American Journal of Medical Genetics 11:415-424 (1982)

A New Form of Metaphyseal Chondrodysplasia in Two Sibs: Surgical Treatment of Tracheobronchial Malacia and Scoliosis

1.1. Kaitila, P. Halttunen, 0. Snellman, and 0. Takkunen

Department of Medical Genetics, Department of Thoracic Surgery, Department of Anesthesiology, University of Helsinki and Orthopedic Hospital of the Invalid Foundation, Finland

We describe a 19-year-old male with a previously unrecognized form of dispropor- tionate short stature, tracheobronchial malacia, and progressive scoliosis and his 28-year-old sister with the same but milder condition. The clinical characteristics were short limbs and digits and thoracolumbar scoliosis. Bone films showed pro- gression from marked metaphyseal dysplasia of tubular bones in childhood to short and broad bones with mild dysplasia of the joints in adulthood. The verte- brae and the intervertebral plates were only mildly affected in spite of marked sco- liosis. Trachea and bronchi were reinforced with surrounding acrylate mesh before surgical treatment of the scoliosis. Affected sibs of both sexes and healthy parents suggest an autosomal recessive mode of inheritance.

Key words: metaphyseal chondrodysplasia; recessively inherited; tracheobronchial malacia; scoliosis; sur- gical therapy

INTRODUCTION

We report on the clinical and radiographic characterstics o f a 19-yr-old male and his 28-yr-old sister presenting a previously unrecognized f o r m o f metaphyseal dysplasia. He also had progressive spinal deformity and tracheobronchial malacia re- quir ing surgical t reatment .

Received for publication February 12, 1981; revision received August 31, 1981.

Address reprint requests to Dr. Ilkka I . Kaitila, Department of Medical Genetics, University of Helsinki, SF-00290 Helsinki 29, Finland.

0148-7299/82/1104-0415$03.000 1982 Alan R. Liss, Inc.

416 Kaitila et al

CLINICAL HISTORIES

Patient I was born as the third child of a 28-yr-old mother and a 32-yr-old fa- ther after an uneventful pregnancy. The delivery was normal except for breech pre- sentation. Birth weight was 3,600 gm and length was 47 cm. Disproportionate body and short limbs were observed immediately. The unrelated parents and their second child were healthy.

Motor development was delayed; he learned to walk at 4 yr. Sexual maturation was thought to have been delayed by the parents. Mental development was normal. He attended primary and secondary schools and continued his studies at a business college.

The patient has been followed at the Orthopaedic Hospital of the Invalid Foun- dation since age 8 yr for severe, disproportionately short stature and progressive sco- liosis. At 9 yr, the angle of the thoracic scoliosis was 45". At 15 yr, the angle was 50", but the spine was flexible and allowed straightening up to 20". The scoliosis curved rapidly to 65" by 17 yr. To prevent progression a Milwaukee brace was constructed to be used day and night. However, respiratory difficulties and discomfort were intoler- able; after 6 mo, plans were made to straighten and fuse the vertebral column. The procedure had to be interrupted at the induction of anaesthesia, owing to abrupt ven- tilatory failure and cyanosis. Over the next year the patient was repeatedly admitted for severe dyspneic episodes precipitated by coughing. On chest films there was an atelectasis of the lower right lobe, which could not be inflated by physical therapy or high pressure ventilation. On bronchoscopy the walls of the right main bronchus and the bronchus of the right upper lobe were soft and collapsing. When the patient coughed, the left main bronchus and trachea also collapsed. This was confirmed by cineradiography. The severe tracheobronchial malacia had evidently caused the ven- tilatory problems at the induction of the anaesthesia. It was decided to strengthen the walls of the trachea and the main bronchi before treating the scoliosis.

