American Journal of Medical Genetics 75:95–100 (1998)

Gracile Bone Dysplasia

Janet A. Thomas,1 David L. Rimoin,2,3 Ralph S. Lachman,2,4 and William R. Wilcox2,3*
1
Department of Pediatrics, Division of Genetic Services, The Children’s Hospital and University of Colorado School of
Medicine, Denver, Colorado
2
Medical Genetics Birth Defects Center, Steven Spielberg Pediatrics Research Center, Cedars-Sinai Burns and Allen
Research Institute, Los Angeles, California
3
Department of Pediatrics, UCLA School of Medicine, Los Angeles, California
4
Department of Radiology, UCLA School of Medicine, Los Angeles, California

Gracile bones are a frequent abnormality strength; thus, fetal hypokinesia results in bones that
associated with fetal hypokinesia of any are slender and have reduced mass [Palacios et al.,
cause. With the exception of thin, undermin- 1992; Spranger et al., 1980]. Any condition that results
eralized bones, the chondro-osseous struc- in fetal hypokinesia, such as fetal neuropathy, myopa-
ture is usually normal in these cases. We thy, or extrinsic constriction, can lead to gracile bones.
present a lethal skeletal dysplasia compris- However, with the exception of being thin and under-
ing minor anomalies, central nervous sys- mineralized, the chondro-osseous structure is normal.
tem abnormalities, gracile long bones, and We report on a previously undescribed lethal skeletal
abnormal chondro-osseous morphology. In dysplasia in two sibs with minor anomalies, gracile
addition to a short, disordered growth plate, long bones, central nervous system abnormalities, and
the chondrocytes contained dilated loops of markedly abnormal chondro-osseous morphology.
rough endoplasmic reticulum, suggesting
an abnormality of an extracellular matrix CLINICAL REPORT
protein. This protein appears to have effects Case 1
on chondro-osseous and on facial and cen-
tral nervous system development. We sug- A stillborn infant was delivered at approximately 35
gest the term ‘‘gracile bone dysplasia’’ to de- weeks of gestation to a 21-year-old primagravid mother
scribe this disorder. Am. J. Med. Genet. 75: and a 35-year-old father. The pregnancy was uncom-
95–100, 1998. © 1998 Wiley-Liss, Inc. plicated, including a normal early ultrasound for dates,
until 34 weeks gestation when the fundal height was
KEY WORDS: gracile bones; skeletal dys- noted to be small for date. A level II ultrasound study
plasia; fetal hypokinesia; in- showed severe oligohydramnios, marked abdominal as-
clusion bodies cites, a small skull with thickening of occipital soft tis-
sue, cerebellar hypoplasia, a large soft tissue mass in
the anterior neck, a poorly visualized spine suggestive
INTRODUCTION of reduced calcification, and short femora. Due to sus-
pected nonviability, labor was induced. Several hours
The process of skeletal morphogenesis and growth is prior to delivery, fetal bradycardia ensued and fetal
determined by the interactive relationship between in- heart rate stopped, and an abnormally appearing male
trinsic properties of chondro-osseous tissue and extrin- infant was delivered.
sic mechanical forces. The physical forces acting on the Birth weight was 1,805 g (∼15th centile), length was
skeleton during development include the pull of muscle 34 cm (<3rd centile), and head circumference (OFC)
attachments, gravity, and the dynamic stresses associ- was 29.5 cm (10th centile). The infant had a narrow
ated with movement. Decreased fetal use of growing abnormally shaped head with plano-occiput, short
bones produces a reduction in modeling and delays the neck, pinched face with glabellar and nasal fold
process of periosteal bone apposition. The major me- creases, a flattened nose, and a high arched palate. The
chanical factor in fetal bone modeling is muscle ears were small (2.4 cm, <2nd centile) and flattened
with large, fleshy lobules and narrow external auditory
canals. The eyes were small and the corneae cloudy.
Contract grant sponsor: NIH; Contract grant number: HD The chest was small and the abdomen markedly pro-
22657. tuberant. There was no hepatosplenomegaly. The ex-
*Correspondence to: William R. Wilcox, M.D., Ph.D., Medical ternal genitalia were normal but the scrotum was
Genetics, Cedars-Sinai Medical Center, 8700 Beverly Blvd., SSB- empty. The hips appeared narrow. There was meso-
3, Los Angeles, CA 90048. E-mail: wwilcox@mailgate.csmc.edu melic shortness of limbs, short stubby hands with
Received 2 June 1997; Accepted 8 August 1997 splayed fingers, redundant skin of arms and legs,
© 1998 Wiley-Liss, Inc.
96 Thomas et al.

