American Journal of Medical Genetics 136A:373–376 (2005)

Clinical ReportDiaphanospondylodysostosis (DSD): Confirmation of aRecessive Disorder With Abnormal Vertebral Ossification andNephroblastomatosisMarie Gonzales,1 Alain Verloes,2* Marie-Helene Saint Frison,1 Chantal Perrotez,1 Odile Bourdet,3

Ferechte Encha-Razavi,4 Nicole Joye,1 Jean-Louis Taillemite,1 Roland Walbaum,5 Rudolf Pfeiffer,6

and Pierre Maroteaux7

1Department of Pathologic Embryology and Cytogenetics, Hopital Saint Antoine, Paris2Clinical Genetics Unit and INSERM U676, Hopital Robert Debre, Paris3Department of Gynecology and Obstetrics, Centre hospitalier de Saint-Denis, France4Fetal and Placentar Pathology Unit, Hopital Necker-Enfants Malades, Paris, France5Department of Pediatrics, Centre Hospitalier de Roubaix, France6Institut fur Humangenetik und Anthropologie, Erlangen, Germany7Department of Medical Genetics, Hopital Necker-Enfants Malades, Paris, France

We report on four patients from three families,with similar radiological findings: absent (orseverely delayed) ossification of vertebral bodiesand associated anomalies. The babies were still-born or died soon after birth of respiratoryinsufficiency. Two patients are sibs (female andmale) born to first cousin Malian parents. The twoothers were non-consanguineous. This perina-tally lethal entity comprises short neck, shortwide thorax, and normally shaped limbs. Asso-ciated, inconstant anomalies are myelomeningo-cele, cystic kidneys with nephrogenic rests (in thesibs), and cleft palate. Radiologically, the hall-marks are absence of ossification of the vertebralbodies and sacrum, abnormal position of thevertebral pedicles, which are lamellar and angu-lated, ribbon-like ribs reduced in number, narrowpelvis, upward widening of the iliac wings, andunusual tilt of the ischiopubic rami, contrastingwith the normal appendicular skeleton. Maro-teaux briefly described one of the patients in the2002 edition of ‘‘Maladies osseuses de l’enfant’’ andthree sibs with similar renal and radiologicalfindings were reported in 2003 in this Journal.Combined with the latter cases, these four newpatients allow delineation of a specific lethal ARsyndrome with ossification defect of the axialskeleton and renal dysplasia. We propose to namethis entity diaphanospondylodysostosis.� 2005 Wiley-Liss, Inc.

KEY WORDS: abnormal ossification; vertebralanomalies; cystic kidneys; vertebraldysostosis

INTRODUCTION

Dysostoses are static skeletal malformations occurringduring blastogenesis (in contradistinction to skeletal dyspla-

sias, which often manifest after this stage and have a moregeneral skeletal involvement and continue to evolve afterbirth). Spinal dysostoses are heterogeneous disorders char-acterized by abnormal segmentation, abnormal modeling orabnormal ossification of the vertebral bodies, occurring singlyor in a syndromal context. Besides some well known gene-ralized vertebral dysostoses (such as the spondylocostal orspondylothoracic dysostosis, the synspondylisms), many mul-tileveled disorders of vertebral formation still requires acorrect classification.

We report on four patients from three families with similarradiological findings comprising an entity of absent (or severelydelayed) ossification of vertebral bodies (VB) and associatedanomalies representing a new AR condition, previously brieflyreported by one of us (PM) and confirming a recent report of asibship with three affected fetuses.

CLINICAL REPORT

Family 1, Patient 1

This boy was born in 1989. He was the sixth child ofconsanguineous parents from Mali (Fig. 1). The mother hadthree healthy children from a previous union. Because of non-compliancewithantenatal care,multiple congenital anomalieswere detected as late as 36 weeks of gestation: lumbo-sacralmeningocele, large cystic and ‘‘dysplastic’’ kidneys and oligo-hydramnios. The child was stillborn at 39 weeks. Birth weight(BW) was 3,460 g, length (BL) 45 cm, occipitofrontal circum-ference (OFC), 36 cm. At inspection (Fig. 2), he had short andbroad trunk, short neck, protruding abdomen, left clubfoot,right talus foot, lumbo-sacral spina bifida aperta, and hypo-plastic nails on the fifth digits. Radiologic survey showed(Fig. 3) absence of ossification of the vertebral bodies andsacrum, abnormal and anarchic position of the vertebralpedicles. The distance between the pedicles wasmuch reducedin the lower segment of the spine. Ribbon-like ribs werereduced in number, the pelvis was narrow, and there wasupward widening of the iliac wings and unusual tilt of theischiopubic rami, contrasting with normal appendicularskeleton. On profile view of the spine, vertebral bodies wereossified at the level of the spina, although this ossification waslimited to the lateral aspect of the vertebral plate, as no bodiesare visible on front view.

