Clin Genet 2014 Printed in Singapore. All rights reserved

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12434

Original Article

Fetal skeletal dysplasias in a tertiary care center: radiology, pathology, and molecular analysis of 112 cases Barkova E., Mohan U., Chitayat D., Keating S., Toi A., Frank J., Frank R., Tomlinson G., Glanc P. Fetal skeletal dysplasias in a tertiary care center: radiology, pathology, and molecular analysis of 112 cases. Clin Genet 2014. © John Wiley & Sons A/S. Published by John Wiley & Sons Ltd, 2014 Fetal skeletal dysplasias are a heterogeneous group of rare genetic disorders, affecting approximately 2.4–4.5 of 10,000 births. We performed a retrospective review of the perinatal autopsies conducted between the years 2002–2011 at our center. The study population consisted of fetuses diagnosed with skeletal dysplasia with subsequent termination, stillbirth and live-born who died shortly after birth. Of the 2002 autopsies performed, 112 (5.6%) were diagnosed with skeletal dysplasia. These 112 cases encompassed 17 of 40 groups of Nosology 2010. The two most common Nosology groups were osteogenesis imperfecta [OI, 27/112 (24%)] and the fibroblast growth factor receptor type 3 (FGFR3) chondrodysplasias [27/112 (24%)]. The most common specific diagnoses were thanatophoric dysplasia (TD) type 1 [20 (17.9%)], and OI type 2 [20 (17.9%)]. The combined radiology, pathology, and genetic investigations and grouping the cases using Nosology 2010 resulted in a specific diagnosis in 96 of 112 cases. Conflict of interest

The authors have declared no conflicting interests.

E. Barkovaa,† , U. Mohanb,† , D. Chitayatc,d , S. Keatinge , A. Toif , J. Frankc , R. Frankc , G. Tomlinsong and P. Glanch a Department of Medical Imaging, South Shore Regional Hospital, Bridgewater, Nova Scotia, Canada, b Department of Obstetrics and Gynecology, University of Calgary, Calgary, Alberta, Canada, c The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, d Department of Paediatrics, Division of Medical and Metabolic Genetics, e Department of Laboratory Medicine and Pathobiology, Perinatal Pathology, Mount Sinai Hospital, f Department of Diagnostic Imaging, Mount Sinai Hospital, g Institute of Health Policy, Management & Evaluation, and h Department of Medical Imaging, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada † These

authors contributed equally.

Key words: autopsy – fetal musculoskeletal dysplasia – molecular analysis – osteochondrodysplasia – pathology – prenatal diagnosis – radiology – skeletal dysplasias Corresponding author: Dr Phyllis Glanc, Department of Medical Imaging, Sunnybrook Health Sciences Centre, University of Toronto, Rm MG160, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5. Tel.: +416 480 6100; fax: +416 480 5855; e-mail: [email protected] Received 16 December 2013, revised and accepted for publication 22 May 2014

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Barkova et al. Fetal skeletal dysplasias are a heterogeneous group of rare genetic disorders, affecting approximately 2.4–4.5 of 10,000 births (1–3). While fetal skeletal dysplasias are generally recognized on prenatal sonography, an accurate diagnosis of a specific skeletal dysplasia can be challenging due to its rarity, the variety of the causative genes and the spectrum of mechanisms associated with their formation. The Nosology and classification of genetic skeletal disorders, 2010 revision (Nosology 2010) (4) provides a mechanism for categorization of the skeletal abnormalities using clinical, radiological, pathological and molecular information. Its use as a guideline can help in directing the investigation and determining the specific diagnosis. Currently 456 disorders are recognized within 40 total Nosology groups (4, 5) and more conditions have been identified and characterized since the Nosology 2010 has been published. Only a few publications reported the utility of the 2010 Nosology classification system (6) and presented the frequency of the different conditions as seen in one tertiary center (6–8). Our study provides information regarding the frequency of different skeletal dysplasia detected perinatally and reinforces the importance of a multidisciplinary team and continued investigation, in accurately diagnosing the condition. Finding the diagnosis is crucial for accurate genetic counseling and reproductive decisions. Methods

