► [Intrasutural islands of bone]
Wormian bones can reflect a developmental variation of calvarial ossification (Hinton et al. 1984) (Fig. 1.21) or aberrant intramembranous ossification, which can occur in association with several bone dysplasias and malformation syndromes, most notably cleidocranial dysostosis and osteogenesis imperfecta. Although not universally applicable, the following criteria may help differentiate clinically significant from nonsignificant wormian bones: number of 10 or more, diameter exceeding 4-6 mm, and arrangement in a general mosaic pattern (Cremin et al. 1982). Furthermore, unlike the developmental variety, pathologic wormian bones do not coalesce with age and often persist into adult life as individual sutural bones. Wormian bones are most frequently located in the lambdoid sutures, followed by the sagittal and the temporosquamosal sutures. Only rarely are they found within fontanels. Abnormal tensile forces applied to the growing skull seem to have little or no effect on the development of wormian bones, whose origin is likely to be entirely under the control of genetic factors (El-Najjar and Dawson 1977; White 1996). Because pathologic wormian bones reflect defective ossification of the calvarial bones, they occur most often in association with persistently open cranial sutures and fontanels. Delayed and/or abnormal dentition is often associated.
In this section,the disorders that include wormian bones as one feature have been divided according to whether aberrant ossification manifests with osteoporosis or osteosclerosis and/or hyperostosis. An additional group of disorders featuring acro-osteolysis and wormian bones is included, whereas some other entities that do not fall in any of these groups are described in an additional category of miscellaneous disorders.
Disorders with Osteoporosis Due to Impaired Bone Formation and Mineralization. Wormian bones are a typical feature of osteogenesis imperfecta (Fig. 1.22a,b), a large general category encompassing some well-defined disorders, such as types I through IV, and other, more elusive forms that do not fit properly into any one of the well-known types. Some of these ill-defined entities are briefly outlined here. Bruck syndrome (OMIM 259450), an association of osteogene-sis imperfecta and arthrogryposis multiplex con-genita with pterygia, is described elsewhere in this
book. A variety of osteogenesis imperfecta with opalescent teeth, blue sclerae, and wormian bones without fractures (OMIM 166230) is possibly distinct from osteogenesis imperfecta type I (OMIM 166200) (Beighton 1981), because it does not involve short stature and joint hyperextensibility. Osteogenesis imperfecta, Levin type (OMIM 166260), in addition to the features of osteogenesis imperfecta, in particular marked coarseness of the trabecular bone and os-teopenia, shows multilocular radiolucent and/or ra-diopaque lesions in the maxilla and mandible, with normal teeth (Levin et al. 1985). Grant syndrome (OMIM 138930) is an autosomal dominant disorder with persistent wormian bones, blue sclerae, mandibular hypoplasia, shallow glenoid fossae with shoulder dislocation, short stature, and bowing of the long bones. It is similar to osteogenesis imperfecta, but fractures and dentinogenesis imperfecta do not occur (Maclean et al. 1986). The combination of cortical defects, wormian bones, and dentinogenesis imperfecta (OMIM 604922) also has features overlapping with those of osteogenesis imperfecta (Suarez and Stickler 1974). Wormian bones are associated with persistently open anterior fontanel. The teeth are small, translucent, and susceptible to caries (Moog et al. 1999). Affected children have short limbs and suffer from multiple fractures. The radiolucent areas at periphery of the long bones representing cortical defects are associated with areas of cortical thickening. Cog-
nitive development is normal. Collagen studies are unremarkable, and no mutations are found in the COL1A1 or COL1A2 genes.Although osteopenia does not occur in it, this condition is described here because of its similarities with osteogenesis imperfecta. Brittle bone disorder (OMIM 603828) is marked by bone fragility, micromelic short stature, dolicho-cephaly with frontal bossing, and midface hypoplasia with prognathism. Multiple calvarial wormian bones, repetitive fractures, bowing of the long bones, and pseudofractures with metaphyseal narrowing are additional manifestations (Nishimura et al. 1999). Both intramembranous and endochondral ossifications are disturbed,resulting in a coarse trabecular pattern involving the entire skeleton. Inheritance is uncertain, possibly autosomal dominant with sex influence or X-linked semidominant. The autosomal recessive osteoporosis-pseudoglioma syndrome (OMIM 259770) is characterized by diffuse osteoporosis, wormian bones, multiple fractures, vertebral collapse, bowing deformity of long bones, muscular hypotonia, joint hypermobility, and ocular abnormalities (microphthalmos, vitreoretinal abnormalities, cataracts, iris and lens abnormalities, ocular calcifications) (Bianchine et al. 1972). The disorder is caused by mutations in the gene encoding low-den-sity-lipoprotein receptor-related protein-5, LRP5, which has been mapped to 11q12-13 (Gong et al. 1996).
