Pacman Dysplasia: Report of Two Affected Sibs

William R. Wilcox,1,2* Barbie C. Lucas,1,2 Barbara Loebel,4 Ronald P. Bachman,4Ralph S. Lachman,1,3 and David L. Rimoin1,2

1Medical Genetics Birth Defects Center, Steven Spielberg Pediatric Research Center, Cedars-Sinai Burns and AllenResearch Institute, Los Angeles, California

2Department of Pediatrics, UCLA School of Medicine, Los Angeles, California3Department of Radiology, UCLA School of Medicine, Los Angeles, California4Department of Genetics, Kaiser Permanente, Oakland, California

We report on two sib fetuses with radiologi-cal and morphological findings similar tothose of the recently described lethal skel-etal dysplasia termed Pacman dysplasia(McKusick, 167220, Am J Med Genet 1993,45:558–561). The first fetus, a male, was elec-tively terminated after a routine ultrasoundstudy at 20 weeks showed short-limb dwarf-ism. The second fetus, a female sib, was alsoelectively terminated after similar, abnor-mal ultrasound findings were noted at 16weeks of gestation. Similar to Pacman dys-plasia, the radiographic appearance wascharacterized by under-mineralized bone,stippling, rhizomelic and mesomelic short-ness, platyspondyly, and a short, broad pel-vis. The metaphyses were dense, but the di-aphyseal cortices were thin with undermod-eled long bones, and there was a deficienttrabecular pattern suggesting marrow re-placement. Chondro-osseous structure wascharacterized by deficient trabecular boneformation, a fibrous marrow, and numer-ous, large, multinucleated osteoclasts liningthe endosteal surfaces of the metaphysealbone. The occurrence of this dysplasia insibs of differing sex suggests autosomal re-cessive inheritance. Am. J. Med. Genet.77:272–276, 1998. © 1998 Wiley-Liss, Inc.

KEY WORDS: Pacman dysplasia; epiphyse-al stippling; skeletal dyspla-sia; osteoclast hyperactivity

INTRODUCTION

The skeletal dysplasias are a heterogeneous group ofover 150 well-defined disorders. Based on similar clini-cal, radiographic, and morphological findings, theyhave been grouped into families of disorders, poten-tially sharing common pathophysiological mechanisms[Beighton et al., 1992]. In 1993, Shohat et al. reporteda new skeletal dysplasia characterized by epiphysealstippling and osteoclast hyperactivity. Histologically,the marrow was replaced by loose fibrous connectivetissue. Numerous, large, multinucleated osteoclastslined the endosteal surface in association with How-ship’s lacunae and were also found in regions devoid oftrabecular bone. The disorder was termed Pacman dys-plasia because the large osteoclasts resembled the Pac-man character in the popular video game. The inheri-tance of Pacman dysplasia was unclear. Autosomaldominant and autosomal recessive inheritance weresuggested because the parents were nonconsanguine-ous and they had one healthy girl prior to their affectedone [Shohat et al., 1993].

We report the clinical, radiographic, and histologicalfindings on two sibling fetuses who demonstrate find-ings similar to the case of Shohat et al. [1993].

CLINICAL REPORTCase 1

The propositus was the product of a 31-year-old Ash-kenazi Jewish woman and a 34-year-old non-Ashkenazi Jewish man. The nonconsanguineouscouple had one healthy child and no family history ofdwarfing conditions. The fetus was noted on routineultrasound study at 20.7 weeks of gestation to haveshortness of the long bones consistent with 15 to 16weeks gestation and bowing of the femora. A thickenednuchal fold was also noted. The fetus was electivelyterminated by dilation and evacuation after the couplewas counseled that the fetus had a severe dwarfingcondition, most likely of a perinatally lethal variety.Cytogenetic examination of fetal tissues showed a46,XY karyotype.

Contract grant sponsor: The National Institutes of Health;Contract grant number: HD22657.

*Correspondence to: Dr. William R. Wilcox, Medical Genetics,Cedars-Sinai Medical Center, 8700 Beverly Boulevard, SSB-3,Los Angeles, CA 90048. E-mail: wwilcox@mailgate.csmc.edu

Received 3 October 1997; Accepted 7 February 1998

American Journal of Medical Genetics 77:272–276 (1998)

© 1998 Wiley-Liss, Inc.

