Hypophosphatasia: Misleading In Utero Presentation for Childhood and Odonto Forms William H. McAlister1, Deborah Wenkert2, Jeffery H. Hersh3, Steven Mumm4, Michael P. Whyte2,4 1Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA; 2Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children, St. Louis, MO, USA 3Weisskopf Center for the Evaluation of Children-Department of Pediatrics, University of Louisville, Louisville, KY, USA 4Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, USA Family 1 Family 2 Family 3 Family 4 Family 5 Family 6 Family 7 Family 8 Patient 4 at 4 months: Patient 5 at 12 months: Patient 6 at 6 years Patient 7: The left tibia in utero Patient 8: In utero (19 weeks) bowing and angulation of the tibia There is mild right femoral There is mild right femoral 8 months: There is mild at 31 weeks had angulation and radius improved on postnatal imaging. Bowdler spurs are bowing. bowing. right femoral bowing. that improved at birth. present. tibia radius II-5 at Birth II-5 at 3 ½ years III-2 at termination The arrows show IV-3 dimples overlying IV-3 areas of in utero bowing III-2 IV-3 II-5 at 3 ½ years II-5 II-6 Family 1 Family 2 Family 3 Proband Mother Father Proband Mother Father Proband Mother Father ALP (IU/L) 102 43 75 80 44 75 40 43 48 IV-3 Alkaline Phosphatase NL: 130-350 NL: 50-130 NL: 50-130 NL: 110-130 NL: 50-130 NL: 50-130 NL: 110-320 NL: 50-130 NL: 50-130 PPI (nmol/gCr) 379 323 120 491 33 122 2048 89 116 Inorganic Pyrophosphate NL: 0-198 NL: 0-115 NL: 0-115 NL: 0-198 NL: 0-115 NL: 0-115 NL: 0-198 NL: 0-115 NL: 0-115 On referral, he was consuming dietary calcium close to the RDA. the exact mutations does not, at this time, seem to be helpful for PLP (nM) 129 976 2104 191 86 235 1377 71 43 Over the next 3½ years, additional difficulties included significant Physical exam (figure) showed dimples overlying his lateral prenatal prognostication except, perhaps, in Japanese patients (3). Conclusions References Pyridoxal 5’-phosphate NL: 5-107 NL: 5-107 NL: 5-107 NL: 5-107 NL: 5-107 NL: 5-107 NL: 5-107 NL: 5-107 NL: 5-107 gastroesophageal reflux and failure to thrive responding to a Nissen forearms and thighs, slight gray sclera; rib flaring, knock-knees, 5º fundoplication with feeding tube. He had bilateral cataracts, flexion contractures of knees and elbows, a wobbly walk and mild None of the individuals tested were taking vitamins or Lowering of dietary calcium and initiation of hydrochloro- strabismus, esotropia, and developmental and speech delay. pelvic girdle muscle weakness. Notably, one of the children (family 2) presenting with this severe 1. Cai G, Michigami T, Yamamoto T, Yasui N, Satomura K, Introduction skeletal dysplasia who had an AD HPP, has a younger brother also •Over the past 5 years, 55 new HPP III-3 at 1 8/12 years III-3 at 1 8/12 years pharmaceuticals known to affect vitamin B6 metabolism. thiazide was followed by 4 episodes of passing multiple kidney Primary teeth were first lost at age 10 months. At age 3 9/12 years patients have been referred to us, 8 of Yamagata M, Shima M, Nakajima S, Mushiake S, Okada S, stones and complete resolution of bilateral calculi on upon referral, he consumed 700 mg calcium daily using Pediasure with the same mutation who did not have in utero difficulties noted Ozono K (1998) Analysis of localization of mutated tissue- subsequent renal ultrasounds. (RDA for age: 500 mg). Laboratory results were remarkable for a low ALP and mild on ultrasound. We follow 14 other HPP patients with the same whom were interpreted as having in nonspecific alkaline phosphatase proteins associated with Hypophosphatasia (HPP) is a heritable form of Molecular studies were performed with leukocyte DNA. hypercalciuria. TNSALP mutation inherited from their mother who have not utero severe skeletal dysplasias and neonatal hypophosphatasia using green fluorescent protein rickets/osteomalacia featuring remarkably variable severity. presented in the perinatal or infantile period nor had dimples on abortions were discussed with parents, chimeras. J Clin Endocrinol Metab 83: 3936–3942 Historically, classification into perinatal, infantile, childhood, adult, Gross motor skills were delayed, physical therapy was Family history was remarkable for HPP in a younger brother with exam. In this particular child, there was also oligohydramnios and Abstract and odonto HPP is based on the patient’s age at presentation instituted, and he walked at age 17-18 months. Tooth loss at normal prenatal ultrasounds and few medical difficulties (II-6). Radiographs (see above) revealed long bone bowing, congenital his in utero bowing may have been compounded by fetal packing. yet all 8 had a non-lethal postnatal form 2. Comstock C, Bronsteen R, Lee W, Vettraino I (2005) Mild dislocation of the radial heads at the