Wormian bones associated with osteoporosis occur in a number of metabolic disorders, including rickets, hypothyroidism, hypophosphatasia, and some states of abnormal copper metabolism, including nutritional copper deficiency, Menkes syndrome, and occipital horn syndrome. Menkes kinky hair syndrome (OMIM 309400), an X-linked recessive condition caused by mutations in the gene encoding the copper-transporting ATPase, alpha polypeptide, which has been mapped to Xq12-q13 (Vulpe et al. 1993; Chelly et al. 1993; Mercer et al. 1993), is characterized by osteoporosis, multiple wormian bones, metaphyseal widening with spurs, multiple fractures, rib flaring, epiphyseal displacement, subperiosteal hemorrhage, periostitis, skin hypopigmentation, and kinky sparse hair (Danks et al. 1972b). Blood copper and ceruloplasmin levels are abnormally low. If the condition is left untreated severe manifestations arise, including profound failure to thrive and central nervous system deterioration, with hypertonia, seizures, intracranial hemorrhage, and hypothermia (Danks et al. 1972a; Bucknall et al. 1973). Occipital horn syndrome (cutis laxa X-linked, OMIM 304150) is allelic to Menkes syndrome (Das et al. 1995; Levin-son et al. 1996). The primary defect in copper metabolism is associated with secondary changes in connective tissue. Major manifestations of this condition include symmetrical occipital horns located behind the foramen magnum, cutis laxa, muscle hypotonia, joint laxity, osteoporosis, multiple wormian bones, dental crowding, broad, hammer-shaped clavicles, carpal fusion, bladder diverticula with recurrent urinary tract infection, chronic diarrhea with stool loos ening, vein varices and arterial aneurysms, and mild mental retardation (Lazoff et al. 1975; MacFarlane et al. 1980). Facial features include narrow face, high forehead, down-slanting palpebral fissures with bilateral ptosis, and prominent, simple ears. Laboratory studies demonstrate low serum copper and cerulo-plasmin levels as well as intestinal nonabsorption of copper (Wakai et al. 1993).
Wormian bones also occur as part of the radiographic spectrum of a group of disorders characterized by premature aging, including progeria, Haller-mann-Streiff syndrome, geroderma osteodysplasti-ca, mandibuloacral dysplasia, and acrogeria. All these disorders are marked by osteoporosis. In Haller-mann-Streiff syndrome (OMIM 234100) the skull is brachycephalic and poorly ossified, with delayed ossification in the sutural areas and numerous wormi-an bones (Gay 1990). There is severe midfacial hy-poplasia, micrognathia with hypoplasia of the rami and obtuse or straight gonial angle, and small teeth. The long bones are thin and gracile, with poor demarcation between the cortex and medullary cavity and metaphyseal widening. Additional findings include skin atrophy (most prominent over the nose and sutural areas of the scalp), thin sparse hair, mi-crophthalmia, cataract, strabismus, narrow and high-arched palate, and a characteristic small, pointed nose (Cohen 1991; Christian et al. 1991). In the autosomal recessive geroderma osteodysplastica hereditaria (Walt Disney dwarfism, OMIM 231070) major features include wrinkling of the skin with a prematurely aged appearance, osteoporosis, and susceptibility to fracture (Bamatter et al. 1950). The bones show multiple lines like the growth rings of trees. The skin is lax, but not hyperelastic as in the Ehlers-Dan-los syndromes. The 'droopy, jowled' face and overall clinical appearance mimic those of Walt Disney creations and are the reason for the designation used for this condition (Hunter et al. 1978; Hunter 1988). Geroderma osteodysplastica and the wrinkly skin syndrome (OMIM 278250) may represent variable manifestations of the same disorder (Al-Gazali et al. 2001). This condition is phenotypically similar to the progeroid syndrome of De Barsy (OMIM 219150) and cutis laxa with bone dystrophy (OMIM 219200). Mandibuloacral dysplasia (OMIM 248370) is an autosomal recessive syndrome characterized by mandibular hypoplasia with severe dental crowding, acro-osteolysis, stiff joints, and atrophy of the skin on hands and feet (Young et al. 1971). The clavicles are hypoplastic or absent. Abnormalities of the cranial bones include calvarial thinning, persistently open fontanels and sutures, and multiple wormian bones.
