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1.
Bone ; 133: 115224, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31923705

RESUMO

Four heterozygous in-frame tandem duplications of different lengths in TNFRSF11A, the gene that encodes receptor activator of nuclear factor κB (RANK), constitutively activate RANK and lead to high turnover skeletal disease. Each duplication elongates the signal peptide of RANK. The 18-base pair (bp) duplication at position 84 (84dup18) causes familial expansile osteolysis (FEO), the 15-bp duplication at position 84 (84dup15) causes expansile skeletal hyperphosphatasia (ESH), the 12-bp duplication at position 90 (90dup12) causes panostotic expansile bone disease (PEBD), and the 27-bp duplication causes early-onset Paget's disease of bone (PDB2). The severity of the associated skeletal disease seems inversely related to the duplication's length. Additional 15- and 18-bp duplications of TNFRSF11A fit this pattern. Herein, we delineate the skeletal disease of a middle-aged man of Mexican descent who we found to harbor a novel 27-bp tandem duplication at position 77 (77dup27) of TNFRSF11A. His disorder shares features, particularly hand involvement, with the single Japanese (75dup27) and Chinese (78dup27) kindreds with PDB2 (PDB2Jpn and PDB2Chn, respectively). However, his distinct hearing loss developed later in adulthood compared to the other 27-bp families. He reported no morbidities during childhood, but in his late 20s developed unexplained tooth loss, low-trauma fractures, post-operative hypercalcemia, and painless enlargement of his fingers. Biochemical studies showed elevated serum alkaline phosphatase (ALP), bone-specific ALP, C-telopeptide, and osteocalcin consistent with rapid bone remodeling. Radiologic imaging revealed remarkably lucent bones with vertebral compression fractures, calvarial lucencies, and thinned long bone cortices. DXA showed extremely low bone mineral density. His disorder genetically and phenotypically fits best with PDB2 and can be called PDB2Mex.

2.
J Bone Miner Res ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31910300

RESUMO

X-linked hypophosphatemia (XLH), the most prevalent heritable renal phosphate (Pi) wasting disorder, is caused by deactivating mutations of PHEX. Consequently, circulating phosphatonin FGF23 becomes elevated and hypophosphatemia in affected children leads to rickets with skeletal deformity and reduced linear growth while affected adults suffer from osteomalacia and forms of ectopic mineralization. In 2015, we reported uniquely mild XLH in six children and four of their mothers carrying the non-coding PHEX 3'-UTR mutation c.*231A>G. Herein, we characterize this mild XLH variant by comparing its features in 30 individuals to 30 age- and sex-matched patients with XLH but without the 3'-UTR mutation. The "UTR" and "XLH" groups, both comprising 17 children (2-17 years, 3 girls) and 13 adults (23-63 years, 10 women), had mean ages of 23 years. Only 43% of the UTR group versus 90% of the XLH group had received medical treatment for their disorder, including 0% versus 85% of the females, respectively (ps< 0.0001). The UTR group was taller: mean (SD) height Z-score (HZ) -1.0 (1.0) versus -2.0 (1.4) (p=0.0034), with significantly greater height for females [-0.9 (0.7) versus -2.3 (1.4), (p=0.0050)] but not males [-1.2 (1.1) versus -1.9 (1.5) (p=0.1541)], respectively. Mean (SD) "arm span Z-score" (AZ) did not differ between the UTR -0.8 (1.3) versus XLH -1.3 (1.8) groups (p=0.2269). Consequently, the UTR group was more proportionate with a mean ∆Z (AZ - HZ) of 0.1 (0.6) versus 0.7 (1.0) (p=0.0158), respectively. Compared to the XLH group, the UTR group had significantly higher fasting serum Pi and TmP/GFR (ps≤0.0060), serum FGF23 concentrations within the reference range (p=0.0068), and similar serum alkaline phosphatase levels (p = 0.6513). UTR lumbar spine bone mineral density Z-score was higher (p=0.0343). Thus, the 3'-UTR variant of XLH is distinctly mild, especially in girls and women, posing challenges for its recognition and management. This article is protected by copyright. All rights reserved.

3.
Bone ; 132: 115190, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31843680

RESUMO

The SIBLINGs are a subfamily of the secreted calcium-binding phosphoproteins and comprise five small integrin-binding ligand N-linked glycoproteins [dentin matrix protein-1 (DMP1), secreted phosphoprotein-1 (SPP1) also called osteopontin (OPN), integrin-binding sialoprotein (IBSP) also called bone sialoprotein (BSP), matrix extracellular phosphoglycoprotein (MEPE), and dentin sialophosphoprotein (DSPP)]. Each SIBLING has at least one "acidic, serine- and aspartic acid-rich motif" (ASARM) and multiple Ser-x-Glu/pSer sequences that when phosphorylated promote binding of the protein to hydroxyapatite for regulation of biomineralization. Mendelian disorders from loss-of-function mutation(s) of the genes that encode the SIBLINGs thus far involve DSPP causing various autosomal dominant dysplasias of dentin but without skeletal disease, and DMP1 causing autosomal recessive hypophosphatemic rickets, type 1 (ARHR1). No diseases have been reported from gain-of-function mutation(s) of DSPP or DMP1 or from alterations of SPP1, IBSP, or MEPE. Herein, we describe severe hypophosphatemic osteosclerosis and hyperostosis associated with skeletal deformity, short stature, enthesopathy, tooth loss, and high circulating FGF23 levels in a middle-aged man and young woman from an endogamous family living in southern India. Both shared novel homozygous mutations within two genes that encode a SIBLING protein: stop-gain ("nonsense") DMP1 (c.556G>T,p.Glu186Ter) and missense SPP1 (c.769C>T,p.Leu266Phe). The man alone also carried novel heterozygous missense variants within two additional genes that condition mineral homeostasis and are the basis for autosomal recessive disorders: CYP27B1 underlying vitamin D dependent rickets, type 1, and ABCC6 underlying both generalized arterial calcification of infancy, type 2 and pseudoxanthoma elasticum (PXE). By immunochemistry, his bone contained high amounts of OPN, particularly striking surrounding osteocytes. We review how our patients' disorder may represent the first digenic SIBLING protein osteopathy.