elbow with radial ulnar and the presence or absence of skeletal disease. FAMILY 1 14 months of age with the root intact, intermittent esotropia, This represents yet another factor which should be taken into of HPP with mild to moderate skeletal hypophosphatasia in utero: bent bones in a family with dental and very mild hyperopia were his only other health concerns. fusions, and characteristic tongues of radiolucency consistent with account for evaluating in utero bowing in HPP. changes. disease. J Ultrasound Med 24: 707-709 Physical exam (figure) revealed a short, microcephalic boy (height Z childhood or infantile HPP. In 1999, 2 separate reports described a total of 5 patients with in Family history included childhood HPP in a maternal uncle and = -3.35, weight Z = -2.39, head circumference < 5th percentile) with 3. Michigami, T, Uchihashi T, Suzuki A, Tachikawa K, Nakajima Hypophosphatasia (HPP) is a rare, heritable By age 3 years, long bone bowing had III-2: A 29-year-old Caucasian woman (5’4”) with a history of spontaneously improved. Developmental utero bowing from HPP but with a relatively benign post-natal his children. The father, 5’9”, had a history of hypertension, flattening of the back of his head. He had bilateral hazy cataracts, Of the “Bent but not broken” patients encountered so far, 10 •21 such cases are now documented. S, Ozono K Toshima (2005) Common mutations F310L and rickets/osteomalacia featuring deficient course, rather than typically lethal “perinatal” disease (4,7). In childhood HPP (premature loss of deciduous teeth, delay in hyperuricemia, and kidney stones. occasional esotropia, and a 1.7 cm leg and 0.3 cm foot length Molecular studies showed G to A mutation at nucleotide 526 appear to be of AD inheritance and 9 of AR inheritance. The T1559del in the tissue-specific alkaline phosphatase gene activity of the “tissue nonspecific” delay, failure to thrive, and cataracts were subsequent publications, 4 more fetuses (2,3,5,6) were reported gross motor skills, waddling gait, radiographic abnormalities, low discrepancy. Strength appeared slightly diminished. Skin revealed leading to A159T substitution and an A to C mutation at nucleotide inheritance of two patients are not reported. Since a severe are related to distinct phenotypes in Japanese patients with isoenzyme of alkaline phosphatase unexplained. Radiographs showed no in whom long bone bowing, without severe hypomineralization, ALP, elevated serum phosphate and elevated 881 leading to a D277A substitution. perinatal lethal course of postnatal HPP has not been reported for Physical examination (figure) at age 19 months revealed dimples on lateral legs, his right thigh, and forearms. •Spontaneous improvement in the hypophosphatasia. Eur J Pediatr 164: 277-282. (TNSALP) from deactivating mutation of rickets (“Odonto-HPP”). The subsequent was documented in utero (“benign prenatal” HPP, aka “Bent but phosphoethanolamine) had frequent metatarsal fractures as an AD disease, a prenatal identification of only one TNSALP mutation skeletal findings of bowing and not Broken”), and 4 subsequent patients (8, 3) with ‘benign adult. She had one healthy child. At 18-19 weeks, fetal weight (10%), length (25%), arm span 72.3 cm, head may also help clinicians recognize some of these patients. 4. Moore CA, Curry CJR, Henthorn PS, Smith JA, Smith JC, the TNSALP gene. We warn that skeletal pregnancy, w/o oligohydramnios, showed prenatal’ HPP for whom no comments were made about prenatal ultrasound of her subsequent pregnancy revealed slight bowing circumference (25%). He had blue-tinged sclerae and was There was low ALP, hypercalcemia, hypercalciuria, and angulation, spurs, dimples, and O’Lague P, Coburn SP, Weaver DD, Whyte MP(1999) Mild deformity in utero may not imply a severe no u/s abnormalities. The patient, mother, ultrasounds. and significant shortening of all four extremities. The head and missing two bottom incisors. He had a 1-1.5 cm hairy nevus hyperphosphatemia. Renal ultrasound: normal. Radiographs hypomineralization can occur in the autosomal dominant hypophosphatasia: in utero presentation outcome. Patients assessed with severe and sibling each carried a single TNSALP thorax were normal in size. Amniocentesis revealed normal on his right aspect of his back and increased pigmentation (above): deformity of all major limb bones in the perinatal period, In the previous reports of mild HPP presenting with concern for third trimester when placental alkaline in two families. Am J Med Genet 86: 410–415 male karyotype. A follow-up ultrasound revealed significant overlying his midface from mid-forehead down to the tip of his Discussion lethal skeletal dysplasia in utero, chest size (where reported), was skeletal findings on fetal ultrasound (u/s) mutation (G188T; Gly46Val).