At admission this 18 10/12-yr-old male had severe, disproportionate short sta- ture and scoliosis (Fig. lA,B). Height was 114 cm, weight 25 kg. There was marked deformity of chest, but no respiratory distress. Limbs were short, especially the mid- dle and distal segments; digits were stubby, short, and about equal in length. The sub- cutaneous tissue of the fingers was redundant and the skin wrinkled. The finger joints were hypermobile, but there was limitation of extension of about 20" at the elbows. The nails were short and broad. The nose was narrow and beaked, deviating slightly to the right (probably due to a previous accident). There was marked hyperplasia of the palatine ridges resulting in a narrowly arched palate. The thorax was shallow and narrow with a large depression of the anterior lower wall. He had mild dorsal lordosis with severe right convex scoliosis. The cardiovascular system was normal. Sexual ma- turation corresponded to Tanner stage IV. The intellectual capacity was normal, but he suffered from reactive mental depression requiring psychosupportive therapy.

Because of the tracheomalacia, intubation for the first operation was preceded by local spray anaesthesia of the larynx and trachea. Walls of the trachea and the bronchi were soft and collapsing. The cartilage rings were irregularly arranged and in patches along most of the trachea and the bronchi. The trachea and the main stem bronchi were surrounded with Marlex meshR and fixed with methylene-N-blue acryl- ate adhesive. Recovery was uneventful and the patient was discharged three wk later. There was an immediate improvement in both subjective and objective well being.

A New Form of Metaphyseal Chondrodysplasia 417

A B Fig. 1A. deformed chest and enlarged clumsy joints. Height is 116 cm, and weight is 24 kg.

Patient I at 18 yr of age presenting with severe disproportionate short stature, short extremities,

Fig. 1B. The back of patient I demonstrating the scoliosis preoperatively.

Operative treatment of the scoliosis was performed in two stages after the rein- forcement of the tracheobronchial tree. Three months later a Harrington rod was in- stalled between T2 and L3 straightening the angle from 62 to 52". Spinal processes were removed from T9 to L1 and spondylodesis was accomplished with tibial trans- plants. The patient was discharged two weeks later with a Milwaukee brace. Four mo later the patient was readmitted, and the rod was lengthened 1 cm with an additional 10" correction of the scoliosis. Spinal processes were removed from T5 to T9, and spondylodesis was performed with tibial transplants. The Milwaukee brace was used postoperatively for 6 mo.

The patient was followed for 3 yr. He had several respiratory infections but no dyspneic episodes and was able to attend business school and to drive a car. However, 3 wk before the 3-yr follow-up examination the patient experienced acute and pro- longed pain in his lower back followed by mild dyspnea at physical effort. At exami- nation progression of the scoliosis to an angle of 88" was observed. The right lower lung was completely compressed, and in radiotomographs, the right stem bronchus was partially obstructed. Radiographs confirmed erosion of the Harrington rod through the T4 and L3, and failure of the spondylodesis. The risks and the probably poor longterm prognosis were considered to markedly exceed the possible benefits of a reoperation. Therefore, efforts were directed to physical, respiratory, and psycho- logical support.

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Fig. 2. stature, mild thoracolumbar scoliosis, and bowing of the legs. Height is 117 cm, and weight is 39.5 kg.

The sister of patient I at 28 yr of age demonstrating the similar disproportionately short-limbed

Patient 11, the sister of patient I, was born as the first child after an uneventful pregnancy. The delivery was normal. Birth weight was 3,100 gm and length 46 cm. Short limbs and disproportionate stature were noted immediately. Motor develop- ment was slow; she sat at 9 mo and walked at 2 1/12 yr. She spoke words at 11 mo and 2-3 word sentences at 12-13 mo. Sexual maturation was slow; menarche occurred at 17 yr. Growth was severely retarded, and owing to crura vara she had bilateral tibia1 osteotomy at 5 yr. The patient had complained of minor discomfort in her back dur- ing physical exercise in her adolescent years, but she had noticed no deformity in the back or chest. However, the hospital records indicated that she had been examined at 17 yr for scoliosis with a radiographic angle of 39" at the lumbar spine and 26-29" at the thoracic spine. No treatment had been instructed. She never had dyspneic epi- sodes during physical exercise or respiratory infections. She had completed her aca- demic studies in social sciences and psychology with excellent grades and had been employed as a kindergarten teacher and psychologist.

