Journal of Medical Genetics (1970). 7, 22.

Severe AchondroplasiaDemonstration of Probable Heterogeneity within this Clinical Syndrome

D. C. WALLACE, LESLEY A. EXTON, D. A. PRITCHARD, Y. LEUNG, andR. A. COOKE

From Queensland Institute of Medical Research, and Royal Brisbane Hospital, Brisbane, Australia

True achondroplasia is a well-delineated anddistinct entity as familiar to the layman as it is to themembers of the medical profession (Maroteaux andLamy, 1964). In the past the designation was oftenassigned to a hotchpotch of entities such asMorquio's disease and spondylo-epiphysial dys-plasia (McKusick, 1966; Maroteaux and Lamy,1959; Jacobsen, 1939). It is considered to be duein all instances to a dominant allele, and is usuallythe result of a new mutation, as the reproductivefitness of sufferers is much lower than normal(M0rch, 1941). Certainly there is little reason tosuppose that there is any genetic heterogeneityamong the sufferers from the more commonly seenform of this disorder. The question of whetherthere might be a different variety of the disease,presenting in a more severe form and with recessiveinheritance, arose when there was born to a youngBrisbane couple a second child afflicted, like theearlier sib, with a very severe form of chrondro-dystrophy associated with multiple congenitaldefects.

The FamilyThe immediate family tree is shown in Fig. 1. Mother

and father were both young and both apparently in excel-lent health. The mother, aged 19 at the date of birth ofthe second affected child, had had two male children bydifferent fathers before she married. These children hadbeen adopted, and in consequence could not be studied,but the information that they were perfectly normalhealthy infants is reliable since any defect would haveprevented their legal adoption. The mother was theyoungest of a family of seven, and had grown up indifficult circumstances, her mother dying by suicidewhen she was young, and she herself having beenbrought up in institutional care. She had one brother,the fourth of the sibship, who was said to have died at theage of 5 days from renal agenesis, but the report, depend-ing as it does only on the mother's impression of what

Received 20 October 1969.

she had been told, is unreliable. Apart from this theimmediate family are living and have no skeletal abnor-mality.The father is aged 20, and his mother was of Maori

descent. He is the eldest of three normal boys. Themother lost stillborn twins, sex unknown, between thesecond and third boys. The more distant family as faras can be ascertained on both sides is normal.The two older boys were born on 27 October 1964 and

21 November 1966, at 40 and 41 weeks' gestation andweighed 2665 g. and 2863 g., respectively. Deliverywas normal. Both had a normal neonatal period andboth were adopted as soon as they were free to leavehospital.

Case 1 (first abnormal child). This child was bornon 26 February 1968, at 36 weeks' gestation, a pheno-typic female. Pregnancy was complicated by somedegree of hydramnios and premature rupture of themembranes. Delivery was normal, and on delivery thebaby was noted to have multiple deformities. A weakheart beat was detected, but efforts at establishing res-piration were unsuccessful. The placenta was normalwith a battledore insertion of the cord, weight 737 g.At necropsy the child was noted to have a weight of

1814 g., crown-rump length of 32 cm., rump heellength of 11 cm., and head circumference of 33 cm.Arms and legs were grossly shortened and the rib cagewas as grossly deformed, with the costochondral junc-tion being much posterior in position. The appearances

FIG. 1. Immediate family tree of the propositi. Black symbolsindicate the affected individuals. Slashed symbol indicates death ininfancy. Small circles indicate stillbirth.

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Severe Achondroplasia 23were those of classical achondroplasia (Fig. 2). Therewas a total cleft palate and a centrally situated defect in _the upper lip of differing appearance to the commonharelip. Internally the larynx was normal with a smallepiglottis. The trachea and main bronchi were smallbut otherwise normal. The pleural cavities were verysmall and the lungs small, pale, and hypoplastic. Thepulmonary vessels were normal in anatomy. Most ofthe thoracic cavity was taken up by heart and thymus.The diaphragm was displaced downwards to a consider-able degree, so that the liver and spleen were totallybelow the costal margin and the abdomen was conse-quently quite distended. The heart and great bloodvessels were normal. The brain showed dilatation ofthe lateral and third ventricles which was quite conspicu-ous and which was the result of stenosis of the cerebralaqueduct through which a probe could not be passed.The fourth ventricle was also dilated. Microscopicalexamination confirmed the presence of pulmonaryhypoplasia. The costochondral junction (Fig. 3)showed the typical abnormality of achondroplasia, withfailure of palisade formation of cartilage cells and irregu-lar ingrowth of capillaries into cartilage. There was arough, uneven plane between cartilage and osseoustissue. Bony trabeculae were large, and solid masses _abutted onto cartilage.

Case 2 (second abnormal child). This child, also aphenotypic female, was bonm on 22 March 1969, at 34weeks' gestation. Pregnancy on this occasion wascomplicated by some pyelonephritis and renal pain FIG. 2. External appearance of Case 1 at necropsy.

A9s

FIG. 3. Low power view of the zone of endochondral ossification at the costochondral junction in Case 1. The disruption of the normalalignment of the cartilage cells and the irregular ingrowth of bone-forning tissue is evident. (Haematoxylin and eosin. x 200.)

