Z. Kinderheilk. 114, 93 110 (1973) �9 by Springer-Verlag 1973

Arthro-Dento-Osteo Dysplasia (Uajdu-Cheney Syndrome)*

Review of a Genet ic "Acro-Os teo lys i s" Synd rome

Jfirgen H e r r m a n n

University of Wisconsin Center for HteMth Sciences - - Medical School, Madison, Wisconsin 53706, USA

Frederick T. Zugibe

Department of Pathology, Columbia University, New York, N.Y., USA

Enid F. Gilbert and John M. Opitz

University of Wisconsin Center for ttealth Sciences Medical School, Madison, Wisconsin 53706, USA

Received December 6, 1972

Abstract. From one personal patient and thirteen reported in the literature, arthro-dente-osteo dysplasia (ADOD) is defined as a heritable connective tissue disorder with the main clinical manifestations of laxity of joints, early loss of teeth, and multiple osteolytic lesions, including acro-osteolysis, on roentgenographic examination. These lesions are likely to represent "pseudo-osteolysis" with faulty primary bone formation rather than true osteolysis of previously normal bone.

ADOD is an example of relational pleiotropism with most elhlical manifestations representing secondary effects and deformities. The cranial sutures frequently re- main uncalcified and contain multiple Wormian bones. Secondary deformities may be progressive and affect primarily the skull, spine, fingers and fingernails. Patho- logic fractures are clinically the most important manifestation of ADOD.

In one family the mother and four of her six children were affected. The other nine ease reports describe sporadic instances. ADOD is presumed to be caused by an autosomal dominant gene, the sporadic cases representing new mutations.

Key words: Connective tissue dysplasia - - Generalized skeletal dysplasia - - Osteolysis - - Aero-osteolysis - - Joint laxity - - Loss of teeth - - Autosomal dominant inheritance Relational pleiotropism.

Introduction

Acro-osteolysis is pr imar i ly a roentgenologie concept and te rm apphed to apparen t ly osteolytie lesions of hands and feet, par t icular ly the distal phalanges. I n the context of this paper t rue acro-osteolysis refers to decreased bone densi ty and apparen t loss of substance in bones known or presumed to have been previously normal . Circumseript, local lesions may be due to physical or ehemicM injuries (burns, electric shock, frostbite,

* Studies supported by PHS/NIH Grants GM 15422 and 1 K04 I-ID-18982. This paper is contributed in part as paper number 1566 of the University of Wisconsin Genetics Laboratory.

7 Z. K i n d e r h e i l k . , ]~d. 11~

94 J. I-Ierrmann et al. : Arthro-Dento-Osteo Dysplasia

polyvinylchloride exposure), denervation, infections and tumors. Sym- metric, non-specific acro-osteolytic lesions in hands and feet occur in systemic disorders such as epidermolysis bullosa, seleroderma, hyper- parathyroidism and others. The pathogenetie relationship of the aero- osteolytic manifestations to the underlying cause is not equally well understood in all conditions.

I t is becoming evident tha t apparent acro-osteolysis is not always true osteolysis with pathologically increased bone destruction. Genetic forms of aero-osteolysis appear particularly likely to include conditions of decreased and/or faulty pr imary bone formation with roentgenographic lesions appearing as "acro-osteolysis". Examples of such "pseudo- osteolysis" are progeria [15] and pycnodysostosis [18] and the van Bogaert-Hozay syndrome [16]. In these conditions the roentgenographic lesions are symmetrical, and patients have other "osteolytic" lesions in addition to those in the distal phalanges. The lesions may be apparently progressive. However, in this case progression occurs in a skeleton tha t

already is abnormal. There probably is a distinct relationship between the pr imary abnormali ty and the rate and kind of progression. Progeria, pycnodysostosis and the van Bogaert-Hozay syndrome are caused by the homozygous state of three different autosomal recessive mutan t genes.

A further "pseudo-osteolysis" syndrome has been reported under different names [2--4, 7, 9, 10, 14, 17], and consists of joint laxity, early loss of teeth, osteo- porosis and progressive deformities of the skull, spine and digits. A patient with this rare condition was re- ported recently in detail [19] and is cited briefly in this paper. An analysis of the phenotypic spectrum and of the genetics is based on the present ease and those reported in the literature.