At 28 yr she had severe, disproportionately short stature with short limbs and mild obesity (Fig. 2). There was a mild lumbar scoliosis to the left and a thoracic scoliosis to the right with an angle of 45" measured from the radiographs (Fig. 3C). Dorsiflexion at wrists, metacarpophalangeal joints, and ankles was slightly in- creased; the range of movement in all other joints was normal. Her height was 117 cm, sitting height 74 cm or 62.2% (normal for adults 52%), span 106 cm, and weight 39.5 kg. The radiographs of her skeleton at 5 years and at 23 and 28 yr (Fig. 3A,B,C) confirmed the diagnosis.

At examination the parents were normal.

A New Form of Metaphyseal Chondrodysplasia 419

B C

Fig. 3A. Radiograph of the hand and of the distal part of the forearm of patient I1 at 23 yr of age demon- strating the short and abnormal phalanges and metacarpals. All growth plates have been fused. Fig. 3B. Radiograph of the leg of patient I1 at 28 yr. Tibia and fibula are short and abnormally modeled, particularly at the metaphyses. The cystic extensions into the metaphyses observed during the growth pen- od (q.v. 4A) have disappeared completely. There are no visible remnants of the osteotomy at 5 yr. Fig. 3C. Radiograph of the spine of patient I1 at 28 yr demonstrates a lumbar and a corresponding thoracic scoliosis with an angle of 45". The vertebrae are about normal in form and height except those at the curvature of the scoliosis.

420 Kaitila et al

A B Fig. 4A. Radiograph of the right lower leg of patient I at 9 yr. The tibia and fibula are short and broad. The metaphyses are grossly irregular and splayed. Cystic translucencies extend deep into the metaphyses and diaphyses at both ends of the fibula and in the distal end of the tibia. The epiphyses are relatively mildly deformed, except in the distal end of the tibia. The growth plates are relatively narrow.

Fig. 4B. Radiograph of the right forearm of patient I at 17 yr. The radius and ulna are short and abnor- mally curved. The epiphysis of the radius and the metaphyses of both bones are broad and deformed. Translucent cysts extend into the diaphysis of the distal ulna.

RADIOGRAPHIC FIN DINGS

The skeletal radiographs of the patients at respective ages are essentially identi- cal (Figs. 3-6). They demonstrate marked shortness of long bones with cone-shaped epiphyses and metaphyseal flare of the distal ulna and radius and with cystic irregu- larities extending to the proximal and distal metaphyses of the fibulae. The proximal epiphyseal plate of the radius is abnormally curved (Figs. 3-5). The mesomelic seg- ments are disproportionately short. The length ratio of the tibia and femur of both patients at 9 and 15 yr is 0.65 as compared to the corresponding ratio of healthy chil- dren at respective ages: 0.82 and 0.83. The tubular bones of hands and feet are short and blunt with expanded metaphyses and cone epiphyses. The distal phalanges are particularly short. At 15 yr, the growth plates of the long bones and of some metacar- pals, metatarsals, and phalanges are still present. The form and size of the epiphyses are relatively normal (Fig. 5 ) , but the fusion of the epiphyses to the metaphyses ap- pears irregular. The radiographs of the spine show marked scoliosis and mild thorac- ic lordosis (Figs. 3C, 6). The height of the vertebrae appears slightly low, but about normal in the lumbar region (Fig. 6). The intervertebral plates are slightly flattened

A New Form of Metaphyseal Chondrodysplasia 421

Fig. 5 . Radiograph of the hand of patient I at 16% yr. The phalanges and the metacarpals are short and abnormally modeled. The growth plates closed irregularly. In addition to the cone epiphysis of the middle phalanx of the forefinger, the metaphyses are abnormally cupped. The fingers are equal in length. The growth plates of the ulna and radius are open. The epiphyses and the metaphyses are deformed and the ulna does not extend to the level of radius as normally.

throughout. The iliac bones are relatively small and the cristae irregular. The proxi- mal femoral epiphyses are about normal, but the adjacent metaphyses are irregular; the growth plates of the proximal femurs are still open at 14 yr (Fig. 7). After fusion of the growth plates the femoral necks are short, but the articular surface is smooth.