4.
Bone ; 130: 115047, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31472299

RESUMO

Bruck syndrome (BRKS) is the rare disorder that features congenital joint contractures often with pterygia and subsequent fractures, also known as osteogenesis imperfecta (OI) type XI (OMIM # 610968). Its two forms, BRKS1 (OMIM # 259450) and BRKS2 (OMIM # 609220), reflect autosomal recessive (AR) inheritance of FKBP10 and PLOD2 loss-of-function mutations, respectively. A 10-year-old girl was referred with blue sclera, osteopenia, poorly-healing fragility fractures, Wormian skull bones, cleft soft palate, congenital fusion of cervical vertebrae, progressive scoliosis, bell-shaped thorax, restrictive and reactive pulmonary disease, protrusio acetabuli, short stature, and additional dysmorphic features without joint contractures. Iliac crest biopsy after alendronate treatment that improved her bone density revealed low trabecular connectivity, abundant patchy osteoid, and active bone formation with widely-spaced tetracycline labels. Chromosome 22q11 deletion analysis for velocardiofacial syndrome, COL1A1 and COL1A2 sequencing for prevalent types of OI, and Sanger sequencing of LRP5, PPIB, FKBP10, and IFITM5 for rare pediatric osteoporoses were negative. Copy number microarray excluded a contiguous gene syndrome. Instead, exome sequencing revealed two missense variants in PLOD2 which encodes procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (lysyl hydroxylase 2, LH2); exon 8, c.797G>T, p.Gly266Val (paternal), and exon 12, c.1280A>G, p.Asn427Ser (maternal). In the Exome Aggregation Consortium (ExAC) database, low frequency (Gly266Val, 0.0000419) and absence (Asn427Ser) implicated both variants as mutations of PLOD2. The father, mother, and sister (who carried the exon 12 defect) were reportedly well with normal parental DXA findings. BRKS2, characterized by under-hydroxylation of type I collagen telopeptides compromising their crosslinking, has been reported in at least 16 probands/families. Most PLOD2 mutations involve exons 17-19 (of 20 total) encoding the C-terminal domain with LH activity. However, truncating defects (nonsense, frameshift, splice site mutations) are also found throughout PLOD2. In three reports, AR PLOD2 mutations are not associated with congenital contractures. Our patient's missense defects lie within the central domain of unknown function of PLOD2. In our patient, compound heterozygosity with PLOD2 mutations is associated with a clinical phenotype distinctive from classic BRKS2 indicating that when COL1A1 and COL1A2 mutation testing is negative for OI without congenital contractures or pterygia, atypical BRKS should be considered.

5.
Bone ; 127: 228-243, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31085352

RESUMO

LRP5 encodes low-density lipoprotein receptor-related protein 5 (LRP5). When LRP5 with a Frizzled receptor join on the surface of an osteoblast and bind a member of the Wnt family of ligands, canonical Wnt/ß-catenin signaling occurs and increases bone formation. Eleven heterozygous gain-of-function missense mutations within LRP5 are known to prevent the LRP5 inhibitory ligands sclerostin and dickkopf1 from attaching to LRP5's first ß-propeller, and thereby explain the rare autosomal dominant (AD) skeletal disorder "high bone mass" (HBM). LRP6 is a cognate co-receptor of LRP5 and similarly controls Wnt signaling in osteoblasts, yet the consequences of increased LRP6-mediated signaling remain unknown. We investigated two multi-generational American families manifesting the clinical and routine laboratory features of LRP5 HBM but without an LRP5 defect and instead carrying a heterozygous LRP6 missense mutation that would alter the first ß-propeller of LRP6. In Family 1 LRP6 c.602C>T, p.A201V was homologous to LRP5 HBM mutation c.641C>T, p.A214V, and in Family 2 LRP6 c.553A>C, p.N185H was homologous to LRP5 HBM mutation c.593A>G, p.N198S but predicting a different residue at the identical amino acid position. In both families the LRP6 mutation co-segregated with striking generalized osteosclerosis and hyperostosis. Clinical features shared by the seven LRP6 HBM family members and ten LRP5 HBM patients included a broad jaw, torus palatinus, teeth encased in bone and, reportedly, resistance to fracturing and inability to float in water. For both HBM disorders, all affected individuals were taller than average for Americans (Ps < 0.005), but with similar mean height Z-scores (P = 0.7606) and indistinguishable radiographic skeletal features. Absence of adult maxillary lateral incisors was reported by some LRP6 HBM individuals. In contrast, our 16 patients with AD osteopetrosis [i.e., Albers-Schönberg disease (A-SD)] had an unremarkable mean height Z-score (P = 0.9401) lower than for either HBM group (Ps < 0.05). DXA mean BMD Z-scores in LRP6 HBM versus LRP5 HBM were somewhat higher at the lumbar spine (+7.8 vs +6.5, respectively; P = 0.0403), but no different at the total hip (+7.9 vs +7.7, respectively; P = 0.7905). Among the three diagnostic groups, only the LRP6 HBM DXA BMD values at the spine seemed to increase with subject age (R = +0.7183, P = 0.0448). Total hip BMD Z-scores were not significantly different among the three disorders (Ps > 0.05), and showed no age effect (Ps > 0.1). HR-pQCT available only for LRP6 HBM revealed indistinct corticomedullary boundaries, high distal forearm and tibial total volumetric BMD, and finite element analysis predicted marked fracture resistance. Hence, we have discovered mutations of LRP6 that cause a dento-osseous disorder indistinguishable without mutation analysis from LRP5 HBM. LRP6 HBM seems associated with generally good health, providing some reassurance for the development of anabolic treatments aimed to enhance LRP5/LRP6-mediated osteogenesis.