Fig. 1. Propositus at age 10 years: shortness of sta- ture, hirsutism; peculiar facial ap- pearance; genua

valga

Case Report

A 10-year-old boy presented because of shortness of stature (< 3rd percentile), peculiar facies, hirsute forehead, long eyebrows and lashes, prominent supraorbital ridges, hyper- telorism, micrognathia, highly arched palate, ~hick tongue, and stenotic ear canals (Fig. 1). Several teeth were loose and some were absent. He had a grade 2/6 systolic murmur along tile left sternal border, and coarse r~les and expiratory wheezes. The liver was palpated 2 cm below the right costal margin and the spleen tip was felt on deep inspiration. Pro- minence of the lumbar spinous processes was noted. The fingers appeared to be shortened, particularly distally, and

left right

left right Fig. 2a and b. Roentgenogram of hands at age 10 (a) and 14 (b) years: "acro-osteo- ]ysis"; non-calcified epiphyseal lines; multiple circumscript radiolucencies in meta- carpals, carpals and forearm bones; plump modelling of fifth metacarpals; campto- dactyly of both index and the left middle fingers at age 14 years. (Courtesy of

Dr. F. N. Silverman)

7*

96 J. Herrmann et a l . :

Fig. 3. Roentgenogram of feet at age 14 years: "acro-osteolysis'; plump modelling; transverse liaear radiolueeney in both fifth metatarsals. (Courtesy of Dr. F. N. Silver-

man)

dubbing of the fingertips was significant. The skin was coarse and thick. Mild atepie dermatitis was present. The voice was low-pitched and speech was slurred. Neurologic examination was otherwise normal.

Pregnancy, delivery and development had been normal. Bilateral inguinal herniae and an umbilical hernia were repaired in infancy. Repeated fractures involved the right leg, and the left arm, fifth finger and ankle. At an early age the parents noticed the peculiar facies, hirsutism, loose joints, and recurrence of resph'atory infections. At one time the diagnosis of the Hurler syndrome had been considered. No similarly affected family members are known, and one brother and two sisters are well. The father has clinical symptoms and radiographic signs con- sistent with Marie-Strfimpel disease (Dr. !~. N. Silverman, Cincinnati).

Laboratory data revealed normal values for urinalysis and hemogram, and for serum levels of potassium, calcium, phosphorus, alkaline phosphatase, fasting blood sugar, immunoglobulins, proteins, and thyroxin. The erythroeyte sedimentation rate was 38 mm/hr. VDI~L was non-reactive. A urinary amino acid determination showed slight increase in beta amino-isobutyric acid. Term amino acid excretion was within normal limits. A 24-hour urine did not contain significantly increased

Arthro-Dento-Osteo Dysplasia 97

Fig. 4. Lateral skull roentgenogram at age 10 years: normal thickness of calvarium with increased translucency; dolichocephaly; multiple Wormian bones; non- calcification of sutures including of the parieto-temporal suture; elongated posterior cranial fossa; enlarged and shallow pituitary fossa; absent frontal sinuses; hypo-

plastic maxilla and mandible

amounts of mucopolysaccharides. Liver secured fresh by needle biopsy did not contain histochemically demonstrable soluble acid mucopolysaccharides, and no pathologic changes were noted with hematoxylin and eosin and PAS staining. May- Griinwald-Giemsa stained smears did not demonstrate Reilly bodies in the peripheral lymphocytes. Slit lamp examination did not uncover corneal opacities. Mild to moderate bilateral hearing loss in the lower frequency ranges and a mild perceptive type hearing loss at 8000 Hz was demonstrated. An intelligence quotient of 86 was obtained on the Stanford-Binct test. The chromosomes appeared normal.

Recently, at the age of 14 years, this patient was studied at the Children's Hospital in Cincinnati, Ohio, under the direction of Drs. Warkany and Silverman.

