Craniometaphyseal Dysplasia Research Articles

Cardiopulmonary Arrest Caused by Craniometaphyseal Dysplasia

Craniometaphyseal dysplasia is a rare congenital disorder that can cause craniofacial skeleton and tubular bone anomalies. A 7-month-old girl, with congenital facial palsy, mouth breathing, and nasal obstruction, was brought to the hospital because she suffered sudden cardiopulmonary arrest. Computed tomography showed bony narrowing of the choanae. The diagnosis was cardiopulmonary arrest triggered by asphyxia caused by severe choanal stenosis. She showed hypoxic encephalopathy and underwent a tracheotomy and an operation to enlarge choanae. When a neonate or young infant shows signs of nasal obstruction, physicians should aggressively search for and consider the possibility of choanal atresia or severe stenosis.

Craniometaphyseal dysplasia unnoticed until 19 years of age: First diagnosed from facial nerve paralysis

Craniometaphyseal dysplasia (CMD) is a rare congenital bone disorder with facial dysmorphism developing from early childhood. We describe an unusual case of CMD unnoticed until the patient was 19 years old. Her disorder was diagnosed for the first time from her facial nerve paralysis, and was treated with high-dose corticosteroids. This report indicates the need for extreme caution in dealing with facial nerve paralysis since early detection and accurate diagnosis is important in the treatment of bone diseases. High-dose corticosteroid could be effective in treating facial nerve paralysis, even when nerves have been directly constricted by a bony overgrowth.

Otologic manifestations in a family with craniometaphyseal dysplasia

Abstract Craniometaphyseal dysplasia is a rare genetic disorder classified as one of the osteochondrodysplasias. Hyperostosis is most evident in craniofacial bones. Diagnosis can be challenging, and relies on clinical and radiographic findings, which includes cranial base sclerosis and metaphyseal widening. Otologic manifestations include mixed to primarily conductive hearing loss. Temporal bone descriptions are scantily described in the literature. This report describes a pedigree of 5 family members seen in our institution with craniometaphyseal dysplasia along with interesting computed tomography images of the temporal bones that are representative of the family's anatomy. To our knowledge it represents one of the largest familial case reports reported in the literature. We discuss the relevant clinical course of the family, which illustrates the difficulty in diagnosis and severe language delays that occur when hearing loss remains unaddressed. In this family, where compliance and a lack of available family history complicated the diagnostic picture, the children remained undiagnosed until myringotomy in the operating room, which revealed a bone-filled middle ear space.

It ANKH Necessarily So

This work was supported in full by funding from the National Institutes of Health, Division of Intramural Research, National Institute of Dental and Craniofacial Research, and National Heart, Lung, and Blood Institute. Disclosure Summary: The authors have nothing to declare. For article see page E189 Abbreviations: ALP, Alkaline phosphatase; Ank, ankylosis protein; CCAL2, chondrocalcinosis-2; CMD, craniometaphyseal dysplasia; DMP1, dentin matrix protein 1; ENPP1, ectonucleotide pyrophosphatase/phosphodiesterase 1; FGF23, fibroblast growth factor 23; HA, hydroxyapatite; Pi, inorganic phosphate; PPi, inorganic pyrophosphate; TNAP, “tissue nonspecific” ALP.

A Phe377del mutation in ANK leads to impaired osteoblastogenesis and osteoclastogenesis in a mouse model for craniometaphyseal dysplasia (CMD)