proximally placed great toes, convex plantar surfaces of hypoplasia of the thumbs of both hands, cupping of the
the feet, and edema of the feet. short tubular bones of the hands, and clinodactyly of
Autopsy demonstrated, in addition, microphthalmia the fifth fingers. The clavicles were thin and the scapu-
(R>L), ankyloglossia, and abdominal ascites (190 cc of lae hypoplastic, especially in the glenoid area. The
fluid removed). The thorax was small with severe pul- chest was short and small and the ribs were thin, with
monary hypoplasia, appendix was absent, and stom- moderate shorteness and mild anterior cupping; the
ach, gallbladder, and kidneys were small. No cardio- twelfth ribs were so thin they could barely be seen. All
vascular anomalies were noted. The brain showed an vertebrae were very flat, with some vertebral wedging
area of laminar necrosis in the right temporal cortex. anteriorly in the thoracic spine. Additionally, ischial
There were multiple, 2–3 mm white opaque lesions in hypoplasia, a flattened acetabular roof, increased
the white matter of the left frontal and parietal and height and decreased width of the ileum, coxa valga,
right parietal lobes consistent with multiple foci of cal- and ulnar dislocation were noted. The skull was sig-
cification and gliosis and reduction of the white matter nificant for microcrania, midface hypoplasia, mandibu-
in the area of the dentate nucleus of the cerebellum. No lar and dental hypoplasia, hypotelorism, and a promi-
abnormalities of the brainstem were seen. A karyotype nent nasal bone. Osteopenia was evident through most
at the 450 band level was normal (46,XY). of the skeleton and soft tissue and nuchal thickening
were present.
Case 2 Skeletal radiographs of Case 2 (Figs. 1C,D) were
The subsequent pregnancy to the couple was termi- similar with abdominal distention, a cystic nuchal
nated at 24 weeks of gestation for a suspected recur- mass, dense platyspondyly, elbow dislocation, ossifica-
rence on ultrasound images. Examination showed a fe- tion delay, and gracile bones. Only 11 ribs could be
male fetus with prominent forehead, flat nasal bridge, seen.
upturned nasal tip, posteriorly angulated ears with Chondro-Osseous Morphology
poorly formed helices and absent antitragi, long phil-
trum, high-arched palate, micrognathia, and short, Chondro-osseous tissue from the femur of both cases
thick neck. The chest circumference was 18 cm (normal and the tibia of Case 2 was examined. The resting car-
17.36 ± 1.77 for 21–25 weeks gestation) and the abdo- tilage was remarkable for pleomorphic chondrocytes
men was markedly distended. The genitalia appeared with regions of acellularity. In the physeal zone, there
to be that of a normal girl and the anus was patent. The was poor columnization with few hypertrophic cells,
limbs showed marked micromelic shortness with re- acellular septae, and nests of cells. The mineralizing
dundant skin folds and dimpling over the elbows and cartilage was patchy and irregular. There was over-
knees, fifth finger hypoplasia and clinodactyly, and growth of cortical bone and ingrowth of mesenchymal
markedly short halluces. tissue at the periphery. The primary spongiosa was
short and the trabeculae thickened. There was marrow
Family History fibrosis in the metaphysis and numerous mononuclear
The children were born to non-consanginous parents cells lining the trablecular surface (Fig. 2).
of Asian-Indian background. The family history was Transmission Electron Microscopy
essentially unremarkable, although the paternal
grandmother had had three pregnancies that resulted Chondrocytes of both cases in the resting zone were
in spontaneous abortion between 3 and 5 months ges- notable for numerous loops of dilated rough endoplas-
tation, in addition to five normal pregnancies. Mater- mic reticulum containing a granular material (Fig. 3).
nal chromosomes were normal. The surrounding cartilaginous matrix had a normal
appearance.
METHODS
DISCUSSION
Formalin fixed chondro-osseous tissue from both
cases were processed undecalcified in glycol and meth- These sibs represent a previously apparently unde-
yl methacrylate. Sections were stained with von Kossa scribed lethal skeletal dysplasia based on evaluation of
trichrome, toluidine blue, and Goldner’s stains. For the clinical, radiographic, and histologic findings and
electron microscopy, cartilage from the resting zone comprising facial and central nervous system abnor-
was examined as described previously [Bogaert et al., malities, short limbs, gracile long bones, and markedly
1992]. abnormal chondro-osseous morphology (Table I).
Gracile bones apparent at birth are a nonspecific
RESULTS manifestation of fetal hypokinesia caused by fetal neu-
Radiographic Findings ropathy, myopathy, or extrinsic factors such as oligo-
hydramnios or uterine tumors [Spranger and Marote-
Review of radiographs obtained on the stillborn in- aux, 1990]. Moessinger [1983] coined the term ‘‘fetal
fant (Case 1; Figs. 1A,B) demonstrated proportionate akinesia deformation sequence’’ to describe the pattern
shorteness of the long bones that had a gracile, stick- of abnormalities resulting from fetal immobilization or
like appearance with almost no cortical bone. The me- akinesia, which includes multiple joint contractures,
taphyses of the long bones were widened and all di- pulmonary hypoplasia, micrognathia, growth retarda-
aphyses slender. The over-tubulation was appreciated tion, short umbilical cord, and polyhydramnios. Rod-
in metacarpals as well as the the long bones. There was rı́guez et al. [1992] investigated the histologic changes
 Fig. 1. Skeletal radiographs. (A) Case 1, oblique view. Note the gracile undermineralized long bones and ribs. (B) Case 1, AP of hand. The first digit
is hypoplastic and the metaphyses are cupped. (C) Case 2, AP. The appearance is similar to Case 1. (D) Case 2, lateral. In addition to gracile long bones
and ribs, there is platyspondyly.
98 Thomas et al.

