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Introduction. Craniometaphyseal dysplasia is a rare hereditary bone disease presenting metaphyseal widening of the tubular bones, sclerosis of craniofacial bones and bony overgrowth of the facial and skull bones. Craniometaphyseal dysplasia occurs in an autosomal dominant (AD) and an autosomal recessive (AR) form. Case report. We present a 32-year-old patient arrived at our unit in May 2009. His main discomfort was a major limitation of the mouth opening, in the context of a craniofacial deformity. Relying on patient’s medical history and the performed diagnostic tests, the diagnosis of craniometaphyseal dysplasia was made.
Conclusion. After careful evaluation of the clinical case, in accordance with the requirements of the patient, we opted for a surgical treatment aimed at correction of functional limitation of temporomandibular joint and aesthetic improvement of the facial bones. The stability of the clinical results led us to suggest and to undertake the surgical path, also due to the lack of safe and consolidated nonsurgical treatments for the specific case.
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An atypical case of craniometaphyseal dysplasia. Case report and surgical treatment
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An atypical case of craniometaphyseal dysplasia. Case report and surgical treatment
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                                                                                                      Case report


    An atypical case of craniometaphyseal dysplasia.
    Case report and surgical treatment




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    Giorgio Novelli MD                                        Introduction

                                                              The term “osteochondrodysplasia” includes a group
    Emanuela Ardito MD

                                                              of uncommon genetic disorders of bone remodeling,
    Fabio Mazzoleni MD




                                                                                            io
                                                              which are characterized by an increased skeletal
    Alberto Bozzetti MD

                                                              density. Some of these disorders are relatively ordi-
    Davide Sozzi MD

                                                              nary; others, that are less common can also be lethal.




                                                                        az
    OU Maxillofacial Surgery (Head: Prof. Alberto Bozzet-     Initially, this heterogeneous group of diseases was
    ti), Department of Medicine and Surgery - School of       grouped under the generic term of “marble bone” or
    Medicine, University of Milano-Bicocca, San Gerardo       Albers-Schonberg diseases. From the critical analysis
    Hospital, Monza, Italy                                    of Gorlin, Spranger and Koszalka (1969), according




                                                                      rn
                                                              to the Paris nomenclature, constitutional disorders of
                                                              bone can be broken down into four subgroups:
                                                              Osteoscleroses, Craniotubular dysplasias, Craniotu-
    Davide Sozzi
    Corresponding author:
                                                              bular hyperostoses, Miscellaneous sclerosing and hy-




                                                       te
    OU Maxillofacial Surgery                                  perostotic disorders. Craniometaphyseal dysplasia to-
    Department of Medicine and Surgery,                       gether with Pyle’s disease is included in the cranio-
    University of Milano-Bicocca
                                                              tubular dysplasia group (1).
    Viale Regina Margherita 5
                                                     In
                                                              The definition Craniometaphyseal dysplasia (CMD)
    20122 Milano, Italy
                                                              was coined by Jackson et al. in 1954 to describe a
    E-mail: davide.sozzi@unimib.it;
                                                              rare hereditary bone disease presenting metaphyseal
    drdavidesozzi@gmail.com
                                                              widening of the tubular bone, sclerosis of craniofacial
                                                              bones and bony overgrowth of the facial and skull
                                ni

                                                              bones (2-4).
                                                              The disease was better framed by Gorlin et al. in
                                                              1969, when it was recognized as a separate clinical
                              io

    Summary
                                                              entity of the autosomal dominant (AD) and autosomal
                                                              recessive (AR) forms of CMD diseases (5).
    Introduction. Craniometaphyseal dysplasia is a

                                                              Patients with the autosomal dominant form are usu-
                            iz



    rare hereditary bone disease presenting metaphy-

                                                              ally in good general health and they lead a normal
    seal widening of the tubular bones, sclerosis of

                                                              lifestyle, their intellect is unimpaired, and have a
    craniofacial bones and bony overgrowth of the fa-

                                                              normal size of the body without evidence of bone
            Ed




    cial and skull bones. Craniometaphyseal dyspla-

                                                              fragility. Clinically, the patient may have mandibular
    sia occurs in an autosomal dominant (AD) and an

                                                              prognathism and malocclusion caused by progres-
    autosomal recessive (AR) form.

