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Childhood Hypophosphatasia with Myopathy: Clinical Report with Recent Update

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Childhood Hypophosphatasia with Myopathy: Clinical Report with Recent Update CASO CLÍNICO Childhood hypophosphatasia with myopathy: clinical report with recent update Silva I 1, Castelão W 1, Mateus M 1, Branco JC 2,1 ACTA REUMATOL PORT. 2012;37:92-96 AbstrAct chondrocytes, osteoblasts and odontoblasts, and then followed by the propagation of the hydroxyapatite into Hypophosphatasia is a rare genetic disease with low tis - the extracellular matrix and between collagen fibrils) 1. sue nonspeficic alkaline phosphatase activity Inorganic pyrophosphate (PPi) inhibits hydroxyapatite (TNSALP), due to ALPL gene mutation. There are 6 formation. Tissue-nonspecific alkaline phosphatase clinical forms. Childhood form is caractheri zed by short (TNSALP) hydrolyses PPi into phosphate (Pi), and this stature, premature loss of decidous teeth and diffuse ba lance is fundamental to the mineralization 1-3 . There bone pain associated with a pathological bone fracture are 4 isomeres of the alkaline phosphatase (AP): in the past. Laboratory findings present low serum le - TNSALP, intestinal, placenta and germ cell. All of them vel of alkaline phosphatase and high levels of serum are homodimeric ectoproteins anchored to the plasma and urinary extracelular metabolytes. It is described a membrane by a phosphatidylinositol glycan (PIG) moie - case report of a 34 years old woman with previous diag - ty. TNSALP clives PPi, pyridoxal-5-phosphate (PLP- an nosis of childhood hypophosphatasia, caryotype activated form of vitamin B 6) and phosphoetha - 46,XX, and molecular screening for the gene ALPL with nolamine (PEA) in its dimeric form at physiologic pH, a c.1426>A p.E476K mutation, who complained of and whose expression changes according to the age 2. proximal muscular weakness intensified with the cold Hyphosphatasia (HP) is a rare genetic disease caused weather, exercise, and a waddling gait. The elec - by a low activity of the TNSALP with defective bone tromyography was compatible with myopathy but the and teeth mineralization 4. Clinical expression varies muscle biopsy was normal. The serum crea tine kinase with the type of mutation and the age of diagnosis 1-4 . levels were normal, as well as the others muscle en - The incidence of the severe forms is estimated in zymes. Clinical and laboratory/ /imaging dissociation is 1/100000 (USA), but because its incomplete pene - frequent in other metabo lic bone diseases as osteoma - trance it is difficult to know the correct prevalence. lacia. The rarity of this case of childhood hypophos - ALPL , the gene encoding TNSALP, presents more than phatasia with “ de novo” non-progressive myopathy of 190 mutations, some of them target specific popula - the lower limbs, justified a case report with literature re - tions or regions 2,4 , and with a good genotype-pheno - vision. type correlation 2,5,6 . There are 6 clinical forms: perina - tal (lethal or benign), infantile, childhood, adult and Keywords: Hypophosphatasia; Myopathy; Alkaline odontohypophosphatasia (Table I) 1-4 . Phosphatase; Osteomalacia. The childhood form is characterised by low bone mineral density and unexplained fractures, premature loss of deciduous teeth (beginning with incisors), short IntroductIon stature and delay in walking, bone pain (bone oede - ma), joint pain (condrocalcinosis and osteoarthritis de - Biomineralization is a process by which hydroxyapatite velop with aging), pseu dofracture in the lateral cortex is deposited in the extracellular matrix (first within ma - of the femoral diaphysis (Looser zones), and sometimes trix vesicles that bud from the surface membrane of a waddling gait 2-4 . Specific diagnostic clues are shown in Table I, but screening for mutations in ALPL is es - sential to confirm the diagnosis 4. Childhood form does 1. Serviço de Reumatologia do Centro Hospitalar de Lisboa Ocidental, Hospital de Egas Moniz, EPE the differential diagnosis with rickets, osteogenesis 2. Faculdade de Ciências Médicas, Universidade Nova de Lisboa imper fecta, dentinogenesis imperfecta, cleidocranial ÓRgÃO OFICIAL dA SOCIEdAdE PORTUgUESA dE REUMATOLOgIA 92 Silva i e col. tAble I. clInIcAl feAtures of hypophosphAtAsIA Type Inheritance Clinical features Dental features Diagnosis Perinatal AR Hypomineralization and Radiographs, ultrasonography – (lethal) osteochondral spurs Perinatal AR or AD Bowing of the long bones, Ultrasonographyd, clinical – (benign) benign evolution evaluation Infantil AR Craniosynostosis, Premature Radiographs, laboratory findings hypomineralization, loss of the and clinical evaluation rachitic ribs, hypercalciuria deciduous teeth Childhood AR (frequent) Short stature, bone Premature loss 1. Radiographs: Bowdler spurs, or AD (rare) fractures/deformity, bone of the deciduous