Fig. 2. Chondro-osseous morphology, Goldner’s stain. (A) Case 1, fe-

mur, 10×. There is poor columnization and acellular septae with nests of
cells. (B) Case 2, tibia, 4×. The appearance of the growth plate is similar to
Case 1. (C) Case 2, tibial diaphysis, 4×. The diaphysis is thin with thick
tabeculae and a diminished marrow space. (D) Case 2, femoral metaphy-
sis, 40×. The marrow is fibrotic and mononuclear cells line the trabecular
surface.

resulting from fetal akinesia using curarized fetal rats.

They demonstrated a decrease of total cross-section
area, reduction of absolute and relative amounts of
bone trabeculae with marked thinning of the perioste-
um, and evidence of an impairment of the membranous
(periosteal) ossification of long bones. They also con-
cluded that no substantial histologic differences ex-
isted between the experimental and control groups [Ro-
drı́guez et al., 1992]. Palacios et al. [1992], studying
long bone growth in rat fetuses subjected to oligohy-
dramnios, also demonstrated no histologic differences
in the femoral metaphyses and diaphyses between con-
trol and experimental groups. nios sequence, two with multiple pterygia, and six with
In humans, the most often reported histologic abnor- intrauterine growth retardation) and have not seen sig-
malities associated with thin long bones are thin cor- nificant abnormalities. In contrast to the animal and
tices and fractures of the growth plate and diaphysis human data, the cases presented herein demonstrate
fractures [Bonaventure et al., 1989; Chen et al., 1995; markedly abnormal chondro-osseous morphology.
Kozlowski and Kan, 1988; Rodrı́guez et al., 1988a,b]. In Ultrastructural abnormalities of the resting carti-
addition, lesions of the growth plate have not been ob- lage is also notable in the cases reported in this paper;
served in histologic studies of bones of patients who specifically, dilated rough endoplasmic reticulum con-
had diseases characterized by osseous fragility, such as taining a granular material. Dilation of the rough en-
osteogenesis imperfecta [Rodrı́guez et al., 1988b]. We doplasmic reticulum (inclusion bodies) implies the ab-
examined the chondro-osseous morphology in nine normal retention of a normally secreted protein within
other cases with gracile bones (one with oligohydram- the rough endoplasmic reticulum. The presence of in-
 Gracile Bone Dysplasia 99