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Wallace, Exton, Pritchard, Leung, and Cooke

FIG 4. xl'

at

FIG. 4. Extemlal appearance of Case 2 at necropsy.

requiring a short period in hospital at six months' gesta-tion, but there was no hydramnios. Delivery wasnormal, and on delivery the baby, like its sib, was notedto have multiple congenital deformities, and died three-quarters of an hour later. Birthweight was 1680 g.,crown-rump length 28-5 cm., crown heel length 38-5cm., head circumference 31-5 cm. The placental weightwas 708 g. and it was of normal appearance.At necropsy the child showed very much the same

appearance as the earlier infant (Fig. 4 and 5). Therewas gross shortening of arms and legs and deformity ofthe rib cage. There was a partial central cleft lip, andalso a defect of the soft palate, with a high arched hardpalate. There was a considerable degree of hydro-cephalus with diastasis of the cranial sutures. The lungsshowed the same hypoplasia as before, but on this occa-sion there was a congenital heart lesion as well. Thepericardium and pericardial cavity were normal. Theheart showed a poorly developed right ventricle, and aconspicuous hypoplastic pulmonary artery, with no pul-monary valve, arose from it. The ductus arteriosus waswidely patent. The mitral, tricuspid, and aortic valveswere normal. There were large atrial and ventricularseptal defects. The myocardium was normal. It wasconsidered that the liver and thymus were both largerthan might have been expected. There was a grosshydrocephalus, with enlargement of the lateral andfourth ventricles. The other organs were normal.

Microscopical findings were not greatly different fromthe previous infant. Cartilage structure itself appearedwithin normal limits, but the formation of bone from

FIG. 5. General appearance of the thorax and abdominal viscera atnecropsy of Case 2. The extreme constriction of the rib cage and thedisplacement of the liver are shown.

cartilage was disordered, as in the earlier child. Thesections of brain showed heavy focal mononuclearaggregations, particularly subependymally (probablyremnants of embryonic tissue) some perivascular cuffing,and a mild increase in glial tissue.

DiscussionThere appears little doubt that these infants were

suffering from the same condition and that its ex-pression, though lethal in both, was more severe inthe second child. The gross anatomical changes,together with the microscopical appearance of theendochondral ossification as shown in the firstchild, make it difficult to describe this condition byany other title than achondroplasia. This disorderin the adult gives rise to a highly characteristicclinical picture. In these infants, where this pic-ture has not had time to develop one must beware ofmistaking the diagnosis, but there is no other well-delineated condition which can be confused withthis. Morquio's disease, fragilitas ossium, Hurler'ssyndrome, and the other forms of dwarfism eachhave their own highly characteristic clinical andhistological picture, and in none of them is the dis-order of ossification of the type shown here manifest.The condition of diastrophic dwarfism (le nanismediastrophique) described by Lamy and Maroteaux(1960) is probably the same condition as seen here.

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Severe Achondroplasia

In their paper they described the radiological andclinical appearances of three surviving cases, andput forward cogent reasons for considering the condi-tion as being distinct from classical achondroplasia,but the paper contained no description of the histo-logical appearances of cartilaginous ossificationwhich in our cases so much resembled that of trueachondroplasia, that we are content to use thisterm to describe the condition.

Achondroplasia is inherited as an autosomaldominant, though as noted already, owing to thelow reproductive fitness of those afflicted with thedisease, a large proportion of cases represents newmutations. The occurrence of the disease in twosibs makes the likelihood of recurrent mutation inthis case so remote as to be well-nigh impossible.The fact that the mother had already given birth totwo perfectly normal infants, and the fact that shewas seen to have had uneventful pregnancies, makesthe possibility of a common intrauterine environ-mental factor almost as remote. No material wasavailable for attempting to karyotype the infants,but as the parents each had a normal karyotype, thepossibility of a chromosomal abnormality being thecause of the condition is extremely unlikely. Themost probable explanation is that one is observingthe expression of a rare recessive allele in the homo-zygous state.

Potter in her textbook (Potter, 1961) states that,of 10 achondroplastic infants in her experienceamong more than 100,000 births in Chicago, all butone child died shortly after birth. She has givenreference (Potter and Coverstone, 1948) to a familywith a normal mother and father and five affectedchildren, but the documentation is poor and thefamily was reported on hearsay evidence only. Shepostulates a mutant clone of cells giving rise toovarian tissue containing the abnormal allele in anotherwise normal individual who can then give birthto multiple affected children. The concept isfeasible in theory, but we are aware of no docu-mented example of such abnormal gonadal tissue ingenetic literature.

