565J Med Genet 1994;31:565-569

Brief papers

Two sibs who are double heterozygotes forachondroplasia and pseudoachondroplasticdysplasia

C G Woods, J G Rogers, V Mayne

AbstractWe report a family in which two sibs haveboth achondroplasia and pseudoachon-droplastic dysplasia. The mother hasachondroplasia and the father has pseu-doachondroplastic dysplasia, which hehad inherited from his father. Both chil-dren appeared typical of achondroplasiaat birth. By 1+ years they had developed afixed lumbar kyphosis with gibbus andhad additional x ray changes unusual forjust achondroplasia and suggestive ofpseudoachondroplastic dysplasia. Subse-quently both children have shown char-acteristic features of both conditions andhave grown less well than expected forachondroplasia. Radiographs show thestriking synergistic effects of the two con-ditions. MRI in both sibs confirmed brainstem compression at the foramen mag-num. This may be an important compli-cation and should be actively sought inany double heterozygote.

(J Med Genet 1994;31:565-569)

11 L F-r Lf--1 2 3 4

III

1 2 3 4 5 6 7

IV1 2 3

U Pseudoachondroplasia

( Achondroplasia

* Both conditions

Figure 1 Family pedigree showing birth order and thosewith skeletal dysplasias.

Victorian ClinicalGenetics Service, TheMurdoch Institute,Royal Children'sHospital, FlemingtonRoad, Parkville,Melbourne, Victoria3052, AustraliaC G WoodsJ G Rogers

Department ofRadiology, RoyalChildren's Hospital,Flemington Road,Parkville, Melbourne,Victoria 3052,AustraliaV Mayne

Correspondence toDr Woods.

Received 17 November 1993Revised version accepted forpublication 3 March 1994

Achondroplasia and pseudoachondroplasticdysplasia are separate and specific autosomaldominant causes of disproportional dwarfism.We describe the double heterozygote effects ofthese conditions in two sibs born of an achon-droplastic mother and a father with pseudo-achondroplastic dysplasia.

Case reportsThe pedigree is shown in fig 1. The father of thechildren, III.1, has pseudoachondroplastic dys-plasia inherited from his father, I. 1. Hisgrandfather was also affected. The mother ofthe children, III.2, has achondroplasia as theresult of a new mutation.The father, III.1, has windswept deformity

of his legs but otherwise both he and themother, III.2, are in good health and have no

significant orthopaedic or neurological symp-

toms. Both have been known to our departmentsince early childhood and their diagnoses are

secure based on longitudinal clinical and radio-logical observation. This couple were coun-

selled after marriage of the 1 in 4 chance of anormal child, 1 in 4 chance of a compound

heterozygote, and 1 in 4 chance of achondropla-sia alone and 1 in 4 chance of pseudoachon-droplastic dysplasia alone.The couple have three children, two females,

IV.1 and IV.2, and a male, IV.3. The childrenIV.2 and IV.3 are shown in fig 2.

CASE 1The first child, IV. 1, was born after anuneventful pregnancy and delivered by caesar-ean section. Achondroplasia was apparent atbirth. She was very short (40 cm, < 3rd centile),with mesomelic limb shortening, a large head(90th centile), spatulate hands with inability toapproximate the fingers in extension, hypoto-nia, and marked hyperextensibility of the wristsand ankles. She had typical radiographic find-ings of achondroplasia in the first year of life(not shown), lucent zones in the proximal fem-ora, narrowing of the interpedicular distancesin the lower lumbar spine, and short lumbarpedicles. The iliac wings were short and squareand the acetabular roof was horizontal withnarrowing of the greater sciatic notch. At 1year, kyphosis of the thoracolumbar spine onsitting was noted and was not totally correctedwhen lying. Spinal bracing with a body jacket

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/Figure 2 Four views offemale III.2 on the right and her brother III.3 on the left.III.2 aged 3f years has achondroplasia and pseudoachondroplastic dysplasia, and III.3aged 18 months has achondroplasia. Note the typical facies, body proportions, and stanceof achondroplasia in both, and that III.2 is shorter than her younger brother III.3. Hisventriculoperitoneal shunt is visible substernally.