                                                              sive bone overgrowth. Distortion of the face in AR is
    Case report. We present a 32-year-old patient ar-

                                                              very severe (2). The paranasal bossing, occurring
    rived at our unit in May 2009. His main discomfort

                                                              during childhood, tends to regress with growth. The
    was a major limitation of the mouth opening, in

                                                              abnormal growth of the facial bones can lead to
 IC




    the context of a craniofacial deformity. Relying on

                                                              nerve compression of the seventh and eighth cranial
    patient’s medical history and the performed diag-

                                                              nerve, with varying degrees of facial palsy and deaf-
    nostic tests, the diagnosis of craniometaphyseal

                                                              ness. In AR CMD cranial nerve compression is se-
    dysplasia was made.

                                                              vere and, in addition, visual loss may result from in-
    Conclusion. After careful evaluation of the clinical
C




                                                              volvement of the optic nerve (2, 6). In severe forms
    case, in accordance with the requirements of the

                                                              of the disease, the narrowing of the foramen mag-
    patient, we opted for a surgical treatment aimed at

                                                              num with compression of the medulla can cause a
    correction of functional limitation of temporo-

                                                              quadriparesis or death (3, 7).
    mandibular joint and aesthetic improvement of the
©




                                                              AD CMD diagnosis is made after the execution of the
    facial bones. The stability of the clinical results led

                                                              radiological examinations, in fact clinical signs with-
    us to suggest and to undertake the surgical path,

                                                              out radiological investigation are not exhaustive. Ra-
    also due to the lack of safe and consolidated non-

                                                              diographic features in AR CMD include non-sclerotic
    surgical treatments for the specific case.

                                                              widening of the metaphysis with cortical thinning and
                                                              sclerosis of the skull; in adulthood, sclerosis may be
    Key words: craniometaphyseal dysplasia, ANKH,
    CMD.

    Annali di Stomatologia 2017;VIII (2):89-94                                                                    89
    G. Novelli et al.


    especially evident along the cranial sutures (8). The       teoblast activity, the long-term results are a reduction
    paranasal bony bossing, featured during childhood,          of bone remodeling without a change in bone density.
    may give an appearance of hypertelorism. The air si-        The low oral intake of calcium promotes, instead, a
    nus obliteration and the mandibular prognathism are         state of hypocalcemia that stimulates the osteoclasts
    common (2).                                                 activation. Calcitriol has the function to stimulate
    The widening of the methaphysis is more visible at          bone absorption, activating the osteoclasts. Somato-
    the lower end of the femur, the metaphyseal flaring         statin seems to have a role in slowing the hyperosto-




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    results in an Erlenmeyer flask appearance in child-         sis progression (7, 8).




                                                                                                 na
    hood, and a club-shaped deformity in adulthood (3,          Surgical treatment is intended to correct the deformity
    7). The bones of the pelvis and spine are normal and        of the skull and providing cranial nerve decompres-
    in the chest a slight modeling defect of the medial         sion. However, the removal of sclerotic bone is rather
    portion of the clavicles and the costochondral junc-        complicated and it often does not produce the desired
    tions may be found (2).                                     results, showing relapse. Nerve decompression ad-




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    Although radiographic examinations are necessary to         dressing the facial nerve and optic nerve is a complex
    make the diagnosis of CMD, the bone abnormalities           surgery, which is not without complications and risks.
    shown are not pathognomonic of CMD; indeed Pyle’s           However, surgical management obtained good re-




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    disease, craniodiaphyseal dysplasia and frontometa-         sults in conductive hearing loss due to ossicular fixa-
    physeal dysplasia may have similar radiological find-       tion, with an improvement of hearing (7, 8).
    ings. A genetic analysis is therefore necessary to pro-
    vide a definitive diagnosis (3, 9).




