: 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 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 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 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 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 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. . TNSALP mutation inherited from their mother who have not utero severe skeletal dysplasias and neonatal hypophosphatasia using green fluorescent protein / 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 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). thought, in retrospect, to be partially attributable to fetal packing. Discussion phosphatase enzyme appears in the from 3 separate families were referred Two of these articles (4,7) describe a severe in utero demineralization of the fetal spine and little change in the nose. Ridging could be felt under this area as well as leading There were no skull, chest or spinal abnormalities. Current found to be normal on the prenatal ultrasounds, and bone 5. Oestreich AE, Bofinger MK (1989) Prominent transverse Family 3: Fetal u/s of a boy with C-HPP presentation (5 patients) in whom there was spontaneous extremities. back towards the top of his forehead. He had palpable radiographs show small epiphyses at the knees with minimal was only mildly decreased. Thus, a careful evaluation maternal circulation and accumulated (Bowdler) bone spurs as a diagnostic clue in a case of with mild ex utero. Abortion improvement in bowing during the third trimester or after birth. metopic and coronal ridges bilaterally and premature closure metaphyseal sclerosis and long bone bowing. Historically, HPP patients diagnosed at birth with clinically apparent of chest size on prenatal ultrasound for prognosticating may be TNSALP sub-strates in the mother fall to neonatal hypophosphatasia without metaphyseal irregularity. had been discussed for each. These 3 boys, showed in utero bowing and dwarfism. He The maternal serum ALP activity has been reported in 7 of these of his anterior fontanel. Dimples overlay his ulnas bilaterally. disease were classified as having the perinatal form of the disease helpful. undetectable levels. Pediatr Radiol 19: 341–342 had 2 TNSALP mutations (G526A; 9 cases, including in the original 5, and was found to be low in Perinatal (lethal) HPP was presumed. The fetus was aborted at He had thick appearing wrists and ankles, as well as which originally seemed uniformly lethal. Patients with true described below, and 13 previously 6. Ozono K, Yamagata M, Michigami T, Nakajima S, Sakai N, reported cases distinguish “benign prenatal Ala159Thr and A881C; Asp277Ala). In each each case. 22 weeks. Genetic analysis elsewhere of TNSALP was shortened thumbs with a slight curvature of his fingers. He TNSALP mutational analysis revealed a G to T mutation at perinatal (lethal) HPP have a compromised chest size and typically reportedly normal after abortion. Post-delivery radiographs had full range of motion throughout with hypermobility, but no nucleotide 188 resulting in a Gly46Val substitution in the patient, his succumb to pulmonary disease soon after delivery. Now, Here, we report one benign prenatal HPP patient (family 1) who •This relatively benign form of HPP is Cai G, Satomura K, Yasui N, Okada S, Nakayama M (1996) HPP” (BP-HPP) from “perinatal” HPP, a of these BP-HPP families, with either revealed profound skeletal hypomineralization (see above) with significant bowing. Deep tendon reflexes were difficult to elicit, younger brother, and their mother. His father carried no mutation. classification and prenatal assessment of HPP must take into had significantly diminished bone mineralization by prenatal Identification of novel missense mutations (Phe310Leu and typically lethal, autosomal recessive form autosomal dominant or recessive To provide additional insight concerning the etiology and fractures and deformity, tongues of radiolucency in the and he had 2 beat ankle clonus bilaterally. account the possibility of a severe in utero expression of HPP with ultrasound. associated with a carrier state in the Gly439Arg) in a neonatal case of hypophosphatasia. J Clin of HPP which also manifests in utero. The 3 inheritance, mothers carried a TNSALP pathogenesis of this new form of relatively benign perinatal HPP, metaphyses of long bones, and seemingly missing vertebrae a mild clinical and skeletal course after delivery. mother and can be autosomal Endocrinol Metab 81: 