Chondrodysplasia punctata—23 cases of a mild and relatively common variety

916

December 1976 The Journal o f P E D I A T R I C S

Chondrodysplasia punctata-23 relatively common variety

cases

of

a

mild and

A common form of chondrodysplasia punctata has been defined by characteristic clinical and radiologic features in 23 patients seen in Melbourne. The patients presented during infancy because of failure to thrive, apparent mental retardation, and/or unusual appearance. The typical facies is almost diagnostic, and the diagnosis is completed by findin~ punctate calcification in the calcaneum in lateral radiographs of the feet, and sometimes in other sites. Growth and developmental progress improved during childhood and the final outcome seems likely to comprise low normal height and intelligence with persistence of the typical facies. MiM cases probably pass unrecognized at present. Seventeen patients were male. Paternal age was significantly increased," however, family data did not support a genetic cause. Hlnesses during pregnancy were unusually frequent, and anticonvulsants taken during pregnancy may have had an etiologic role in some patients.

Leslie J. Sheffield, M.R.A.C.P., D.C.H.,* David M. Danks, M.D., F.R.A.C.P.,** Valerie M a y n e , M.B., B.S., M.C.R.A., and L u e i l l e A. H u t c h i n s o n , B.Se., Dip.Soc.Studs.,*** M e l b o u r n e , A u s t r a l i a

CHONDRODYSPLASIA PUNCTATA is a name given to

a group of bone dysplasias that can be divided into a number of subcategories>'-' All previous descriptions have indicated that these conditions are rare, but experience in Melbourne indicates that the earlier studies have neglected a relatively common but mild form. This paper describes 23 cases of this mild variety which can be diagnosed clinically and confirmed radiologically, especially during infancy. A very characteristic evolution of clinical and radiologic features became apparent during the study. Physical and mental development appear retarded in the early years, but it seems probable that these patients become small adults (approximately tenth percentile for height) with borderline low intelligence. *Holder of National Health and Medical Research Council Postgraduate Medical Scholarship. **Reprint address: Royal Children's Hospital Research Foundation, Flemington Road, Parkville, Victoria,Australia 3052. ***Supported by grantsfrom the Myer Foundation, R.E. Ross Trust. Morris Family Trust. and Little People'sAssociation of A ustralasia.

Vol. 89, No. 6, pp. 916-923

METHOD

OF STUDY

The patients were found during a search for all persons with bone dysplasias in Victoria, using the files of all teaching hospitals and canvassing all pediatricians and orthopedic surgeons. Most cases of chondrodysplasia punctata were ascertained from the radiologic records of the two pediatric teaching hospitals which have a total of about 80% of the pediatric beds in Victoria. The infants had been investigated for various symptoms, including failure to thrive. Some infants were diagnosed clinically among children with unusual facies referred to the Genetics Research Unit. Abbreviation used DPH: diphenylhydantoin Punctate calcification was recognized in roentgenograms of 44 patients, who could be classified by radiologic and clinical criteria. Twenty-three patients seemed to represent a distinct entity which is the subject of this report. Among the remaining 21 cases were several entities already well described in the literature (e.g.,

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Chrondrodysplasia punctata

9 17

Fig. 1. Progressive changes in the foot of patient shown in Fig. 3b. A, Puncta are seen in and around the calcaneum (age seven weeks). B, The calcaneum has ossified from two centers and now shows a "cleft" (age four years, nine months). C, The cleft is now represented as a sclerotic area and the calcaneum is shorter than normal (age six years).

Zellweger syndrome and some severe rhizomelic forms). However, some of these patients did not fit comfortably into any of the recognized categories. 1.~ They will be reported separately, with discussion of the inadequacies of the current classification. The living patients were located in person and examined by one or other of the authors. Longitudinal growth studies were begun in all patients and some have now been followed for three to four years. Past measurements were available in several others. The two adult patients supplied photographs showing their appearances as infants. Detailed histories of pregnancy and of the family were recorded from the parents of 21 of the 23 patients (including two who had died in infancy); 20 of the patients were seen in person. The parents of one infant who had died could not be contacted, and only the hospital records and postmortem reports were available.