shortening of the long bones, low pain, waddling gait teeth (incisors) bone mineral density 2. Laboratory: low activiy of AP, serum and urinary elevation of PEA, PLP, PPi, normal phosphocalcium metabolism, normal parathormone and vitamin D levels 3. Bone biopsy: low mineralization of the cartilage, normal cells 4. Bone MRI: hyperemia and metaphyseal edema Adult AR or AD Stress fractures: metatarsal, Radiographs, laboratory findings – tibia; chondrocalcinosis and clinical evaluation Odontohypo- AR or AD Alveolar bone loss Dental caries Laboratory, clinical and dental phosphatasia evaluation Legend: AR= autosomal recessive; AD= autosomal dominant; AP= alkaline phosphatase; PEA = phophoethanolamine; PLP = pyridoxal-5-phosphate; PPi = inorganic pyrophosphate; MRI = magnetic resonance imaging. dysostosis, Cole-Carpenter syndrome, idiopatic juve - hour. Her complaints intensified with physical de - nil osteoporosis and renal osteodystrophy 2. Milder manding activities and with cold weather. She pre - forms of hypophosphatasia pose a pro blem for an ac - sented previous history of early delivery at 30 weeks, curate diagnosis 7. Symptomatic treatment is applied, growth retardation, dental caries, pathologic coccyx with orthopedic management 1-5,8 . Positive response to fracture and the diagnosis of childhood hypophos - teriparatide as been reported and enzyme replacement phatasia (caryo type 46,XX; autosomal recessive; mu - therapy (ERT) looks promi sing 7. tation c.1426G>A p.E476K heterozygote – Institut für It is presented a case report of hypophosphatasia Humangenetik, Universitatsklinikum Schleswig- with myopathy and a literature revision. -Hols tein, Kiel, Germany) when she was 20 years old. The physical examination revealed short stature (weight 48 Kg; height 140 cm) (Figure 1), shorte ning cAse report of the 4th metatarsals, mild (grade 4/5) proximal mus - cle weakness in the lower limbs with difficulty in get - A 34-year-old woman was referred to our clinic with di - ting off the floor and in climbing stairs and a waddling fuse bone pain and myalgias of the lower limbs and of gait. Deep tendon reflexes were normal and the mus - the pelvic girdle that lasted for 10 years. Two years be - cles were not tender. fore she started with mild proxi mal muscle weakness Serum AP showed low levels (28 U/L) without in her lower limbs and pelvic girdle, with difficulty in other abnormality in the muscle enzymes. Serum, uri - walking and inability to climb stairs. She also com - nary and immunologic analysis were normal (PPi, PLP plained of morning muscle stiffness for more than an and PEA were not performed). Radiologi cal examina - ÓRgÃO OFICIAL dA SOCIEdAdE PORTUgUESA dE REUMATOLOgIA 93 childhood hypophoSphataSia with Myopathy: clinical RepoRt with Recent Update fi gu re 3. Hip radiography with acetabular dysplasia fi gu re 1. Short stature (weight 48 Kg and height 140 cm) showed cortical osteoporosis (T-score: -2,5) and lum - bar vertebral magnetic resonance imaging was normal. The patient was diagnosed with myopathy associa - ted with metabolic bone diseases. She star ted on sympto matic treatment with vigilance of stress frac - tures, pseudofractures and dental care. The cortical os - teoporosis was treated with teriparatide. dIscussIon We describe a case report of a woman with the previ - ous diagnosis of childhood hypophosphatasia who complains of myalgias and severe diffuse bone pain of the lower limbs for 10 years . Symptons of “ de novo ” myopathy of the lower limbs and pelvic girdle began 2 years ago. The radiologic and biochemical findings were characteristic of hypo phosphatasia. The elec - fi gu re 2. Feet radiograph with short 4th metatarsals tromyography of the lower limbs showed myopathy, but the biopsy did not showed pathognomonic alte - rations. The bone densitometry study showed cortical tion showed widening of the bone structures in the osteoporosis. We explored the myopathy etiology in knee joint, shortening of the 4th metatarsals (Figure 2) this patient. Adults with myopathy usually present and acetabular dysplasia (Figure 3). Electromyogra - proximal and symmetric muscle weakness, myalgias phy of the lower limbs showed spontaneous fibrilla - at rest, exercise intolerance, serum elevation of creatine tions, polyphasic and low amplitude motor action po - kinase (CK) or myoglobinuria. The patient had typi - tentials. Muscle biopsy specimens of the left quadri - cal symptons of myopathy: weakness, myalgia and ceps were exa mined by light microscopy and histo - stiffness. Her symptons worsened with demanding chemistry, showing freezing artefacts, periferic metabolic exercises but sometimes persisted even in nucleus, type I muscular fibres predominance, with rest periods. normal dia meter. The image was not available by the First it was excluded non-neuromuscular episodic patholo gist and the patient refused
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