Case 2

The couple returned 7 months later with an intra-uterine pregnancy at 16.4 weeks of gestation for ascreening ultrasound study that showed a biparietaldiameter, head circumference, and abdominal circum-ference of 16.2 weeks with long bone lengths appropri-ate for 13.5 weeks. The bowel was noted to be slightlyechogenic. A dwarfing syndrome was diagnosed andthe pregnancy was terminated. Fetal tissue sent forcytogenetic evaluation showed a 46,XX karyotype.

RESULTSRadiographic Findings

Results of radiological examination of both fetuseswere similar (Table I, Figs. 1 and 2). Platyspondyly andcoronal clefting were present. The clavicles, whichcould not be identified in case 1, appeared fairly normalin case 2. The chest in case 2 appeared normal; in case1, assessment was difficult because of disruption, butthere did not appear to be any major anomalies. In case1, there were dense lines at the metaphyseal borders ofthe scapulae, and in both cases, there was glenoid hy-poplasia. In both cases, the fetal pelvis appearedrounded with an increased lateral dimension; case 1had sacral stippling and precocious coccygeal ossifica-tion. In both fetuses there was severe rhizomelic andmesomelic shortness of the long bones with osteopenia,dense metaphyses, and stippled epiphyses; the handsappeared normal. The skulls could not be evaluated. Inboth cases, there were scattered radiolucenciesthroughout the marrow space without good cortex for-mation, more so in case 1 than 2, suggesting replace-ment of the marrow.

Chondro-osseous Morphology

Examination of chondro-osseous tissues from thetibia, rib, and hand of case 1 (not shown) showed nor-mal resting cartilage, an irregular growth plate withnormal columns, peripheral in-growth of mesenchymaltissue into the physis, and mild overgrowth of peri-chondral bone. The most striking finding was excessiveresorption of bone in the metaphyses with numerousosteoclasts closely associated with trabecular bone. Nu-merous mononuclear cells were also seen associatedwith trabecular bone and the marrow was largely re-placed with fibrous tissue. The density of fibrous re-placement was greatest in the metaphysis, correspond-ing to the radiodense metaphyseal bands. There wasvery inadequate cortical bone formation. The histologi-cal findings in the femur of case 2 (Fig. 3) were verysimilar, but the trabecular bone was better preservedin the diaphysis. The multinuclear cells and many ofthe mononuclear cells showed histochemical stainingfor acid phosphatase [Gruber et al., 1988; not shown].The areas of radiographic stippling were not present inthe sections examined. Electron microscopic examina-tion of both cases showed normal-appearing osteoclastswith numerous secretory vesicles, normal osteocytes,and normal resting cartilage (not shown).

DISCUSSION

We have studied sibs with a severe, presumably peri-natally lethal, short-limb skeletal dysplasia character-ized by dense metaphyses, epiphyseal stippling, osteo-clastic hyperactivity, and marrow fibrosis. The occur-rence of this disorder in two sibs of differing sexsuggests autosomal recessive inheritance. Alterna-tively, germline mosaicism for an autosomal dominantmutation in one of the parents could account for thesecases.

The present cases are similar in many respects tothat reported by Shohat et al. [1993] as Pacman dys-plasia (Table I). Like our cases, the Shohat et al. [1993]case had severe rhizomelic and mesomelic shortness,platyspondyly, glenoid hypoplasia, osteopenia, densemetaphyses, and epiphyseal stippling. In all threecases the hands were spared of significant radiographicabnormalities and the chondro-osseous morphologyshowed significant fibrosis of the marrow cavity andosteoclastic hyperactivity with resorption of bone.There were several additional findings in the Shohat etal. [1993] case not seen in our sibs including medialwidening of the clavicles, short ribs, periosteal cloakingof the long bones, and greater severity of the glenoidhypoplasia. Histologically, there was greater preserva-tion of the trabeculae in the present cases, and theosteoclasts were smaller in size. Furthermore, therewere no osteoclasts seen unassociated with bone, incontrast to the Shohat et al. [1993] case in which manywere surrounded only by mesenchymal tissue. How-ever, most of the differences between the Shohat et al.