RADIOLOGIC

FEATURES

The diagnostic features comprise fine ("paint-spattered") cartilaginous calcification with a very characteristic distribution plus a distinctive disturbance of ossifica-

tion of the calcaneum (Fig. 1) and of the vertebrae (Fig. 2). The most valuable radiologic examination was the lateral view oLthe foot which revealed punctate calcification in all 19 patients who were examined in the first year of life. Puncta were present in the calcaneum in 16 infants, elsewhere in the tarsus in two infants and in the phalanges of the toes in the remaining infant. The n u m b e r of puncta in each calcaneum varied from one to six, and they could be discerned only in lateral views in some infants. Puncta were seen in additional sites in m a n y patients. The lateral masses of the sacrum and coccyx were involved most often (ten patients) followed by lateral masses of other vertebrae (four patients), greater trochanter of femur (eight patients), and upper end of humerus (one patient). These puncta became indistinguishable from the ossified epiphyses once the latter enlarged sufficiently to include the region of cartilage involved. Tarsal puncta were still visible after two years of age in only five of the 23 patients, but were present at four years of age in two children. However, abnormal ossification of the calca-

9 18

SheffieM et al.

Fig. 2. Paravertebral puncta are shown and a prominent sagittal cleft in the seventh thoracic vertebra (age three weeks).

neum was apparent in 12 infants in whom two centers developed (Fig. 1, B) and later fused leaving a vertical cleft in the ossified bone visible until five to ten years of age. The calcaneum ended up abnormally short in some patients (Fig. 1, C). Disturbance of ossification of vertebral bodies was also frequent, producing coronal clefts in 11 infants and additional sagittal clefts in two infants. No residual deformity was seen in vertebrae of older patients. Hypoplasia of distal phalanges was seen in four infants, two of whom were born to mothers who took diphenylhydantoin during pregnancy? Distortion of the epiphyses of the femoral head occurred bilaterally in two older children and unilaterally in one child. One of the former children also had abnormal lower femoral epiphyses and was considered to have multiple epiphyseal dysplasia. PHYSICAL

APPEARANCE

The most constant physical feature was the characteristic facial appearance, especially the unusual shape of the nose. The tip of the nose was flattened as the result of a shortened columella and produced the appearance of a small child with his nose pressed flat onto a shop window (Fig. 3). (This nasal shape is normal in some races,

The Journal of Pediatrics December 1976

limiting the use of this diagnostic sign to Caucasians.) This appearance was present in all 20 patients who were seen personally and was visible in studio photographs available of another patient. It was first pointed out to the authors by the late Dr. Brian Turner of Sydney. An additional change in the nose, seen less constantly, was a depressed nasal bridge (Fig. 4). This has been described in the literature as a "saddle nose deformity" and was present in 16 of the 21 patients. The degree of flattening varied, but several had respiratory problems in the neonatal period owing to the inadequate nasal airway. This led to feeding difficulties, inhalation pneumonia, and head retraction in some infants. The degree of depression of the nasal bridge lessened with age (Fig. 5). Two patients, however, needed subsequent plastic surgery to improve appearance. In five patients the bridge of the nose was high and broad. General physical examination revealed little of note other than small size with relatively normal body proportions. Minimal postaxial polydactyly was present in the hands of two patients and in the foot of another. Cataracts were not detected in any of these patients. Strabismus was present in three infants, one of whom also had nystagmus. Nystagmus alone was present in one infant, and a pale optic disc in another. Careful clinical examination revealed no ocular abnormality in 14 patients. INVESTIGATIONS Viral studies failed to provide evidence of intrauterine viral infection in the five patients in whom they were performed. Normal karyotypes were demonstrated in the five infants studied. Two infants known to have chromosomal abnormalities and chondrodysplasia punctata were excluded from the group reported. NEONATAL

COURSE

Seventeen of these infants needed medical attention in the neonatal period. It is possible that other infants with the condition who had no neonatal illness remain unascertained. Three were referred because of abnormal appearance. Down syndrome was suspected in two and Hurler syndrome in the third. Hepatosplenomegaly was noted in four young infants, two of whom had persistent neonatal jaundice. Six suffered from respiratory distress partly or wholly attributable to the small nasal airway. Failure to thrive and difficulty in feeding were apparent in the neonatal period in six patients. GROWTH

PATTERNS

The average birth weight was 2.64 kg despite the fact that prematurity was not more frequent than expected in

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Ckrondrodysl)lasia punctata

9 19

Fig. 3. Typical nasal shape seen m chondrodysplasia punctata showing shortened columella.