Necropsy showed enlarged kidneys (weight 80 g, N: 31� 6 g)(Fig. 4a,b) with tubular and glomerular cysts of variablesize, scattered in cortical and medullary regions, lung hypo-plasia (28 g, N: 65� 14 g), and a ‘‘round’’ but otherwise

*Correspondence to: Alain Verloes, Unite de Genetique Clin-ique, Hopital Robert Debre, 75019 Paris, France.E-mail: alain.verloes@rdb.aphp.fr

Received 10 August 2004; Accepted 22 September 2004

DOI 10.1002/ajmg.a.30537

� 2005 Wiley-Liss, Inc.

normally formed brain. Histologically, the kidneys showeda combination of macroscopic cysts and generalized nephro-blastomatosis (Fig. 4c,d).

Family 1, Patient 2

This girl, born 5 years before case 1, was the product of thesecond pregnancy of the same couple. Ultrasonography at30 weeks showed: IUGR. Control at 37 weeks documentedoligohydramnios and cystic kidneys. The child died shortlyafter delivery at 39 weeks. BW was 2,840 g, BL was 44 cm,and OFC was 33 cm. She had large fontanels, short thorax,prominent abdomen, and genua recurvata (Fig. 5), withoutspina bifida. Necropsy showed enlarged cystic kidneys (80�2 g) that were nephroblastomatous at histology. The onlyradiograph (Fig. 6) demonstrated anomalies similar to those ofher brother. No vertebral bodies were visible on profile view.

Family 2, Patient 3

Few clinical data are available on this child, whose filewas sent toPrMaroteaux by the lateR.Walbaum.This boywasthe fifth child of non-consanguineous parents. Mother was31-years-old. Pregnancy was marked by oligohydramnios.Delivery occurred at 41 weeks. The baby died neonatally ofrespiratory insufficiency. The infant had a short and broadtrunk and neck with redundant skinfolds, flat nose, andhypoplastic nails on the index fingers. Autopsy did not showvisceral abnormalities.Radiographs (Fig. 7)were similar to thepreviously described cases. A striking difference was notedbetween the appearance of the cervicothoracic pedicles (whichappeared wide or tilted to a frontal plane, and the lumbarpedicles, which were very hypoplastic and/or sagittally

rotated. On profile view, some thoracic vertebral bodies werevisible, but their median part was not detected on frontal X-rays films. Bone and cartilage histology were reported to benormal.

Family 3, Patient 4

This family was sent to P. Maroteaux by R. Pfeiffer in 1980.Few clinical data are available. This boy was the first childof non-consanguineous parents aged 38 (father) and 28. BWwas 3,100 g, BL was 47 cm. The child had a cleft palate.Necropsy was declined. On the only radiograph that subsists,similar findings are observed: absence of vertebral bodies andirregular vertebral pedicles (Fig. 8).

DISCUSSION

We have reported on four patients with a perinatally lethalcondition with similar manifestations: short neck, short dis-proportionately wide thorax, normally shaped limbs, nailhypoplasia and, in family 1, enlarged cystic and blastomatouskidneys. Radiologically, the hallmarks are absence of ossifica-tion of the vertebral bodies, abnormally shaped or orientedpedicles, with a lamellar or hooked aspect, reduced number ofribs, which appeared ribbon-like, unossified and probablyhypoplastic sacrum, leading to narrow pelvis with upwardwidening of the iliacwings on frontal view (pelvic anteversion),and unusual tilt of the ischiopubic rami. The appendicularskeleton was normal.

Maroteaux and Le Merrer [2002] briefly illustrated patient2 in the 2002 edition of ‘‘Maladies osseuses de l’enfant.’’Recently, Prefumo et al. [2003] described the same conditionin three sibs with similar renal and X-rays findings, abortedduring the second trimester. The characteristics observed inthose three cases were absent ossification of an apparentlynormal cartilaginous spinal column, rib abnormalities withunossified segments and posterior gaps, thoracic hypoplasia,multiple intralobar nephrogenic remnants in the kidneys andincreased nuchal translucency. These four new patients havethe same disorder as those of Prefumo et al. [2003] the onlydifference being rib gaps in the latter. They confirmthe existence of a specific lethal AR syndrome of vertebralanomalies, with persistence of ossification defect till term. Wepropose to designate this entity diaphanospondylodysostosis(DSD), in reference with the abnormal radiolucency of thespine.

Fig. 1. Pedigree of family 1. No data available on the spontaneousabortion.

Fig. 2. Patient 1: Postmortem view. Note thoracic deformity, andabsence of facial dysmorphism.

Fig. 3. Patient 1: X-rays. a: General aspect. Note the abnormal shapeof the pelvis. b: Close-up view of the spine. Note differences between upperand lower vertebrae. c: Profile of thoracolumbar junction. The visiblevertebral bodies are located at the level of the spina bifida aperta.