Table I. Summary of Findings in Pacman Dysplasia Cases

Parameters

Shohatet al.[1993] Case 1 Case 2

Gestation (weeks) 28 21 16Radiology

StipplingProximal femoral

epiphysis + + +Sacrum + + −Tarsus/calcaneous + + +

Osteopenia + + +Abnormal modeling + + +Poor cortex formation + + +Periosteal cloaking + − −Dense metaphyses + + +Rhizomelia and

mesomelia + + +Femoral bowing + + +Vertebrae − coronal clefts ? + −Vertebrae − sagittal clefts + + −

MorphologyPlane of growth plate Normal Irregular NormalChondrocyte columns Normal Normal NormalResting cartilage Normal Normal NormalNumber and size of

osteoclasts Increased Increased IncreasedMarrow fibrosis + + +Osteoclasts unassociated

with bone + − −Cortical bone formation Poor Poor PoorUltrastructure of bone

and cartilage Normal Normal Normal

Pacman Dysplasia 273

[1993] case and our cases are probably because of dif-ferences in gestational age. Indeed, in the younger fe-tus (case 2), there was less metaphyseal density in thescapulae and limbs, less platyspondyly, and less stip-pling present. Histologically, there was less marrowfibrosis and better trabecular preservation. Thus, theadditional findings in the Shohat et al. [1993] case maybe nothing more than an illustration of the same dys-plasia at a more advanced gestational age.

The differential diagnosis of syndromes with epiph-yseal stippling includes a number of disorders [Poznan-ski, 1994; Taybi and Lachman, 1996]. Mucolipidosistype II is characterized by osteopenia, bone destruc-

tion, and stippling of the calcaneus [Lemaitre et al.,1978]. However, ultrastructural changes include lyso-somal storage [Kornfield and Sly, 1995], which was notseen in our cases. Punctate calcifications are seen invarious forms of chondrodysplasia punctata, but thereis no osteopenia or modeling abnormalities of the bones[Poznanski, 1994], and chondro-osseous structureshows focal degeneration and calcification of cartilage[Sillence et al., 1979]. Neonatal hyperparathyroidismcomprises osteopenia, coarse trabeculae, and subperi-osteal bone resorption, but there is no stippling [Blairand Carachi, 1991].

Although osteoclast hyperactivity and marrow fibro-

Fig. 1. Skeletal radiographs of case 1, 21-week gestation. A: Lower limb and pelvis. B: Upper limb. C: Lateral spine. Note the stippling in the proximalfemoral epiphysis, bowing of the femur, dense metaphyses, deficient cortical bone formation, abnormal modeling, and vertebral clefts.

274 Wilcox et al.

sis are found in hyperparathyroidism, Paget’s disease[Fitzpatrick, 1996], and multifocal osteolysis [Resnickand Niwayama, 1995], shortness of the limbs andepiphyseal stippling are not seen in those disorders.

Pacman dysplasia is an example of a new class ofskeletal dysplasia characterized by dwarfism with os-teoclast hyperactivity. The pathophysiological basis isunknown, but overproduction of an osteoclast-stimulating factor or decreased expression of an inhibi-tory factor are possible explanations depending on themode of inheritance of the disorder. If Pacman dyspla-sia is an autosomal recessive disorder, then deficiencyof an osteoclast inhibitory factor [Roodman, 1996]would be the most likely pathogenesis. However, if Pac-man dysplasia is caused by dominant new mutations,activation of an osteoclast stimulatory factor is mostplausible.

In conclusion, we have confirmed the existence ofPacman dysplasia as a distinct type of lethal dwarfismwith epiphyseal stippling and osteoclast overactivity.Autosomal recessive inheritance is the most likely.

ACKNOWLEDGMENTS

This work was supported by the National Institutesof Health program project Grant #HD22657 (WRW,

DLR, RSL). We acknowledge the support of the Ah-manson Department of Pediatrics and the StevenSpielberg Pediatric Research Center. We thank Mary-Ann Priore and Sheilah Levin for administering theInternational Skeletal Dysplasia Registry, and wethank Betty Mekikian and Loyda Nolasco for technicalassistance.

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Fig. 2. Skeletal radiograph of case 2, 16-week gestation. Note the stip-pling in the tarsus/calcaneous, bowing of the femur, dense metaphyses,poor cortical bone formation, and abnormal modeling.

Fig. 3. Chondro-osseous morphology of metaphyseal bone from the tibiaof Case 2. Goldner’s stain; magnification, ×40. A: Note the numerous mono-nuclear cells lining the surface of the bone and marrow fibrosis. B: Thereare numerous, large osteoclasts actively resorbing bone.

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