Metaphyseal Anadysplasia: Evidence ofGenetic Heterogeneity

Gen Nishimura,1* Shiro Ikegawa,2 Takeshi Saga,3 Toshiro Nagai,3 Misaki Aya,4 and Toshio Kawano5

1Department of Radiology, Dokkyo University School of Medicine, Tochigi, Japan2Laboratory of Molecular Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan3Department of Pediatrics, Dokkyo University School of Medicine Koshigaya Hospital, Saitama, Japan4Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan5Division of Neonatology, National Children’s Hospital, Tokyo, Japan

We report on two unrelated children, a girland a boy, with regressive metaphyseal dys-plasia. Both children had bow legs and atransient growth decline in early childhood.Metaphyseal modifications of the longbones in the children were most conspicu-ous at an early age and then subsided by age2 to 3 years. The father of the boy may havehad the same disorder, because he wasshorter than his sibs and showed mild modi-fications of the vertebral end plates withmild narrowing of the interpediculate dis-tance of the lumbar spine. The evolution ofthe metaphyseal dysplasia in the childrenclosely resembled that of metaphyseal ana-dysplasia (MAD), which is X-linked reces-sive in inheritance. By contrast, the occur-rence of an isolated, affected girl and pos-sible father-to-son transmission reportedhere were consistent with autosomal domi-nant transmission, suggesting heterogene-ity of MAD. Molecular studies of the type Xcollagen gene in the boy did not demon-strate any disease-causing mutation. Am. J.Med. Genet. 82:43–48, 1999.© 1999 Wiley-Liss, Inc.

KEY WORDS: skeletal dysplasia; metaphy-seal dysplasia; metaphysealanadysplasia; autosomaldominant; type X collagen;COL10A1

INTRODUCTIONRegressive metaphyseal dysplasia refers to a group

of benign skeletal dysplasias characterized by general-

ized metaphyseal modifications that regress spontane-ously in childhood. Among these, metaphyseal anady-splasia (MAD) is a relatively well-defined entity inher-ited as an X-linked recessive trait [Maroteaux et al.,1991]. In addition, there are several unclassifiablecases of regressive metaphyseal dysplasia. We describehere two unrelated children, a girl and a boy, who hadskeletal changes consistent with MAD. The father ofthe boy most likely had the same disorder. Our obser-vation may indicate heterogeneity of MAD.

CLINICAL REPORTSPatient 1

The patient, a Japanese girl, was the only child ofhealthy, nonconsanguineous parents. The family his-tory was unremarkable. The father was 167 cm (−0.6SD) tall, and the mother 160 cm (+0.4 SD). The patientwas delivered spontaneously at term after an unevent-ful pregnancy. The father was 27 years old and themother 24 at the birth of the patient. Birth length was47 cm (−1.0 SD), weight 2,400 g (−1.8 SD), and OFC 31cm (−1.6 SD). There was a temporary dip in her growth,centered around age 16 months and coincident withincreased bowing of the legs (Fig. 1A). When referred tous at age 16 months, her height was 70.6 cm (−2.6 SD)and weight 7,900 g (−1.7 SD). Lower limbs were bowedand mildly short. Results of laboratory examinationswere normal, including calcium, phosphate, alkalinephosphatase, vitamin D, and intact parathyroid hor-mone. Radiographic examination demonstrated con-spicuous irregularities with sclerosis in the distal femo-ral, proximal tibial, and distal tibial metaphyses (Fig.2A). Gena vara were evident. Mild metaphyseal alter-ations were found in the distal radii. Subsequently, thepatient showed significant catch-up growth and spon-taneous regression of the bow legs and lower limbshortness. At age 3 2/12 years, height was 91.6 cm (−0.4SD), weight 12.1 kg (−0.9 SD), and OFC 46.2 cm (−0.9SD). Radiographic examination documented disap-pearance of the metaphyseal alterations (Fig. 2B).