Craniometaphyseal dysplasia (CMD) is a rare genetic disorder with hyperostosis of craniofacial bones and widened metaphyses in long bones. Patients often suffer from neurological symptoms due to obstruction of cranial foramina. No proven treatment is available and the pathophysiology is largely unknown. A Phe377 (TTC(1130-1132)) deletion in exon 9 of the pyrophosphate (PPi) transporter ANK leads to CMD-like features in an Ank(KI/KI) mouse model. Here, we investigated the effects of CMD-mutant ANK on mineralization and bone mass at a cellular level. Ank(KI/KI) osteoblast cultures showed decreased mineral deposition. Expression of bone mineralization regulating genes Mmp13, Ocn, Osxand Phex was reduced in Ank(KI/KI) osteoblasts, while the Fgf23 mRNA level was highly elevated in Ank(KI/KI) calvarial and femoral bones. Since ANK is a known PPi transporter, we examined other regulators of Pi/PPi homeostasis Enpp1 and Tnap. Significantly increased ENPP1 activity may compensate for dysfunctional mutant ANK leading to comparable extracellular PPi levels in Ank(+/+) osteoblasts. Similar to Ank(KI/KI) bone marrow-derived macrophage cultures, peripheral blood cultures from CMD patients exhibited reduced osteoclastogenesis. Cell-autonomous effects in Ank(KI/KI) osteoclasts resulted in disrupted actin ring formation and cell fusion. In addition, Ank(KI/KI) osteoblasts failed to adequately support osteoclastogenesis. Increased bone mass could partially be rescued by bone marrow transplants supporting our hypothesis that reduced osteoclastogenesis contributes at least in part to hyperostosis. We conclude that the Phe377del mutation in ANK causes impaired osteoblastogenesis and osteoclastogenesis resulting in hypomineralization and a high bone mass phenotype.

Autosomal Recessive Mental Retardation, Deafness, Ankylosis, and Mild Hypophosphatemia Associated with a NovelANKHMutation in a Consanguineous Family

Mutations in ANKH cause the highly divergent conditions familial chondrocalcinosis and craniometaphyseal dysplasia. The gene product ANK is supposed to regulate tissue mineralization by transporting pyrophosphate to the extracellular space. We evaluated several family members of a large consanguineous family with mental retardation, deafness, and ankylosis. We compared their skeletal, metabolic, and serological parameters to that of the autosomal recessive progressive ankylosis (ank) mouse mutant, caused by a loss-of-function mutation in the murine ortholog Ank. The studied patients had painful small joint soft-tissue calcifications, progressive spondylarthropathy, osteopenia, mild hypophosphatemia, mixed hearing loss, and mental retardation. After mapping the disease gene to 5p15, we identified the novel homozygous ANK missense mutation L244S in all patients. Although L244 is a highly conserved amino acid, the mutated ANK protein was detected at normal levels at the plasma membrane in primary patient fibroblasts. The phenotype was highly congruent with the autosomal recessive progressive ankylosis (ank) mouse mutant. This indicates a loss-of-function effect of the L244S mutation despite normal ANK protein expression. Interestingly, our analyses revealed that the primary step of joint degeneration is fibrosis and mineralization of articular soft tissues. Moreover, heterozygous carriers of the L244S mutation showed mild osteoarthritis without metabolic alterations, pathological calcifications, or central nervous system involvement. Beyond the description of the first human progressive ankylosis phenotype, our results indicate that ANK influences articular soft tissues commonly involved in degenerative joint disorders. Furthermore, this human disorder provides the first direct evidence for a role of ANK in the central nervous system.

Three novel mutations in the ANK membrane protein cause craniometaphyseal dysplasia with variable conductive hearing loss

Craniometaphyseal dysplasia (CMD) is a rare, sclerosing skeletal disorder caused by mutations in ANKH, which encodes a putative pyrophosphate transporting membrane protein. Six distinct ANKH mutations have been described to date. We report here on three novel mutations in simplex patients with CMD. The c.1015T>C (p.Cys339Arg) mutation found in Patient A was associated with congenital facial palsy, early-onset conductive hearing loss, and a generalized undermodeling of the long bones. The c.1172T>C (p.Leu391Pro) mutation in Patient B was associated with facial palsy, progressive conductive hearing loss, and generalized undermodeling of tubular bones. A milder phenotype without cranial nerve affection was observed in Patient C, associated with a c.1001T>G (p.Leu334Arg) mutation. All affected residues lie in evolutionarily conserved sequence blocks. These additional cases and the associated mutations contribute to an improved appreciation of the variability of this rare skeletal dysplasia. (c) 2010 Wiley-Liss, Inc.