LABORATORY FINDINGS

The results of routine laboratory studies of patient I , including assays for urin- ary aminoacids, oligosaccharides, and organic acids, were normal.

DISCUSSION

Radiographic abnormalities at the metaphyses of the tubular bones of our pa- tients merit classification of the disease to metaphyseal chondrodysplasia. The obvi- ous mode of inheritance was autosomal recessive.

Spinal deformity is frequently associated with the platyspondylic types of the skeletal dysplasias [Rimoin, 1975; Kopits, 1976; Moe et al, 19781, and it is almost al- ways observed in Diastrophic dysplasia and in the Acromesomelic dysplasias in which the dysplasia of the vertebrae is mild [Maroteaux et al, 1971; Campailla et al,

422 Kaitila et al

Fig. 6 . Radiograph of the spine of patient I at 16 yr. The vertebrae are only mildly flattened and the inter- vertebral spaces are normal. There is a severe lumbar and a corresponding thoracic scoliosis with an angle of 60".

1971; Walker et al, 19721. Spinal deformity has rarely been observed in the metaphys- eal osteochondrodysplasia [see Kozlowski, 1976; Spranger, 19761. There is little pub- lished information on treatment and outcome of spinal deformity in osteochondro- dysplasias [Kopits, 1976; Moe et al, 19781.

Tracheobronchomalacia is a relatively common problem of infancy in many forms of skeletal dysplasias, but it has not been reported in adult patients [Houston et al, 1972; Taber et al, 19731. Methods to reinforce collapsing airways have been de- scribed [Herzog, 1958; Rainer et al, 1968; Halttunen et al, 19731. These have not been applied to patients with osteochondrodysplasias.

Metaphyseal osteochondrodysplasias are a heterogeneous group of skeletal dis- eases of which some are clinically and genetically well defined and could be easily ex- cluded from the diagnoses of our patients [see Spranger, 19761. The extensive cysts or radiolucencies with flaring of the metaphyses and with relatively normal epiphyses during growth also allow us to differentiate most metaphyseal osteochondrodyspla- sias. Jansen and Schmid types are both autosomal dominant. Metaphyseal chondro- dysplasia with exocrine pancreatic insufficiency and cyclic neutropenia is an autoso- ma1 recessive metaphyseal dysplasia associated with malabsorption and recurrent respiratory infections [Taybi et al, 19691. Marked flaring of the metaphyses with dys-

A New Form of Metaphyseal Chondrodysplasia 423

Fig. 7. Radiograph of the pelvis of patient I at 14 yr with mild involvement of the hip joints. The femoral necks are slightly short and the rnetaphyses appear hypoplastic. Both the articular spaces and the joint sur- faces are about normal. The iliac wings are small and the cristae hypoplastic and irregular.

plastic epiphyses and premature fusion of the growth plates was observed in a 6 6112-yr-old boy who clinically resembled our patients [Rupprecht et al, 19711.

Metaphyseal osteochondrodysplasia, type McKusick, must be carefully ruled out because of its high incidence in the Finnish population [Kaitila and Perheentupa, 19801. It is an autosomal recessive disorder with marked rhizomelic shortening of the extremities, genu vara, short fingers with marked ligamentous laxity of finger joints. Hair is usually thin and sparse, and eyebrows may be absent, but, in these respects, phenotypic variability is quite marked. There appears to be a defect in cell-mediated immunity of variable degree, which occasionally may have clinical significance [Viro- lainen, et al, 19781. Spinal deformity consists of exaggerated lumbar lordosis, where- as scoliosis is rarely observed. Radiographic abnormalities are marked flaring of the metaphyses and irregular wavelike border of the growth plate-metaphysis junction.