Roentgenographic examination at 10 and at 14 years of age reveMed multiple abnormalities. "Acro-osteolytie" lesions in the hands (Fig. 2) and feet (Fig. 3) were striking, but represent only one aspect of a generalized skeletal dysplasia present in this patient. Generalized osteoporosis was marked. There was nonealcification of cranial sutures and epiphyseal lines, and there was no progression of calcification between 10 and 14 years of age. Difference in technique of the skull roentgenograms at 10 and 14 years did not allow for quantitative evaluation of the progression of the skull deformity. However, it was apparent (Figs. 4 and 5) that progressive basilar invagination led to elongation of the posterior cranial fossa, to increasing

Fig

. 5a

and

b.

Lat

eral

an

d p

oste

rior

-ant

erio

r ro

entg

enog

ram

of

skul

l at

age

14

yea

rs:

doli

choc

epha

ly a

nd

brac

hyee

phal

y;

pers

iste

nt n

omca

lcif

icat

ion

of s

utur

es;

prog

ress

ive

elon

gati

on o

f po

ster

ior

cran

ial

foss

a;

app

aren

t pr

ogre

ssio

n of

def

orm

ity

of t

he b

ase

of t

he s

kull

; m

alpo

siti

on a

nd

hyp

opla

sia

of m

axil

lary

and

man

dib

ula

r te

eth.

(C

ourt

esy

of D

r. F

. N

. Sil

verm

an)

o �9 o �9

9~

a

Fig

. 6

a an

d b.

]~

oent

geno

gram

of

the

pelv

is a

t ag

e 10

(a)

and

14

(b)

year

s: s

pina

bif

ida

occu

lta;

pos

sibl

e co

mpr

essi

on f

ract

ure

of

L5;

no

n-ca

lcif

icat

ion

of

sutu

res

and

epip

hyse

al

line

s;

"hea

rt-s

hape

d"

pelv

ic

inle

t at

ag

e 14

; m

arke

d os

teop

oros

is.

(Cou

rtes

y of

Dr.

F.

N.

Silv

erm

an)

100 J. Herrmann et al. :

Fig. 7. t~oentgenogram of thorax at age 14 years: osteoporosis; variable height of vertebral bodies; modelling abnormality of ribs; abnormal course and structure of

right ninth and tenth ribs. (Courtesy of Dr. F. 1~. Silverman)

steepness of the clivus, and to anterior displacement of the pituitary fossa as evidence of a complex continuing deformation of the base of the skull. A similar ongoing deformation may be occurring in the pelvic structures (Fig. 6). Roen~geno- grams of the spine (Figs. 7 and 8) revealed variable height of vertebral bodies and intervertebral discs. Biconcave "fishbone" deformity and circumscript radiolucent lesions in some vertebral bodies were seen in lateral roentgenograms (Fig. 8). Osteoporosis and plump modelling was present in the long bones (Fig. 9). An intra- venous pyelogram was normal (Fig. 6a).

Review of Literature

A . P h e n o t y p e

Thir teen pat ients from nine families have been reported [2--4, 7, 9, 10, 14, 17, 19] with a condit ion var iably manifested by joint laxity, early

Arthro-Dento-Osteo Dysplasia 101

Fig. 8. Lateral roentgenogram of lumbar spine at age 14 years : variable height of vertebral bodies and intervertebral discs; biconcave "fish-bone" shape of L2; anterior superior radiolueent lesions in D 12, L 1 and L4. (Courtesy of Dr. 1~'. N. Sil-

verman

loss of tee th , and general ized osteoporosls and osteolysis, inc luding acro- osteolysis. Table 1 contains ident i fy ing in format ion and general symp- toms, and shows which organs or areas are affected in each of the 14 cases. The i ta l ic numbers in the following s u m m a r y refer to the eases in Table 1.

General. 7 females and 7 males have been descr ibed wi th an age range f rom l0 to 65 years a t the t ime of examina t ion . Two pa t i en t s were seen in the i r first, four in the i r second, five in the i r th i rd , and one each in the fourth, fifth, and s ixth decade of life. Pa t i en t s have been aware of the i r shor tened and c lubbed fingers as long as t hey can r emember (4, 5, 11, 12). A pho to revea led the skull affected (1) at an ear ly age. No ins tance