Novel ANKH mutation in a patient with sporadic craniometaphyseal dysplasia

Craniometaphyseal dysplasia is caused by mutations in ANKH (ankylosis, progressive homolog [mouse]) in the majority of cases, and all of the reported mutations are single amino acid changes. Genomic DNA from an affected patient, his biological parents, and a sibling was amplified and ANKH was sequenced. The affected patient had a complex heterozygous mutation in exon 7 (c.936T > C, c.938C > G, c.942_953delTGGTTGACGGAA), predicting p.Try290Gln and p.Trp292_Glu295del. We studied the effect of the predicted mutation on the subcellular distribution of ANKH protein. Immunofluorescent labeling of COS-7 cells transduced with normal or mutant Ank (murine progressive ankylosis), showed that normal Ank localized to both the plasma membrane and cytoplasm, whereas mutant Ank was detected only in the cytoplasmic compartment. We propose that this craniometaphyseal dysplasia mutation causes a loss of ANKH protein expression and activity in the plasma membrane as a result of aberrant intracellular protein trafficking.

Introduction of a Phe377del Mutation in ANK Creates a Mouse Model for Craniometaphyseal Dysplasia

Craniometaphyseal dysplasia (CMD) is a monogenic human disorder characterized by thickening of craniofacial bones and flaring metaphyses of long bones. Mutations for autosomal dominant CMD have been identified in the progressive ankylosis gene ANKH. Previous studies of Ank loss-of-function models, Ank(null/null) and Ank(ank/ank) mice, suggest that Ank plays a role in the regulation of bone mineralization. However, the mechanism for Ank mutations leading to CMD remains unknown. We generated the first knockin (KI) mouse model for CMD expressing a human mutation (Phe377 deletion) in ANK. Homozygous Ank knockin mice (Ank(KI/KI)) replicate many typical features of human CMD including hyperostosis of craniofacial bones, massive jawbones, decreased diameters of cranial foramina, obliteration of nasal sinuses, fusion of middle ear bones, and club-shaped femurs. In addition, Ank(KI/KI) mice have increased serum alkaline phosphatase and TRACP5b, as reported in CMD patients. Biochemical markers of bone formation and bone resorption, N-terminal propeptide of type I procollagen and type I collagen cross-linked C-terminal telopeptide, are significantly increased in Ank(KI/KI) mice, suggesting increased bone turnover. Interestingly, Ank(KI/KI) bone marrow-derived macrophage cultures show decreased osteoclastogenesis. Despite the hyperostotic phenotype, bone matrix in Ank(KI/KI) mice is hypomineralized and less mature, indicating that biomechanical properties of bones may be compromised by the Ank mutation. We believe this new mouse model will facilitate studies of skeletal abnormalities in CMD at cellular and molecular levels.

Craniometaphyseal dysplasia and chondrocalcinosis cosegregating in a family with an ANKH mutation