The severe metaphyseal dysplasia detectable in childhood, with essentially no platyspondyly but progressive spinal disease in our patients, is compatible with the diagnosis of metaphyseal dysplasia. However, there are several peculiar features in- cluding severe scoliosis, mild thoracic lordosis, mesomelic shortening of limbs, short and even-length fingers, mild hip dysplasia, hyperplastic gingiva with high and nar- row palate, and, finally, tracheobronchial malacia that have not been observed in previously delineated forms. Therefore, it seems to us that our patients represent a previously unrecognized form of metaphyseal dysplasia with an autosomal recessive inheritance. The surgical treatment provided patient I relief for three years.

ACKNOWLEDGMENTS

Sincere thanks are due to Professor Rudolf Lemberg, Umes, Sweden, for his kind cooperation concerning patient I1 and to Professors David L. Rimoin and Ralph Lachman, Los Angeles, for reading the manuscript and giving valuable suggestions.

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REFERENCES

Campailla E, Martinelli B (1971): Deficit staturale con micromesomelia. Presentazione di due casi famili-

Halttunen P (1973): EDH-Adhesive plastic support in the surgical treatment of tracheobronchial col-

Herzog H (1958): Expiratorische Stenose der Trachea und der grossen Bronchien durch die ershlaffte Pars

Houston CS, Awen CF, Kent HP (1972): Fatal neonatal dwarfism. J Can Assoc Radio1 23:45-61. Kaitila I, Perheentupa J (1980): Cartilage-hair hypoplasia in Finland. In Spranger J , Tolksdorf, M (eds):

Kopits S (1976): Orthopedic complications of dwarfism. Clin Orthop 114:153-179. Kozlowski K (1976): Metaphyseal and spondylometaphyseal chondrodysplasias. Clin Orthop 114:83-93. Maroteaux P, Martinelli B, Campailla E (1971): Le nanisme acromesomelique. Presse Medicale 79:

Moe JH, Winter RB, Bradford DS, Lonstein JE (1978): Dwarfs. In “Scoliosis and Other Spinal Deformi-

Rainer WG, Newby JP, Kelble DL (1968): Long term results of tracheal support surgery for emphysema.

Rimoin DL (1975): The chondrodystrophies. Adv Hum Genet 5:l-118. Rupprecht E, Kozlowski K, Hinkel GK (1971): Sonderform einer epimetaphysaren Osteochondrodyspla-

sie. Helv Ped Acta 26:311-318. Spranger JW: Metaphyseal Chondrodysplasia. In Schimke RN (ed): “Growth Problems and Clinical Ad-

vances.” New York: Alan R. Liss for The National Foundation-March of Dimes, BD:OAS XI1

Taber P, Freedman S, Lackey DA (1973): Inspiratory stridor with cyanosis with defective cartilagenous support of the larynx and trachea in diastrophic dwarfism. In: “Progress in Pediatric Radiology” Basel: S Karger. pp 152-166.

Taybi H, Mitchell AD, Friedman GD (1969): Metaphyseal dysostosis and the associated syndrome of pan- creatic insufficiency and blood disorders. Radiology 93:563-571.

Walker BA, Scott CI, Hall JG, Murdoch JL, McKusick VA (1972): Diastrophic Dwarfism. Medicine 51: 41-59.

Virolainen M, Savilahti E, Kaitila I, Perheentupa J (1978): Cellular and humoral immunity in cartilage- hair hypoplasia. Pediatr Res 12:961-966.

Edited by John M. Opitz

ari. Minerva Ortop 22:180-184.

lapse. Acta Chir Scan Suppl440, 34 pp.

membranacea. Operative Korrektur durch Spanplastic. Thoraxchirurgie 5/4:281.

“Klinische Genetik in der Pardiatrie.” Stuttgart, New York: George Thieme Verlag, pp 68-73.

1839-1 842.

ties.” Philadelphia: WB Saunders Comp. pp. 569-595.

Dis Chest 53:765-772.

(6):33-46, 1976.