JMed Genet 1998;35:49-53 49 Syndrome of the month J Med Genet: first published as 10.1136/jmg.35.1.49 on 1 January 1998. Downloaded from

Atelosteogenesis type 2

Ruth Newbury-Ecob

Atelosteogenesis type 2 (AO2) (MIM 256050) sia or spondylohumeral dysplasia" 13 and there is a neonatally lethal chondrodysplasia charac- is a suggestion of overlap with boomerang terised by severe limb shortening and deficient dysplasia.14 Atelosteogenesis type 3 was re- ossification of parts of the skeleton. Other fea- cently delineated by Stern et al'5 with features tures include facial dysmorphism, cleft palate, in common with otopalatodigital syndrome talipes, and abducted thumbs and toes. Pheno- (OPD). typic overlap with non-lethal diastrophic dys- plasia (DTD) suggested a common aetiology Clinical features and it has recently been confirmed that both Table 1 summarises the clinical and radiologi- syndromes result from in the cal features. A02 may be suspected prenatally DTDST ( sulphate trans- because of short limbs. At birth all cases are porter) gene. disproportionately short owing to rhizomelic (7Med Genet 1998;35:49-53) short limbs, which are bowed. Length falls way below the 3rd centile with relative Keywords: atelosteogenesis type 2; diastrophic dyspla- macro- sia; DTDST gene cephaly. The condition is invariably lethal with death occurring as a consequence of a History combination of pulmonary hypoplasia and tra- cheobronchomalacia. Cases may have laryn- Atelosteogenesis is one of a group of rare neo- geal anomalies. The chest is narrow and bell natal osseous dysplasias characterised by in- shaped and the abdomen protuberant. All have complete formation. The first case was cleft palate. Facial dysmorphism consists of a described by Kozlowski et and al' the syndrome flat, depressed nasal bridge, prominent epican- was named atelosteogenesis (Greek: ateles=incomplete; for- thic folds, midfacial hypoplasia, and microg- osteon-genesis=bone nathia. All have radial deviation of the thumb, mation) by Maroteaux et in The con- af 1982. the so called "hitch-hiker thumb", and a gap http://jmg.bmj.com/ dition was subdivided by Sillence et ar into between the first and second toes. There is types 1 and 2 when in 1987 he reclassified four usually ulnar deviation of the fingers and cases referred to as severe diastrophic dysplasia talipes equinovarus. Dislocations of the elbows as atelosteogenesis type 2 and that recognised and knees have been reported. The spine is these cases had features in common with cases curved owing to spinal , cervical described by McAlister et at' (McAlister dysplasia), Spranger and Maroteaux,5 and kyphosis, and lumbar hyperlordosis.

Salonen.6 This latter case was subsequently on September 26, 2021 by guest. Protected copyright. rediagnosed as atelosteogenesis type 1 by Radiological features Whitley et al.7 These, together with cases previ- The long show metaphyseal and epiphy- ously known as de la Chapelle dysplasia seal abnormalities characterised by short tubu- (DLCD),' have come to be known as A02 fol- lar bones with metaphyseal flaring and minimal lowing recognition that the clinical and his- irregularity of the epiphyses. The humerus topathological features overlap.7 Sillence et ar shows some of the most characteristic abnor- made the observation that cases of atelosteo- Table 1 Summary ofclinical and radiologicalfeatures in genesis were "diastrophic-like" but the severe atelosteogenesis histological changes in A02 distinguished the two syndromes. Schrander-Strumpel et at' dis- Clinicalfeatures Radiologicalfeatures cussed the phenotypic overlap further and sug- Polyhydramnios Wide flared gested a common aetiology. In total, 11 cases of Low birth weight U or V depression distal humerus A02 have been published and in this review we Relative macrocephaly Bowed tibia/fibula/radius/ulna Cleft palate Short, round metacarpals and add a further case. The cases of Bruer and metatarsals Brudner'° would also be classified as A02. Epicanthic folds Short, small phalanges The syndromes are characterised by hypo- Micrognathia Short ribs Depressed nasal bridge Thin clavicles plasia of the femora and humeri distally and Short stature Small scapulae Clinical Genetics absence of ossification in, for example, the Rhizomelic limb Platyspondyly Institute of Service, fibula, which may be absent. Similarity to meso- shortening Child Health, Bristol Bowed limbs Cervical kyphosis Royal Hospital for Sick melic , particularly the ulna, fibula, Hitch-hiker thumbs Hypoplastic ilia Children, St Michaels and mandible types, has been noted. " Atel- Small chest Flat acetabular roofs osteogenesis type 1 (AO 1) includes cases Scoliosis Unossified pubic rami Hill, Bristol, UK Laryngeal anomalies Small sacroiliac notches R Newbury-Ecob previously known as giant cell chondrodyspla- 50 Newbury-Ecob