6.
Bone ; 122: 231-236, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30825650

RESUMO

Hypophosphatasia (HPP) is the inborn-error-of-metabolism characterized enzymatically by insufficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP) and caused by either mono- or bi-allelic loss-of-function mutation(s) of the gene ALPL that encodes this cell surface phosphomonoester phosphohydrolase. In HPP, the natural substrates of TNSALP accumulate extracellularly and include inorganic pyrophosphate (PPi), a potent inhibitor of biomineralization. This PPi excess leads to rickets or osteomalacia in all but the most mild "odonto" form of the disease. Adults with HPP understandably often also manifest calcium PPi dihydrate deposition, whereas enthesopathy and calcific periarthritis from hydroxyapatite (HA) crystal deposition can seem paradoxical in face of the defective skeletal mineralization. In 2015, asfotase alfa (AA), a HA-targeted TNSALP, was approved multinationally as an enzyme replacement therapy for HPP. AA hydrolyzes extracellular PPi (ePPi) and in HPP enables HA crystals to grow and mineralize skeletal matrix. In direct contrast to HPP, deficiency of ePPi characterizes the inborn-errors-of-metabolism generalized arterial calcification of infancy (GACI) and pseudoxanthoma elasticum (PXE). In GACI and PXE, deficiency of ePPi leads to ectopic mineralization including vascular calcification (VC). Therefore, in HPP, ectopic mineralization including VC could hypothetically result from, or be exacerbated by, the persistently high circulating TNSALP activity that occurs during AA treatment. Herein, using a routine computed tomography (CT) method to quantitate coronary artery calcium, we found no ectopic mineralization in the heart of an elderly woman with HPP before or after 8 months of AA treatment. Subsequently, investigational high-resolution peripheral quantitative CT and dual-energy X-ray absorptiometry showed absence of peripheral artery and aortic calcium after further AA treatment. Investigation of additional adults with HPP could reveal if the superabundance of ePPi protects against VC, and whether long-term AA therapy causes or exacerbates any ectopic mineralization.

7.
Bone ; 116: 321-332, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30077757

RESUMO

Sclerosteosis (SOST) refers to two extremely rare yet similar skeletal dysplasias featuring a diffusely radiodense skeleton together with congenital syndactyly. SOST1 is transmitted as an autosomal recessive (AR) trait and to date caused by ten homozygous loss-of-function mutations within the gene SOST that encodes the inhibitor of Wnt-mediated bone formation, sclerostin. SOST2 is transmitted as an autosomal dominant (AD) or AR trait and to date caused by one heterozygous or two homozygous loss-of-function mutation(s), respectively, within the gene LRP4 that encodes the sclerostin interaction protein, low-density lipoprotein receptor-related protein 4 (LRP4). Herein, we investigated two teenagers and one middle-aged man with SOST in three families living in the state of Tamil Nadu in southern India. Next generation sequencing of their genomic DNA using our high bone density gene panel revealed SOST1 in the teenagers caused by a unique homozygous nonsense SOST mutation (c.129C > G, p.Tyr43X) and SOST2 in the man caused by homozygosity for one of the two known homozygous missense LRP4 mutations (c.3508C > T, p.Arg1170Trp). He becomes the fourth individual and the first non-European recognized with SOST2. His clinical course was milder than the life-threatening SOST1 demonstrated by the teenagers who suffered blindness, deafness, and raised intracranial pressure, yet his congenital syndactyly was more striking by featuring bony fusion of digits. All three patients were from consanguineous families and heterozygosity for the SOST mutation was documented in the mothers of both teenagers. Thus, on the endogamous genetic background of Indian Tamils, SOST1 from sclerostin deficiency compared to SOST2 from LRP4 deactivation is a more severe and life-threatening disorder featuring complications due to osteosclerosis of especially the skull. In contrast, the syndactyly of SOST2 is particularly striking by involving bony fusion of some digits. Both the SOST and LRP4 mutations in this ethnic population likely reflect genetic founders.