TABLE I. Summary of Findings in Gracile Bone

Dysplasia Cases
Spranger et
al. [1980]
Case 1 Case 2 Patient 2
Clinical
Gestational age (wks) 35 24 38
Facial anomalies + + +
Nuchal mass + + +
Small chest + + +
CNS calcifications + ? +
Radiologic
Micromelia + + +
Gracile, stick-like long bones + + +
Short, thin ribs + + +
Dense platyspondyly + + +
Ischial hypoplasia + + +
Osteopenia + + +
Chondro-osseous morphology
Poor column formation + + ?
Bony overgrowth + + ?
Mesenchymal ingrowth + + ?
Marrow fibrosis + + ?
rER inclusion bodies + + ?

have demonstrated inclusion bodies on ultrastructural

examination. Also, patients with Dyggve-Melchior-
Clausen dysplasia have microcephaly and often severe
psychomotor retardation. Chondro-osseous studies in
these patients also disclose cytoplasmic inclusions
[Taybi and Lachman, 1996]. However, none of these
syndromes are associated with gracile long bones as
seen in the cases presented.
Our cases are distinct from previously reported
Fig. 3. Electron micrograph of resting cartilage from the tibia of Case 2. cases, with the exception of a case reported as cerebro-
The arrow indicates a rER inclusion body. N 4 nucleus. 9,100×. arthrodigital syndrome by Spranger et al. [1980]. Their
Patient 2 had a similar radiographic appearance to our
clusion bodies suggests the disorder is due to an abnor- cases and also demonstrated ‘‘several foci of minute
mality in an extracellular matrix protein. perivascular calcifications’’ in ‘‘the white matter of the
Inclusion bodies are common in many skeletal dys- cerebral cortex’’ (see Table I). Chondro-osseous tissues
plasias. For example, in osteogenesis imperfecta, mu- were not examined in their case. The other cases pre-
tations in the type I collagen genes producing qualitia- sented in their report have quite different radiographic
tive defects result in intracellular retention of abnor- features. Toriello et al. [1985] reported on two sibs with
mal type I collagen molecules within the endoplasmic similar findings as our cases, including fetal edema,
reticulum. Similarly, achondrogenesis type II, hypo- facial anomalies, and evidence of fetal akinesia defor-
chondrogenesis, spondyloepiphyseal dysplasia conge- mation sequence. Postmortem radiographs showed
nita, spondyloepimetaphyseal dysplasia, and Kniest thin and poorly ossified ribs and narrow and gracile
dysplasia are due to dominant mutations in the type II long bones. The skull, spine, and pelvis were normal in
collagen gene and have intracellular inclusion bodies the first child but the second child also had tall and
containing abnormal type II collagen [Byers, 1995]. In narrow vertebral bodies. Histologic examination, in
those disorders, the abnormal protein primarily affects contrast to our patients, demonstrated normal resting
chondro-osseous development. However, in our pa- cartilage, a high proliferative zone, and normal bone
tients the abnormal protein appears to also be involved [Toriello et al., 1985]. Osteocraniostenosis has gracile
in the development of the central nervous system. bones, flared metaphyses, normal mineralization, cra-
Central nervous system involvement in skeletal dys- niosynostosis, and splenic hypoplasia. Although chon-
plasias is not infrequent [Lachman, 1997] and several drocytes in the resting zone were pleomorphic and the
disorders with central nervous system involvement columns short and irregular, there was no bony over-
and inclusion bodies have been reported. For example, growth, mesenchymal ingrowth, or acellular septae
atelosteogenesis type I has been associated with en- with nests of chondrocytes [Verloes et al., 1994]. The
cephaloceles and forebrain abnormalities, and short rib chondro-osseous structure in our cases is similar to
polydactyly syndrome type II has also been associated that seen in other platyspondylic lethal skeletal dys-
with brain anomalies, including arhinencephaly, ver- plasias (thanatophoric variants) [Horton et al., 1979;
mis hypoplasia, arachnoid cysts, and cerebral dysgen- van der Harten et al., 1993] and Schneckenbecken dys-
esis [Lachman, 1997]. In our experience, both disorders plasia [Borochowitz et al., 1986], but the radiographic
100 Thomas et al.