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    ANKH is the only gene which is known to be associa-
    ted with CMD: sequence analysis of ANKA detects
                                                                Case report

    mutations in about 90% of affected individuals.             The patient LS, male, 32 years old, referred to our
    The autosomal dominant form is linked to chromoso-          unit in 2009. His chief complaint was a major limita-




                                                         te
    me 5p15.2-p14.1, within a region harboring the hu-          tion of his mouth opening, in the context of a cranio-
    man homolog (ANKH) of the mouse progressive                 facial deformity.
    ankylosis gene (ank) (3, 10). ANKH encodes a 429-           The anamnestic evaluation reported natural birth from
                                                       In
    amino acid multipass transmembrane protein that is          non consanguineous parents. The birth weight was
    involved in transport or cotransport of intracellular py-   3,450 kilos. By the age of 3, the patient reported an
    rophosphate (PPi) into extracellular matrix (8, 11, 12).    initial appearance of gingival hypertrophy and frontal
    Experimental studies have shown that CMD muta-              bossing.
    tions in ANK lead to decreased PPi levels in bone ex-       From early childhood, mental and physical develop-
                             ni

    tracellular matrix, which in turn cause increased den-      ment was slowed compared to his peers, with a delay
    sity and progressive thickening of cranial bones (11,       in speech and in locomotion.
    13).                                                        At the age of 10, the patient presented dorso-lumbar
                           io


    AR form of CMD has been mapped to a 7cM interval            S Italic scoliosis with a moderate rotation of the lum-
    on chromosome 6q21-22 (11, 14).                             bar bodies, associated with a misalignment of the
    AR form is more severe, more difficult to diagnose,         pelvis, where the right iliac wing was raised com-
                         iz



    and rarer than the dominant form (3). The CMD is in         pared to the contralateral.
    differential diagnosis with Methaphyseal dysplasia          One meaningful piece of date in the remote patholog-
    (Pile’s disease), Craniodiaphyseal dysplasia, Paget’s       ical anamnesis is the hospital admission, to a pedi-
           Ed




    disease, osteopetrosis (as previously mentioned).           atric clinic of another centre, when he was 11 years
    Pile’s disease is an autosomal recessive disease pre-       old, for a diagnostic work up for a possible genetic
    senting gross metaphyseal widening, and where               syndrome, suggested by a skull X ray analysis.
    pelvic bone and thoracic cage are expanded (1, 7).          Those radiographic examinations showed a severe
    The skull is spared, apart from a broadening of the         thickening of the cranial bones and an alteration of
    supraorbital rims, which is normally associated to this     the bony density of the maxillary bones.
 IC




    disease (7, 9).                                             From the performed diagnostic tests (spine, hands,
    The patients are clinically normal, except for valgus       elbows, chest, pelvis, skull and legs X-ray; rx opt; Ct
    deformities of the knees. Craniodiaphyseal dysplasia        skull; blood tests; chromosome map and ophthalmol-
    is characterized by a more significant flaring of the di-   ogy examination), the diagnosis was a dysplasia of
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    aphyseal region, without metaphyseal involvement,           Mellnick-Needles. This diagnosis has been recently
    with severe sclerosis and hyperostosis of the skull.        excluded.
    There is a medical therapy for CMD, based on the            When he was 18 years old, the patient was subjected
    control of calcium homeostasis and the regulation of        to the Wechsler Intelligence test for adults, showing
©




    the activity of osteoclasts and osteoblasts, through        slight mental retardation. Over the years, the bilateral
    the consumption of somatostatin, calcitriol, calcitonin,    hearing loss due to poor transmission progressively
    or a low calcium intake (3, 6, 8).                          become worse with the persistence of a walking drag
    Calcitonin therapy reduces bone resorption by inhibit-      with incorrect right limb. The skull deformities also in-
    ing osteoclast activity and secondarily by impeding         creased over the years, especially the frontal,
    bone formation through feedback coupling to limit os-       mandibular and mastoid hyperostosis.

