1000.

1 Pfeiffer RA, Junemann G, Polster J, Bauer H. Epiphysealdysplasia of the femoral head, severe myopia and perceptivehearing loss in three brothers. Clin Genet 1973;4:1414.Spranger J. The epiphyseal dysplasias. Clin Orthop1976;114:46-60.

12 Rimoin DL, Silberberg R, Hollister DW. Chondro-osseouspathology in the chondrodystrophies. Clin Orthop1976;114:137-52.

Correspondence and requests for reprints to Dr K DMacDermot, The Kennedy-Galton Centre forClinical Genetics, Harperbury Hospital, HarperLane, Shenley, Radlett, Herts WD7 9HQ.

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