Research ethics board approval was obtained. A retrospective review of the 2002 fetal or perinatal autopsies conducted in the years 2002–2011 at a tertiary referral center, was performed at Mount Sinai Hospital, Toronto, Ontario, Canada. The study population consisted of affected pregnancies interrupted in their second or third trimesters, following parental decision, fetuses that were stillborn and live-born infants who died shortly after birth. The data were entered into a standardized and anonymized web-based reporting system. The web-based reporting system included detailed autopsy findings, including histopathology, X-rays and molecular analysis using extracted DNA where available. In a small number of cases, the autopsies were limited to external evaluation including X-rays/Faxitron imaging and photos, based on parental wishes. Anteroposterior and lateral radiographs, using a Faxitron Cabinet X-ray system (Hewlett-Packard, McMinnville, OR) were obtained in all cases, following parental/women consent. The Faxitron images were read by a single perinatal radiologist with more than 30 years of experience in obstetrical imaging and external consultation was obtained as needed. The cases with skeletal dysplasia were identified and then classified in accordance with Nosology and classification of genetic skeletal disorders: 2010 revision system (4), based on the final radiological, pathological and genetic/molecular analysis results.

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Results

Within this retrospective cohort of 2002 autopsied fetuses, 112 (5.6%) were identified as having skeletal dysplasia. These were classified under 17 of the 40 groups according to the Nosology 2010 (4). There were 62 males and 50 females (male: female ratio of 1.24:1). Eight cases had a family history of a skeletal dysplasia of which three cases (2.7%) were confirmed recurrences and one was transmission of an autosomal dominant type (0.9%), the remaining four cases had a non-specific or limited history. The three recurrent cases were respectively a Group 4, diastrophic dysplasia type; a Group 9, asphyxiating thoracic dystrophy type and a Group 21 CDP Conradi–Hunerman type (CDPX2). A single case of heterozygous achondroplasia was related to maternal transmission. The highest degree of consanguinity was a single case of second cousins, whose fetus was affected by short-rib polydactyly (SRP) type 1/3 (Saldino-Noonan/Verma-Neumoff type). Complete autopsy was consented and performed in 88 cases (78.6%), while limited autopsy, consisting of Faxitron X-ray images and external examination only, were performed in the remaining 24 cases (21.4%). Genetic analysis was available in 96 cases (85.7%). Classification to one of the groups in Nosology 2010 was achieved in 111 cases (99%), and a specific diagnosis was achieved in 96 cases (85.7%). Outside expert consultation was obtained in some of the cases. A combination of radiological, gross morphology and genetic studies were used to determine a final diagnosis. The most common groups encountered as per the Nosology 2010 were as follows: Osteogenesis imperfecta (OI) and decreased bone mineral density (Group 25) in 27 (24.1%); FGFR3 chondrodysplasia (Group 1) in 27 (24.1%); limb hypoplasia-reduction defects (Group 38) in 12 (10.7%); short-rib dysplasia ± polydactyly (Group 9) in 9 (8%); chondrodysplasia punctata (Group 21) in 9 (8%); craniosynostosis syndromes (Group 4) in 4 (3.6%), and dysostoses with predominant craniofacial involvement in 4 (3.6%). Each of the remaining groups contained three or fewer cases (Table 1). The most common specific diagnoses encountered were OI type 2 in 20 (17.9%), and thanatophoric dysplasia (TD) types 1 and 2 in 25 (22.3%). Other common specific diagnoses included chondrodysplasia punctata type unknown in six (5.4%), OI type 3 in four (3.6%), de Lange syndrome in four (3.6%), hypophoshatasia, perinatal lethal and infantile forms in three (2.7%), asphyxiating thoracic dysplasia in three (2.7%) and SRP type 4 (Beemer short-rib polydactyly without polydactyl) in three (2.7%). The rest of the specific diagnoses contributed to two or fewer cases (Table 1). The pathological and radiological musculoskeletal (MSK) features seen in all 20 cases of OI type 2, were decreased chest circumference and pulmonary hypoplasia, abnormal bone mineralization, severe micromelia, and multiple fractures/angulations of the long bones and ribs. Findings present in only some of the 20 cases included platyspondyly (n = 6) and cranial abnormalities such as deformed calvarium/dolicocephaly/Wormian