102 J. Herrmann et al. : Arthro-Dento-0steo Dysplasia

Fig. 9. Roentgenogram of left upper extremity at age 14 years: osteoporosis, plump modelling. (Courtesy of Dr. F. N. Silverman)

showed proven symptoms at birth. Progressive diminution of stature (7, 8), and decrease of foot length (1) was noted. Serial roentgenographic studies revealed no or only slight progression of skeletal lesions over 11 years (1) and 5 years (3). Pain appeared related to skeletal lesions particularly in the skull, vertebral column, knees, arms, hands and feet. Pain was severe and intermittent (1, 6--9), and shooting (2) in character. I t was particularly associated with motion in joints (7, 12, 13), arthritis (12, 13) and fracture (3). Severe high cervical ache and occipital headache could be precipitated by exertion, bending forward, or pro- longed upright position (1, 7--9). Several patients had suffered pain for many years.

Shortness of stature was marked (1, 6--9, 12, 14). Cheney's adult patients (6--9) were 5 feet (9) or smaller (6--8). As indicated by

Table 1

K e y for case

!

0 r..? Q ~ c~

Z ,.= ,.= ' ~ o

1 2 3 4 5 6 7 8 9 10 11 12 13 a 14

Identif icat ion sex age in years

General S y m p t o m s early onset • • x x x x

progression x x • x •

pain x • x • • • x • • shor tness • x X • x • x generalized osteoporosis • • • • x

multiple fractures X • • x • • x X X

Areas affected eMvarium occiput frontal sinuses sella turcica maxilla mandible teeth spine pelvis long bones fingers fingernails metacarpals proximal phalanges - - hand • • • • middle phalanges - - hand X • X X • • distal phalanges - - hand x X • • x x x • x x x x x x

toes X x • X • X x X •

meta tarsa l s x x ;4 x • • x

proximal phalanges - - feet X X • • X • middle phalanges - - feet X • X

distal phalanges - - feet x x • x x x x x • • • x

joints • x x x x x x x • •

skin • x •

eyes • • hearing X X

neck • x • x •

M M M F F F M F M F M F F M 37 43 20 23 33 57 35 26 21 13 39 65 35 10

X X X X )4 X X X X X X X

X ?4 X X X X X X X X

X X X X X X X X X

X X X X X

X X X X X X X X X X X X

X X X X X X X X X X X X

X X X X X X X X X X ;K X X

X X X X X X X X X X

X X X

X X X X X X X X

X X X X X X X X • X X X X X

X X X X

X X X X X X

a Possibly, b u t no t certainly a case of the ADOD syndrome. Da ta for skull and tee th inferred f rom reference 17 wi thout being explicity stated. Pa t ien t had no osteoporosis and no skull film was published.

104~ J. Herrm~nn et al. :

measurements for arm span (64~") and height (61~2") in case 1, short- ness mainly appeared to be due to vertebral involvement.

Generalized osteoporosis was pointed out repeatedly (1, 5--7, 12, 14). Multiple fractures have involved the spine (1, 6--9, 11), long bones (9-- 11, 14), hand or feet (3, 4, 11, 14). Two instances required surgical inter- vention (8, 11). The greatest number of fractures was seven per patient (11). Most fractures healed without complication, but callus formation has not been documented radiographically.

Cranial and Facial Skeleton. A dolichocephalic calvarium (4, 5, 7, 9, 11) with particular prominence of the occipital area (1, 4, 6, 7, 9, 10, 14) was frequently noted. The sutures were wide (1, 5, 7, 9) and ununited (1) including sutures that normally are not apparent radiographically. Wormian bones along the lambdoid (1, 4, 5, 7--9, 11) and other (1, 4, 7, 9) sutures were seen. Basilar impression (1, 6--11) was striking in some instances. The site of the anterior fontanelle was depressed (1, 7--10) and the frontal sinuses were absent (1, d~-lO, 12, 14). The sella tureica has been seen enlarged (5--9) with a high (7, 9), small (1), or normal (2, 4) dorsum. Absence of the alveolar process of both the maxilla and the mandible was striking (2, 4--7, 9, 11--13). The maxilla and mandible may appear small, and either one may recede more than the other.

