Prenatal diagnosis of osteopathia striata with cranial sclerosis Alexandre Vasiljevic1, Caroline Azzi2, Audrey Lacalm3, Daniele Combourieu2, Sophie Collardeau-Frachon1, Frédérique Dijoud1, Jerôme Massardier2, Wim Van Hul4, Caroline Fromageoux5, Laurent Guibaud2,3, Pascal Gaucherand2, Marie-Pierre Cordier2,6 and Mona Massoud2* 1
Laboratoire de Pathologie, Hôpital Femme Mère Enfant, Université Claude Bernard Lyon I, Lyon, France Centre Pluridisciplinaire de Diagnostic Prénatal, Hôpital Femme Mère Enfant, Lyon, France 3 Département d’imagerie Pédiatrique et Fœtale, Hôpital Femme Mère Enfant, Université Claude Bernard Lyon I, Lyon, France 4 Department of Medical Genetics, University of Antwerp, Antwerp, Belgium 5 Service d’Obstétrique, clinique de Guilherand-Granges, Guilherand-Granges, France 6 Service de Génétique, Hôpital Femme Mère Enfant, Université Claude Bernard Lyon I, Lyon, France *Correspondence to: Mona Massoud. E-mail: [email protected]
Funding sources: None Conﬂicts of interest: None declared
Osteopathia striata with cranial sclerosis (OS-CS) or Horan– Beighton syndrome is a rare X-linked dominant inherited bone dysplasia, characterized by longitudinal striations of long bones and cranial sclerosis. More than 100 patients have been described to date, with a prevalence of 0.1 per one million.1 All cases were diagnosed postnatally. The etiology of this disorder is related to a mutation in the gene Wilms tumor on the X chromosome (WTX) also known as FAM123B, an inhibitor of WNT signaling, associated with increased skeletal ossiﬁcation in mice and humans and other sclerosing bone dysplasias. Age at diagnosis and clinical presentation are variable, ranging from asymptomatic to neonatal lethal cases. The prenatal diagnosis of OS-CS is challenging because fetal clinical presentation is highly variable and mothers with OS-CS can be misdiagnosed. We report here the ﬁrst prenatal case of OS-CS with sonographic and autopsy ﬁndings and discuss the possibility of a prenatal diagnosis when the WTX mutation is identiﬁed in the mother.
CASE REPORT A healthy 36-year-old woman, gravida 4 para 1, without any particular medical or familial history, was referred to our institution for an ultrasound examination because of her obstetrical history. The woman and her husband were not genetically related. A termination of pregnancy at 24 weeks of gestation (WG) was performed for the ﬁrst pregnancy because the male fetus had a polymalformative syndrome associating macrosomia, a cleft hard palate, limb malformations with syndactyly, and a bilateral ﬁbular agenesis. Autopsy of the fetus conﬁrmed these anomalies and revealed a macrocephaly, a hypertelorism, an abnormal palate, and enlarged kidneys. Both fetal and parents’ karyotypes were normal. Investigations for ﬁlamin alpha and T-box5 transcription factor mutations Prenatal Diagnosis 2014, 34, 1–3
excluded the diagnosis of oto-palato-digital syndrome type II and the Holt Oram syndrome, respectively. The second pregnancy was unremarkable, and a girl was born at term with normal development. A miscarriage at the ﬁrst trimester occurred for the third pregnancy. The current pregnancy was obtained by assistance for procreation with an in vitro fertilization and a transfer of two embryos. The ﬁrst trimester ultrasound showed a dichorionic diamniotic pregnancy with normal nuchal translucency for gestational age. The ultrasound examination performed at 22 WG in our department noted a male twin pregnancy with macrosomia, polyhydramnios, and bilateral ﬁbular agenesis in both twins (Figure 1A). The cephalic extremity was difﬁcult to investigate in both. Ultrasound follow-up at 25 WG showed additional craniofacial dysmorphism with macrocephaly, hypertelorism, cleft hard palate, micrognathia, and glossoptosis (Pierre Robin’s sequence) (Figure 1B) in both fetuses associated with an abnormal cystic lesion below the stomach, a syndactyly of digits III to IV in fetus 1 (Figure 1C) and an ulnar deviation of the index in fetus 2 (Figure 1D). The recurrence of this polymalformative syndrome in the male fetuses was suggestive of an X-linked dominant inherited syndrome. Indeed, a careful clinical examination of the mother revealed a craniofacial dysmorphism with hypertelorism and wide nasal bridge, but without any intellectual disability. Her X-ray imaging showed longitudinal striations of long bones with sclerosis of the skull suggestive of OS-CS (Figure 2A, B). Considering the polymalformative syndrome, the male sex, and the possible diagnosis of OS-CS, the parents elected for termination of pregnancy. Pathological analysis conﬁrmed prenatal ultrasound ﬁndings. Both male fetuses were macerated and presented with macrosomia (biometry consistent with 29 WG). External © 2014 John Wiley & Sons, Ltd.
