Craniometaphyseal dysplasia: a case report and review of medical and surgical management

2.1. Craniometaphyseal dysplasia (CMD) 

In 1954, Jackson et al. coined the term craniometaphyseal dysplasia (CMD) [8]. By 1997, 65 cases had been documented [9]. CMD is generally divided into two major types, autosomal dominant and autosomal recessive, although other variants have been documented [10].

Autosomal dominant CMD is the most common form. Most cases involve familial clusters of Caucasian descent. In a large German pedigree, autosomal dominant CMD was localized to within approximately 4 cM on the 5p chromosome locus [11]. The disease can present in infancy with bilateral choanal narrowing secondary to bony sclerosis, paranasal bossing, and ocular hypertelorism [9], [12] These features tend to regress with growth and may be absent by adulthood [13]. Visual impairment or facial paralysis occasionally occur, and most patients develop a mixed hearing loss with sparing of labyrinthine function [13]. Olfactory problems are often overlooked [14]. Frontonasal hyperostosis and sclerosis lead to prominence of the forehead. Prognathism is common. Other radiographic features include non-sclerotic widening of the metaphyses with cortical thinning that is most obvious at the lower end of the femur. The metaphyseal flaring results in an Erlenmeyer flask appearance in childhood, and a club-shaped deformity in adulthood. Diaphyseal hyperostosis and sclerosis can be seen in the young but disappears with age [15]. Short tubular bones have similar changes, and the pelvis and spine are normal. The cognitive prognosis for these patients is good, since the disease normally abates during the third decade of life. As is true in most autosomal dominant genetic disorders, there is considerable variability of expression in this syndrome.

The autosomal recessive form of CMD is less common. The carrier frequency is not known. The autosomal recessive CMD locus, from a four generation inbred family with ten affected individuals, was recently located to a 7 cM interval on chromosome 6q21–22 [18]. Craniofacial features are similar to the autosomal dominant form, except that there appears to be more pronounced facial involvement. Cranial nerve involvement is also more common, and the skull and mandible are larger and thicker. Marked nasofrontal bulging is evident in most cases and nasal obstruction is generally complete. Metaphyseal flaring is similar to the dominant form. Diaphyseal sclerosis is more apparent in the recessive form and can be found in adults with the disease [16].

2.2. Pathogenesis of CMD 

The specific abnormalities in bony remodeling that result in CMD remain unknown. Recent research points towards abnormal osteoclastic activity in the development of CMD. Yamamoto and colleagues discovered that osteoclast-like cells from a patient with CMD lacked expression of an osteoclast-reactive vacuolar pump [17]. The authors postulated that osteoclast regulatory dysfunction could alter bone resorption, thereby increasing bony remodeling and resulting in increased bone formation. Reichenberger et al. identified mutations in the ANK gene in five families with inherited and five cases of sporadic autosomal dominant CMD [18]. ANK is a transmembrane multipass protein that is involved in the transport or cotransport of intracellular pyrophosphate (PPi) into the extracellular matrix [19]. The authors proposed that the mutations inhibit proper complex formation with skeletal PPi, resulting in increased bone density and preventing osteoclasts from remodeling cranial bone at a normal rate [18].

Others believe that either a defect in osteoblast activity or differentiation is the major factor in the increased bone remodeling based on histological specimens revealing abnormal levels or formations of osteoblasts [9], [16], [20].

2.3. Medical therapy of CMD 

Because data is scarce concerning the specific pathogenesis of CMD, medical treatment has been based on the understanding of calcium homeostasis and the regulation of osteoblasts and osteoclasts. There are two major treatment regimens for CMD.

The first is calcitonin therapy. Calcitonin inhibits bone resorption primarily through osteoclast suppression and secondarily by impeding bone formation through feedback coupling to limit osteoblast activity. The perceived long-term result is one of decreased bone remodeling with no overall change in bone density [21]. Fanconi et al. reported a sporadic case of CMD presenting at 6 weeks of age with nasal obstruction and mild bilateral facial paralysis [20]. The patient was found to have hypocalcemia and secondary hyperparathyroidism, and calcitonin treatment was begun. The serum levels of calcium and parathyroid hormone normalized, but the disease continued to progress. In 1996, Haverkamp et al. evaluated calcitonin therapy in a patient with CMD and found no success [12].