malities including severe underossification and Histology a "club shape" with rounded proximal end and The primary abnormalities are radiating tapered distal end.'6 Also characteristic is a U threads of fibrous material in the or V shaped depression of the distal humerus. matrix giving a Swiss cheese appearance of There may be premature ossification of the acellular areas interspersed with areas of J Med Genet: first published as 10.1136/jmg.35.1.49 on 1 January 1998. Downloaded from proximal . The femora have a "dumb normal cellularity. Lacunar haloes consisting of bell" shape similar to the humerus (fig 1). The concentric rings around the chondrocytes are hands show absent ossification of the proximal characteristic in the resting zone." There may phalanges and better ossification of the distal be large multinucleated "giant cells" in acellu- phalanges (fig 2A). There is preaxial deviation lar areas, hence the name giant cell chondro- of the thumbs and the metacarpals tend to be dysplasia, but these are not pathognomonic for short and round (fig 2A). In the the meta- this condition. Secondary abnormalities con- tarsals are broad and short with small sist of focal areas of hypocellularity and matrix phalanges (fig 2B). There is wide separation of degeneration in the resting zone, extending the first and second toes (fig 2B). Characteris- into the growth plate with disruption of tically there is bowing of the radius and tibia; column formation. The growth plate has a nar- the ulna is row proliferation zone and a wide, irregular short and bowed and the fibula may hypertrophic zone showing irregular vascular be poorly ossified (fig 2). All have invasion and fibrosis replacing hypertrophic platyspondyly (fig 1B) and have hypoplastic or and columnar zones.3 Other abnormalities dysplastic vertebrae. There may be incomplete include abnormal persistence of cartilage in the ossification or hypoplasia of the upper thoracic metaphysis. These abnormalities are seen in vertebrae and coronal clefts of the lumbar and the cartilage of long bones, trachea, bronchi, lower thoracic vertebrae. The sacrum is either and larynx. angulated or underdeveloped. The ilia tend to The histology further distinguishes A02 be round and hypoplastic with flaring of the from AO 1 in which the reserve zone cartilage is iliac wings (fig 1A). All cases have flat acetabu- essentially normal but rather hypocellular with lar roofs and small sacroiliac notches. The occasional giant cells. pubic rami are often incomplete (fig 1A) or Diastrophic dysplasia (DTD) shows similar unossified with additional ossification centres. histological changes to A02 with cystic areas in The clavicles are thin and the ribs thin and the resting cartilage owing to irregular myxoid short (fig 1A). The scapulae are short and the degeneration and also haloes around chondro- glenoid fossae small and shallow. The skull cytes and occasional multinucleated cells. 1 shows no abnormalities. These abnormalities are found in the same http://jmg.bmj.com/ on September 26, 2021 by guest. Protected copyright.

Figure 1 X rays of a baby boy with A02 delivered by caesarian section forfetal distress. A single dating scan had been carried out at 13 weeks. Small size before delivery was thought to be the result ofgrowth retardation, so labour was induced 12 days post-term. The baby livedfor 45 minutes. (A) AP view showing short long bonies, short ribs, curved tibiae, spinal scoliosis, round ilia with flat acetabular roofs, and incomplete pubic rami. (B) Lateral view showing platyspondyly, horizontal sacrum, and dumb bell shape offemora. Atelosteogenesis type 2 51 J Med Genet: first published as 10.1136/jmg.35.1.49 on 1 January 1998. Downloaded from