    90                                                                             Annali di Stomatologia 2017;VIII (2):89-94
    An atypical case of craniometaphyseal dysplasia. Case report and surgical treatment


    At the time of hospitalization in May 2009, the exami-           dance with the requirements of the patient, we opted
    nation showed bone bossing in the frontal, mastoid               for a surgical treatment aimed at correction of func-
    and occipital regions, bone bossing of smaller thick-            tional limitation of temporomandibular joint and aes-
    ness at the angles and mandibular symphysis.                     thetic improvement of the facial bones.
    The CT allowed us to highlight, in addition, the sub-            The patient was subjected to 2 surgeries under gen-
    version of the normal anatomy of the temporo-                    eral anesthesia. In the first, performed in May 2009,
    mandibular joints in the lower jaw, which was causing            the patient was subjected to partial right mastoidecto-




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    limitations in the mandibular movements. The inspec-             my, right coronoidectomy and removal of multiple ex-




                                                                                                        na
    tion of the oral cavity highlighted a class II type mal-         ostoses of the right mandibular body.
    occlusion, associated with gingival hypertrophy and              In the second surgery, performed one month after the
    hyperostosis of the upper and lower alveolar bone.               first, we proceeded to left coronoidectomy and to the
    The patient also presented skin folds in the nuchal re-          removal of the massive cranial exostoses, which
    gion (Figs. 1, 2). The patient had, moreover, hearing            were in the frontal area (a median one and a lateral




                                                                                                      io
    loss with severe bilateral transmission deficit and an           one) and at the level of the right superior orbital
    X-ray of the knee showed a deterioration of the bony             frame (Fig. 3).
    component with cortical thickness reduction and                  Histological examination showed fragments of lamel-




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    widespread reduction in calcium content.                         lar cortical bone which was mature compact, dense
    After careful evaluation of the clinical case, in accor-         with medullary component containing blood forming




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    Figure 1. (A, B) Clinical aspects; (C) Intraoral view showing gingival hypertrophy, hyperostosis of the upper and lower alveo-
    lar and bone; (D) Major limitation of the mouth opening.

    Annali di Stomatologia 2017;VIII (2):89-94                                                                                 91
    G. Novelli et al.




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    Figure 2. (a-d) 3D CTscan showing bone bossing in the frontal, mastoid and occipital regions and bone bossing of smaller
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    thickness at the angles and mandibular symphysis.


    tissues and adipocytes; those findings are compatible         the disease in the resected areas. There is a good
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    with osteoma. During the first surgery a sampling of          mandibular function and, thanks to the correction of
    skin from the nuchal region has also been performed           facial aesthetics, the patient has improved his social
    with a diagnostic outcome of small chronic dermal fi-         relations (Fig. 4).
    brosis with mild periadnexal inflammation and papillo-
©




    matosis of the epidermis.
    To complete diagnosis, we decided to subject the pa-
    tient to a genetic study, which was negative for ex-
                                                                  Discussion and conclusions

    plorable syndromic genetic diseases.                          The dysplastic disease which affects facial bones, and
    At the moment, the patient is being followed up with          particularly diseases presenting abnormal growth of
    monthly checks. After 2 years there is no relapse of          bone or fibro-osseous tissue, often generates serious

    92                                                                                Annali di Stomatologia 2017;VIII (2):89-94
    An atypical case of craniometaphyseal dysplasia. Case report and surgical treatment




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    Figure 3. (A, B) Frontal bone resection; (C) Mandibular symphysis resection; (D) Mastoid resection.
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    Figure 4. (A, B) Post-operative clinical aspects; (C) Post-operative mandibular function.
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    functional problems originating from a mutated                    significant clinical need for function and aesthetics
    eurhythmy of the face which causes psychological and              arising from the patient.
    social issues.                                                    Our choice for a surgical approach, even if a genetic
    A diagnosis of these forms is often very difficult and it         confirmation was not provided, derived from a careful
©




    is not rare to find cases with sporadic genetic muta-             clinical and radiological evaluation of the pathology.
    tions which are not yet classifiable in existing syndro-          Therefore, we chose, with a first surgery, to unlock the
    mes or can be defined as new kind of diseases or va-              mandibular function and partially reshape facial bones
    riation of existing ones.                                         to improve patient’s aesthetics.
    In the case we reported, apart from a dutiful clinic and          In the second surgery, we performed a global
    nosological framework of the disease, we had a                    remodeling of the face, particularly of the voluminous