Patient 2

This Japanese boy was the only child of nonconsan-guineous parents. The father was 165 cm (−0.9 SD) tall,

*Correspondence to: Gen Nishimura, MD, Department of Ra-diology, Dokkyo University School of Medicine, 880 Kitakobaya-shi, Mibu, Shimotsuga-gun, Tochigi-ken, 321-02 Japan. E-mail:gen-n@dokkyomed.ac.jp

Received 2 April 1998; Accepted 11 June 1998

American Journal of Medical Genetics 82:43–48 (1999)

© 1999 Wiley-Liss, Inc.

and the mother 160 cm (+0.4 SD). The paternal grand-father of the patient was apparently short (152 cm),and the father was reportedly shorter than his sibswhen young. The patient was delivered spontaneouslyat 41 weeks of gestation after an unremarkable preg-nancy. Birth length was 51 cm (+0.6 SD), weight 3,816g (+1.5 SD), and OFC 33 cm (mean). He was referred tous at age 4 months because of bow legs. Length was60.7 cm (−1.1 SD), weight 7,250 g (mean), and OFC 40cm (−1.2 SD). Other than bow legs, no abnormality wasfound on physical examination. Results of laboratoryexaminations were normal, including calcium, phos-phate, alkaline phosphatase, parathyroid hormone,and urine calcium/creatinine ratio. Radiological exami-nation demonstrated striking metaphyseal irregulari-ties of the long bones and gena vara (Fig. 3A and B).The proximal femoral metaphyses were oriented verti-cally. Psychomotor development was normal. Length

remained within approximately −1.0 SD of the meanduring the first year of age. However, height decreasedto −1.7 SD because of a transient growth decline thatstarted at age 12 months and ceased at age 2 years(Fig. 1B). Bow legs were aggravated in late infancy, butgradually resolved after 1 year of age. At age 3 1/12years, height was 89.8 cm (−1.1 SD) and weight 12.4 kg(−1.0 SD). Metaphyseal alterations alleviated with ageand normalized after 2 years of age (Fig. 3C, D, and E).

Patient 3

This was the father of patient 2. He was 165 cm tall(−1.0 SD), and reportedly some 10 cm shorter than hissibs. He was of stocky build and occasionally had backpain. Radiographic examination demonstrated end-plate depression of the lumbar vertebral bodies second-ary to notochordal remnants and mild narrowing of the

Fig. 1. Growth curves of patient 1 (A), and patient 2 (B).

44 Nishimura et al.

interpediculate distance of the lower lumbar spine (Fig.4 A and B). We concluded that he had the same disor-der as that of his son, although no remarkable abnor-mality was evident radiologically in the long bones, andthe endplate modifications could be a normal variant.

MOLECULAR INVESTIGATION

A blood sample was obtained from patient 2 with theinformed consent of his guardian, and type X collagengene (COL10A1) was examined for a mutation. Theentire coding region and the exon-intron junctions ofCOL10A1 from genomic DNA were amplified by poly-merase chain reaction (PCR), and direct sequencingwas performed as reported previously [Ikegawa et al.,1997]. Two missense mutations were identified: onewas C80T (Thr27Met) in the N-terminal globular do-main and the other C1499A (Pro500His) in the triplehelical domain; however, these mutations are commonpolymorphisms among the Japanese [Ikegawa, unpub-lished data].

DISCUSSION

The unique skeletal evolution in regressive metaph-yseal dysplasia most likely causes the entity to be eas-ily overlooked, unless the clinical manifestations in af-fected individuals draw medical attention at an earlyage. Therefore, the nosological status of regressive me-taphyseal dysplasia remains incomplete. We reviewhere the clinical and radiological manifestations of a

few groups of regressive metaphyseal dysplasia, whichare compared with those of our patients.

MAD is the only regressive metaphyseal dysplasiawhose clinical and genetic characteristics have beenwell elucidated. MAD was first reported by Wiedemannand Spranger [1970] and further defined by Maroteauxet al. [1991]. Only five affected boys including two ma-ternally related first cousins have been described.Thus, X-linked recessive inheritance was proposed. Itsclinical findings comprise slight shortness with mildvarus deformity of the legs appreciable in infancy andregressive in childhood. The height of affected indi-viduals is within the normal range but may be shorterthan that of relatives [Wiedemann, 1992]. The radio-logical findings comprise metaphyseal irregularities ofthe long bones particularly in the hip and knee andvertically oriented proximal femoral metaphyses withshort femoral necks. The metaphyseal alterations ame-liorate after age 2 years and subside in childhood. Mildplatyspondyly and multiple coronal clefts of the lumbarspine may be present in infancy. Distinctive histologi-cal findings of the cartilage were described in an af-fected individual [Maroteaux et al., 1991].