Assuntos
Hiperostose/patologia , Sindactilia/patologia , Adolescente , Sequência de Bases , Proteínas Morfogenéticas Ósseas/genética , Osso e Ossos/metabolismo , Análise Mutacional de DNA , Família , Feminino , Marcadores Genéticos/genética , Humanos , Hiperostose/diagnóstico por imagem , Hiperostose/genética , Índia , Proteínas Relacionadas a Receptor de LDL/genética , Masculino , Pessoa de Meia-Idade , Minerais/metabolismo , Linhagem , Sindactilia/diagnóstico por imagem , Sindactilia/genética
8.
J Bone Miner Res ; 33(11): 2071-2080, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29933504

RESUMO

Pediatric granulomatous arthritis (PGA) refers to two formerly separate entities: autosomal dominant Blau syndrome (BS) and its sporadic phenocopy early-onset sarcoidosis (EOS). In 2001 BS and in 2005 EOS became explained by heterozygous mutations within the gene that encodes nucleotide-binding oligomerization domain-containing protein 2 (NOD2), also called caspase recruitment domain-containing protein 15 (CARD15). NOD2 is a microbe sensor in leukocyte cytosol that activates and regulates inflammation. PGA is characterized by a triad of autoinflammatory problems (dermatitis, uveitis, and arthritis) in early childhood, which suggests the causal NOD2/CARD15 mutations are activating defects. Additional complications of PGA were recognized especially when NOD2 mutation analysis became generally available. However, in PGA, hypercalcemia is only briefly mentioned, and generalized osteosclerosis is not reported, although NOD2 regulates NF-κB signaling essential for osteoclastogenesis and osteoclast function. Herein, we report a 4-year-old girl with PGA uniquely complicated by severe 1,25(OH)2 D-mediated hypercalcemia, nephrocalcinosis, and compromised renal function together with radiological and histopathological features of osteopetrosis (OPT). The classic triad of PGA complications was absent, although joint pain and an antalgic gait accompanied wrist, knee, and ankle swelling and soft non-tender masses over her hands, knees, and feet. MRI revealed tenosynovitis in her hands and suprapatellar effusions. Synovial biopsy demonstrated reactive synovitis without granulomas. Spontaneous resolution of metaphyseal osteosclerosis occurred while biochemical markers indicated active bone turnover. Anti-inflammatory medications suppressed circulating 1,25(OH)2 D, corrected the hypercalcemia, and improved her renal function, joint pain and swelling, and gait. Mutation analysis excluded idiopathic infantile hypercalcemia, type 1, and known forms of OPT, and identified a heterozygous germline missense mutation in NOD2 common in PGA (c.1001G>A, p.Arg334Gln). Thus, radiological and histological findings of OPT and severe hypercalcemia from apparent extrarenal production of 1,25(OH)2 D can complicate NOD2-associated PGA. Although the skeletal findings seem inconsequential, treatment of the hypercalcemia is crucial to protect the kidneys. © 2018 American Society for Bone and Mineral Research.


Assuntos
Artrite/genética , Granuloma/complicações , Granuloma/genética , Hipercalcemia/complicações , Mutação/genética , Proteína Adaptadora de Sinalização NOD2/genética , Osteosclerose/complicações , Vitamina D/análogos & derivados , Sequência de Aminoácidos , Artrite/complicações , Artrite/diagnóstico por imagem , Sequência de Bases , Medula Óssea/diagnóstico por imagem , Medula Óssea/patologia , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Pré-Escolar , Análise Mutacional de DNA , Feminino , Granuloma/diagnóstico por imagem , Humanos , Hipercalcemia/diagnóstico por imagem , Proteína Adaptadora de Sinalização NOD2/química , Osteosclerose/diagnóstico por imagem , Membrana Sinovial/patologia , Vitamina D/efeitos adversos
9.
Bone ; 101: 145-155, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28434888

RESUMO

Melorheostosis (MEL) is the rare sporadic dysostosis characterized by monostotic or polyostotic osteosclerosis and hyperostosis often distributed in a sclerotomal pattern. The prevailing hypothesis for MEL invokes postzygotic mosaicism. Sometimes scleroderma-like skin changes, considered a representation of the pathogenetic process of MEL, overlie the bony changes, and sometimes MEL becomes malignant. Osteopoikilosis (OPK) is the autosomal dominant skeletal dysplasia that features symmetrically distributed punctate osteosclerosis due to heterozygous loss-of-function mutation within LEMD3. Rarely, radiographic findings of MEL occur in OPK. However, germline mutation of LEMD3 does not explain sporadic MEL. To explore if mosaicism underlies MEL, we studied a boy with polyostotic MEL and characteristic overlying scleroderma-like skin, a few bony lesions consistent with OPK, and a large epidermal nevus known to usually harbor a HRAS, FGFR3, or PIK3CA gene mutation. Exome sequencing was performed to ~100× average read depth for his two dermatoses, two areas of normal skin, and peripheral blood leukocytes. As expected for non-malignant tissues, the patient's mutation burden in his normal skin and leukocytes was low. He, his mother, and his maternal grandfather carried a heterozygous, germline, in-frame, 24-base-pair deletion in LEMD3. Radiographs of the patient and his mother revealed bony foci consistent with OPK, but she showed no MEL. For the patient, somatic variant analysis, using four algorithms to compare all 20 possible pairwise combinations of his five DNA samples, identified only one high-confidence mutation, heterozygous KRAS Q61H (NM_033360.3:c.183A>C, NP_203524.1:p.Gln61His), in both his dermatoses but absent in his normal skin and blood. Thus, sparing our patient biopsy of his MEL bone, we identified a heterozygous somatic KRAS mutation in his scleroderma-like dermatosis considered a surrogate for MEL. This implicates postzygotic mosaicism of mutated KRAS, perhaps facilitated by germline LEMD3 haploinsufficiency, causing his MEL.