    Annali di Stomatologia 2017;VIII (2):89-94                                                                             93
    G. Novelli et al.


    frontal and mandibular sinuses.                                      6.    Kim YH, Roh DH, Choi BY, Oh SH Craniometaphyseal dys-
    The histological examination of excised bone and the                       plasia. Acta Otolaryngol. 2005;125(7):797-800.
    clinical controls, showing no relapse, confirmed the                 7.    Ahmad FU, Mahapatra AK, Mahajan H. Craniofacial surgery
    correct indication for the programmed surgery.                             for craniometaphyseal dysplasia. Neurol India. 2006;54(1):97-
                                                                               99.
    The stability of the clinical results led us to suggest and
                                                                         8.    Sheppard WM, Shprintzen RJ, Tatum SA, Woods CI. Cran-
    implement the surgical path, also because of lack of                       iometaphyseal dysplasia: a case report and review of med-
    safe and consolidated non-surgical treatments for the




                                                                                                                  li
                                                                               ical and surgical management Int. J Pediatric Otorhinolaryngol.
    specific case.                                                             2003;67:687-693.
    Currently, we are performing other genetic analysis,




                                                                                                                na
                                                                         9.    McKay DR, Fialkov JA. Autosomal dominant craniometa-
    more specific, to identify a possible genetic mutation                     physeal dysplasia with atypical features. Br J Plast Surg.
    which might help us to frame this particular form into                     2002;55(2):144-148.
    CMD or assess it as a new rare form of the disease.                  10.   Nürnberg P, Thiele H, Chandler D, et al. Heterozygous mu-
                                                                               tations in ANKH, the human ortholog of the mouse progressive




                                                                                                              io
                                                                               ankylosis gene, result in craniometaphyseal dysplasia. Nat
                                                                               Genet. 2001;28(1):37-41.
    References                                                           11.   Reichenberger E, Tiziani V, Watanabe S, et al. Autosomal
                                                                               dominant craniometaphyseal dysplasia is caused by muta-




                                                                                     az
    1.   Beighton P, Horan F, Hamersma H. A review of the os-                  tions in the transmembrane protein ANK. Am J Hum Genet.
         teopetroses. Postgard Med J. 1977;53(622):507-516.                    2001;68(6):1321-1326.
    2.   Beighton P. Craniometaphyseal dysplasia (CMD), autoso-          12.   Ho AM, Johnson MD, Kingsley DM. Role of the mouse ank
         mal dominant form. J Med Genet. 1995;32(5):370-374.                   gene in control of tissue calcification and arthritis. Science.
    3.   Lamazza L, Messina A, D’Ambrosio F, Spink M, De Biase.                2000;289(5477):265-270.




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         A Craniometaphyseal dysplasia: a case report. Oral Surg Oral    13.   Gurley KA, Reimer RJ, Kingsley DM. Biochemical and ge-
         Med Oral Pathol Oral Radiol Endod. 2009;107(5):23-27.                 netic analysis of ANK in arthritis and bone disease. Am J Hum
    4.   Gorlin RJ, Spranger J, Koszalka MF. Genetic craniotubular             Genet. 2006;79(6):1017-1029.
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                                                                 te
         Defects. 1969;5(4):79-95.                                             MR. Mapping of the autosomal recessive (AR) cran-
    5.   Gorlin RJ, Koszalka MF, Spranger J. Pyle’s disease (famil-            iometaphyseal dysplasia locus to chromosome region 6q21-
         ial metaphyseal dysplasia). A presentation of two cases and           22 and confirmation of genetic heterogeneity for mild AR
         argument for its separation from craniometaphyseal dysplasia.
                                                               In
                                                                               spondylocostal dysplasia. Am J Med Genet. 2000;95(5):
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    94                                                                                           Annali di Stomatologia 2017;VIII (2):89-94