Of 11 families reported by one group, 5 were Italian (Tudisco et al. 2000). Insulin resistance resulting in marked hypermetabolism and lipodystrophy is also a feature (Cutler et al. 1991). The pattern of body fat distribution is dual, one pattern (type A) manifesting with loss of subcutaneous fat in the extremities and normal or slight excess in the neck and trunk and the other (type B) showing generalized loss of subcutaneous fat involving the face, trunk, and extremities. Phenotypic overlap is recognized with Hutchinson-Gilford progeria (OMIM 176670), Yunis-Varon syndrome (OMIM 216340), and disorders with acro-os-teolysis, including pyknodysostosis (OMIM 265800), Hajdu-Cheney syndrome (OMIM 102500), cleidocranial dysplasia (OMIM 119600),and acrogeria (OMIM 201200) (Parkash et al. 1990; McKusick 1991). The disorder can be caused by mutations in the gene encoding lamin A/C, LMNA, which lies in the 1q21.2 region (Novelli et al. 2002). Disruption of this region may also cause Dunnigan-type familial partial lipodystrophy (OMIM 151660), another condition with insulin resistance, diabetes, and loss of subcutaneous fat. Mandibuloacral dysplasia associated with a type B lipodystrophy phenotype is caused by mutations at sites other than that of LMNA, which have not yet been identified. Thus, mandibuloacral dysplasia appears to be phenotypically and genetically heterogeneous (Simha et al. 2003). Acrogeria, Gottron type (OMIM 201200), is an autosomal recessive, progeria-like disorder characterized by failure of growth, skin atrophy, easy skin bruising, micrognathia with ante-gonial notching, acro-osteolysis, clavicular osteoly-sis, avascular necrosis of the femoral heads, soft tissue calcifications, and generalized osteoporosis. Features in the skull include multiple wormian bones and delayed suture and fontanel closure (Ho et al. 1987).
Disorders with Osteosclerosis and/or Hyperostosis. Pyknodysostosis (Maroteaux-Lamy disease,OMIM 265800), an autosomal recessive disorder with universal os-teosclerosis, is differentiated from osteopetrosis on the basis of the pattern of skull involvement (more severe basal sclerosis, multiple wormian bones, wide sutures and fontanels, small facial bones, hypoplastic paranasal sinuses, obtuse mandibular angle), presence of tuftal and clavicular osteolysis, spinal segmentation defects, and patency of the medullary cavity in the long bones (characteristically obliterated in osteopetrosis) (Fig. 1.23a,b). Lethal short-limb skeletal dysplasia, Al Gazali type (OMIM 601356) involves a large head, corneal clouding, atretic auditory canals, severe acromesomelic dwarfism with short
1st metacarpal, bilateral clubfoot, sclerosis of bones, multiple wormian bones, wide anterior fontanel, platyspondyly, and early death (Al Gazali et al. 1996). On the basis of parental consanguinity, autosomal recessive inheritance has been suggested. Schinzel-Giedion midface-retraction syndrome (OMIM 269150) is characterized by severe midface retraction, sclerosis of tubular bones and skull base, multiple wormian bones, wide cranial sutures and fontanels, congenital heart defect, hydronephrosis, megacalycosis, brain anomalies,clubfeet,hand and foot syndactyly,hyper-trichosis, hypoplasia of dermal ridges, and genital anomalies (Schinzel and Giedion 1978; Rodriguez et al. 1994; Elliott et al. 1996). Affected babies usually die in the neonatal period, and growth is severely retarded in any survivors. Embryonal tumors, such as malignant sacrococcygeal teratoma and hepatoblas-toma, occur with elevated frequency (Robin et al. 1993; Antich et al. 1995). Most reported cases have been sporadic. Familial instances of the syndrome are possibly the result of a dominant gene with go-nadal mosaicism in one parent or of an unbalanced structural chromosome