374 Gonzales et al.

Differential diagnosis of DSD is limited. In spondylomegae-piphyseal metaphyseal dysplasia [Silverman and Reiley,1985], vertebral bodies may show a similar defect of ossifica-tion, but the vertebral pedicles are normally placed and thereare misshaped epiphyses (which resemble the anomaliesobserved in cleidocranial dysostosis). Twootherpapers deservenote. Bohring et al. [1999] reported clinical, pathological, andradiological findings in 15 cases of lower spine agenesis withadditional anomalies of the axial skeleton and internal organs.

Fig. 5. Patient 2: Postmortem view.

Fig. 6. X-rays of patient 2. a: General aspect, (b) close up view of thespine, illustrating the anarchic shape and orientation of vertebral archsegments.

Fig. 4. Patient 1: Renal pathology (a), macroscopic appearance of kidneys (b), section of the kidney revealing cysts (c), and (d) microscopic examination,showing cystic changes and nephroblastomatous islets.

Diaphanospondylodysostosis 375

The authors concluded that all of these findings are defects ofblastogenesis, originate in the primary developmental fieldand/or the progenitor fields, thus representing polytopicfield defects. In their series of patients, 14/15 cases had alevel of agenesis at the thoracolumbar junction. Among thesepatients, four sibs were born to consanguineous Pakistaniparents with a somewhat different pattern of anomalies. Theauthors commented on the fact that in this family, there wasmore probably a delayed ossification of a misshapen spinethan true spinal agenesis. Thus, these patients could representDSD, but the cephalocaudal gradient of defect present in thecases of Bohring et al. [1999] is not observed in our patients.Among the 11 other sporadic cases, only their case 14resembles our patients, having only some fused cervicalvertebrae and a few ribs associated with diaphragmatic herniaand imperforate anus. Here also, the difference in the overallpattern prevents us to merge this patient with DSD. Nisbetet al. [1999] reported a MCA syndrome with superficialsimilarities to our patients in 23-week-old DZ twin fetusesborn to non-consanguineous Afrocaribbean parents. One hadomphalocele and both had rib gaps and cleft vertebral bodieswhich were different from seen in our patients. There were novertebral bodies below T2. Finally, Semerci et al. [2001]described a fetus with complete absence of thoracic, lumbar,and sacral vertebrae, bilateral renal agenesis, VSD, meningo-myelocele, imperforate anus, and teratoma. All of thosepatients are different from our cases, as the vertebral defectis agenesis rather than absence of mineralization probablyassociated with some degree of hypoplasia.

Our observations and those of Prefumo et al. allow delinea-tion of an entity different from other spondylodysostosis,

characterized by absent ossification of vertebral bodies, andkidney dysplasia, recessively inherited.

REFERENCES

Bohring A, Lewin SO, Reynolds JF, Voigtlander T, Rittinger O, Carey JC,KopernikM, SmithR, Zackai EH,LeonardNJ,GritterHL,Bamforth JS,Okun N, McLeod DR, Super M, Powell P, Mundlos S, Hennekam RC,van Langen IM, Viskochil DH, Wiedemann HR, Opitz JM. 1999.Polytopic anomalies with agenesis of the lower vertebral column. Am JMed Genet 87:99–114.

Maroteaux P, Le Merrer M. 2002. Maladies osseuses de l’enfant. Paris:Flammarion Medecine-Sciences. 265p.

Nisbet DL, Chitty LS, Rodeck CH, Scott RJ. 1999. A new syndromecomprising vertebral anomalies and multicystic kidneys. Clin Dysmor-phol 8:173–178.

Prefumo F, Homfray T, Jeffrey I, Moore I, Thilaganathan B. 2003. A newlyrecognized autosomal recessive syndrome with abnormal vertebralossification, rib abnormalities, and nephrogenic rests. Am J Med Genet120A:386–388.

Semerci CN, Bebitoglu I, Kacar A, Yurttagul S, Ercakmak S, Ertoy D,Ozaltin F, Balci S. 2001. An unusual fetus with complete absence ofthoracic, lumbar and sacral vertebrae, bilateral renal agenesis, VSD,meningomyelocele, imperforate anus, and teratoma. Clin Dysmorphol10:57–60.

Silverman FN, Reiley MA. 1985. Spondylo-megaepiphyseal-metaphysealdysplasia: A new bone dysplasia resembling cleidocranial dysplasia.Radiology 156:365–371.

Fig. 8. X-rays of patient 4 after evisceration.Note the shape of thepelvis,and abnormal tilt of the ischiopubic rami.

Fig. 7. X-rays of patient 3. Note partial ossification of some thoracicvertebrae, visible on the profile (b) but not on the frontal (a) vie.

376 Gonzales et al.