Teeth. At the time of examination complete or almost complete edentulism was present in several (1, 5--7, 11), and absence of a signif- icant number of teeth in other (2--4, 14) cases. Remaining teeth were loose (2, 4, 14) and showed partial resorption (4) or hypoplasia (11) of roots with absence of the lamina dura. In two instances, however, the lamina dura was intact (8, 9). Unerupted maxillary and mandibular teeth were noted (5, 8--10).

Spine and Pelvis. Generalized vertebral demineralization (1, 5--7, 9) and osteolytie changes (14) apparently lead to biconcave "fish-bone" vertebra (1, 5 -7 , 9, 14), particulmqy in the lower thoracic and lumbar area. Kyphosis (2, 6--9, 12) and scoliosis (1, 2, 9, 12) were clinical manifestations. Single observations included fused cervical spinous proc- esses (7), narrowed cervical discs (2), spina bifida oeeulta (1), deformed sacrum (5), and early degenerative changes (13). l~oentgenographically the pelvis was normal in most instances examined, but changes in the symphysis pubis (5, 8, 13) and hypoplasia of the iliae bones (13) were seen.

Long Bones. These are less frequently, but symmetrically involved. Osteoporosis (1, 5, 6, 12) or cystic lesions in humerus (1), ulnar styloid (1, 2, 11), radius (1), carpals (1, 2), femur (14) and tibia, (1) were seen. Modelling defects were seen in the humerus (12) ulna and radius (1, 12, 14), ribs (I4), distal femur (4, 11, 12), patella (12), and proximal tibia (11, 12). In one instance (5) the radial head was dislocated.

Arthro-Dento-0steo Dysplasia 105

Fingers and Toes. The fingers were clinically affected in all instances. They appeared short (1--11, 14) - - particularly distally, and clubbed (1, 3, 6, 7, 9--12, 14). The fingernails showed corresponding changes (g, 5, 9, 12). Although not pointed out in the text, photos demonstrate that the fingernails were deformed on the affected fingers only (4, 9). Weak- ness of fingers is mentioned twice (7, 9). The toes were essentially similarly affected (1, 3--7, 11--14), but no mention of abnormal toenails WaS m a d e .

Short Tubular Bones. Metacarpals were involved infrequently with radiolucent lesions (1, 2, 6, 11), thin cortex (2, 6), and shortness (8, 12). The metatarsals were affected more frequently with osteolytic or cystic changes (1, 3, 11), shortness (11), and united (4) or ununited (3, 14) fractures. The proximal phalanges revealed lyric lesions both in the hands (1, 2, 7) and feet (1--5). Similar lesions in the middle phalanges were observed in the hands (2, 3, 5, 7, 11) and feet (1--3). The distal phalanges of the fingers showed osteolysis in all cases, but changes may be asymmetric (5), of variable extent, and some fingers were spared (g, 8, 9). In most instances the medial portion of the phalanx was most severely affected (1--7, 9, 11, 14), in others osteolysis involved the tufts (8--10, 12, 13). Lyric changes were less consistent in the distal phalanges of the toes (1, 2, 4, 5, 7, 9--12, 14), but when present led to the apparent absence of the tufts in 3 eases (1, 9, 13).

Joints. t typerextensibili ty in interphalangeal (2, 3, 5, 7--9, 14) and knee (5) joints can be part of general joint laxity (14). Subluxation (1), dislocation (5) and narrow joint spaces (1, 6, 11) were observed. Limited mobility was seen in elbows (1, 5, 11) and fingers (13). Irregular roent- genographie defects were present in the carpal joints (1), and degener- ative changes in multiple joints (13) were present in one instance each.

Skin. Various problems included aene rosaeea (1), recurrent eczema (2), mild atopie dermatitis (14), coarse texture (14) and hirsutism (14).

Sensory. Blurred vision, myopia, pallor of optic discs, restricted visual fields and coarse lateral nystagmus were all noticed in one case (1), and hyperopia in another (2). Bilateral hearing difficulties were present in two instances (1, 14).

Neurologie examination was normal in most eases (2--4, 8, 12--14), but a few neurologic abnormalities were noted: right sixth nerve palsy (1), right diminished ankle jerk (1), hypotonia (5), fingers "sore to touch" (9), and slurred speech (14).

Miscellaneous cfinieal findings included unusual facial features (1, 12, 14), low pitched voice (14) and extensive bronehieetasis (5).