Figure 2 The same child as in fig 1. (A) Right lower arm showing bowed ulna and radius, abducted "hitch-hiker" thumb, "semilunar" metacarpals, hypoplastic proximal phalanges, and relatively normal terminal phalanges. (B) Leftfoot showing curved tibia and short hypoplastic fibula, abducted hallux, and wide space between first and second toes. cartilage as in A02, that is, trachea, vertebrae, A02 and DTD show greatest similarity; and long bones. However, the growth plate has both have short limbs and mid thoracic spinal normal hypertrophic and proliferative zones abnormalities, talipes equinovarus, abducted and a normal columnar zone. thumbs and big toes, and cleft palate. In many respects, clinically A02 might be seen as a more severe variant of DTD.22 One major Differential diagnosis difference is that although Gustavson et a/2 The diagnosis of A02 may be suggested radio- described lethal and non-lethal forms of http://jmg.bmj.com/ logically but A02 needs to be distinguished diastrophic dysplasia, no survivors have been from other lethal dwarfing conditions. The described with atelosteogenesis. Other differ- lethal short rib polydactyly syndromes which ences include a normal trunk in DTD and also have short limbs, narrow thorax, and pro- cystic swelling of the . Radiologically both tuberant abdomen, for example, SRPDS type show major abnormalities in the femora and 2 Majewski,'8 can be differentiated by the pres- humeri. The skull is normal in both. Radiologi- ence of polydactyly and internal organ defects. cal differences include normal tubular bones in on September 26, 2021 by guest. Protected copyright. In campomelic dysplasia'9 the long bones are DTD apart from the long bones. As mentioned bowed and additional abnormalities include above, A02 and DTD share the same histopa- hydrocephalus and cardiac and renal defects. thology and the diagnosis can rarely be certain The telephone receiver femora of thanato- until this has been analysed. phoric dwarfism are recognisable is the most severe form of radiologically.20 In achondrogenesis there is chondrodysplasia. Limb shortening is extreme. undermineralisation of the skull and through- (ACG1B) shows his- out the skeleton.' Maroteaux and Spranger2 tological similarity to A02 and DTD although still suggest that A02 and de la Chapelle it is phenotypically distinct. A02, ACG1B, and dysplasia (DLCD) are distinct with DLCD DTD are now known to represent the spec- showing more severe hypoplasia of the verte- trum of chondrodysplasias caused by muta- bral bodies, ulnae, and fibulae.2 tions in the DTDST gene (see below). Atelosteogenesis type 1 (AO 1) is A comparison of the clinical and radiological distinguished from A02 by better development features of A02, ACG1B, and DTD is shown of the distal humeri and femora and better in table 2. ossification in vertebral bodies and pubic bones. Hitch-hiker thumbs and toes are not a feature of AO1 in which cleft palate is rare. AO1 has coronal clefts of the vertebrae and Aetiology and genetics A02 less marked vertebral anomalies. In A02 Of 14 cases ofA02 described to date, five have the femora and humeri have a dumb bell shape been isolated. Evidence for probable recessive with bifid distal ends. The fibula is usually inheritance comes from three sets of sibs,4 hypoplastic whereas in AO1 it is often absent. of which one set of three sibs was born to con- 52 Newbury-Ecob

