Katherine L Madson

Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy.

Generalized arterial calcification (AC) of infancy (GACI) is an autosomal recessive disorder that features hydroxyapatite deposition within arterial elastic fibers. Untreated, approximately 85% of GACI patients die by 6 months of age from cardiac ischemia and congestive heart failure. The first‐generation bisphosphonate etidronate (EHDP; ethane‐1‐hydroxy‐1,1‐diphosphonic acid, also known as 1‐hydroxyethylidene‐bisphosphonate) inhibits bone resorption and can mimic endogenous inorganic pyrophosphate by blocking mineralization. With EHDP therapy for GACI, AC may resolve without recurrence upon treatment cessation. Skeletal disease is not an early characteristic of GACI, but rickets can appear from acquired hypophosphatemia or prolonged EHDP therapy. We report a 7‐year‐old boy with GACI referred for profound, acquired, skeletal disease. AC was gone after 5 months of EHDP therapy during infancy, but GACI‐related joint calcifications progressed. He was receiving EHDP, 200 mg/day orally, and had odynodysphagia, diffuse opioid‐controlled pain, plagiocephaly, facial dysmorphism, joint calcifications, contractures, and was wheelchair bound. Biochemical parameters of mineral homeostasis were essentially normal. Serum osteocalcin was low and the brain isoform of creatine kinase and tartrate‐resistant acid phosphatase 5b (TRAP‐5b) were elevated as in osteopetrosis. Skeletal radiographic findings resembled pediatric hypophosphatasia with pancranial synostosis, long‐bone bowing, widened physes, as well as metaphyseal osteosclerosis, cupping and fraying, and “tongues” of radiolucency. Radiographic features of osteopetrosis included osteosclerosis and femoral Erlenmeyer flask deformity. After stopping EHDP, he improved rapidly, including remarkable skeletal healing and decreased joint calcifications. Profound, but rapidly reversible, inhibition of skeletal mineralization with paradoxical calcifications near joints can occur in GACI from protracted EHDP therapy. Although EHDP treatment is lifesaving in GACI, surveillance for toxicity is crucial.

Asfotase alfa therapy for children with hypophosphatasia

Background. Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Consequently, cell-surface deficiency of TNSALP phosphohydrolase activity leads to extracellular accumulation of inorganic pyrophosphate, a natural substrate of TNSALP and inhibitor of mineralization. Children with HPP can manifest rickets, skeletal pain, deformity, fracture, muscle weakness, and premature deciduous tooth loss. Asfotase alfa is a recombinant, bone-targeted, human TNSALP injected s.c. to treat HPP. In 2012, we detailed the 1-year efficacy of asfotase alfa therapy for the life-threatening perinatal and infantile forms of HPP. Methods. Here, we evaluated the efficacy and safety of asfotase alfa treatment administered to children 6-12 years of age at baseline who were substantially impaired by HPP. Two radiographic scales quantitated HPP skeletal disease, including comparisons to serial radiographs from similarly affected historical control patients. Results. Twelve children receiving treatment were studied for 5 years. The 6-month primary endpoint was met, showing significant radiographic improvement. Additional significant improvements included patient growth, strength, motor function, agility, and quality of life, which for most patients meant achieving normal values for age- and sex-matched peers that were sustained at 5 years of treatment. For most, pain and disability resolved. Mild to moderate injection-site reactions were common and were sometimes associated with lipohypertrophy. Low anti-asfotase alfa antibody titers were noted in all patients. No evidence emerged for clinically important ectopic calcification or treatment resistance. Conclusions. Asfotase alfa enzyme replacement therapy has substantial and sustained efficacy with a good safety profile for children suffering from HPP. Trial Registration. ClinicalTrials.gov NCT00952484 (https://clinicaltrials.gov/ct2/show/NCT00952484) and NCT01203826 (https://clinicaltrials.gov/ct2/show/NCT01203826). Funding. Alexion Pharmaceuticals Inc. and Shriners Hospitals for Children.

Multicentric carpotarsal osteolysis syndrome is caused by only a few domain-specific mutations in MAFB, a negative regulator of RANKL-induced osteoclastogenesis

Multicentric carpotarsal osteolysis syndrome (MCTO), an autosomal dominant disorder that often presents sporadically, features carpal–tarsal lysis frequently followed by nephropathy and renal failure. In 2012, mutations in the single‐exon gene MAFB were reported in 13 probands with MCTO. MAFB is a negative regulator of RANKL‐mediated osteoclastogenesis. We studied nine MCTO patients (seven sporadic patients and one affected mother and son) for MAFB mutation. We PCR‐amplified and selectively sequenced the MAFB region that contains the transactivation domain in this 323 amino acid protein, where mutations were previously reported for MCTO. We found five different heterozygous missense defects among eight probands: c.176C > T, p.Pro59Leu; c.185C > T, p.Thr62Ile; c.206C > T, p.Ser69Leu (four had this defect); c.209C > T, p.Ser70Leu; and c.211C > T, p.Pro71Ser. All 5 mutations are within a 13 amino acid stretch of the transactivation domain. Four were identical to the previously reported mutations. Our unique mutation (c.185C > T, p.Thr62Ile) involved the same domain. DNA available from seven parents of the seven sporadic patients did not show their childs MAFB mutation. The affected mother and son had an identical defect. Hence, the mutations for 7/8 probands were suspected to have arisen spontaneously as there was no history of features of MCTO in either parent. Penetrance of MCTO seemed complete. Lack of nonsense or other truncating mutations suggested a dominant‐negative pathogenesis. Our findings indicate that only a few transactivation domain‐specific mutations within MAFB cause MCTO.