Laboratory data have been normal for hemogram, m-inalysis, total serum protein, glucose, BUN, calcium, phosphorus, alkaline phosphatase (1--5, 7--10, 12--14), serum protein electrophoresis and immun-

106 J. Herrmann et al. :

electrophoresis (14), serum thyroxin level (14), buccal smear for sex ehromatin (8), chromosome analysis (14), urine amino acids, and urine and liver for acid mucopolysaccharides (14). An electrocardiogram showed right axis deviation in one ease (1), and was normal in another (3). By the Stanford-Binet test an IQ of 86 was found in one patient (14). In the rest the IQ was not mentioned and may have been normal.

The past medical history included repeated respiratory infections and expiratory wheezes (14), chronic cough (1, 5), emphysema and asthma (11), tuberculosis (7), rickets in childhood (12, 13), nephritis (2) and repaired umbilical and bilateral inguinal herniae (14).

Follow-up examinations revealed no bone changes on X-ray over an 8 month (5), 5 year (3), and 11 year (1) period, or following intensive Vitamin D therapy (12). Progressive weakness in the upper extremities and recurrent analgesia in fingers and occasionally in toes was seen in one patient (2).

Pathologic data were available in three instances. Chawla reported that Hajdu and Kauntze's patient died 11 years after the original report with signs of increased intracranial pressure, probably secondary to progressive basilar impression. From the patient of Greenberg and Street a bone biopsy from a lyric area in the head of the first metatarsal showed dense and cellular fibrous tissue with a few bone spicules (case 3). A further bone biopsy report from the distal phalanx of the left fifth finger reads (case 9) : "The sections of bone include periosteum. The bone is of the spongy type and displays a striking process of necrosis. This consists of a conversion of multiple foei of bone to a grayish amorphous necrotic material in which are present numerous spicules and very small particles of bone, the bone undergoing the process of necrosis. The process also involves the adjacent adipose tissue of the marrow spaces. Viable bone adjacent to necrotic material displays an absence of the normal endosteal lining. No osteoblasts are seen and no tissue reaction to the necrotic process is evident."

B. Genetics In Cheney's family the mother and four of her six children were

affected (cases 6--10 in Table 1). The affected children were two boys and two girls. A paternal uncle reportedly was affected in Schulze and Gulbin's second family (case 13). Several affected individuals had normal children: case 3 had a 3-year-old and a newborn child who were exam- ined both clinically and roentgenologically; case 5 had daughters age 12 and 15 years; ease 12 had 2 children and one grandchild; and case 13 had 4 children. The patients' parents and siblings were examined and re- ported as unaffected in three instances (cases 3, 5, 14). Case 1 was married but childless.

Arthro-Dento-0steo Dysplasia 107

The observation of generalized osteoporosis with particular involve- ment of the skull, spine and digits in association with multiple fractures, recurrent pain, shortness of stature, persistent cranial sutures, multiple Wormian bones, absence of the frontal sinus, clubbing of fingernails, early loss of teeth, and joint laxity appears to be an unlikely concurrence by chance alone. Cheney's family suggests a genetic etiology and auto- soma] dominant inheritance. Sporadic instances may represent a new mutation of an autosomal dominant condition. Non-familial occurrence is not an argument against a genetic etiology.

Discussion

Aero-osteolysis in general has not been characterized beyond its descriptive appearance and no concrete quantitative and qualitative characteristics of osteolysis have been defined in different disorders. When the European Society of Pediatric Radiology in 1969 devised a nomen- clature [12] for constitutional (intrinsic) diseases of bones, aero-osteolysis was classified as an idiopathic osteolysis under the "constitutional disease of bones with unknown pathogenesis."

The pathogenesis of aero-osteolysis probably differs depending on its cause: physical or chemical injury, infection, nutritional, endocrine or other local or systemic disturbance. Few pathophysiologie data are available to support various hypotheses. In Gorham's massive osteolysis [6] locally increased vaseularity was seen and probably associated with increased osteoelast activity [11]. Premature death of osteocytes occurs in several osteolytie conditions [5], some of which are associated with aero-osteolysis. Non-osteoelastie resorption, probably dependent on para- thormone-stimulated large osteoeytes, was demonstrated [1] in dogs with osteolysis occurring in the middle of trabeeulae of cancellous bone, and in the interstitial lamellae of compact bone. The pathophysiology remains completely obscure in most other "osteolytie conditions", including systemic disorders like I~aynaud's disease, seleroderma or various in- fectious or genetic diseases.