4458–4461 mutation. The BP-HPP skeleton seems to we describe 3 additional patients with either mild autosomal interpreted as pathognomonic of severe HPP. However, from dominant or autosomal recessive HPP. mothers carry different TNSALP missense dominant (AD) or recessive HPP, who were assessed as having samples submitted to us after the fetus was aborted, we found Labs were remarkable for low ALP, hypercalciuria, but with Bony angulation on prenatal ultrasound improved during the third 7. Pauli RM, Modaff P Sipes SL, Whyte MP (1999) Mild mutations. At birth, each boy had mild limb improve during the 3rd trimester of severe skeletal dysplasia in utero. In one family, this in utero one structural TNSALP mutation (A1133T, Asp361Val) in the normal phosphate. Radiographs (above) revealed mild FAMILY 3 The 3 cases presented here, as well as the 13 previously trimester for 2 patients (family 1 and 2) as reported previously for hypophosphatasia mimicking severe bowing and shortening and then pregnancy. presentation was accompanied by significant hypomineralization fetus and the mother. The father carried no mutation. sclerosis of metaphyses with few small tongues of A 2-2/12 year old Caucasian boy (II-3) was a 5 lb 9 oz, 35-week boy published, and our 5 additional patients, cumulatively represent one other patient (7) and bone mineralization improved as well •A single TNSALP mutation in the fetus in utero: bent but not broken. Am J Med Genet 86: 434–438 manifested delayed walking and early in the 2 affected fetuses. This led to the elective abortion of one radiolucency and a long ulna and a gibbus with a hook-shaped born to a 25-year-old G3P0-1A2 whose previous pregnancies had children who had disease that was severe enough to manifest (family 1). Bone changes also improved for Family 7 and 8 between the in utero and postnatal imaging. suggests a mild postnatal course. 8. Uras I, Uras N, Karadag A, Yavuz OY, Atalar H (2005) tooth loss. Thus, BP-HPP must be considered when fetus with AD HPP (sibling to one of these patients). Elsewhere, vertebra. Skull radiographs showed no suture fusion. been lost at 6-11 weeks gestation. Seven prenatal ultrasounds in utero yet had a comparatively mild presentation at birth (bowing, Bilateral transverse (Bowdler) fibular spurs with physician recommendations were given for abortions in 2 more of III-3: The product of this couple’s third pregnancy was Mutational analysis revealed a single TNSALP mutation starting at 19 weeks gestation showed in utero bowing and dwarfism. skin dimples, radial-ulnar fusion and gastroesophageal reflux). prenatal u/s shows fractures or bowing. evaluated at age 19 months for HPP. Chorionic villus sampling hypophosphatasia in an adolescent girl. Korean J Radiol 6: these patients. identical to that found in his mother and the aborted fetus. His family was counseled concerning possible termination of the Because of the increased use of prenatal ultrasounds, some •A normal chest size suggests a mild 52-54 Family 1: Fetal u/s of 2 pregnancies to a Analysis of fetal or parental TNSALP would tested elsewhere at 11 weeks gestation for chromosomal children with fairly mild HPP are being identified prior to birth. In Of interest, in at least 19 of the 21 cases encountered so far of pregnancy. Premature labor and delivery was complicated by fetal “mild prenatal HPP”, the mother seemed to be carrying a TNSALP postnatal course. mother with “childhood” HPP (C-HPP) identify possible BP-HPP. A single mutation abnormalities was normal. A 15-week prenatal ultrasound distress. Concerns regarding his skeletal abnormalities led to C- the pre-ultrasound era, the presence of dimples may have signified 9. Whyte MP, Landt M, Ryan LM, Mulivor RA, Henthorn PS, in the fetus or only 1 parent would suggest In each of these 3 new cases, each patient’s mother carried a showed bowing of his femurs. 