American Journal of Medical Genetics Part AVolume 149A, Issue 6 p. 1331-1333 Research Letter Craniometaphyseal dysplasia and chondrocalcinosis cosegregating in a family with an ANKH mutation† Gareth Baynam, Corresponding Author Gareth Baynam [email protected] Genetic Services of Western Australia, Princess Margaret Hospital for Children and King Edward Memorial Hospital for Women, Western Australia, Australia School of Paediatrics and Child Health, University of Western Australia, Perth, AustraliaGenetic Services of Western Australia, Level 3 Agnes Walsh House, King Edward Memorial Hospital, 6008 Western Australia, Australia.Search for more papers by this authorJack Goldblatt, Jack Goldblatt Genetic Services of Western Australia, Princess Margaret Hospital for Children and King Edward Memorial Hospital for Women, Western Australia, Australia School of Paediatrics and Child Health, University of Western Australia, Perth, AustraliaSearch for more papers by this authorLyn Schofield, Lyn Schofield Genetic Services of Western Australia, Princess Margaret Hospital for Children and King Edward Memorial Hospital for Women, Western Australia, AustraliaSearch for more papers by this author Gareth Baynam, Corresponding Author Gareth Baynam [email protected] Genetic Services of Western Australia, Princess Margaret Hospital for Children and King Edward Memorial Hospital for Women, Western Australia, Australia School of Paediatrics and Child Health, University of Western Australia, Perth, AustraliaGenetic Services of Western Australia, Level 3 Agnes Walsh House, King Edward Memorial Hospital, 6008 Western Australia, Australia.Search for more papers by this authorJack Goldblatt, Jack Goldblatt Genetic Services of Western Australia, Princess Margaret Hospital for Children and King Edward Memorial Hospital for Women, Western Australia, Australia School of Paediatrics and Child Health, University of Western Australia, Perth, AustraliaSearch for more papers by this authorLyn Schofield, Lyn Schofield Genetic Services of Western Australia, Princess Margaret Hospital for Children and King Edward Memorial Hospital for Women, Western Australia, AustraliaSearch for more papers by this author First published: 15 May 2009 https://doi.org/10.1002/ajmg.a.32875Citations: 12 † How to cite this article: Baynam G, Goldblatt J, Schofield L. 2009. Craniometaphyseal dysplasia and chondrocalcinosis cosegregating in a family with an ANKH mutation. Am J Med Genet Part A 149A:1331–1333. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume149A, Issue6June 2009Pages 1331-1333 RelatedInformation

The Erlenmeyer flask bone deformity in the skeletal dysplasias

Erlenmeyer flask bone deformity (EFD) is a long-standing term used to describe a specific abnormality of the distal femora. The deformity consists of lack of modeling of the di-metaphysis with abnormal cortical thinning and lack of the concave di-metaphyseal curve resulting in an Erlenmeyer flask-like appearance. Utilizing a literature review and cohort study of 12 disorders we found 20 distinct disorders were associated with EFD. We interrogated the International Skeletal Dysplasia Registry (ISDR) radiographic database (1988-2007) to determine which skeletal dysplasias or syndromes were highly associated with EFD, whether it was a uniform finding in these disorders, and if forms of EFD could be differentiated. EFD was classified into three groups. The first catogory was the typical EFD shaped bone (EFD-T) resultant from absent normal di-metaphyseal modeling with relatively normal appearing radiographic trabecular bone. EFD-T was identified in: frontometaphyseal dysplasia, craniometaphyseal dysplasia, craniodiaphyseal dysplasia, diaphyseal dysplasia-Engelmann type, metaphyseal dysplasia-Pyle type, Melnick-Needles osteodysplasty, and otopalatodigital syndrome type I. The second group was the atypical type (EFD-A) due to absence of normal di-metaphyseal modeling with abnormal radiographic appearance of trabecular bone and was seen in dysosteosclerosis and osteopetrosis. The third group was EFD-marrow expansion type (EFD-ME) in which bone marrow hyperplasia or infiltration leads to abnormal modeling (e.g., Gaucher disease). Further, radiographic review determined that it was not always a consistent finding and that there was variability in both appearance and location within the skeleton. This analysis and classification aided in differentiating disorders with the finding of EFD.

Craniometaphyseal dysplasia: A case report

Craniometaphyseal dysplasia (CMD) is a rare genetically transmitted bone dysplasia characterized by alterations in the development of the craniofacial bones with abnormal remodeling of the metaphyses. Sclerosis of the skull bones can lead to cranial nerve compression that finally may result in hearing loss and facial palsy. CMD occurs in an autosomal dominant (AD) (MIM 123000) and an autosomal recessive (AR) form (MIM 218400). Sclerosis of cranial bones is usually much more severe in the AR form. We present a 36-year-old male with a previous diagnosis of Paget disease. The examination reveals prognathism, ocular hypertelorism, mixed bilateral hypoacusia, nasal bossing, a class III malocclusion and a narrow palatal vault. The patient necessitated several dental extractions, surgical procedures were conducted, and a biopsy of the alveolus was performed and the sample underwent histological examination. The histological report led to an exclusion of the previous diagnosis of Paget disease. The final diagnosis of autosomal dominant CMD was confirmed by the molecular testing of the CMD gene (ANKH).