findings distinguish those disorders. Further, several Chen H, Blackburn WR, Wertelecki W (1995): Fetal akinesia and multiple
perinatal fractures. Am J Med Genet 55:472–477.
other skeletal dysplasias, such as achondrogenesis type
Horton WA, Rimoin DL, Hollister DW, Lachman RS (1979): Further het-
II and hydrops-ectopic calcification-moth-eaten skel- erogeneity within lethal neonatal short-limbed dwarfism: The platy-
etal dysplasia, present with some findings similar to spondylic types. J Pediatr 94:736–742.
those of our patients and chondrocyte inclusion bodies, Kozlowski, Kan A (1988): Intrauterine dwarfism, peculiar facies and thin
but do not demonstrate gracile long bones [Taybi and bones with multiple fractures–a new syndrome. Pediatr Radiol 18:394–
Lachman, 1996]. 398.
We propose that our cases are examples of a previ- Lachman RS (1997): Neurologic abnormalities in the skeletal dysplasias: A
clinical and radiological perspective. Am J Med Genet 69:33–43.
ously undescribed lethal syndrome with profound pre-
Moessinger AC (1983): Fetal akinesia deformation sequence: An animal
natal effects on chondro-osseous, facial, and central model. Pediatrics 72:857–863.
nervous system development. Autosomal recessive in-
Palacios J, Rodrı́guez JI, Ruiz A, Sanchez M, Alvarez I, DeMiguel E (1992):
heritance or somatic mosaicism for a new dominant Long bone development in extrinsic fetal akinesia: An experimental
mutation could be postulated as the mode of inheri- study in rat fetuses subjected to oligohydramnios. Teratology 46:79–84.
tance in our family. We term this disorder ‘‘gracile bone Rodrı́guez JI, Palacios J, Garcia-Alix A, Pastor I, Paniagua R (1988a):
dysplasia.’’ This disorder cannot be easily differenti- Effects of immobilization on fetal bone development. A morphometric
study in newborns with congenital neuromuscular diseases with intra-
ated clinically or radiologically from other disorders uterine onset. Calcif Tissue Int 43:335–339.
with gracile bones unless chondro-osseous morphology Rodrı́guez JI, Garcia-Alix A, Palacios J, Paniagua R (1988b): Changes in
is examined. the long bones due to fetal immobility caused by neuromuscular dis-
ease. J Bone Joint Surg 70:1052–1060.
ACKNOWLEDGMENTS Rodrı́guez JI, Palacios J, Ruiz A, Sanchez M, Alvarez I, DeMiguel E (1992):
Morphological changes in long bone development in fetal akinesia de-
This work was supported by a NIH program project formation sequence: an experimental study in curarized rat fetuses.
grant (HD 22657). The authors wish to thank Maryann Teratology 45:213–221.
Priore and Sheilah Levin for administering the Inter- Spranger J, Maroteaux P (1990): The lethal osteochondrodysplasias. In
Harris H, Hirschhorn K (eds): ‘‘Advances in Human Genetics.’’ New
national Skeletal Dysplasia Registry, Betty Mekikian York: Plenum, pp 88–90.
and Loyda Nolasco for technical assistance, and Dr. Spranger JW, Schinzel A, Myers T, Ryan J, Giedion A, Opitz JM (1980):
Cynthia Tifft, Children’s Hospital National Medical Cerebroarthrodigital syndrome: A newly recognized formal genesis
Center, Washington DC, for referring the cases to the syndrome in three patients with apparent arthromyodysplasia and sa-
Registry. cral agenesis, brain malformation and digital hypoplasia. Am J Med
Genet 5:13–24.
Taybi H, Lachman RS (1996): ‘‘Radiology of Syndromes, Metabolic Disor-
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