For the particular disorder reviewed above, the term arthro-dento- osteo dysplasia (ADOD) is suggested, since systemic skeletal lesions, laxity of joints and early loss of teeth appear to be the most prominent clinical manifestations. While probably all eases of ADOD in Table 1 were selected for aero-osteolysis, the other manifestations are quite variable in regard to severity and organ involvement. Investigations to detect an ongoing defect of calcium or phosphorus metabolism have been unsuccessful. No affected individuals have been studied at bh%h, but by history, manifestations were noted in early childhood. In no case has it been shown that a previously normal distal phalanx showed aero-

108 J. Herrmann et al . :

Table 2. Mainfestations in the ADOD mesenehymM dysplasia. (Faulty fibrocyte function and fibrocyte-osteoblast transformation ?)

CraniofaciM skeleton Persistent wide cranial sutures Large anterior fontanelle Multiple Wormian bones Dolichocephaly Progressive basilar invagination Occipital prominence Absent frontal sinuses Faulty lamina dura Early loss of teeth, edentulism Absent alveolar processes Small maxilla Small mandible

Spine Roentgenographic "osteoporosis" "Fishbone" vertebrae Compression fractures Kyphosis

Scoliosis Shortness of stature

Extremities Roentgenographic "osteoporosis" "Lytic" lesions Fractures Modelling defects "Acro-osteolysis" Shortness and clubbing of fingers,

toes Deformed nails

Joints Laxity Hypercxtensibility Subluxation Dislocation Abnormal joint spaces ' 'Weakness"

osteolysis later on. Repeatedly, photos show the fingernails deformed only when acro-ostcolysis is present in that particular finger. In several cases the cranial sutures apparently never calcified; similarly, apparent acro-"osteolysis" may have always been present in the distal phalanges either because of an abnormally slow rate of bone formation or because of formation of faulty material.

I)efective formation of connective tissue primarily in bones and ligaments conceivably could lead to early loss of teeth and to deformity of fingernails, skull and other bones, and to subsequent fractures - - all as secondary manifestations. AI)OI) might represent an example of relational pleiotropy as defined by t tadorn [8]. Most of the manifestations summarized in Table 2 could be related to faulty fibrocyte-osteoblast transformation. The various clinical manifestations are differentially far removed from the pr imary defect. The distance is not necessarily related to the ehnieal severity and/or frequency of the manifestation. The teeth themselves, for instance, may be normal while the lamina dura is in- competent to hold them in place. Sparse histologic reports from bone biopsies so far describe necrosis and increased fibrosis and lack of inflam- matory reaction or of increased osteoelastic activity in ADOD patients. Additional data are urgently needed to support specific pathogenetic or pathophysiologic hypotheses.

The combination of sites of the roentgcnographic lesions (skull sutures, frontal sinuses, mandible and maxilla, vertebrae, distal phalanges) may be specific for an unknown site-specific developmental phenomenon. I t is

Arthro-Donto-Osteo Dysplasia 109

remarkable t h a t at the same sites apparent ly similar lesions are seen in pycnodysostosis while the overall bone densi ty is, of course, increased.

I n sporadic cases of A D O D the variabil i ty of the clinical manifestat ions apparent ly is as great as in familial cases. Severely affected pat ients are presumably more likely to be reported, and the presence of part icular manifestat ions m a y have a t t rac ted the special interest of the respective authors. No correlation with age or any other single factor is apparent . I n sporadic cases of A D O D the diagnosis is based on clinical manifesta- tions alone. Diagnosis of a condition in the phase of a "formal genesis syndrome "[13] remains somewhat a rb i t ra ry unti l the pathogenet ie inter- relationship of the manifestat ions is unders tood or a diagnostic test independent of the clinical manifestat ions is devised. No t until then is the extent of the variabil i ty and the "diagnostic weight" of a given manifestat ion correctly appreciated. Present ly i t cannot be decided whether differences in these 14 cases indicate clinical variabil i ty of the same condition and/or a certain amoun t of etiologic heterogeneity. I f counseling in regard to natura l history, t he rapy and genetic risk for future children is required, A D O D should presently be regarded as a heritable disorder of connective tissue with relational pleiotropic mani- festations and as caused by an autosomal dominant gene. Sporadic cases presumably represent new mutat ions .