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Figure 1 Prenatal ultrasound ﬁndings. Fetus 1: (A) Fibular agenesis in a sagittal plane and an axial plane. (B) Sagittal plane showing the hard palate cleft and the retrognathia. (C) Digits III–IV syndactyly. Fetus 2: (D) Ulnar deviation of the index
Figure 2 X-rays of the mother. (A) Longitudinal striations of the long bones. (B) Sclerosis of the skull examination revealed similar craniofacial dysmorphic features. Their faces were squared with hypertelorism and misshaped small ears. A posterior cleft palate with glossoptosis and retrognathia was observed in both (Figure 3A). In fetus 1, the terminal phalanx of digit II was duplicated, and this was conﬁrmed on radiographs. It was associated with a digits III to IV syndactyly and radial deviation of the distal phalanges (Figure 3B). In fetus 2, digit II was angulated with a large ﬁrst phalanx and no syndactyly (Figure 3C). Radiologically, there was no true duplication of the terminal phalanges in digit II but a split aspect was present (Figure 3C). Terminal phalanges of digits were variously enlarged and spatulate in both twins. Their feet presented a “rocker bottom” deformation, and radiographs showed bilateral ﬁbular agenesis and curved tibias. There was neither obvious cranial sclerosis nor metaphyseal striation. Visceral examination disclosed intestinal malrotation and hypoplastic lungs in the two fetuses. In fetus 1, the stomach was duplicated along the greater curvature. In fetus 2, kidneys were large and globular (total weight = 21.9 g, normal weight = 14.4 g). Microscopically, the metanephrogenic blastema was abnormally thick and focally nodular in fetus 1. In fetus 2, Prenatal Diagnosis 2014, 34, 1–3
Figure 3 Autopsic and radiological ﬁndings in fetuses 1 and 2. (A) Cleft palate and glossoptosis. (B) X-ray examination: duplication of the terminal phalanx of right digit II and digits III-IV syndactyly with radial deviation. (C) Abnormal and enlarged ﬁrst phalanges in digits II to IV and ulnar deviation of digit II with splitting of the terminal phalanx. (D) Perilobular nephrogenic rests in renal cortex perilobular nephrogenic rests were identiﬁed in the kidneys (Figure 1D). The brains were not well preserved, allowing only a partial study. No signiﬁcant abnormality was found. The partially fused placentas were eutrophic without any signiﬁcant lesion, and dichorionic diamniotic pregnancy was conﬁrmed. The karyotype of fetus 1 was normal (46, XY). The karyotype of fetus 2 was not available. Molecular genetic analysis of the mother allowed the identiﬁcation of a heterozygous de novo deletion Del 867_868AG (p.T289fs+33X) in WTX gene. Further study of the two fetuses found a hemizygous deletion for the same mutation, conﬁrming our prenatal hypothesis. © 2014 John Wiley & Sons, Ltd.
Prenatal diagnosis of osteopathia striata with cranial sclerosis
Osteopathia striata with cranial sclerosis is an X-linked disease caused by mutations involving WTX (FAM123B), a repressor of WNT signaling. Mutations appear de novo or are inherited within families. OS-CS typically affects female, whereas male fetuses generally have fetal or neonatal lethality. To our knowledge, this is the ﬁrst report of prenatal suspicion of OS-CS. Age at diagnosis varies from the neonatal period to the ﬁfth decade.2 In female cases, this sclerosing bone dysplasia is characterized by cleft palate and craniofacial dysmorphism including macrocephaly, hypertelorism, ﬂat nasal bridge, and dental anomalies. Bony sclerosis of the skull may commonly cause ophthalmoplegia, hearing loss, chronic otitis media, and nasal obstruction. Heart defects, scoliosis, and rib and vertebral anomalies may rarely occur. Mild learning disabilities are common, but intellectual disability is rare. Conversely, affected male cases present with either a severe phenotype with multiple structural malformations usually resulting in fetal or neonatal lethality or with a mild form characterized by short stature and neuromuscular abnormalities. The severe phenotype is characterized by severe heart defects and gastrointestinal malformations and is often associated with bilateral ﬁbular aplasia.3 In 2009, Jenkins et al.,4 identiﬁed germline mutations in WTX (FAM123B, RefSeq NM_152424.3) on Xq11.1 in affected families with OSCS, conﬁrming a previously hypothesized X-linked inheritance pattern. Perdu et al.3 reported three new WTX gene defects associated with OS-CS in a series of eight families. WTX was ﬁrst identiﬁed as a key regulator of the canonical WNT signaling pathway. In the absence of functional WTX, enhanced WNT signaling is associated with increased