Introduction

Lenz–Majewski syndrome (LMS) (OMIM 151050) is a rare sclerosing bone dysplasia, first described by Braham (1969) in 1969 and subsequently named Lenz–Majewski hyperostotic dwarfism (Lenz and Majewski 1974; Robinow et al. 1977). Only nine affected individuals have been reported to date, and all were sporadic (Braham 1969; Macpherson 1974; Kaye et al. 1974; Lenz and Majewski 1974; Robinow et al. 1977; Gorlin and Whitley 1983; Chrzanowska et al. 1989; Nishimura et al. 1997; Saraiva 2000; Wattanasirichaigoon et al. 2004). The skeletal changes include progressive hyperostosis of the craniofacial bones with delayed closure of the fontanelles, diaphyseal cortical thickening of the tubular bones, and brachymesophalangy with proximal symphalangism. In addition, affected individuals show moderate to severe mental retardation, severe growth failure, cutis laxa, enamel hypoplasia, choanal atresia, nasolacrimal duct obstruction, and webbed fingers and toes. The prognosis is guarded. Most patients that have been reported died during childhood (Braham 1969; Macpherson 1974; Kaye et al. 1974; Majewski 2000). We report here on a Japanese boy whose manifestations can be considered to be a mild variant of LMS. Our experience raises the suspicion that the phenotypic range of LMS is broader than currently believed.

Clinical report

The patient was a 17-year-old Japanese boy born to non-consanguineous healthy parents who were respectively 25 (mother) and 30 (father) years old at his birth. The family history was unremarkable. He was vaginally delivered at 40 weeks of gestation after an uneventful pregnancy. Apgar scores at 1 and 5 min were 8 and 10, respectively. Birth weight was 2300 g (−2.25 SD), length was 45 cm (−1.9 SD), and head circumference was 32.5 cm (−0.7 SD). Cutis laxa and prominent veins in the scalp and abdominal wall attracted medical attention in infancy, but a skin biopsy was not contributory. Psychomotor development was mildly retarded, with the infant showing head control at 6 months, walking alone at 20 months, and speaking meaning words at 24 months. Deciduous teeth were reported to have erupted at 2 years of age. The lack of eruptions of some permanent teeth in the upper jaw at 13 years of age was the basis for his referral to our hospital for further evaluation. His four maxillary permanent teeth of central and lateral incisors did not erupt. He had also a follicular cyst around the anterior teeth, necessitating surgical extirpation. Enamel dysplasia was histologically confirmed. He showed a distinctive, progeroid facial appearance with sparse hair, large auricles, maxillar hypoplasia, high-arched palate, and prognathism (Fig. 1a, b). He had inter-digital webbing (Fig. 1c) and mild cubitus valgus. The skin was wrinkled and loose, and prominent veins were noted in the abdominal wall. He had mild mental retardation with a total intelligence quotient of 60. Radiological examination showed cranial hyperostosis, particularly of the skull base, a sclerotic, thick mandible, broad clavicles and ribs, and diaphyseal undermodeling of the tubular bones. Diaphyseal hyperostosis was not evident, while epimetaphyseal sclerosis or longitudinal sclerotic striation was found in the long bones. Metaphyseal equivalents of the axial skeleton showed dense sclerosis (Fig. 2a–g). Bone scintigraphy showed an increased accumulation of radiopharmaceuticals, corresponding with sclerotic regions on the roentgenograms. During follow-up to 17 years of age, he showed a stable clinical course. At 17 years of age, he had a muscular build, a height of 164.5 cm (−1.0 SD) and a head circumference of 54 cm (−1.3 SD) and weighed 56.2 kg (−0.54 SD). He underwent a surgical correction for severe anterior occlusion with prognathism. Mutation analyses for the transforming growth factor-beta1 gene (TGFB1) and the LDL receptor-related protein 5 gene (LRP5) yielded normal findings.

Fig. 1
figure 1

Clinical photographs at 17 years of age. a, b A progeroid facial appearance with sparse hair, large auricles, and prognathism. c Interdigital webbing

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Fig. 2
figure 2

Radiological findings at 17 years of age. a, b Hyperostosis of the calvaria, skull base and mandible. c Broad clavicles (arrows) and ribs, and sclerosis of metaphyseal equivalents of the spine. d Undermodeling of the short tubular bones and sclerosis of the carpal bones. e Metaepiphyseal sclerosis of the distal humerus, proximal ulna, and proximal radius. f Sclerosis of the sacrum, acetabulum, and proximal femur. g Sclerotic striations in the distal femur and proximal tibia

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Discussion

We describe a boy with a disorder that is classifiable into a group of sclerosing bone dysplasias. The disorder was radiologically characterized by cranial hyperostosis, metaepiphyseal sclerosis, and diaphyseal undermodeling. In addition, it was uniquely associated with cutis laxa, enamel dysplasia, and mental retardation. According to the ‘Nosology and Classification of Genetic Skeletal Disorders: 2006 revision’ (Superti-Furga and Unger 2007), sclerosing bone dysplasias are subclassified into three groups: (1) neonatal osteosclerotic dysplasia group, (2) increased bone density group (without modification of bone shape), and (3) increased bone density group with metaphyseal and/or diaphyseal involvement. A few disorders in the third group, such as Camurati–Engelmann disease, craniometaphyseal dysplasia, craniodiaphyseal dysplasia, and endosteal hyperostosis, share some radiological features with the present disorder. However, the unique constellation of skeletal, skin, dental, and mental abnormalities in the present disorder excludes the possibility of these disorders. In fact, molecular analyses for TGFB1 (the gene of Camurati–Engelmann disease) and LRP5 (the gene of endosteal hyperostosis, Worth type) were negative.

In the differential diagnosis, LMS deserves to be discussed. The disorder is characterized by craniodiaphyseal hyperostosis and brachymesophalangy with proximal symphalangism. It is complicated by mental retardation, somatic growth failure, cutis laxa, enamel hypoplasia, and webbed fingers and toes. The manifestations of previously reported LMS patients, LMS-like patients, and the present patient are summarized in Table 1. Most findings in LMS were shared by the present disorder. However, the differences include the absence of somatic growth failure and brachymesophalangy with proximal symphalangism in the present patient. LMS patients typically exhibit diaphyseal hyperostosis and metaepiphyseal radiolucency, while the present patient had only diaphyseal undermodeling and showed metaepiphyseal sclerosis. However, the degree of diaphyseal hyperostosis is described to vary considerably among LMS patients, and some patients with metaepiphyseal sclerosis are reported in the literature (Chrzanowska et al. 1989; Spranger et al. 2002). Thus, it is tempting to assume that the present disorder may fall at the mildest end in the phenotypic continuum of LMS, suggesting that the clinical spectrum of the disorder may be broader than currently thought.

Table 1 Clinical and radiological findings of Lenz–Majewski syndrome (LMS)
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