for six months failed to prevent progressivekyphosis.From 9 months of age, x rays showed pro-

gressive anterior wedging of vertebrae particu-larly at the apex of the kyphosis, typical ofpseudoachondroplastic dysplasia (fig 3B, C, D,and E). The gibbus became fixed by 1i years.By 5 years severe radiographic changes charac-teristic of pseudoachondroplastic dysplasiawere apparent as well as those expected forachondroplasia. Wedging, anterior tongue-likeprotrusions, and kyphoscoliosis were present aswas delayed capital femoral epiphysis ossifica-tion (fig 3A). The marked epiphyseal changes ofpseudoachondroplastic dysplasia and combinedshortening of long bones seen in both con-ditions are shown in fig 3 F-K.Her development and health have been nor-

mal apart from the acquisition of gross motorskills. She had min'or dilatation of the cerebralventricles suspected:clinically and confirmed byultrasonography which did not progress after 1year of age. From the age of 2 years her bodyshape, gait, and posture has become typical ofpseudoachondroplastic dysplasia. Her growthhas been slower than expected in achondropla-sia.I From the age of 3 years she had instability

of the knees and ankles, a waddling gait, slightbowing of the knees, and found it difficult towalk. Her wrists are also lax. Recently herexercise tolerance has diminished although shehas no respiratory or cardiac symptoms nordiscomfort on walking. Brain stem or spinalcord compression was suspected and an MRIscan performed (fig 3 L, M, N). This confirmedcompression of the brain stem at the level of theforamen magnum with posterior flattening, butno obvious brain stem damage. A narrowedlower spinal canal beneath the corda aquina wasalso seen. A decompression of the foramenmagnum and posterior cranial fossa was per-formed. The bone in the region of the foramenmagnum was deeply shelved and difficult toremove. Postoperatively her gait is steadier, butshe still falls and is clearly weak in her lowerlimbs.

CASE 2The second child, IV.2, was bom after anuneventful pregnancy and delivered by caesar-ean section. A clinical diagnosis of achondro-plasia was made at birth. Her head circumfer-ence at birth was 28 cm (on the 25th centile for

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Two sibs who are double heterozygotes for achondroplasia and pseudoachondroplastic dysplasia

Figure 3 X rays and MRI scans offemale III.1 at 5 years unless otherwise stated. (A) AP pelvis, (B) AP spine, (C) lateral spine at 21 months,(D) lateral spine at I year, (E) lateral spine at 9 months, (F) right femur at S years, (G) AP left forearm, (H) left lower leg, (I) left foot, (J)left hand, (K) AP left shoulder, (L) Ti weighted MRI of brain showing brain stem compression at the foramen magnum, (M) Ti weighted MRI ofspinal cord showing gibbus and mild lumbar stenosis, (N) T2 weighted MRI of brain showing stem compression at the foramen magnum but with nofeatures of brain stem damage.

Figure 4 X rays offemale III.2. (A) Lateral spine at 17 months showing kyphosisand anterior wedging of lumbar vertebrae, (B) lateral spine at 3 years showingkyphosis, lumbar gibbus, and more marked anterior wedging of lumbar vertebrae, (C)AP spine and pelvis at 3 years showing lumbar platyspondyly and interpeduncularnarrowing of lumbar vertebrae.

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EF_ ' ^.Figure 5 X rays of male III.3. (A) AP spine at 22 months, (B) lateral spine at 15 months, (C) CT scan of brainat 11 months, (D) left hand at 22 months, (E) AP pelvis at 22 months.

achondroplasia2), by 3 months it was on the50th centile, and by 18 months it was on the75th centile. Thereafter growth followed the75th centile. Ultrasound scans of her headduring this period showed mild dilatation of thelateral and third ventricles. By 1 year she haddeveloped a fixed lumbar kyphosis. Radio-graphs taken at 17 months and 3 years of ageconfirmed that she too had pseudoachondro-plastic dysplasia as well as achondroplasia (fig

4). As with her sister, motor milestones weredelayed, but otherwise developmental progresshas been normal. She has not had any ENTproblems, joint stiffness, swelling, or pain. Shehas grown less well than expected for achon-droplasia after the first year of life. On examina-tion at 31 years she had typical findings ofachondroplasia, a fixed lumbar gibbus, a wad-dling gait, and marked laxity of her wrists,knees, and ankles. Her strength and reflexes

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Two sibs who are double heterozygotes for achondroplasia and pseudoachondroplastic dysplasia

were normal but tone was reduced. An MRIscan of the neuraxis showed stenosis of thecraniocervical junction with indentation ofstructures by the posterior margin of the fora-men magnum. She developed signs of progres-sive urinary retention. She had the same opera-tion as her older sib and with identical findingsof a deeply shelved foramen magnum. Posto-peratively the urinary retention has resolvedand her mother feels her gait has improved.