9 subsequent ultrasounds were in utero presentation. gene mutation. In the 2 remaining cases, the mother’s biochemical showed severe “skeletal bowing” and section delivery. Skeletal survey at birth showed mid-diaphyseal and genetic status are not reported. Accordingly, perhaps a Fedde KN, Mahuren JD, Coburn SP (1995) Alkaline this outcome. With two TNSALP mutations, deactivating TNSALP mutation implicating the intra uterine interpreted as consistent with a lethal skeletal dysplasia; bowing in femurs, humerus, radius, and ulna with sclerosis Phosphatase: Placental and Tissue-nonspecific Isoenzymes demineralization. The 1st was terminated. environment as intensifying the skeletal manifestations of HPP. however, his parents felt that the skeletal mineralization was FAMILY 2 combination of a TNSALP defect and the associated metabolic normal chest size, adequate skull interpreted as skeletal dysplasia of unknown type. Karyotyping and disturbances in the mother as well as the baby help explain the Hydrolyze Phosphoethanolamine, Inorganic Pyrophosphate, The 2nd produced a boy with C-HPP. He, his better than in the previously aborted fetus. A second opinion A 3-9/12 year old Caucasian boy (II-5) was 3 lbs 14 oz at birth. testing for hypochondroplasia (FGF-R3) were normal. He was felt to Moderate-to-severe long bone bowing in utero can be due to and Pyridoxal 5’-Phosphate Substrate Accummulation in mother, and the aborted fetus each carried mineralization, or presence of in utero deemed his skeletal dysplasia was not necessarily lethal. He Induction was at 38 weeks for a 27 year old G4P3-4A0 whose several other disorders with poor outcomes including osteogenesis degree of skeletal disturbance seen early on in utero that appears have a short-limbed dwarfism. Dimples on the lateral aspects of both to heal during the third trimester and after birth. This spontaneous Carriers of Hypophosphatasia Corrects during Pregnancy. J a single TNSALP mutation (A1133T; packing may help distinguish BP-HPP from Materials and Methods was a 37-week, 6 lb 8 oz boy delivered by repeat C-section (to pregnancy was complicated by gestational , thighs were noted at 15-months of age. imperfecta (type II and III), thanatophoric dysplasia, campomelic Clin Invest 95:1440-1445 Asp361Val). severe perinatal, but not infantile, forms of avoid fracturing in baby). At birth, there was slight bowing and hypertension, and oligohydramnios. Probable fractures of a dysplasia, et cetera. improvement corresponds to the timing of serum ALP increases HPP. shortening of arms, legs, and thumbs with dimples overlying his humerus, radius, femurs and tibiae on prenatal ultrasounds occurring in the last trimester of pregnancy when placental ALP 10.Coburn SP, Mahuren JD. 1983. A versatile cation-exchange Quantitation of a natural substrate of TNSALP that accumulates arms bilaterally. Radiographs were consistent with some were interpreted as osteogenesis imperfecta. After he lost his first tooth at 15-months of age, serum ALP was isoenzymes appear in the maternal circulation. During this time in procedure for measuring the seven major forms of vitamin B6 Family 2: Fetal u/s showed endogenously in plasma in HPP, pyridoxal 5’-phosphate (PLP), angulation of femurs and ulnas bilaterally with apparent new found to be low and he was diagnosed with HPP. His development The 3 cases presented here, as well as additional patients for the mother, accumulated TNSALP substrates essentially plummet in biological samples. Anal Biochem 129:310-317 oligohydramnios, small size, and “extremity We have since studied 5 additional cases of was determined by cation-exchange, high-performance, liquid bone formation, without fractures. Early infancy was was remarkable only for a delay in walking (19 months). whom genetic analysis is complete, reflect both AD and AR to undetectable levels in maternal blood and . However, it is fractures” interpreted as OI. BP-HPP who postnatally had mild to chromatography (Coburn and Mahuren, 1983) using plasma complicated by reflux treated from 1 to 4 months of age with At birth, congenital bowing, a leg length discrepancy, and inheritance for different mutation(s) of the TNSALP gene, and are not known if fetal levels are affected by placental TNSALP. Other 11.Aylsworth AS, Mornet E, Cardenas L, Taillandier A, Roche moderate HPP. Some radiographs and specimens obtained after an 8-hour fast. cereal thickened breast milk as well as Zantac and Reglan dimples overlying lateral forearms, right thigh and left leg, different from those mutations already published in the literature for factors that condition may be playing a role in the in MI, Wright JT, (2001) “Benign prenatal” hypophosphatasia: followed by Prevacid and Mylanta. Hematuria and dysuria were noted, and reported briefly elsewhere (11). mild clinical disease after in utero presentation. Thus, knowing utero expression of the disease. Further evidence for a dominant-negative mechanism and sonograms of these 5 patients are shown. signaled bilateral renal calculi and hydronephrosis. possible maternal effects. Smith Workshop 2001: 162-163.