Fetal skeletal dysplasias in a tertiary care center Table 1. Distribution of musculoskeletal dysplasias detected at our center Nosology Nosology group group number name and subtypes 25

1

38

9

21a

33

34

35

Osteogenesis imperfecta (OI) and decreased bone density OI type 2 OI type 3 OI type 1 OI type unknown OI type 4 FGFR 3 chondrodysplasia Thanatophoric dysplasia type 1 Thanatophoric dyplasia type 2 Thanatophoric dyplasia type unknown Achondroplasia Limb-hypoplasia-reduction defects DeLange syndrome Femoral hypoplasia-unusual facies Holt-Oram syndrome Unknown Okihiro syndrome Roberts syndrome Short-ribs dysplasias (±polydactyly) (SRPS) Asphyxiating thoracic dystrophy SRPS type 4 SRPS type 1/3 Chondroectodermal dysplasia Chondrodysplasia punctata (CDP) CDP type unknown CDP Conradi–Hunnerman type CDP tibial–metacarpal type Craniosynostosis syndromes Pfeiffer syndrome Apert syndrome Dysostoses with predominant craniofacial involvement Hemifacial microsomia Frontonasal dysplasia Acrofacial dysostoses (Nager type) Unknown Dystostoses with predominant vertebral (±costal involvement) Unknown

Number out of 112

(%)

27

24.1

Table 1. continued Nosology group number

26 20 4 1 1 1 27 20

4 24.1 2

3 2 2 12

10.7 39

4 2 5 2 2 1 1 9

18 8.0 11

3 3 2 1 9

17 8.0 14

6 2

1 3.6

2 2 4

3.6

1 1 1

2

Klippel Feil anomaly with laryngeal malformation Abnormal mineralization Hypophosphatasia, perinatal lethal and infantile forms Sulfation disorders group Diastrophic dysplasia Ateleosteogenesis type 2 Type 2 collagen group and similar disorders Hypochondrogenesis Spondyloeiphyseal dysplasia congenita Achondrogenesis type 2 Polydactyly–syndactyly– triphalangism Postaxial polydactyly Perlecan Dyssegmental dysplasia (Silverman-Handmaker type) Bent bone dysplasias Campomelic dysplasia Metaphyseal dysplasias Cartilage-hair hypoplasia (CHH; metaphyseal dysplasia, mcKusick type) Mesomelic and rhizomelic dysplasias Unknown Severe sponylodysplastic dysplasias Achondrogenesis type 1a Unknown

Number out of 112

(%)

1

3 3

2.7

3 2 1

2.7

3

2.7

1 1 1 2

1.8

2 1 1

0.9

1 1 1 1

0.9

1

0.9

1 1

0.9

0.9

1 1

0.9

a Two

4

1 3

Nosology group name and subtypes

2.7

cases in Group 21 had maternal factors. Please see text for additional details.

bones (n = 9). Common facial features included triangular face with a high forehead, frontal bossing and prominent eyes (n = 13), abnormal ears (11/20), mandibular abnormalities such as micrognathia (n = 12), and nuchal thickening/cystic hygroma (n = 8). In the 25 cases of TD types 1 and 2, common pathological and radiological MSK features included decreased chest circumference and pulmonary hypoplasia (all cases), normal mineralization (all cases), bowed long bones (n = 24) with a single case of TD type 2 not featuring femur bowing (n = 24), trident hand/brachydactyly (n = 20), ‘spiked’ pelvis (n = 15), and hypoplastic scapula (n = 11). Common facial/brain features included