Assuntos
Exoma/genética , Melorreostose/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adolescente , Predisposição Genética para Doença/genética , Humanos , Masculino , Mosaicismo , Mutação , Nevo/genética , Osteopecilose/genética , Osteosclerose/genética
10.
J Bone Miner Res ; 32(1): 188-195, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27449958

RESUMO

Skeletal fluorosis (SF) is endemic in many countries and millions of people are affected worldwide, whereas in the United States SF is rare with occasional descriptions of unique cases. We report a 28-year-old American man who was healthy until 2 years earlier when he gradually experienced difficulty walking and an abnormal gait, left hip pain, loss of mobility in his right wrist and forearm, and progressive deformities including enlargement of the digits of both hands. Dual-energy X-ray absorptiometry (DXA) of his lumbar spine, femoral neck, total hip, and the one-third forearm revealed bone mineral density (BMD) Z-scores of +6.2, +4.8, +3.0, and -0.2, respectively. Serum, urine, and bone fluoride levels were all elevated and ultimately explained by chronic sniffing abuse of a computer cleaner containing 1,1-difluoroethane. Our findings reflect SF due to the unusual cause of inhalation abuse of difluoroethane. Because this practice seems widespread, particularly in the young, there may be many more such cases. © 2016 American Society for Bone and Mineral Research.


Assuntos
Doenças Ósseas/induzido quimicamente , Computadores , Exposição por Inalação/efeitos adversos , Adulto , Doenças Ósseas/diagnóstico por imagem , Doenças Ósseas/patologia , Cotovelo/diagnóstico por imagem , Colo do Fêmur/diagnóstico por imagem , Colo do Fêmur/patologia , Análise de Elementos Finitos , Humanos , Hidrocarbonetos Fluorados , Masculino , Pelve/diagnóstico por imagem , Tomografia Computadorizada por Raios X
11.
J Bone Miner Res ; 32(4): 757-769, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27862258

RESUMO

In 1985, we briefly reported infant sisters with a unique, lethal, autosomal recessive disorder designated congenital sclerosing osteomalacia with cerebral calcification. In 1986, this condition was entered into Mendelian Inheritance In Man (MIM) as osteomalacia, sclerosing, with cerebral calcification (MIM 259660). However, no attestations followed. Instead, in 1989 Raine and colleagues published an affected neonate considering unprecedented the striking clinical and radiographic features. In 1992, "Raine syndrome" entered MIM formally as osteosclerotic bone dysplasia, lethal (MIM #259775). In 2007, the etiology emerged as loss-of-function mutation of FAM20C that encodes family with sequence similarity 20, member C. FAM20C is highly expressed in embryonic calcified tissues and encodes a kinase (dentin matrix protein 4) for most of the secreted phosphoproteome including FGF23, osteopontin, and other regulators of skeletal mineralization. Herein, we detail the clinical, radiological, biochemical, histopathological, and FAM20C findings of our patients. Following premortem tetracycline labeling, the proposita's non-decalcified skeletal histopathology after autopsy indicated no rickets but documented severe osteomalacia. Archival DNA revealed the sisters were compound heterozygotes for a unique missense mutation and a novel deletion in FAM20C. Individuals heterozygous for the missense mutation seemed to prematurely fuse their metopic suture and develop a metopic ridge sometimes including trigonocephaly. Our findings clarify FAM20C's role in hard tissue formation and mineralization, and show that Raine syndrome is congenital sclerosing osteomalacia with cerebral calcification. © 2016 American Society for Bone and Mineral Research.


Assuntos
Anormalidades Múltiplas , Calcinose , Caseína Quinase I , Cérebro/patologia , Fissura Palatina , Exoftalmia , Proteínas da Matriz Extracelular , Microcefalia , Osteomalacia , Osteosclerose , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Adulto , Calcinose/diagnóstico por imagem , Calcinose/genética , Calcinose/metabolismo , Caseína Quinase I/genética , Caseína Quinase I/metabolismo , Cérebro/diagnóstico por imagem , Cérebro/metabolismo , Fissura Palatina/diagnóstico por imagem , Fissura Palatina/genética , Fissura Palatina/metabolismo , Exoftalmia/diagnóstico por imagem , Exoftalmia/genética , Exoftalmia/metabolismo , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Feminino , Humanos , Recém-Nascido , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/genética , Microcefalia/metabolismo , Osteomalacia/diagnóstico por imagem , Osteomalacia/genética , Osteomalacia/metabolismo , Osteosclerose/diagnóstico por imagem , Osteosclerose/genética , Osteosclerose/metabolismo
12.
Endocr Pract ; 22(8): 941-50, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27042741