Rapid Skeletal Turnover in a Radiographic Mimic of Osteopetrosis

Among the high bone mass disorders, the osteopetroses reflect osteoclast failure that prevents skeletal resorption and turnover, leading to reduced bone growth and modeling and characteristic histopathological and radiographic findings. We report an 11‐year‐old boy with a new syndrome that radiographically mimics osteopetrosis (OPT), but features rapid skeletal turnover. He presented at age 21 months with a parasellar, osteoclast‐rich giant cell granuloma. Radiographs showed a dense skull, generalized osteosclerosis and cortical thickening, medullary cavity narrowing, and diminished modeling of tubular bones. His serum alkaline phosphatase was >5000 IU/L (normal <850 IU/L). After partial resection, the granuloma re‐grew but then regressed and stabilized during 3 years of uncomplicated pamidronate treatment. His hyperphosphatasemia transiently diminished, but all bone turnover markers, especially those of apposition, remained elevated. Two years after pamidronate therapy stopped, bone mineral density (BMD) Z‐scores reached +9.1 and +5.8 in the lumbar spine and hip, respectively, and iliac crest histopathology confirmed rapid bone remodeling. Serum multiplex biomarker profiling was striking for low sclerostin. Mutation analysis was negative for activation of lipoprotein receptor‐related protein 4 (LRP4), LRP5, or TGFβ1, and for defective sclerostin (SOST), osteoprotegerin (OPG), RANKL, RANK, SQSTM1, or sFRP1. Microarray showed no notable copy number variation. Studies of his nonconsanguineous parents were unremarkable. The etiology and pathogenesis of this unique syndrome are unknown.

PHEX 3′‐UTR c.*231A>G Near The Polyadenylation Signal Is a Relatively Common, Mild, American Mutation That Masquerades as Sporadic or X‐Linked Recessive Hypophosphatemic Rickets

Heritable forms of hypophosphatemic rickets (HR) include X‐linked dominant (XLH), autosomal recessive, and autosomal dominant HR (from deactivating mutations in PHEX, DMP1 or ENPP1, and activating mutations in FGF23, respectively). Over 30 years, we have cared for 284 children with HR. For those 72 deemed sporadic XLH, we preliminarily reported mutation analysis for 30 subjects. Eleven had PHEX mutations. However, the remaining 19 lacked readily identifiable defects in PHEX, DMP1, or FGF23. In 2008, a novel single‐base change near the polyadenylation (pA) signal in the 3′‐UTR of PHEX was identified in XLH by other investigators. This c.*231A > G mutation is 3‐bp upstream of the putative pA signal (AATAAA) in PHEX. Accordingly, we investigated whether this 3′‐UTR defect accounted for HR in any of these 19 sporadic XLH patients. PCR amplification and sequencing of their 3′‐UTR region showed the c.*231A > G mutation in four unrelated boys. Then, among an additional 22 of our 72 “sporadic” XLH patients, one boy and one girl were found to have the 3′‐UTR defect, totaling six patients. Among these 52 sporadic XLH patients with PHEX analysis, 36 were girls and 16 were boys; ie, a ∼2:1 gender ratio consistent with XLH. However, finding five boys and only one girl with this 3′‐UTR mutation presented an unexplained gender bias (p = 0.02). Haplotyping for the five boys, all reportedly unrelated, showed a common core haplotype suggesting a founder. Five of their six mothers had been studied clinically and biochemically (three radiologically). Remarkably, the seemingly unaffected mothers of four of these boys carried the 3′‐UTR mutation. These healthy women had normal height, straight limbs, lacked the radiographic presentation of XLH, and showed normal or slight decreases in fasting serum Pi levels and/or TmP/GFR. Hence, PHEX c.*231A > G can masquerade as sporadic or X‐linked recessive HR.

Auricular ossification: A newly recognized feature of osteoprotegerin-deficiency juvenile Paget disease.

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.

Response to: A Rapid Skeletal Turnover in Radiographic Mimic of Osteopetrosis Might Be Secondary to Systemic Mastocytosis: Response to: Rapid Skeletal Turnover in Radiographic

Michael P Whyte, Katherine L Madson, William H McAlister, Steven Mumm, Deborah V Novack, Jo C Blair, and Nicholas J Shaw Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO, USA Division of Bone and Mineral Diseases, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO, USA Department of Pediatric Radiology, Mallinckrodt Institute of Radiology at St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, USA Department of Pathology, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO, USA Department of Endocrinology, Alder Hey Children’s National Health Service Foundation Trust, Liverpool, UK Department of Endocrinology and Diabetes, Birmingham Children’s Hospital, Birmingham, UK