3

Barkova et al. temporal lobe dysplasia (all 24 cases in which complete autopsy was performed), mild ventriculomegaly (n = 12), abnormal cranium including macrocranium, frontal bossing (n = 23), and nuchal thickening (n = 10). In the nine cases of the short-rib dysplasia ± polydactyly group, common MSK pathological and radiological features were short ribs with decreased chest circumference and pulmonary hypoplasia (n = 8), bowing/metaphyseal flaring (n = 4), hands’ polydactyly (n = 4), foot polydactyly (n = 2), and spiked pelvis (n = 6). Other common non-skeletal features included nuchal thickening (n = 5), abnormal ears (n = 5), genitourinary abnormalities (n = 7), renal abnormalities such as enlarged kidneys (n = 3), and ambiguous genitalia (n = 2). Cardiac anomalies were seen in three cases including two with arch abnormalities and atrioventricular septal defect (AVSD, Fig. 3). In the nine cases of the chondrodysplasia punctata group, common MSK pathological and radiological features included abnormal ossification in all cases (i.e. epiphyseal stippling), decreased chest circumference with pulmonary hypoplasia (n = 4) and digital abnormalities (clinodactyly, n = 4; brachydactyly, n = 4; syndactyly, n = 2). Other common non-skeletal features include nuchal thickening (n = 5), dysmorphic facies (n = 6), and flat profile (n = 4). Of note, within this group maternal factors included one mother affected with systemic lupus erythematosus (current medications included prednisone, azathioprine, dalteparin and hydroxychloroquine) and another mother had factor V Leiden deficiency treated with warfarin. One fetus was affected with trisomy 21. Histopathological analysis of the growth plates and bones was part of the autopsy protocol. However, in none of the cases were these results crucial for making a diagnosis.

(a)

(b)

Discussion

The osteochondrodysplasias are etiologically a heterogenous group of disorders with more than 456 conditions currently recognized and classified in 40 total Nosology groups (4, 5, 9). Most cases are single gene with autosomal dominant, autosomal recessive and X-link modes of inheritance; however, some are the results of microscopic and submicroscopic chromosome abnormalities as well as, maternal diseases and maternal exposures (10, 11). Despite the rarity of the individual conditions we found that a combination of radiology, pathology and molecular analyses enabled us to classify 99% of the cases to a specific group in the Nosology 2010 classification and make a specific diagnosis within the group in 85.7% of the cases. Thus, the classification according to the Nosology 2010 provided us with a useful framework for categorization of skeletal dysplasia and helped in making a diagnosis (4, 12). The most common Nosology groups encountered in our study were OI and decreased bone density, FGFR3 chondrodysplasia, limb hypoplasia reduction defect,

4

Fig. 1. Osteogenesis imperfecta type 2. (a) Anteroposterior (AP) radiograph showing a small thorax, poor ossification of the calvarium and fractures in multiple ribs and extremities. (b) AP specimen demonstrates severe micromelia and small thorax.

short-ribs dysplasias (+polydactyly), and chondrodysplasia punctata group. In the 2011 study by Stevenson et al. (6), (a population based study also using Nosology 2010 classification)(4), there were similar findings except that type 2 collagen disorders (0.2/10,000) and bent bone dysplasias (0.12/10,000) were among the five most common Nosology groups encountered rather than limb hypoplasia reduction defect or short-ribs dysplasias( with or without polydactyly) detected in our study. The most common specific disorders in our study were TD type 1, and OI type 2, comparable to the numbers quoted in the literature (6–8, 13–15). A solitary case of achondrogenesis type 2 was seen in our study (1.1%), a lower frequency than reported in the literature where the

Fetal skeletal dysplasias in a tertiary care center Table 2. Common and distinguishing features associated with the five most common skeletal dysplasias investigated by us over a 10-year period and classified according to the Nosology 2010 Count out of 112 (%) 27

Percentage (%)

Group number

24.1

25

Group name

Distinguishing group features

OI and decreased bone density

Demineralization resulting in fracture (s) • OI type 2 characterized by: o Multiple fractures within single bone o Severe micromelia, pulmonary hypoplasia, dysmorphic facies

27

24.1

1

FGFR3 chondrodysplasia

Macrocranium, platyspondyly, thanatophoric dysplasias characterized by: • severe micromelia • pulmonary hypoplasia • trident hand • temporal lobe dysplasia

12

10.7

38

Limb hypoplasiareduction defects

9

8

9

Short-ribs dysplasias ±polydactyly

9

8

21

Chondrodysplasia punctata

May vary from hypoplasia to amelia. Includes split hand–foot deformities Short-ribs polydacytyly • Variably present in SRPS Beemer type and asphyxiating thoracic dystrophy • Spiked/trident pelvis Premature stippling of epiphyses; multiple calcified cartilaginous foci paravertebral; asymmetric shortening long bones flat facial profile