RESUMO

OBJECTIVE: Hypophosphatasia (HPP) is a rare inherited metabolic bone disease from deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Reportedly, teriparatide (parathyroid hormone 1-34) can benefit the adult form of HPP, including fracture healing. We studied 2 women with adult HPP given teriparatide and reviewed the reports of 6 additional patients. METHODS: A 68-year-old black woman (patient 1) described low-trauma fractures and had subnormal serum alkaline phosphatase (ALP) activity. Biochemical findings were consistent with HPP. Mutation analysis revealed a heterozygous defect in exon 10 of TNSALP (ALPL). Teriparatide was injected daily for 2 years. Four years later, she fractured her right hip. Treatment was resumed for 8 months without further fractures. A 53-year-old white woman (patient 2) reported low-trauma fractures and had subnormal serum ALP. Mutation analysis revealed a heterozygous defect in exon 8 of TNSALP. She injected teriparatide daily for 2 years. One year later, bone mineral density (BMD) declined and treatment was resumed for 3 months. When she sustained a sacral fracture, teriparatide was administered for a further 18 months. RESULTS: Patient 1's serum ALP increased while receiving teriparatide and returned to baseline after its discontinuation. BMD remained unchanged, but no fractures were sustained. Patient 2's serum ALP increased, but the improvement was not sustained. Femoral neck BMD increased significantly during the first cycle, declined significantly afterwards, and was regained during a second course of teriparatide. CONCLUSION: Teriparatide shows some benefit for adult HPP. ABBREVIATIONS: ALP = alkaline phosphatase BMD = bone mineral density BSAP = bone-specific alkaline phosphatase CTX = C-telopeptide DXA = dual-energy X-ray absorptiometry FN = femoral neck HPP = hypophosphatasia LS = lumbar spine PEA = phosphoethanolamine PLP = pyridoxal 5'-phosphate PTH = parathyroid hormone SQ = subcutaneous TNSALP = tissue-nonspecific isoenzyme of alkaline phosphatase TPTD = teriparatide.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Hipofosfatasia/tratamento farmacológico , Teriparatida/uso terapêutico , Idoso , Densidade Óssea , Feminino , Fraturas do Fêmur/tratamento farmacológico , Fraturas do Fêmur/etiologia , Fraturas do Quadril/tratamento farmacológico , Fraturas do Quadril/etiologia , Humanos , Hipofosfatasia/complicações , Pessoa de Meia-Idade , Fraturas por Osteoporose/tratamento farmacológico , Fraturas por Osteoporose/etiologia
13.
J Bone Miner Res ; 31(9): 1774-82, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27005479

RESUMO

Widely distributed osteosclerosis is an unusual radiographic finding with multiple causes. A 42-year-old premenopausal Spanish woman gradually acquired dense bone diffusely affecting her axial skeleton and focally affecting her proximal long bones. Systemic lupus erythematosus (SLE) diagnosed in adolescence had been well controlled. She had not fractured or received antiresorptive therapy, and she was hepatitis C virus antibody negative. Family members had low bone mass. Lumbar spine bone mineral density (BMD) measured by dual-photon absorptiometry (DPA) at age 17 years, while receiving glucocorticoids, was 79% the average value of age-matched controls. From ages 30 to 37 years, dual-energy X-ray absorptiometry (DXA) BMD Z-scores steadily increased in her lumbar spine from +3.8 to +7.9, and in her femoral neck from -1.4 to -0.7. Serum calcium and phosphorus levels were consistently normal, 25-hydroxyvitamin D (25OHD) <20 ng/mL, and parathyroid hormone (PTH) sometimes slightly increased. Her reduced estimated glomerular filtration rate (eGFR) was 38 to 55 mL/min. Hypocalciuria likely reflected positive mineral balance. During increasing BMD, turnover markers (serum bone-specific alkaline phosphatase [ALP], procollagen type 1 N propeptide [P1NP], osteocalcin [OCN], and carboxy-terminal cross-linking telopeptide of type 1 collagen [CTx], and urinary amino-terminal cross-linking telopeptide of type 1 collagen [NTx and CTx]) were 1.6- to 2.8-fold above the reference limits. Those of bone formation seemed increased more than those of resorption. FGF-23 was slightly elevated, perhaps from kidney disease. Serum osteoprotegerin (OPG) and TGFß1 levels were normal, but sclerostin (SOST) and receptor activator of nuclear factor kappa-B ligand (RANKL) were elevated. Serum multiplex biomarker profiling confirmed a high level of SOST and RANKL, whereas Dickkopf-1 (DKK-1) seemed low. Matrix metalloproteinases-3 (MMP-3) and -7 (MMP-7) were elevated. Iliac crest biopsy revealed tetracycline labels, no distinction between thick trabeculae and cortical bone, absence of peritrabecular fibrosis, few osteoclasts, and no mastocytosis. Then, for the past 3 years, BMD Z-scores steadily decreased. Skeletal fluorosis, mastocytosis, myelofibrosis, hepatitis C-associated osteosclerosis, multiple myeloma, and aberrant phosphate homeostasis did not explain her osteosclerosis. Mutation analysis of the LRP5, LRP4, SOST, and osteopetrosis genes was negative. Microarray showed no notable copy number variation. Perhaps her osteosclerosis reflected an interval of autoimmune-mediated resistance to SOST and/or RANKL. © 2016 American Society for Bone and Mineral Research.


Assuntos
Lúpus Eritematoso Sistêmico/complicações , Osteosclerose/complicações , Absorciometria de Fóton , Adolescente , Adulto , Biomarcadores/sangue , Biópsia , Medula Óssea/patologia , Análise Mutacional de DNA , Feminino , Quadril/diagnóstico por imagem , Quadril/patologia , Humanos , Ílio/patologia , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/diagnóstico por imagem , Lúpus Eritematoso Sistêmico/genética , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Osteosclerose/sangue , Osteosclerose/diagnóstico por imagem , Osteosclerose/genética , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/patologia , Imagem Corporal Total , Adulto Jovem
14.
Bone ; 84: 289-298, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26746779