Acknowledgements. The cooperation of Drs. G. A. Shawkey, Charleston, West Virginia, and Drs. J. Warkany and F. N. Silverman, Cincinnati, Ohio, is gratefully appreciated.

References

1. B@langer, L. F., Robichon, J. : Parathormone-induced ost~olysis in dogs. J. Bone Jt Surg 46-A, 1008--1012 (1964).

2. Chawla, S. : Cranio-skeleta] dysp]asia with aero-os~olysis. Brit. J. Radiol. 37, 702--705 (i964).

3. Cheney, W. D. : Acro-osteolysis. Amer. J. Roentgenol. 94, 595--607 (1965). 4. Dorst, J. P., McKusiek, V. A. : Acro-osteolysis (Cheney syndrome). Birth Defects

Orig. Art. Series V/3, 215--217 (1969). 5. Frost, H. M.: tn vivo osteoeyte death. J. Bone J t Surg. 42-A, 138--143 (t960). 6. Gorham, L. W., Stout, A. P. : Massive osteolysis (acute spontaneous absorption

of bone, phantum bone, disappearing bone). J. Bone J t Surg ~7-A, 985--1004 (1955).

7. Greenberg, B. E., Street, D. M. : Idiopathic non-familiM aero-osteolysis. Radio- logy 69, 259---262 (1957).

8. Hadorn, E. : Developmental genetics and lethal factors. London: Methuen and Co 1961.

9. Hajdu, N., Kauntze, R. : Cranioskeletal dyspl~sia. Brit. J. R~diol. 21, 4 2 ~ 8 (1948).

10. Harnasch, H. : Die Akroosteo]ysis, ein neues Kr~nkheitsbild. :Fortschr. R6ntgen- str. 72, 352--359 (1950).

8 z. Kinderheilk., Bd. 114

110 J. Herrmann et al. : Arthro-Dento-Osteo Dysplasia

11. Milner, S. M., Baker, S. L. : Disappearing bones. J. Bone J t Surg. 40-B, 502--513 (i958).

12. Nomenclature internationale des maladies ossenses constitutionelles. Ann. Radiol. 18, 455--464 (1970).

13. Opitz, J. M., Herrmann, J., Dicker, H.: The study of malformation syndromes in man. Birth Defects Original Article Series u 1--10 (1969).

14. Papavasiliou, C. G., Gargano, F. P., Walls, W. L.: Idiopathic non-familial aero-osteolysis associated with other bone abnormalities. Amer. J. Roentgenol. 88, 687--691 (1960).

15. Reichel, W., Bailey, J. A., Zigel, S., Garcia-Bunual, R., Knox, G. : Radiologie findings in progeria. J. Amer. Geriat. Soe. 19, 657--674 (1971).

16. Rohwedder, H. J. : Sonstige Syndrome. In: Handbuch der Kinderheilkunde 1/1. H. Opitz and F. Schmidt (eds.). Berlin-Heidelberg-New York: Springer 1971.

17. Sehulze, R., Gulbin, 0. : Beitrag zum Problem der Akroosteolyse (gleichzeitig ein Beitrag zur Kenntnis der Patella profunda). Fortschr. RSntgenstr. 109, 209--216 (1968).

18. Sedano, H. D., Gorlin, 1~. ~., Anderson, V. E. : Pycnodysostosis. Amer. J. Dis. Child. 116, 70--77 (1968).

19. Zugibe, F. T., Herrmann, J. Opitz, J. M., Gilbert, E. F., McMillan, G. : Arthro- dento-osteo dysplasia. Birth Defects Orig. Art. Series V (in press).

Jiirgen Herrmann, M.D. Assistant Professor of Pediatrics University of Wisconsin Center for Health Sciences - - Medical School Madison, Wisconsin 53 706, USA