Fig. 4. Dizygotic twins aged 2I~ years. The one on the left failed to thrive and was recognized as chondrodysplasia punctata; his twin did not fail to thrive and so was not examined roentgenographically as an infant. The nasal appearances are very similar, however, and both required subsequent plastic surgery of the nose. Both had terminal phalangeal shortening on their roentgenograms as adults.

Melbourne ~(Table I). When birth weights were compared with expectation for normal infants of comparable gestation, ~ 16 babies were below the fiftieth percentile, but only two weighed less than the third percentile. Inspection of Table II suggests that growth was poor in the first six months, because more than 50% of the infants weighed less than the third percentile by that age. These figures

must be interpreted with caution because no allowance was made for the influence of prematurity from three months onward. However, study of the individual growth charts confirmed a falloff in growth in the early months of life with some degree of later catch-up. Serial measurements of length were available for only 11 patients, but they show a similar pattern.

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Sheffield et al.

The Journal of Pediatrics December 1976

Fig. 5. Changes in appearance with growth in a patient with chrondrodysplasia punctata. A, Aged one year. B, Same patient aged 18 years (the nasal bridge has filled out but the shape of the nose is still characteristic).

Table I. Gestation period of patients with chondrodysplasia punctata Observed Gestation

No.

%

Expected (%)

< 28 wk 28-31 32-35 36-40 41 +

l 2 13 5

0 4.8 9.5 61.9 23.8

3.4 5.5 15.1 54.1 21.9

21

regarded as mildly retarded. No patient was performing better than average at school, but eight younger children were showing near normal motor development. It is difficult to make any confident statement about mental development in children with chondrodysplasia punctata because a number of patients were referred originally because of suspected mental retardation and these may have produced a bias in this series. However, two impressions emerged-that most patients were dull normal or mildly retarded and that the degree of retardation was often overestimated when the patients were first seen during infancy. MORTALITY

The two adults in the series were on the third and thirtieth percentiles for height, respectively. The latter had very tall parents. The head circumference at birth was known in only six patients and all were above or on the fiftieth percentile. Head growth paralleled weight and length in these infants, showing a lag in the first six months. MENTAL DEVELOPMENT Formal assessments were made in very few patients. Both the adult patients seemed dull in conversation-one was in steady employment as a factory process worker and the other was unemployed after failing to complete a trade apprenticeship. Six of the nine older children were

Four babies died at seven days, nine months, 15 months, and 26 months, respectively. The causes of death were bronchiolitis, acute gastroenteritis, cardiac failure plus bronchopneumonia, and sudden infant death syndrome, resPectively. All these babies had thrived poorly from birth. PREGNANCY HISTORY Facts recorded about the pregnancy were compared with information collected on an identical protocol from parents of children with achondroplasia. Comparisons of recorded complications and of the mother's description of her health during pregnancy were analyzed. No one pregnancy complication was particularly frequent, but the

Volume 89 Number 6

Table

ChrondrodysDlasia punctata

921

II. Chondrodysplasia punctata--weight changes with age

Percentage of patients Percentiles

Birth

-<3 3-9 10-49 50-89 90-97 > 97 Total patients

1

lO yr (No. of patients)

3 mo

6 mo

9 18 46 27 -

54 23 14 9 --

54 23 9 9 5 --

52

22

22

22

27.5 36

24 19 5

42 17 12 23 6

21

17

11

--

27.5 9

(2)* (1)*

*Actual number of patients.

proportion of uncomplicated pregnancies was significantly lower for chondrodysplasia punctata mothers (X'-' = 8.28, 0.001 < p < 0.01) as was the proportion reporting average or better than average health during pregnancy (X-~ = 5.84, 0.01 < p < 0.02). The frequencies of roentgenographic exposures during pregnancy, reported viral illnesses, planned and unplanned pregnancies, and reported psychiatric problems were similar in the two groups. Economic, social, or marital stress were reported by more mothers of infants with chondrodysplasia punctata, but this may merely reflect the fact that more of these mothers felt unwell. Drug ingestion did not differ significantly, but two epileptic women who took anticonvulsants deserve mention. One took diphenylhydantoin together with phenobarbitone and the other DPH, diazepam, and sulthiame. (Their two affected children also had digital hypoplasia as mentioned above.) No mother took anticoagulants in pregnancy. Hydramnios was reported in two cases. INCIDENCE Ascertainment has been consistent and fairly complete for patients presenting to the Royal Children's Hospital since 1966. Seventeen new patients have been seen there in this period. If one assumed that all patients born in Victoria came to this one large hospital an incidence of one in 30,000 live births would be calculated. This assumption is too extreme and the incidence must therefore be higher. SEX INCIDENCE There were 17 males and six females in the series. FAMILY

HISTORY

Twenty-six parents were seen personally and details were obtained regarding 14 parents who were not seen.