Progressive Ankylosis Gene (ank) Regulates Osteoblast Differentiation

The progressive ankylosis gene (ank) is a transmembrane protein that transports intracellular pyrophosphate to the extracellular milieu. Human mutations of ank lead to craniometaphyseal dysplasia, a disease which is characterized by the overgrowth of craniofacial bones and osteopenia in long bones, suggesting that ANK plays a regulatory role in osteoblast differentiation. To determine the role of ANK in osteoblast differentiation, we suppressed ANK expression in the osteoblastic MC3T3-E1 cell line using siRNA and determined the expression of osteoblastic marker genes and the transcription factors osterix and runx2. In addition, we determined the osteoblastic differentiation of bone marrow stromal cells isolated from the bone marrow of ank/ank mice, which express a truncated, nonfunctional ANK protein, or wild-type littermates. Suppression of ANK expression in MC3T3-E1 cells led to a decrease in bone marker gene expression, including alkaline phosphatase, bone sialoprotein, osteocalcin and type I collagen. In addition, osterix gene expression was decreased in ANK expression-suppressed MC3T3 cells, whereas runx2 expression was increased. Bone marrow stromal cells isolated from ank/ank mice cultured in the presence of ascorbate-2-phosphate for up to 35 days showed markedly reduced mineralization compared to the mineralization of bone marrow stromal cells isolated from wild-type littermates. In conclusion, these findings suggest that ANK is a positive regulator of differentiation events towards a mature osteoblastic phenotype.

Chiari Malformation Caused by Craniometaphyseal Dysplasia: Case Report and Review of Literature

Chiari malformation is commonly considered a congenital condition. To our knowledge, reports of progressively symptomatic Chiari Iota malformation with craniometaphyseal dysplasia are rare. The authors present a case of progressively symptomatic Chiari Iota malformation occurring in an 11-month-old infant with craniometaphyseal dysplasia. The patient presented with a typical facial appearance and radiological skeletal survey. Posterior fossa decompression was performed. In the meantime, the patient was given Rocaltrol (calcitriol) and adopted a low calcium diet. His neurological symptoms were markedly improved after surgery. The clinical presentations, radiographical features and prognosis of the patient are discussed with reference to the literature.

Optic nerve sheath fenestration and bilateral expansile cranioplasty for raised intracranial pressure in craniometaphyseal dysplasia: a case report

Raised intracranial pressure (ICP) has been previously associated with craniometaphyseal dysplasia (CMD). To our knowledge, expansile cranioplasty has not previously been described as a treatment for raised ICP in this setting. We describe our evaluation and surgical management of a patient presenting with seizures, headaches, and CMD. An 18-year-old male presented with seizures, headaches, and diminished visual acuity, and was found to have chronic bilateral papilledema. Lumbar puncture demonstrated raised opening pressure (50 cm of water). Plain skeletal radiographs revealed long-bone dysplasia, and computed tomography (CT) of the head demonstrated diffuse thickening of the calvarium, diminished subarachnoid spaces, and slit ventricles. The raised ICP was managed with bilateral fronto-parieto-temporal expansile cranioplasty and right optic nerve sheath fenestration. At 6 months follow-up, the headaches and papilledema completely resolved. The visual acuity improved as did the seizure control. Follow-up CT demonstrated the normalization of the subarachnoid spaces and ventricles. Expansile cranioplasty, in conjunction with optic nerve sheath fenestration, may represent a safe and effective treatment for raised ICP associated with CMD.

Foramen magnum decompression and expansile duroplasty for acquired Chiari type I malformation in craniometaphyseal dysplasia

Craniometaphyseal dysplasia (CMD) is a rare genetic bone remodelling disorder characterized by undertubulation of the long bones and sclerosis and hyperostosis of the skull base with cranial nerve impairment. To our knowledge there are no previous reported cases of autosomal dominant CMD and acquired Chiari type 1 malformation with cervicomedullary compression. We outline the clinical and radiological features of this condition and describe the surgical management.

