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Syndrome of the Month J Med Genet: First Published As 10.1136/Jmg.33.11.957 on 1 November 1996

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Syndrome of the Month J Med Genet: First Published As 10.1136/Jmg.33.11.957 on 1 November 1996 J Med Genet 1996;33:957-961 957 Syndrome of the month J Med Genet: first published as 10.1136/jmg.33.11.957 on 1 November 1996. Downloaded from Achondrogenesis type 1B Andrea Superti-Furga Historical notes which tried to provide a quantitative basis (the In 1952, the name achondrogenesis (Greek for "femoral cylinder index") for qualitative "not producing cartilage") was given by Marco changes, did not prove helpful and was later Fraccaro, a young Italian pathologist (later to abandoned. In the late 1980s, it was shown become a well known cytogeneticist), to the that achondrogenesis type II was caused by condition he observed in a stillborn female structural mutations in collagen II and thus with severe micromelia and marked histological constituted the severe end of the spectrum of changes of cartilage.' Fraccaro noted a similar the collagen II chondrodysplasias.l'" case published by Parenti in 1936.2 Fraccaro's Borochowitz et al'4 provided convincing report (written in Italian) came to the know- histological criteria for the further subdivision ledge ofHans Grebe, who in 1939 had observed of achondrogenesis type I into IA (with ap- sisters (aged 7 and 11 years, born to con- parently normal cartilage matrix but inclusions sanguineous parents from the Black Forest re- in chondrocytes) and IB (with abnormal car- gion of Germany) with markedly short limbs tilage matrix; see below). These findings were and digits but normal trunk. Grebe became confirmed by another group shortly there- convinced that his patients were affected by after.'5 Using these criteria, some older pub- the same achondrogenesis as Fraccaro's short lished cases can be unequivocally diagnosed as limbed stillborn patient, and he had his report type IB,'617 others as type IA,'8 while Parenti's (written in German) published in the same case probably should be classified as type II.2 14 journal.' However, the condition described by The classification of achondrogenesis type IB Grebe was different (although superficially sim- as a separate group has recently been confirmed ilar to Fraccaro's achondrogenesis because of by biochemical and molecular findings (see limb shortening) and has later become known below). The history of achondrogenesis shows as Grebe chondrodysplasia or Grebe syndrome. how subjective clinical and radiological clas- The name achondrogenesis was then used sifications can be. Histology and ultrastructure to characterise the most severe forms of chon- have allowed a more solid classification and drodysplasia in humans, invariably lethal before provided the basis for biochemical and mo- http://jmg.bmj.com/ or shortly after birth. Precise figures on the lecular studies. incidence of achondrogenesis are not available, The present classification ofachondrogenesis but it is not exceedingly rare: reviews with large is shown in table 1. Recessive inheritance of numbers of patients have been published.45 achondrogenesis type IA is not formally proven, In the 1970s, the heterogeneity of achon- and this type may still contain different sub- drogenesis was recognised. Using a com- groups. To avoid misunderstandings in the era bination ofradiological and histological criteria, of gene symbols and computerised databases, achondrogenesis type I (then also called Frac- it is advisable (though regrettable) to convert on October 1, 2021 by guest. Protected copyright. caro-Houston-Harris type) and type II (called Roman numerals to Arabic numerals. Ac- Langer-Saldino type) were distinguished.67 In cordingly, the following abbreviations are pro- 1976, it was found that chondrocytes of some posed: achondrogenesis type IA (ACGGA), (though not all) type I patients contained cyto- achondrogenesis type lB (ACGIB), and plasmic inclusions.8 In 1983, a new clas- achondrogenesis type 2 (ACG2). Division of Metabolic and Molecular sification of achondrogenesis (types I to IV) Diseases, Department was proposed9 and adopted in the McKusick of Pediatrics, catalogue. This radiological classification, University Children's Clinical features of achondrogenesis type Hospital, lB Steinwiesstrasse 75, (JrMed Genet 1996;33:957-961) CH-8032 Zurich, Newborns with ACGGB frequently present Switzerland Key words: achondrogenesis type 1B; cartilage; differ- in breech position. After delivery, their ap- A Superti-Furga ential diagnosis. pearance is immediately perceived as abnormal Table 1 Classification of achondrogenesis Name Former eponyms Abbreviation Inheritance Molecular basis Achondrogenesis type IA Houston-Harris type ACGIA AR (?) Unknown Achondrogenesis type lB Fraccaro type ACGIB AR Mutations in sulphate transporter gene, DTDST, on 5q Achondrogenesis type 2 Langer-Saldino type ACG2 AD (de novo) Mutations in collagen II gene, COL2A1, on 12q 958 Superti-Furga proven ACG1B,'41519 22 as well as in pub- lished cases who could be classified as ACGlB by their histological features.' 