OI, osteogenesis imperfecta, SRPS, Short-ribs dysplasias (±polydactyly).

quoted frequency was as high as 8.2% (13, 16). We also noted that campomelic dysplasia was under-represented in our study. This may relate to the fact that our center is not an international skeletal registry and thus investigates only cases referred to us from our catchment area, rather than the ‘interesting’ or difficult to diagnose cases which are more likely to be referred to international registry (13). These differences may better reflect our general population than an international skeletal registry. An alternative explanation is that some of these cases may have been missed prenatally and have survived the early neonatal period thus were not a part of our autopsy cohort. Common and distinguishing features seen in the OI and decreased bone density group (Nosology Group 25) include fractures and decreased bone density with the subtype OI type 2 (20/27) characterized by multiple fractures within a single bone, severe micromelia, pulmonary hypoplasia and dysmorphic facies including a flat profile and triangular face with prominent eyes and gray sclera. The large fontanelle associated with this condition

result in high resolution of the intracranial structures and the low skull mineralization results in indentation when pressure is being applied to the skull by the ultrasound probe. These observations help in making the diagnosis of hypomineralized skull. OI type I and IV are usually characterized by asymmetrical bent/fractured long bones especially the femur. This demineralization and fractures are not common in the other four most commonly identified Nosology groups (Fig. 1, Table 2). Common and distinguishing features seen in FGFR3 chondrodysplasia (Nosology Group 1) as represented by TD include macrocrania and platyspondyly and the TD is characterized by severe micromelia, pulmonary hypoplasia, trident hand and temporal lobe dysplasia. Macrocranium and temporal lobe dysplasia are not common in the other four most commonly identified Nosology groups (Fig. 2). Achondroplasia, in the homozygous form, is similar to TD in the early onset, skeletal characteristics and poor prognosis. It can be diagnosed by molecular analysis and the fact that usually both parents are affected with achondroplasia. Cases

5

Barkova et al. (a)

(b)

Fig. 2. Thanatophoric dysplasia type 1. (a) Anteroposterior (AP) radiograph shows normal mineralization, short, curved femurs, platyspondyly with U-shaped vertebral bodies, and narrow thorax. (b) AP photograph demonstrates severe micromelia and small thorax.

with achondroplasia typically present late in the second trimester with relatively large head and progressive shortening of the long bones but chest circumference and rib length are within the normal range. The limb hypoplasia-reduction defects (Nosology Group 38) is etiologically very heterogeneous with most cases being sporadic and probably caused by fetal vascular injury to the developing limbs (17). They are usually isolated and asymmetrical, and their distinguishing features include limb reduction defects that may vary from hypoplasia to amelia. However, a few inherited cases were detected including split hand–foot deformities, some being inherited from an affected parent. Although asymmetric limb shortening can be seen in the chondrodysplasia punctata group (Nosology Group