RESUMO

Congenital insensitivity to pain (CIP) comprises the rare heritable disorders without peripheral neuropathy that feature inability to feel pain. Fracturing and joint destruction are common complications, but lack detailed studies of mineral and skeletal homeostasis and bone histology. In 2013, discovery of a heterozygous gain-of-function mutation in SCN11A encoding voltage-gated sodium channel 1.9 (Nav1.9) established a distinctive CIP in three unrelated patients who suffered multiple painless fractures, self-inflicted mutilation, chronic diarrhea, and hyperhidrosis. Here, we studied a mother and two children with CIP by physical examination, biochemical testing, radiological imaging including DXA, iliac crest histology, and mutation analysis. She suffered fractures primarily of her lower extremities beginning at age two years, and had Charcot deformity of both ankles and joint hypermobility. Nerve conduction velocity together with electromyography were normal. Her children had recurrent major fractures beginning in early childhood, joint hypermobility, and chronic diarrhea. She had an excoriated external nare, and both children had hypertrophic scars from scratching. Skin collagen studies were normal. Radiographs revealed fractures and deformities. However, lumbar spine and total hip BMD Z-scores, biochemical parameters of mineral and skeletal homeostasis, and iliac crest histology of the mother (after in vivo tetracycline labeling) were normal. Genomic DNA from the children revealed a unique heterozygous missense mutation in exon 23 (c.3904C>T, p.Leu1302Phe) of SCN11A that is absent in SNP databases and alters an evolutionarily conserved amino acid. This autosomal dominant CIP reflects the second gain-of-function mutation of SCN11A. Perhaps joint hypermobility is an unreported feature. How mutation of Nav1.9 causes fracturing remains unexplained. Lack of injury awareness is typically offered as the reason, and was supported by our unremarkable biochemical, radiological, and histological findings indicating no skeletal pathobiology. However, low-trauma fracturing in these patients suggests an uncharacterized defect in bone quality.


Assuntos
Osso e Ossos/patologia , Fraturas Ósseas/complicações , Fraturas Ósseas/genética , Genes Dominantes , Mutação/genética , Insensibilidade Congênita à Dor/complicações , Insensibilidade Congênita à Dor/genética , Sequência de Aminoácidos , Sequência de Bases , Osso e Ossos/diagnóstico por imagem , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Fraturas Ósseas/diagnóstico por imagem , Humanos , Lactente , Recém-Nascido , Masculino , Dados de Sequência Molecular , Canal de Sódio Disparado por Voltagem NAV1.9/química , Canal de Sódio Disparado por Voltagem NAV1.9/genética , Insensibilidade Congênita à Dor/diagnóstico por imagem , Linhagem , Adulto Jovem
15.
Am J Med Genet A ; 170A(4): 978-85, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26762549

RESUMO

We report auricular ossification (AO) affecting the elastic cartilage of the ear as a newly recognized feature of osteoprotegerin (OPG)-deficiency juvenile Paget disease (JPD). AO and auricular calcification refer interchangeably to rigid pinnae, sparing the ear lobe, from various etiologies. JPD is a rare Mendelian disorder characterized by elevated serum alkaline phosphatase activity accompanied by skeletal pain and deformity from rapid bone turnover. Autosomal recessive transmission of loss-of-function mutations within TNFRSF11B encoding OPG accounts for most JPD (JPD1). JPD2 results from heterozygous constitutive activation of TNFRSF11A encoding RANK. Other causes of JPD remain unknown. In 2007, we reported a 60-year-old man with JPD1 who described hardening of his external ears at age 45 years, after 4 years of treatment with bisphosphonates (BPs). Subsequently, we noted rigid pinnae in a 17-year-old boy and 14-year-old girl, yet pliable pinnae in a 12-year-old boy, each with JPD1 and several years of BP treatment. Cranial imaging indicated cortical bone within the pinnae of both teenagers. Radiologic studies of our three JPD patients without mutations in TNFRSF11B showed normal auricles. Review of the JPD literature revealed possible AO in several reports. Two of our JPD1 patients had experienced difficult tracheal intubation, raising concern for mineralization of laryngeal elastic cartilage. Thus, AO is a newly recognized feature of JPD1, possibly exacerbated by BP treatment. Elastic cartilage at other sites in JPD1 might also ossify, and warrants investigation.


Assuntos
Pavilhão Auricular/patologia , Estudos de Associação Genética , Ossificação Heterotópica/genética , Ossificação Heterotópica/patologia , Osteíte Deformante/diagnóstico , Osteíte Deformante/genética , Osteoprotegerina/deficiência , Adolescente , Idoso , Osso e Ossos/patologia , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Mutação , Fenótipo , Tomografia Computadorizada por Raios X , Adulto Jovem
16.
J Bone Miner Res ; 31(1): 163-72, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26178921

RESUMO

Heritable disorders that feature high bone mass (HBM) are rare. The etiology is typically a mutation(s) within a gene that regulates the differentiation and function of osteoblasts (OBs) or osteoclasts (OCs). Nevertheless, the molecular basis is unknown for approximately one-fifth of such entities. NF-κB signaling is a key regulator of bone remodeling and acts by enhancing OC survival while impairing OB maturation and function. The NF-κB transcription complex comprises five subunits. In mice, deletion of the p50 and p52 subunits together causes osteopetrosis (OPT). In humans, however, mutations within the genes that encode the NF-κB complex, including the Rela/p65 subunit, have not been reported. We describe a neonate who died suddenly and unexpectedly and was found at postmortem to have HBM documented radiographically and by skeletal histopathology. Serum was not available for study. Radiographic changes resembled malignant OPT, but histopathological investigation showed morphologically normal OCs and evidence of intact bone resorption excluding OPT. Furthermore, mutation analysis was negative for eight genes associated with OPT or HBM. Instead, accelerated bone formation appeared to account for the HBM. Subsequently, trio-based whole exome sequencing revealed a heterozygous de novo missense mutation (c.1534_1535delinsAG, p.Asp512Ser) in exon 11 of RELA encoding Rela/p65. The mutation was then verified using bidirectional Sanger sequencing. Lipopolysaccharide stimulation of patient fibroblasts elicited impaired NF-κB responses compared with healthy control fibroblasts. Five unrelated patients with unexplained HBM did not show a RELA defect. Ours is apparently the first report of a mutation within the NF-κB complex in humans. The missense change is associated with neonatal osteosclerosis from in utero increased OB function rather than failed OC action. These findings demonstrate the importance of the Rela/p65 subunit within the NF-κB pathway for human skeletal homeostasis and represent a new genetic cause of HBM.