None was affected. There was no instance of parental consanguinity. Inquiry was made about heights and facial appearances of siblings, aunts, uncles, and first cousins in each family. If there was any suggestion of chondrodysplasia punctata, the relative was either seen personally or a photograph was examined. Roentgenograms were taken when appropriate. Forty-six siblings were judged unaffected, and two were affected. One was a dizygotic twin of an index case (Fig. 4), and the other was a sibling of an index patient from a different family. In the latter family the index case also had a dizygotic twin whose roentogenograms showed a cleft calcaneum and cone-shaped phalangeal epiphyses, although no puncta were seen. She may have been minimally affected. Thus this latter family probably had three affected children resulting fiom two pregnancies; during each pregnancy the mother was taking DPH and phenobarbitone. A sibling of another patient was said to be short, but no further details were available. There were 151 unaffected first cousins. One first cousin was said to resemble the index case, but could not be examined. No other relative was found to be affected. PARENTAL

AGE

The age of both parents at the time of birth of the children with chondrodysplasia punctata was higher than expected (Tables III and IV). (The figures for expected ages were calculated from published yearly figures for births in the State of Victoria.) Both tables were analyzed by dividing the five-year age categories into two groups, using 30 years as the cut-off point for mothers and 35 years for fathers. These were the highest cut-off points which gave numbers large enough for valid X-' testing in the older age groups. There were highly significant excesses of older parents (maternal

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Shejfield et al.

The Journal of Pediatrics December 1976

Table III. Age of parents at the time of birth of infants with chondrodysplasia punctata Mothers

Fathers

Age (yr)

Observed No.

Expected No.*

Observed No.

Expected No.*

< 19 20-24 25-29 30-34 35-39 40-44 45-49 > 50

3 5 1 4 8 0 1 0

1.46 7.07 7.36 3.84 1.75 0.49 0.03 0

0 4 1 3 4 5 0 2

0.24 3.33 6.45 4.72 2.58 1.18 0.38 0.12

Totals

22

22.00

19

19.00

*See texl for details.

Table IV. Effects of maternal age, paternal age, and birth order in chondrodysplasia punctata Observed sample-population difference minus expected sample-population difference

Paternal age increase adjusted for maternal age increase Paternal age increase adjusted for birth order increase Maternal age increase adjusted for paternal age increase Maternal age increase adjusted for birth order increase Birth order increase adjusted for paternal age increase Birth order increase adjusted for maternal age increase

Standard error

2.15

1.17

2.93

1.58

--0.20

1.94

1.35

1.36

0.23

0.26

0.09

0.31

X'-' = 9.25 0.001 < p < 0.005, paternal X-' = 11.78 0.0005 < p < 0.001). A similar procedure was carried out for birth order revealing only a slight excess of later births (0.4 < p < 3) which was interpreted as merely reflecting the higher parental ages. To separate further the influence of maternal age,, paternal age, and birth order, another statistical procedure was employed? This method was modified ~; to correct for the year-to-year variation that occurred in parental ages over the period of the study. It was found