She is shown with her brother, IV.3, who hasachondroplasia in fig 2.

CASE 3The third child was a boy, IV.3. At birth he hadachondroplasia with characteristic changes con-

firmed radiologically. Rapid head growth was

confirmed by 9 months. Ultrasound scanning at6 months showed moderate dilatation of thelateral ventricles and to a lesser extent the thirdventricle. A CT scan confirmed hydrocephalusand a ventriculoperitoneal shunt was inserted(fig 5C). Lateral spine x rays taken at 15 and 22months (fig 5A and B) were clearly differentfrom those of his two sisters, showing only thekyphosis and interpeduncular narrowing ofachondroplasia. He has no clinical or otheradditional radiological findings other than thoseexpected for achondroplasia (fig 5 D and E).

DiscussionAt birth the two females, IV. 1 and IV.2,appeared to have achondroplasia. The develop-ment of a fixed lumbar gibbus, unusual spinalchanges, increasing joint laxity of the hands,and characteristic gait and hand posture madethe presence of the pseudoachondroplastic dys-plasia apparent. The two females now havetypical clinical and radiological findings ofachondroplasial and pseudoachondroplasticdysplasia,4 whereas the brother, IV.3, has onlythe findings of achondroplasia.With the occurrence of both conditions in

our patients, we note that the followingfeatures suggest synergy of the primary skeletaldefects. The development of anterior tongues

in vertebral bodies in pseudoachondroplasticdysplasia is unusual before the age of 2 years,but was seen earlier in these two females. Bothchildren are unusually short and growingpoorly. Both children have required posteriorfossa surgery for cord compression at the levelof the foramen magnum. This is a knowncomplication of achondroplasia,5 but its occur-rence in both III.1 and III.2 may in-dicate that it is a common complicationof achondroplasia/pseudoachondroplastic dys-plasia double heterozygotes. In view of thisexperience we feel that an MRI scan should beperformed at the earliest opportunity as thecord damage appears to be progressive. If com-pression is confirmed early, surgery may lead toa reduction in neurological deficit.A previously described child with achon-

droplasia and pseudoachondroplastic dysplasiahad similar clinical and x ray findings to thosedescribed here.6 In contrast to our cases whohad foramen magnum compression, only a nar-rowed lumbar spinal canal was found on MRIimaging.The interaction of the two conditions in these

children seems relatively mild in comparisonwith homozygous achondroplasia which causesa more severe phenyotype.7The appearance of the x rays of the spine and

the demonstrable narrowing of the canal onMRI scan raises questions about the futureproblems and their management for these sibs.

We gratefully acknowledge the expert assistance of Dr EthnaPhelan and Professor David Danks.

1 Horton WA. Standard growth curves for achondroplasia. 7Pediatr 1978;93:435-8.

2 Dawson DV. Confidence bands for the growth of head cir-cumference in achondroplastic children during the first yearof life. Am 7 Med Genet 1980;7:529-32.

3 Spranger JW, Langer LO, Wiedemann HR. Bone dysplasias:an atlas of constitutional disorders of skeletal development.Philadelphia: Saunders, 1974:55-61.

4 Hall JG. Pseudoachondroplasia. Birth Defects 1975;11(6):187-202.

5 Hecht JT. Long term neurological sequelae in achondroplasia.Eur J Pediatr 1984;143:58-60.

6 Langer LO, Schaefer GB, Wadsworth DT. Patient withdouble heterozygosity for achondroplasia and pseudo-achondroplasia. Am J Med Genet 1993;47:772-81.

7 Pauli RM, Conroy MM, Langer LO, et al. Homozygousachondroplasia with survival beyond infancy. Am 7 MedGenet 1983;16:459-73.

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