Table 2 Comparison of clinical and radiologicalfeatures diagnosed atelosteogenesis by ultrasound in a in ACG1B, A02, and diastrophic dysplasia 21 week fetus with short limbs, coronal clefts, ACGIB A02 characteristic shaped humeri, abducted DTD thumbs and toes, and talipes equinovarus. A Clinical features second affected fetus was detected at 15 weeks. J Med Genet: first published as 10.1136/jmg.35.1.49 on 1 January 1998. Downloaded from Neonatal death + + Short limbs + + + Usually, however, establishing the diagnosis in Cleft palate - + + a case of short limb dwarfism requires detailed Hitch-hiker thumbs - + + Gap toes I andII - + + radiological assessment and histological confir- Radiological features mation and, in A02, biochemical diagnosis Platyspondyly + + - based on defective sulphate transport in Rounded iliac bones + + - fibroblast cultures. Horizontal acetabula + + - Distal femoral hypoplasia + + - Identification of mutations in DTDST Distal ulnar hypoplasia + + - means that it is now possible to carry out DNA First metacarpal hypoplasia + + + based prenatal diagnosis for A02, DTD, and ACG1B. This reinforces the importance of sanguineous parents. Cases consist of equal obtaining DNA samples from all cases of lethal numbers of males and females.9 short limbed dwarfism. Superti-Furga (per- Defective sulphate transport and defective sonal communication) recently successfully sulphation of proteoglycans have been shown undertook prenatal diagnosis for A02 by DNA in fibroblast cultures from patients with A02, analysis of amniocytes at 15 weeks. DTD, and ACG1B.`4 Proteoglycan undersul- phation has a marked effect on the composition The author would like to thank Professor Ian Young and Dr of the extracellular matrix of cartilage. The Andrea Superti-Furga for their helpful comments. diastrophic dysplasia sulphate transporter gene (DTDST) has been identified by positional 1 Kozlowski K,Tsurata T, Kameda Y, Kan A, Leslie G. New cloning25 following localisation of DTD to forms of neonatal dwarfism, report of three cases. Pediatr Radiol 1981;10:155. chromosome 5q."6 The gene encodes a ubiqui- 2 Maroteaux P, Spranger J, Stanescu V, et al. Atelosteogenesis. tously expressed sulphate transporter AmJMed Genet 1982;13:15-25. 3 Sillence DO, Kozlowski K, Rogers JG, Sprague PL, Cullity (DTDST). Mutations in DTDST have been GJ, Osborn RA. Atelosteogenesis: evidence for heterogene- identified in patients with DTD and ACG1B27 ity. Pediatr Radiol 1987;17:112-18. 4 McAlister WH, Crane JP, Bucy RP, Craig RB. A new and in 1996 Hastbacka et af' reported neonatal short limbed dwarfism. Skeletal Radiol 1985;13: mutations in the DTDST gene in three 271-5. 5 Spranger J, Maroteaux P. The lethal osteochondrodyspla- patients with A02. Evidence suggests that sias. Adv Hum Genet 1990;19:1-103. mutations in DTDST cause reduced DTDST 6 Salonen R. Neonatal osseous dysplasia I: 2nd report. In: Skeletal dysplasias. New York: Alan R Liss, 1982:171-2. expression in ACG1B, A02, and DTD. The 7 Whitley CB, Burke BA, Granroth G, Gorlin RG. De la variable phenotype reflects the amount of Chapelle dysplasia. Am J Med Genet 1986;25:29-39. 8 De la Chapelle A, Maroteaux P, Havu N, Granroth G. Une residual activity of the sulphate transporter.29 rare dysplasie osseuse lethale de transmission recessive ACGGB is produced by homozygosity or com- autosomique. Arch Fr Pediatr 1972;29:759-70. 9 Schrander-Stumpel C, Havenith M, Linden EVD, Maertz- pound heterozygosity and appears to be the dorfW, Offermans J, Van der Harten J. De la Chapelle dys- null phenotype. Mutations in both alleles occur plasia (atelosteogenesis type II): case report and review of http://jmg.bmj.com/ the literature. Clin Dysmorphol 1994;3:318-27. invariably in the coding region leading to an 10 Bruer J, Brandner M. Pathologisch-anatomische und early stop codon. In A02 mutations occur in radiologische Untersuchungen bei zwei fruhgeborenen Geschwistern mit diastrophischem Zwergwuchs und aus- the coding region but may be frameshift or gepragten Wirbelsaulen-veranderungen. Virchows Arch missense, causing partial loss of function. In 1974;364: 165-77. 11 Evans MI, Zador IE, Queresin F. Ultrasonographic prenatal DTD one may be in the coding diagnosis and fetal pathology of Langer mesomelic region but never both, the other mutation dwarfism. Am JMed Genet 1988;31:915-20. 12 Yang SS, Roskamp J, Frates R, Singer DB. Two lethal chon- occurring in the extracellular loops or cytoplas- drodysplasias with giant chondrocytes. Am J Med Genet on September 26, 2021 by guest. Protected copyright. mic tail, that is, A02 and DTD may result from 1983;15:615-25. 13 Sillence DO, Lachman RS, Jenkins T, Riccardi VM, Rimoin compound heterozygosity with a presumed DL. Spondylohumerofemoral hypoplasia (giant cell reduced expression allele. Expression studies chondrodysplasia): a neonatally lethal short limb skeletal dysplasia. Am J Med Genet 1982;13:7-14. show low levels but not zero DTDST mRNA.29 14 Hunter AGW, Carpenter BF. Atelosteogenenesis I and boo- An elegant diagram illustrating the sites of the merang dysplasia: a question of nosology. Clin Genet 1991; 39:471-80. various mutations is provided by 15 Stern HJ, Graham JJ, Lachman RS. Atelosteogenesis type Superti-Furga.3" III: a distinct skeletal dysplasia with features overlapping atelosteogenesis and oto-palato-digital syndrome type II. In conclusion, the same mutation in AmJMed Genet 1990;36:183-95. DTDST may cause a different phenotype 16 Temple K, Hall CA, Chitty L, Baraitser M. A case of atelosteogenesis. Jf Med Genet 1990;27: 194-7. depending on the mutation on the other chro- 17 Qureshi F, Jacques SM, Johnson SF, Hume RF, Evans MI, mosome. Other factors also appear to be Yang SS. Histopathology of fetal diastrophic dysplasia. Am J'Med Genet 1995;56:300-3. relevant since sibs with identical genotype 18 Sillence D, Kozlowski K, Bar-Ziri, et al. Perinatally lethal (homozygous for the common Finnish ances- short rib polydactyly syndrome. Variability in known syndromes. Paediatr Radiol 1987;17:474-80. tral mutation) have variable phenotypes, sug- 19 Mansour S, Hall CM, Pembrey ME, Young ID. A clinical gesting a role of modifier genes or epigenetic genetic study of campomelic dysplasia. J Med Genet 1995: factors. 32:415-20. Atelosteogenesis type 2, achondrogen- 20 Van der Harten H, Brons, T, Dijkstra PF, et al. Some esis type 1B, and diastrophic dysplasia appear variants of lethal . Clin Dysmorphol caused 1993,2: 1-19. to represent a phenotypic spectrum by 21 Borochowitz Z, Lachman R, Adonnan GE, et al. Achondro- mutations in the DTDST gene. genesis type 1: delineation of further heterogeneity and identification of two distinct subgroups. J7Pediatr 1988;1 12: 23-3 1. Prenatal diagnosis 22 Qureshi F, Jacques SM, Johnson SF. Diastrophic dysplasia and atelosteogenesis II: different manifestations of a com- Ultrasound may be useful in detecting A02, as mon chondrodysplasia. Am J Hum Genet Suppl 1994;3: illustrated by Nores et al,3' who successfully A90. Atelosteogenesis type 2 53