Assuntos
Doenças Genéticas Inatas/genética , Mutação de Sentido Incorreto , Osteopetrose/genética , Transdução de Sinais/genética , Fator de Transcrição RelA/genética , Adulto , Substituição de Aminoácidos , Feminino , Doenças Genéticas Inatas/diagnóstico por imagem , Doenças Genéticas Inatas/metabolismo , Humanos , Recém-Nascido , Masculino , Osteopetrose/diagnóstico por imagem , Osteopetrose/metabolismo , Radiografia , Fator de Transcrição RelA/metabolismo
18.
Bone ; 75: 229-39, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25731960

RESUMO

Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) within the gene TNSALP that encodes the "tissue-nonspecific" isoenzyme of alkaline phosphatase (TNSALP). In HPP, inorganic pyrophosphate, an inhibitor of mineralization and substrate for TNSALP, accumulates extracellularly often leading to rickets or osteomalacia and tooth loss, and sometimes to craniosynostosis and calcium crystal arthropathies. HPP's remarkably broad-ranging expressivity spans stillbirth from profound skeletal hypomineralization to adult-onset dental problems or arthropathies without bone disease, which is largely explained by autosomal recessive versus autosomal dominant transmission from among several hundred, usually missense, TNSALP mutations. For clinical purposes, this expressivity has been codified according to absence or presence of skeletal disease and then patient age at presentation and diagnosis. Pediatric patients are reported principally with "odonto", "childhood", "infantile", or "perinatal" HPP. However, this nosology has not been tested using a cohort of patients, and the ranges of the clinical and laboratory findings have not been defined and contrasted among these patient groups. To evaluate the extant nosology for HPP in children, we assessed our 25 years experience with 173 pediatric HPP patients. Data were exclusively from inpatient studies. The childhood form of HPP was further designated "mild" or "severe". Here, we focused on demographic, clinical, and dual-energy X-ray absorptiometry parameters compared to data from healthy American children. The 173-patient cohort comprised 64 individuals with odonto HPP, 38 with mild childhood HPP, 58 with severe childhood HPP, and 13 with infantile HPP. None was a survivor of perinatal HPP. TNSALP analysis revealed a mutation(s) in all 105 probands tested. Thirteen mutations were unique. Most patients represented autosomal dominant inheritance of HPP. Mutant allele dosage generally indicated the disorder's severity. Gender discordance was found for severe childhood HPP; 42 boys versus 16 girls (p=0.006), perhaps reflecting parental concern about stature and strength. Key disease parameters (e.g., height, weight, numbers of teeth lost prematurely, grip strength, spine and hip bone mineral density) were increasingly compromised as HPP was designated more severe. Although data overlapped successively between the four patient groups, body size (height and weight) differed significantly. Thus, our expanded nosology for HPP in children organizes the disorder's broad-ranging expressivity and should improve understanding of HPP presentation, natural history, complications, and prognosis.


Assuntos
Hipofosfatasia , Adolescente , Fosfatase Alcalina/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Hipofosfatasia/epidemiologia , Hipofosfatasia/genética , Hipofosfatasia/fisiopatologia , Lactente , Masculino , Mutação , Adulto Jovem
20.
J Bone Miner Res ; 30(4): 606-14, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25363158

RESUMO

Lenz-Majewski hyperostotic dwarfism (LMHD) is an ultra-rare Mendelian craniotubular dysostosis that causes skeletal dysmorphism and widely distributed osteosclerosis. Biochemical and histopathological characterization of the bone disease is incomplete and nonexistent, respectively. In 2014, a publication concerning five unrelated patients with LMHD disclosed that all carried one of three heterozygous missense mutations in PTDSS1 encoding phosphatidylserine synthase 1 (PSS1). PSS1 promotes the biosynthesis of phosphatidylserine (PTDS), which is a functional constituent of lipid bilayers. In vitro, these PTDSS1 mutations were gain-of-function and increased PTDS production. Notably, PTDS binds calcium within matrix vesicles to engender hydroxyapatite crystal formation, and may enhance mesenchymal stem cell differentiation leading to osteogenesis. We report an infant girl with LMHD and a novel heterozygous missense mutation (c.829T>C, p.Trp277Arg) within PTDSS1. Bone turnover markers suggested that her osteosclerosis resulted from accelerated formation with an unremarkable rate of resorption. Urinary amino acid quantitation revealed a greater than sixfold elevation of phosphoserine. Our findings affirm that PTDSS1 defects cause LMHD and support enhanced biosynthesis of PTDS in the pathogenesis of LMHD.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Deficiência Intelectual/genética , Mutação , Transferases de Grupos Nitrogenados/genética , Fosfosserina/urina , Anormalidades Múltiplas/diagnóstico por imagem , Sequência de Aminoácidos , Aminoácidos/urina , Animais , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Osso e Ossos/metabolismo , Osso e Ossos/fisiopatologia , Feminino , Homeostase , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Dados de Sequência Molecular , Transferases de Grupos Nitrogenados/química , Radiografia , Homologia de Sequência de Aminoácidos
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