6

21), the presence of stippled epiphyses and calcified paravertebral foci help distinguishing between these two groups. In addition, chondrodysplasia punctata group diagnoses frequently demonstrate dysmorphic facies including hypoplastic nasal bone, flat facial profile and some show low UE3 on maternal serum screening in the second trimester known to be associated with abnormal cholesterol metabolism. In the short-ribs dypslasias (±polydactyly) group (Nosology Group 9) the main findings are short ribs with a very narrow chest and occasionally, but not in all cases, polydactyly. Other characteristic findings which can be detected on fetal ultrasound or radiographs are spiked/trident pelvis. The presence of polydactyly, although not found in all cases in this group, is not usually in the other four most commonly diagnosed Nosology groups (Fig. 3, Table 2). The single unclassified case was initially felt to represent Group 1/FGFR3 chondrodyplasia, a non-lethal variant. Spontaneous intrauterine demise occurred at 39 weeks gestation. The prenatal ultrasound findings were characterized by mild to moderate rhizomelic limb shortening, facial dysmorphism including frontal bossing, absent nasal bone and midface hypoplasia. Autopsy and radiograph findings demonstrated marked restricted growth plate primarily in the long bones and cortical bone proliferation in the diaphysis of the long bones. Additional findings included wormian bones, overlapping digits with brachydactyly, trident acetabulum configuration and external hip rotation. Direct mutation analysis was negative for all mutations in the FGFR3 gene and external consultation was not helpful in achieving a diagnosis. There are several key limitations of this study. First and foremost, this is a perinatal autopsy cohort which included terminations of second and third trimester fetuses, stillbirths and live-born neonates who demised shortly after birth and for whom either partial or complete autopsy permission was obtained. We are unable to control the type of counseling provided to the families involved or to access the decision-making process as to whether to terminate or continue a pregnancy. In addition, as a single tertiary referral center, certain cases were probably not sent to us for evaluation for an unknown variety of reasons. This may in part account for the low incidence of type 2 collagenopathies and campomelic dysplasia in our study as compared with population registry studies. Our report is one of the largest retrospective single center study (n = 112) performed (Table 2). The study reinforces the importance of the interaction between sonographers, geneticists, radiologists, pathologists and laboratory medicine to achieve a specific diagnosis and thus provide information regarding the prognosis, recurrence risk and prenatal/pre-implantation diagnosis for the parents/mother involved. Unlike information provided by registries of skeletal dysplasias who are usually consulted on complicated or undiagnosed cases, the information obtained by our center is based on cases referred to and seen by us prenatally, as a tertiary center. We believe that our series provides a good representation

Fetal skeletal dysplasias in a tertiary care center Table 3. Results of mutation analysis in the cases where mutations were identified Nosology group 1 NM_000142.4

2 COL2A1 NM_001844.4 4 NM_000112.3 5 NM_008305.3 9 NM_153717.2 17 NM_013059.1 25 COL1A1 (NG_007400.1) COL1A2 (NG_007405.1)

26 NM_013059.1 33 FGFR2 NM_022970.3

38 NM_133433.3

Study number

Disorder type

Gene mutation

Protein mutation

26

Thanatophoric dysplasia type 1

FGFR3 c.742C>T

p.Arg248Cys

114 205 213 234 258 281 297 340 373 424 432 566 619 687 693 819 820 825 462

Thanatophoric dysplasia type 1 Achondroplasia Thanatophoric dysplasia type 1 Thanatophoric dysplasia type 1 Thanatophoric dysplasia type 1 Thanatophoric dysplasia type 1 Thanatophoric dysplasia type 1 Thanatophoric dysplasia type 1 Thanatophoric dysplasia type 1 Thanatophoric dysplasia type 1 Thanatophoric dysplasia type 1 Thanatophoric dysplasia type 1 Achondroplasia Thanatophoric dysplasia type 2 Thanatophoric dysplasia type 1 Thanatophoric dysplasia type 1 Thanatophoric dysplasia type 1 Thanatophoric dysplasia type 1 Hypochondrogenesis

FGFR3 c.742C>T FGFR3: c.1138G>A FGFR3 c.742C>T FGFR3 c.742C>T FGFR3 c.742C>T FGFR3 c.1118A>G FGFR3 c.1118A>G FGFR3 c.742C>T FGFR3 c.2418A>C FGFR3 c.1108G>T FGFR3 c.2417G>C FGFR3 c.742C>T FGFR3 c.1138G>A FGFR3 c.1948A>G FGFR3 c.1108G>T FGFR3 c. 1118A>G FGFR3 c. 1118A>G FGFR3 c.742C>T COL2A1 c.2487_2513del27

p.Arg248Cys p.Gly380Arg p.Arg248Cys p.Arg248Cys p.Arg248Cys p.Tyr373Cys p.Tyr373Cys p.Arg248Cys p.*807Serext140 p.Gly370Cys p.*807Serext140 p.Arg248Cys p.Gly380Arg p.Lys650Glu p.Gly370Cys p.Tyr373Cys p.Tyr373Cys p. Arg248Cys Pro832_Gly840del

226

Atelosteogenesis type 2 (AO2)