23 Gustavson KH, Holmgren G, Jagell S, Jorulf H. Lethal and dysplasia sulphate transporter gene. Nat Genet 1996;12: non-lethal diastrophic dysplasia. Clin Genet 1985;28:321-34. 100-2. 24 Superti Furga A. A defect in the metabolic activation of sul- 28 Hastbacka J, Superti-Furga A, Wilcox WR, Rimoin DL, phate in a patient with achondrogenesis type 1 B. Am 7 Hum Cohn DH, Lander ES. Atelosteogenesis type II is caused Genet 1994;55:1137-45. by mutations in the diastrophic dysplasia sulphate trans- 25 Hastbacka de la Chapelle A, Mahtani MM, et al. The porter gene (DTDST); evidence for a phenotypic series J, J Med Genet: first published as 10.1136/jmg.35.1.49 on 1 January 1998. Downloaded from diastrophic gene a involving three chondrodysplasias. Am Hunm Genet 1996; dysplasia encodes novel sulfate 58:255-62. transporter; positional cloning by fine structure linkage 29 Rossi van disequilibrium mapping. Cell 1994;78: 1073-87. A, der Harten HJ, Beemer FA, et al. Phenotypic and genotypic overlap between atelosteogenesis type 2 and 26 Hastbacka J, Kaitila I, Sistonen P, de la Chapelle A. diastrophic dysplasia. Hum Genet 1996;98:657-61. Diastrophic dysplasia gene maps to the distal long arm of 30 Superti-Furga A. Achondrogenesis type 1B. Med Genet . Proc NatlAcad Sci USA 1990;87:8056-9. 1996;33:957-61. 27 Superti-Furga A, Hastbacka J, Wilcox WR, et al. Achondro- 31 Nores JA, Rotmensch S, Romero R, Avila C, Inati M, genesis type 1B is caused by mutations in the diastrophic Hobbins JC. Atelosteogenesis type II: sonographic and radiological correlation. Prenat Diagn 1992;12:741-53. http://jmg.bmj.com/ on September 26, 2021 by guest. Protected copyright.