The other treatment is a low calcium diet and calcitriol. A low oral intake of calcium promotes a hypocalcemic state that stimulates osteoclast activation. Calcitriol is then prescribed to stimulate the resorption of bone. In primate blood marrow, calcitriol has been found to cause the formation of multinucleated osteoclasts on actively remodeling bone surfaces [22]. Key et al. reported an infant with CMD who responded to treatment with a low calcium diet for 1 week (10 mg/kg per day) followed by calcitriol therapy [23]. The infant's facial paralysis improved, and there was decreased density of the skull. Mandibular and calvarial sclerosis were present early in the course of the disease and had improved prior to therapy. Although the patient's disease may have regressed without treatment, the authors concluded that spontaneous regression would be rare in a case that presented with cranial nerve problems in infancy. A low calcium diet followed by calcitriol therapy was credited with halting the progression of a facial abnormality in a 2-year-old female with CMD [24].

2.4. Surgical therapy of CMD 

Most patients with CMD will develop some degree of a mixed hearing loss. Since foraminal narrowing is a rare event in CMD, early SNHL is generally not evident. In 1969, Kietzer and Paparella reported findings in four patients who underwent exploratory tympanotomies; all had a mixed hearing loss and all had bony overgrowth including the annulus, the ossicles, and the footplate [25]. The mastoids were minimally if at all aerated. One stapedotomy was attempted. The hearing was subjectively better, but no audiogram was obtained. Other attempts at stapedotomy were aborted. In 1981, Shea et al. were able to document a significant decrease the air-bone gap in a CMD patient after stapedectomy and placement of a total ossicular reconstruction prosthesis [26]. In 1996, Franz et al. operated on two patients with CMD [27]. The stapes was mobile, but the malleus and incus were fixed. An insertion of a Wehr's prosthesis was successful, and there was documented closure of the air-bone gap in at least one ear in both patients. Of note, there was no long-term follow up in this report.

The craniofacial aberrations seen in CMD can be extremely disfiguring impacting both the form and function of the craniofacial skeleton. In 1967, Millard et al. reported the first two cases of craniofacial surgery in CMD [28]. The first case was performed on a male aged 17 and involved bony remodeling of the patient's forehead, nose, maxilla, and mandible. An aesthetically pleasing cosmetic result was obtained and the patient's quality of life was markedly improved. Bony decompression was performed in a similar manner on the patient's younger sister and resulted in a postoperative death within 24 h. An autopsy revealed a narrowed foramen magnum and chronic acute herniation of the cerebellar tonsil. Laurian and colleagues reported successful Leforte I advancement in a CMD patient with Class III occlusion [29]. Fanconi and colleagues, in 1988, performed a bifrontal craniectomy with orbital roof resection and decompression of cranial nerves on a 20-month-old with severe CMD [20]. A repeat procedure was performed at 5 years of age secondary to restenosis. By 8 years of age, the patient had again worsened and was suffering from foramen magnum compression, impaired hearing and vision. Satoh et al. performed bilateral optic nerve decompressions on a 6-year-old with deteriorating vision that resulted in immediate postoperative bilateral blindness [30]. The authors noted that there has been no successful report of optic canal decompression for threatened visual deterioration in CMD. The authors speculated that the optic nerve was receiving its blood supply from the thick surrounding bone of the optic canal and that damage can occur from an ischemic event. In 1996, Haverkamp et al. performed a bilateral inferior turbinate conchotomy with shortening of the posterior nasal septum and relieved nasal obstruction in a neonate with CMD [12]. Feingold reported 28-year follow up in a patient with CMD [31]. The patient had undergone a radical osteoplasty of the mandible, bilateral optic nerve decompression (twice), and also experienced post surgical osteomyelitis of his frontal bone requiring surgery. The patient has had no significant change over the last 10 years, but was legally blind with moderately severe mental retardation.