17 The following should be noted: (1) there is a certain degree J Med Genet: first published as 10.1136/jmg.33.11.957 on 1 November 1996. Downloaded from of variability, and no single feature should be regarded as obligatory; (2) contrary to what has been reported,'4 distinction between ACGIB and ACGlA on radiographs is not always possible; (3) the degree of ossification is age dependent, and caution is needed in comparing radiographs from patients at differ- ent gestational ages. In ACGGB, the skull is only mildly affected: it is slightly less ossified than expected for gestational age, and the orbits may be extended laterally and superiorly. The disproportion be- tween the skull of almost normal size and the hypoplastic skeleton is noticeable. The clavicles are mildly affected; they are ossified, and, albeit somewhat short, of near normal shape. The scapulae are small and their contour is irregular. The vertebral bodies are usually not ossified; Figure I (Left) Clinical appearance of a patient with ACGIB, born at 34 weeks and at most, rudimentary calcification in the central died 25 minutes after birth. Note the flat face, the narrow thorax with protuberant part is seen. The vertebral lateral pedicles are abdomen, and particularly the severe nicronmelia with short stubby finigers anld toes. usually ossified, and part of the neural arches (Right) X ray of the same newborn. Following the resuscitation attempts, there is air in the stomach and intestine but not in the lungs. For details of the skeletal systeni, refer to may also be. The ribs are slightly thinner and the text. For radiographs of other newborns with ACGIB, see refs 14, 15, 16, 17, or 21. much shorter than normal; they are usually not (Reprintedfrom ref 19, with perniission of the publisher.) fractured (although occasionally, one or two fractures have been seen) and show slight cup- ping at their distal ends. The iliac bones are (fig 1, left). The abundance of soft tissue rel- smaller than usual and only their upper (cra- ative to the short skeleton gives these newborns nial) half is ossified, often in an irregular fash- a fat or hydropic appearance. There is a dis- ion; their shape can be compared to that of a proportion between the head, which is of nor- crescent or a paraglider. The ischium is not mal or near normal size, and the rest of the ossified or only minimally. body, which is much shorter than normal. The The tubular bones are those most markedly face is flat, the neck short, and the soft tissue affected (fig 1). Femora and humeri are usually of the neck may be thickened. The thorax shortened to a degree where no major axis can is narrow and the abdomen is protuberant. be recognised. As some metaphyseal spurring Umbilical or inguinal herniae are frequent. The occurs, these bones end up resembling cartoon most striking abnormality concerns the limbs. stars, thorn apples, or, for the haematological http://jmg.bmj.com/ They are severely shortened, sometimes re- expert, acanthocytes. The tibiae and fibulae sembling flippers, sometimes, when an articular are similarly misshapen and the fibulae are not crease at the hip or shoulder is present, re- ossified in more premature cases. In most cases, sembling sausages. The fingers and toes are the ulnae are amorphous, while the radii show similarly short and stubby. The feet and toes some tubulation and may have a peculiar distal are rotated inwards in a fashion reminiscent dichotomy thereby resembling a waterfork. The of diastrophic dysplasia. The external genital carpals and phalanges are usually very poorly on October 1, 2021 by guest. Protected copyright. organs are unremarkable. Death may occur ossified and can rarely be identified on whole before birth for causes which are not un- baby x rays. Sometimes bipartite ossification derstood. Even when heart action is present at of the medial phalanges can be seen. birth, respiratory insufficiency follows shortly. Fetuses with achondrogenesis may be as- certained by the observation of short femora Histology of cartilage on routine ultrasonography during pregnancy. In ACG1B, the cartilage matrix is rarefied and Other ultrasonographic signs may be nuchal partially replaced by a larger number of cells. oedema, reduced rump length, poor os- After haematoxylin-eosin staining, the matrix sification of the vertebral bodies and of the does not have the characteristic homogeneous, limb bones (leading to difficulties in de- ground glass appearance; instead, it shows termining their length), and polyhydramnios. coarsened collagen fibres. The fibres are often If pregnancy is interrupted, it is imperative to radially arranged around individual chon- obtain
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