Heterogeneity of MAD was suggested recently by LeMerrer and Maroteaux [1997]. They proposed a distinc-tive entity, ‘‘MAD type II’’, based on six sporadic casesconsisting of three boys and three girls, whereas theytermed MAD ‘‘MAD type I’’. The clinical hallmarks ofMAD type II include enlarged costochondral junctionsand knobby wrists but normal height. The metaphysealchanges are evident at birth or within the first month

Fig. 2. Radiographs of the leg (A) at age 16 months and radiograph of the knee (B) at age 3 years in patient 1. Note the metaphyseal dysplasia andits spontaneous regression.

Metaphyseal Anadysplasia 45

after birth and progressively become normal. The me-taphyseal changes predominate at the knee and wristand are reminiscent of ‘‘a fine tooth comb’’. The upperfemoral metaphyses are blurred and the iliac crestsirregular. However, these clinical and radiological

manifestations of MAD type II overlap considerablywith those of MAD; therefore, it remains unresolvedwhether MAD type II represents a distinctive entity orvariable expression of MAD.

Three familial cases (a mother, her son, and daugh-

Fig. 3. Radiographs of the leg (A) and the arm (B) at age 4 months, and radiographs of the leg at 9 months (C), at 14 months (D), and at 2 years and4 months of age (E) in patient 2. Note the metaphyseal dysplasia and its spontaneous regression.

46 Nishimura et al.

ter) reported by Beluffi et al. [1982] as examples ofmetaphyseal dysplasia type Schmid represent autoso-mal dominant metaphyseal dysplasia in which theearly regression of metaphyseal changes resembledthat of MAD. However, conspicuous shortness of thesepatients may not warrant describing the entity as re-gressive (4ana) metaphyseal dysplasia. Maroteaux etal. [1991] mentioned four children with ‘‘early regres-sive metaphyseal dysplasias,’’ and described that thesechildren may constitute a heterogeneous set of disor-ders characterized by less prominent early metaphyse-al changes and less severely affected upper femoral me-taphyses. As in Beluffi’s cases, the term, regressive me-taphyseal dysplasia, may be inappropriate in thesechildren, because they had a short stature between −2and −3 SD.

The clinical and radiological constellation in the pre-sent children were identical to that of MAD, including

bow legs with mild shortness of the lower limbs at anearly age and, more importantly, distinctive evolutionof metaphyseal dysplasias. However, possible father-to-son transmission in the present family and a spo-radic case of an affected girl were consistent with au-tosomal dominant inheritance as opposed to the X-linked recessive inheritance proposed for MAD.

The present children showed a transient dip in thegrowth curve in their late infancy and early childhood.It remains unknown whether this growth decline is anessential part of the present disorder. The growth dipmay have been related to the transient aggravation ofbow legs. Additional reports on early somatic growth inregressive metaphyseal dysplasia may benefit the no-sology of the entity.

The cause of the metaphyseal dysplasias was un-known until recently. However, recent molecular inves-tigations have identified several genes causing me-

Fig. 4. Frontal (A) and lateral (B) radiographs of the lumbar spine in patient 3. Note mild interpediculate distance narrowing of the lower lumbarspine and mild modification of the vertebral endplates.

Metaphyseal Anadysplasia 47

taphyseal dysplasias: the type X collagen gene is re-sponsible for metaphyseal dysplasia type Schmid[Warman et al., 1993], and the PTH-PTHrP receptorgene is responsible for metaphyseal dysplasia typeJansen [Schipani et al., 1995]. The gene of metaphysealdysplasia type McKusick was assigned to chromosome9 [Sulsalo et al., 1993]. Because of the radiographicsimilarities among metaphyseal dysplasia typeSchmid, MAD, and the present disorder, we focusedour investigation on the type X collagen gene but failedto find any significant mutation. It remains possiblethat mutations other than those in the coding se-quence, such as those in the 58-promoter region, causethe present disorder.

In summary, our observation suggested a subset ofMAD, which is not inherited as an X-linked recessivetrait. Additional case documentation of regressive me-taphyseal dysplasia is mandatory to complete the no-sology of this entity.

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