abnormality (Al-Gazali et al. 1990). Craniofacial dysostosis with diaphyseal hyperplasia (osteosclerosis Stanescu type, OMIM 122900) is characterized by short stature, brachycephaly, and short limbs with massive cortical thickening (Stanescu et al. 1963). Additional craniofacial findings include thin calvarial bones, sclerosis of skull base, depressions over the frontoparietal and occipitopari-etal sutures, wormian bones, calcification of the falx cerebri, and mandibular hypoplasia (Horovitz et al. 1995). Thickening of bone cortex occurs during or after puberty and increases with age (Maximilian et al. 1981). The inheritance pattern is probably autosomal dominant. The disorder referred to as primary empty sella turcica with generalized dysplasia (OMIM 130720) is a familial association of empty sella, multiple spinal meningoceles, generalized osteosclerosis, wormian bones in the lambdoid sutures, platybasia, basilar impression, short stature, and a facial appearance reminiscent of Treacher-Collins syndrome, with down-slanting palpebral fissures, micrognathia, and malar hypoplasia (Lehman et al. 1977). Central nervous system maldevelopment and distended menin-geal spaces resulting in the enlargement of several cranial and spinal recesses and foramina, including the sella turcica and intervertebral foramina, are major manifestations. Pituitary dysfunction is common (Yokoyama et al. 1992). Nonfamilial empty sella commonly occurs as an isolated finding with normal pituitary function in the elderly. It is caused by the combined effect of pituitary gland involution and expansion of the subarachnoid space into the sella tur-cica through the diaphragm.
Disorders with Acro-osteolysis. Several syndromes with acro-osteolysis, including Hajdu-Cheney syndrome (OMIM 102500), neurogenic acro-osteolysis (Giaccai type acro-osteolysis, OMIM 201300), pyknodysostosis (OMIM 265800), cleidocranial dysostosis (119600), acrogeria (OMIM 201200), and mandibuloacral dysplasia (248370),show multiple wormian bones as one feature. Some of these disorders are discussed under different headings in this section, the remainder having been described in other parts of the book.
Miscellaneous Disorders. Distinct features of cleidocranial dysplasia (OMIM 119600) include clavicular aplasia/hypoplasia and a poorly ossified skull, with wide fontanels and sutures and multiple wormi-an bones. The mandible is broad, and the paranasal sinuses are underdeveloped. Stratton-Parker syndrome (OMIM 185120) is a combination of short stature due to growth hormone deficiency, wormian bones, dextrocardia, brachycamptodactyly, and other defects, such as hypospadias, unilateral kidney hy-poplasia, and imperforate anus (Stratton and Parker 1989). Hemimegalencephaly with unilateral enlargement of the ventricle may also occur (Gabrielli et al. 1994). The genetics of this condition is unknown. Craniometadiaphyseal dysplasia, wormian bone type (Schwarz-Lelek syndrome, OMIM 269300) has been described as a distinct craniotubular bone dysplasia comprising a large head with mild basal sclerosis and prominent forehead, multiple wormian bones, and abnormal modeling of the tubular bones (Schwarz 1960; Langer et al. 1991). Parental consanguinity points to autosomal recessive inheritance. Long bones are wide, with lack of normal dia-physeal constriction and poor metaphyseal flaring. Short tubular bones, ribs, and clavicles are also widened. The bones are osteoporotic, with thin cortices. Ossification of the cranial vault is delayed, with wide open anterior fontanel and calvarial thinning with multiple wormian bones. Mild sclerosis of the skull base, maxilla, and mandible is noted. The paranasal sinuses are obliterated (Santolaya et al. 1998).
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