SLC26A2 c.1824A>C

p.Leu599Phe

153

Dyssegmental dysplasial Silverman-Handmaker type Ellis-van Creveld

HSPG2 c.del1356-27_1507+59

no functional HSPG2 protein

EVC c.1127C>T, c.2758C>T

p.ALA376Val, p.Leu920Phe

ROR2 c.754T>A, c.2083G>A

p.Cys252Ser, p.Gly695Arg

COL1A1 c.2023-2025dup

p.Ala675dup

539 298 21

40 203 328 339 366 370 385 608 620 674 814 816 822 823 482

Mesomelic and rhizomelic dysplasia – unknown OI type 2

COL1A2 c.1406 G>T COL1A1 c.860G>T COL1A2 c.2756G>A COL1A2 c.1874G>A COL1A2 c.1271G>T COL1A1 c.1804G>A COL1A2 c.1271G>T COL1A2 c.2575G>A COL1A1 c.3226G>A COL1A1 c.1075G>A COL1A2 c.2747G>A COL1A2 c.983G>T COL1A1 ex.20 c.1353+1G>T COL1A1 c.1201G>A ALPL c.815G>T

p.Gly469Val p.Gly287Val p. Gly919Asp p.Gly625Asp p.Gly424Val p.Gly602Arg p.Gly928Val p.Gly859Ser p.Gly1076Ser p.Gly359Arg p.Gly916Glu p.Gly328Val – p.Gly401Ser p.Arg255Leu

131

OI type 2 OI type 2 OI type 2 OI type 2 OI type 2 OI type 2 OI type 2 OI type 3 OI type 3 OI type 2 OI type 2 OI type 2 OI type 2 OI type 3 Hypophosphatasia perinatal lethal and infantile forms Apert syndrome

FGFR2 c.758C>G

p.Ser252Trp

170 345 484 222

Apert syndrome Pfeiffer syndrome (FGFR2-related) Pfeiffer syndrome (FGFR2-related) De Lange syndrome

FGFR2 c.758C>G FGFR2 c.1019A>G FGFR2 c.1019A>G NIPBL c.2389C>T

p.Pro253Arg p.Tyr340Cys p.Tyr340Cys p.Arg797X

OI, osteogenesis imperfecta.

7

Barkova et al. (a)

analysis at different clinical and research laboratories according to their expertise are important elements in achieving a diagnosis. Familiarity with imaging and pathological findings, the distribution and lethality of various perinatal skeletal dysplasias, good pattern recognition skills and a method of grouping these disorders using the Nosology 2010 classification scheme are of utmost importance to provide appropriate counseling for the couples/mothers regarding the etiology and inheritance of the affected pregnancies and the implications the diagnosis may have on their future reproductive plans. Acknowledgements

(b)

This study was supported by the Comprehensive Research Experience for Medical Students (CREMS) Summer Research Program 2010, University of Toronto, ON, Canada. We would like to thank Dr. Sheila Unger and Dr Gen Nishimura for their help in reviewing the fetal X-rays.

References

Fig. 3. Short-rib polydactyly (SRP) type 2. (a) Anteroposterior (AP) radiograph showing narrow thorax and short ribs, normal mineralization and trident pelvis. (b) AP specimen photograph highlights severe micromelia and upper extremity polydactyly.

of the distribution of different skeletal dysplasias in the general community. Furthermore, our center pursued DNA analysis in every case suspected of being caused by a single gene disorder and was able to diagnose 86% of such cases (Table 3), using clinical and research labs and reviewing the initially undiagnosed cases repeatedly in view of the most recent publications. In some of the cases the DNA quality was not sufficient for analysis and some cases took a long time to resolve. Conclusion

Making a specific diagnosis in cases with skeletal dysplasias is a difficult task due to the low incidence of this group of conditions and the rarity of many of the specific conditions. A team approach, familiarity with numerous rare conditions and performing the DNA

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Fetal skeletal dysplasias in a tertiary care center: radiology, pathology, and molecular analysis of 112 cases.

Fetal skeletal dysplasias are a heterogeneous group of rare genetic disorders, affecting approximately 2.4-4.5 of 10,000 births. We performed a retros...
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