Biochemical and Genetic Analysis of ANK in Arthritis and Bone Disease

Mutations in the progressive ankylosis gene (Ank/ANKH) cause surprisingly different skeletal phenotypes in mice and humans. In mice, recessive loss-of-function mutations cause arthritis, ectopic crystal formation, and joint fusion throughout the body. In humans, some dominant mutations cause chondrocalcinosis, an adult-onset disease characterized by the deposition of ectopic joint crystals. Other dominant mutations cause craniometaphyseal dysplasia, a childhood disease characterized by sclerosis of the skull and abnormal modeling of the long bones, with little or no joint pathology. Ank encodes a multiple-pass transmembrane protein that regulates pyrophosphate levels inside and outside tissue culture cells in vitro, but its mechanism of action is not yet clear, and conflicting models have been proposed to explain the effects of the human mutations. Here, we test wild-type and mutant forms of ANK for radiolabeled pyrophosphate-transport activity in frog oocytes. We also reconstruct two human mutations in a bacterial artificial chromosome and test them in transgenic mice for rescue of the Ank null phenotype and for induction of new skeletal phenotypes. Wild-type ANK stimulates saturable transport of pyrophosphate ions across the plasma membrane, with half maximal rates attained at physiological levels of pyrophosphate. Chondrocalcinosis mutations retain apparently wild-type transport activity and can rescue the joint-fusion phenotype of Ank null mice. Craniometaphyseal dysplasia mutations do not transport pyrophosphate and cannot rescue the defects of Ank null mice. Furthermore, microcomputed tomography revealed previously unappreciated phenotypes in Ank null mice that are reminiscent of craniometaphyseal dysplasia. The combination of biochemical and genetic analyses presented here provides insight into how mutations in ANKH cause human skeletal disease.

Progressive facial disfigurement and deafness in craniometaphyseal dysplasia

Progressive facial disfigurement and deafness in craniometaphyseal dysplasia

Role of the progressive ankylosis gene in cartilage mineralization

Among the myriad of players in the calcification of cartilage, ANK is a relatively new entrant. It is a multipass transmembrane protein that regulates the transport of inorganic pyrophosphate between the cell and the extracellular space. Mutations in ANK result in two distinct calcification disorders: craniometaphyseal dysplasia and familial calcium pyrophosphate dihydrate deposition disease. The purpose of this review is to highlight recent work on the role of ANK in physiological and pathological calcification of articular and growth plate cartilage. New information on the function of ANK suggests that the protein is part of a constellation of critical components that interact to regulate the elaboration of inorganic pyrophosphate. In addition to ANK, these components include alkaline phosphatase, the ectoenzyme PC-1, and osteopontin. ANK expression is also regulated by a variety of growth factors and cytokines that may further affect the transport of inorganic pyrophosphate and may be particularly relevant to the increased levels of expression of ANK in cartilage from chondrocalcinosis and osteoarthritis patients. Additional studies will be required to understand the contribution of ANK in shaping the fine balance of components necessary for crystal deposition in degenerating articular cartilage. Furthermore, the precise role of inherited mutations in ANK on the elaboration of inorganic pyrophosphate, and the ultimate deposition of either basic calcium phosphate or calcium pyrophosphate dihydrate crystals, remains unclear.

Craniofacial surgery for craniometaphyseal dysplasia

Craniometaphyseal dysplasia (CMD) is a rare congenital bone dysplasia with abnormal bony overgrowth leading to characteristic facial features and cranial nerve compression. We present a 10-year-old child with bony swelling at the nasal root since birth along with decreased hearing in both ears. She had normal developmental milestones and intelligence. On examination, she had bossing of forehead with very broad nasal root, short septum, hypertelorism and epicanthic folds. CT scan with 3D reconstruction revealed grossly thickened calvarium and hyperostosis and sclerosis of the cranial base. As the major concern of the parents was cosmetic, craniofacial reconstruction was performed with good cosmetic outcome.