skeletal ossiﬁcation in mice and humans, as well as with other sclerosing bone dysplasias. Interestingly, WTX is inactivated in some cases of nephroblastomas (Wilms tumor), but OS-CS patients seem not to be predisposed to such tumors. In one fetus, perilobular nephrogenic rests were identiﬁed as previously reported by Holman et al.5 These lesions are a precursor of Wilms tumors but spontaneously involute for the vast majority. Jenkins et al.4 suggested a possible genotype–phenotype correlation that relates the position of the mutations in WTX with survival in male fetuses. This correlation was not found in Perdu’s series, underlying the unpredictability of male survival and the high phenotypic variability between female carriers of the mutation and their affected sons. The deletion Del 867_868AG (p.T289fs+33X) found in our three cases has been described in a previous
female patient with sclerosis and striations of bones, a developmental delay, without cardiac anomaly, hearing impairment, and cleft palate.4 This deletion has not been described before in male patients. It is located 5′ to the β-catenin binding domain of WTX and is predicted to produce a truncating protein. The severe phenotype of both fetuses described here is consistent with the genotype–phenotype correlation proposed by Jenkins et al.4 Because of the wide variety of clinical signs, prenatal diagnosis of OS-CS is challenging in the absence of a family history suggesting the diagnosis. Perdu et al.3 described a prenatal male case with bilateral ﬁbular agenesis associated with a hypoplastic left heart, which was interrupted at 21 WG because of the severity of the heart defect. The diagnosis of OS-CS in the mother and the fetus was performed in the postnatal period because the mother had a craniofacial dysmorphism with hearing loss and her radiographs showed cranial sclerosis and metaphyseal striations. Similar unspeciﬁc ultrasound ﬁndings were described by Herman et al.,6 Perdu et al.,7 and Barbosa et al.8 In conclusion, this case report highlights the possibility to achieve a prenatal diagnosis of OS-SC. The identiﬁcation in a male fetus of bilateral ﬁbular aplasia together with duplicated phalanges, syndactyly, and gastrointestinal malformations may be suggestive of a severe phenotype of OS-CS. In this setting, it emphasizes also the importance of a watchful clinical examination of mothers to search dysmorphic features. If the mutation is identiﬁed in a female pregnant patient, it seems relevant to propose fetal sex determination from maternal blood and then a prenatal diagnosis using a chorionic villous sampling in male fetuses.
WHAT’S ALREADY KNOWN ABOUT THIS TOPIC? • Osteopathia striata with cranial sclerosis is a rare bone dysplasia, characterized by longitudinal striations of long bones and cranial sclerosis. Age at diagnosis and clinical presentation are variable, ranging from asymptomatic to neonatal lethal cases.
WHAT DOES THIS STUDY ADD? • Prenatal diagnosis is challenging because fetal presentation is variable and mothers with OS-CS can be misdiagnosed. We report the ﬁrst prenatal case of OS-CS with sonographic and autopsy ﬁndings and discuss the possibility of a prenatal diagnosis when the Wilms tumor on the X chromosome mutation is identiﬁed in the mother.
REFERENCES 1. Berenholz L, Lippy W, Harrell M. Conductive hearing loss in osteopathia striata-cranial sclerosis. Otolaryngol Head Neck Surg 2002;127(1):124–6. 2. Winter R, Crawfurd M, Meire H, et al. Osteopathia striata with cranial sclerosis: highly variable expression within a family including cleft palate in two neonatal cases. Clin Genet 1980;18(6):462–74. 3. Perdu B, Lakeman P, Mortier G, et al. Two novel WTX mutations underscore the unpredictability of male survival in osteopathia striata with cranial sclerosis. Clin Genet 2011;80(4):383–8. 4. Jenkins ZA, van Kogelenberg M, Morgan T, et al. Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis. Nat Genet 2009:41(1):95–100.
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5. Holman SK, Daniel P, Jenkins ZA, et al. The male phenotype in osteopathia striata congenita with cranial sclerosis. Am J Med Genet A 2011;155A(10):2397–408. 6. Herman SB, Holman SK, Robertson SP, et al. Severe osteopathia striata with cranial sclerosis in a female case with whole WTX gene deletion. Am J Med Genet A 2013;161A(3):594–9. 7. Perdu B, de Freitas F, Frints SG, et al. Osteopathia striata with cranial sclerosis owing to WTX gene defect. J Bone Miner Res 2010;25(1):82–90. 8. Barbosa M, Perdu B, Senra V, et al. Osteopathia striata with cranial sclerosis. Acta Med Port 2010;23(6):1147–50.
© 2014 John Wiley & Sons, Ltd.