that paternal age was the factor most likely to be determining the occurrence of chondrodysplasia punctata. The method involves determining the difference between the m e a n paternal age of the chondrodysplasia punctata patients and the mean paternal age of the Victorian population (observed sample - population difference). A formula allows one to calculate the increase in paternal age expected due solely to the rise in maternal age in the chondrodysplasia punctata patients (expected s a m p l e - p o p u l a t i o n difference). Subtraction of the expected figure from the observed figure gives a measure of the increase in paternal age per se, after elimination of any increase secondary to an increase in maternal age. Similar calculations allow consideration of the independent effects of maternal age and birth order (Table IV). Only paternal age had a significant effect. DISCUSSION The syndrome described here is quite distinct from the forms of chondrodysplasia punctata emphasized in previous reviews, although individual cases have undoubtedly been included in some reports. Clinical recognition can be achieved by the characteristic facies and by lateral roentgenograms of the foot that reveal "paint-spattered" calcification. The characteristic course of calcaneal ossification may allow confirmation in older children, but proof of the diagnosis is not possible in adults. Short adults with the typical nasal deformity are seen in the general population; one such woman presented for study, but was not included because proof was lacking. Some of the patients have thrived satisfactorily and appear to be developing normally. It may be argued that such cases should not be classified as chondrodysplasia punctata. However, these cases appear to form part of a syndrome which is widespread enough to affect the nasal cartilage and so produce the diagnostic facies. Every patient ascertained because of calcaneal puncta had this facies. The majority of cases have slight shortening in height and mild mental retardation. The condition is not rare and it may be nmch more c o m m o n than the present study would suggest. If this is true, then this study may have overestimated the severity of the clinical effects, because those cases not ascertained are likely to be less severe. Assuming that ascertainment is sufficient to allow some comment regarding etiology, the striking features are an excess of males, very few affected relatives, increased parental age-(especially paternal), and some hints of miscellaneous pregnancy complications. The paternal age effect is the most striking finding and would ordinarily suggest new gene mutations. However,

Volume 89 Number 6

there is no evidence of dominant inheritance in the families and a high proportion of new mutants would not be expected in such a benign condition. No satisfactory explanation of the age effect is apparent. Most bone dysplasias have a genetic cause and so other modes o f inheritance must be considered. The frequency of siblings is too low to fit with autosomal recessive inheritance and there was no incidence of parental consanguinity. The excess of males might imply X-linked inheritance, but no support was found in the family histories. The clinical course is reminiscent of intrauterine virus infections, but no evidence is available to support this conjecture. The ingestion of anticonvulsants during pregnancy by two mothers is interesting and may have a parallel with several cases of chondrodysplasia punctata recently described following pregnancies in which Warfarin was taken by the mother. 7, ~ These patients and three others 9 reported under a different title appear to have had the form of chondrodysplasia punctata under discussion. One infant was also exposed to D P H and primidone in utero. 9 Some anticonvulsants, including DPH, cross the placenta and, like Warfarin, may antagonize vitamin K - d e p e n d e n t blood-clotting factors in the fetus. TM The punctate calcifications may be caused by small hemorrhages in developing cartilage which later calcify. 7 Differentiation of this condition from other forms of chondrodysplasia punctata should allow more appropriate prognostication and genetic advice. Recognition of this f o r m of chondrodysplasia punctata may solve some problems'in syndrome identification and provide a diagnosis in some infants who are failing to thrive.

Chrondrodysplasia punctata

923

The authors are very grateful to the many doctors who referred patients from the Royal Children's Hospital and elsewhere for our study of bone dysplasias. Grateful acknowledgement also is given to Miss A. A. Robbins who has maintained and organized our radiotogical library in a most painstaking way and Dr. R. J. Fisher who assisted with the statistical technique in the parental age analysis. REFERENCES

1. Spranger JW, Opitz JM, and Bidder V: lteterogeneity of chondrodysplasia punctata, Humangenetik I 1:190, 1971. 2. Bailey JA: Disproportionate short stature, Philadelphia, 1973, WB Saunders Company, p 383. 3. Loughnan PM, Gold H, and Vance JC: Phenytoin teratogenicity in man, Lancet 1:70, 1973. 4. Kitchen WH: The relationship between birthweight and gestational age in an Australian hospital population, Aust Paediatr J 4:29, 1968. 5. Smith CAB: Note on the estimation of parental age effects, Ann Hum Genet 35:337, 1972. 6. Erickson JD, and Cohen MM: A study of parental age effects on the occurrence of fresh mutations for the Apert syndrome, Ann Hum Genet 38:89, 1974. 7. Becker MH, Genieser NB, Finegold M, Miranda D, and Spackman T: Chondrodysplasia punctata, ls maternal Warfarin therapy a factor? Am J Dis Child 129:356, 1975. 8. Shaul WL, Emery H, and Hall JG: Chondrodysplasia punctata and maternal Warfarin use in pregnancy, Am J Dis Child 129"360, 1975. 9. Pettifor JM, and Benson R: Congenital malformations associated with the administration of oral anticoaggulants during pregnancy, J PEmAXR86:459, 1975. 10. Mountain KR, Hirsch J, and Gallus AS: Neonatal coagulation defect due to anticonvulsant treatment in pregnancy, Lancet 1:265, 1970.