Achondroplasia has been the subject of analysis inregard to mutation rates (Morch, 1941; Popham,1953) and the rates estimated of 4 x 10-5 per gameteare very high. It has been suggested (Stern, 1960)that this is a falsely high estimate owing to thedisease consisting of several distinct genetic enti-ties. The distinction of syndromes such as the onedescribed here gives strong support to such sug-gestions.The matter was discussed at some length by

Maroteaux and Lamy. They noted that in 1964though the existence of an autosomal recessive mode

of transmission in achondroplasia had been thesubject of numerous discussions, not a single pub-lished observation was adequate to prove such aclaim. They remarked that the examples offeredin support of such a claim concerned not achon-droplasia, but similar affections. The matter isprobably one of semantics. If one accepts the termachondroplasia as referring to the disease causedby the dominantly effective allele, then obviouslythe disease in these two children, being due to adifferent allele, quite possibly at a different locus, isnot achondroplasia. However, if one uses theterm to describe a specific defect of endochondralossification, then these children do indeed sufferfrom achondroplasia of a demonstrably differentform, with a high probability of being due to reces-sive inheritance.The separation of distinct genetic entities with

different patterns of inheritance, and the laterdemonstration of different clinical appearances inthese diseases, has been shown for several groups ofdisease such as icthyosis and ovalocytosis (Wells andKerr, 1965; Morton, 1956).There are several diseases in animals which lead

to lethal effects from skeletal disorders similar toachondroplasia and which are the effect of a homo-zygous recessive allele. Such are the 'bulldogcalves' obtained by cross-breeding 'Dexter' cattleand also the achondroplastic condition in rabbits.The presence of hydrocephaly and hypoplasia of thelungs in the two infants under discussion as well asthe harelip and cleft palate could be explained assecondary results of development of the skeleton.The congenital heart lesion in the second case maywell have had a similar cause. One speculateswhether some of the cases of grave achondroplasia,such as those described by Thurner (Thurner,Mignani, and Hussl, 1959), might be due to muta-tions at the same locus as has possibly given rise tothe condition seen in the cases described here.We conclude that the balance of the evidence

favours the action of a genetic entity distinct fromclassical achondroplasia in this family. There aregood clinical grounds for differentiating the con-ditions because of the presence of the additionalmanifestations of harelip, hydrocephalus, and in oneof the infants, congenital heart disease. Equallywell, there is evidence from the population geneticsof achondroplasia for doubting whether it has asingle genetic cause. The only alternative hy-pothesis which occurs to us, that of a mutant clone ofcells giving rise to abnormal gonadal tissue fromwhich ovum or sperm may have been derived,seems in consequence to be a less likely explanationof the phenomena reported here.

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Wallace, Exton, Pritchard, Leung, and Cooke

Summary

A description is given of two severely affectedachondroplastic sibs, with multiple additional con-

genital abnormalities including harelip, hypoplasticlungs, and hydrocephaly. The parents were pheno-typically normal and unrelated. The mother hadhad two normal children by previous unions.Grounds are given for suspecting that this is an

example of recessive inheritance and that achon-droplasia may consist of more than one geneticentity.

We are indebted to Dr. A. Knyvett, General MedicalSuperintendent of the Royal Brisbane Hospital for per-mission to publish these cases, and to Mr. B. Stewart forhis assistance in the preparation of the photographs.

REFRNCEs

Jacobsen, A. W. (1939). Hereditary osteochondrodystrophia de-formans. A family with 20 members affected in 5 generations.Journal of the American Medical Association, 113, 121-124.

Lamy, M., and Maroteaux, P. (1960). Le nanisme diastrophique.Presse Midicale, 68, 1977-1980.

McKusick, V. A. (1966). Heritable Disorders of Connective Tissue,3rd ed., p. 339. C. V. Mosby, St. Louis.

Maroteaux, P., and Lamy, M. (1959). Les formes pseudoachon-droplasiques des dysplasies spondylo-epiphysaires. Presse Medi-cale, 67, 383-386.

, and - (1964). Achondroplasia in man and animals.Clinical Orthopaedics and Related Research, 33, 91-103.

Morch, E. T. (1941). Chondrodystrophic Dwarfs in Denmark (Sup-plemented with Investigations from Sweden and Norway) withSpecial Reference to the Inheritance of Chondrodystrophy. Munks-gaard, Copenhagen.

Morton, N. E. (1956). The detection and estimation of linkagebetween genes for elliptocytosis and the Rh blood type. AmericanJournal ofHuman Genetics, 8, 80-96.

Popham, R. E. (1953). The calculation of reproductive fitness andmutation rate of the gene for chondrodystrophy. ibid., 5, 73-75.

Potter, E. L. (1961). Pathology of the Fetus and Infant, 2nd ed.,p. 520. Year Book Publishers, Chicago.

, and Coverstone, V. A. (1948). Chondrodystrophia foetalis.American Journal of Obstetrics and Gynecology, 56, 790-793.

Stem, C. (1960). Principles of Human Genetics, 2nd ed., p. 455.W. H. Freeman, San Francisco.

Thurner, J., Mignani, G., and Hussl, B. (1959). Chondrodysplasia(-dystrophia) fetalis hyperplastica in mikroradiographischenUntersuchungen. Virchows Archiv Abteilung A. PathologischeAnatomie, 332, 407-419.

Wells, R. S., and Kerr, C. B. (1965). Genetic classification ofichthyosis. Archives of Dermatology, 92, 1-6.

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