Clinical, genetical, radiological, and anatomopathological survey of 17 patients with lethal osteochondrodysplasias

Clinical, genetical, radiological, and anatomopathological survey of 17 patients with lethal osteochondrodysplasias

Marcial Francis Galera, Francy Reis da S. Patrício, Mirlene Cecília S. Pinho Cernach, Henrique Manoel Lederman and Decio Brunoni

Disciplina de Genética, Departamento de Morfologia da Universidade Federal de São Paulo, Escola Paulista de Medicina, Rua Botucatu, 740. Edifício Leitão da Cunha, 04023-062 São Paulo, SP, Brasil. Send correspondence to M.F.G.

ABSTRACT

Seventeen patients thought to have lethal osteochondrodysplasias were evaluated. Diagnosis was established through clinical evaluation, radiological studies and necropsy. Genetic counseling was provided to the affected patient's families. Specific diagnosis was confirmed in 16 cases. Nosologic diagnosis was done through clinical evaluation. However, the most efficient method for verifying the diagnosis was a skeletal radiological study. This fact corroborates the orientation of the International Classification of Osteochondrodysplasias (International Working Group on Constitutional Disease of Bone, 1992) in which a radiological criterion was adopted as the most relevant for classification of osteochondrodysplasias. An anatomopathological study was also done to detect internal anomalies, and was effective in identifying abnormalities in epiphyseal growth plate in a bone fragment study. This method had low specificity, but in two cases it was especially decisive for diagnostic differentiation.

INTRODUCTION

Osteochondrodysplasias are a heterogeneous group of constitutional bone diseases and are among the main causes of perinatal morbidity and mortality involving genetic etiology. Clinically, bone length, shape, and density changes have been observed in skull, limbs and the spinal column. Disproportionate low stature, restriction and change of the chest shape, other structural abnormalities, and undetermined constitutional changes may cause intrauterine death or severe, generally lethal, neonatal complications. In these cases, death occurs due to severe respiratory insufficiency secondary to pulmonary hypoplasia related to the small size of the thorax (Sillence et al., 1979; Rimoin and Lachman, 1983; Escobar et al., 1990).

Due to improved public health care in recent decades, infant mortality has decreased in many countries.

This fact is reflected in perinatal causes of death. Infections and gestational disorders were the main causes of perinatal mortality but now congenital malformations and especially genetic diseases have become important causes of perinatal mortality (Machin, 1975; Naye, 1977; Edouard and Alberman, 1980). Several reports have demonstrated the importance of the malformation syndrome group which causes perinatal death through congenital malformations (Gillerot et al., 1982; Young et al., 1986; Perez and Brunoni, 1995).

Epidemiological reports differ depending on sample type and the population studied. The highest rate incidence in neonates was observed by Gustavson and Jorulf (1975), 1:2,117, and the lowest, 1:8,900, by Connor et al. (1985). Other authors have revealed intermediary rates in their studies (Harris and Patton, 1971; Camera and Mastroiacovo, 1982; Stoll et al., 1989; Andersen-Jr., 1989; Andersen-Jr. and Hauge, 1989).

Few studies have been made to determine the incidence and prevalence of osteochondrodysplasias in Brazil. The only Brazilian study was published by Orioli et al. (1986), which presented data from ECLAMC (Estudo Colaborativo Latino Americano de Malformações Congênitas). The records covered data from 1978 to 1983 with 349,470 births. The prevalence rate was 2.3:10,000, based on 80 patients (70 live birth, 10 stillbirth).

The current classification of osteochondrodysplasias is an update of the International Classification of Osteochondrodysplasias (International Working Group on Constitutional Disease of Bone, 1992) and is based simply on radiological criterion. The former mixture of clinical, pathogenetic, and radiological criteria was abandoned because it was not able to adequately characterize cases in which clinical similarity was not reflected in radiography. Spranger (1989) created a classification of lethal osteochondrodysplasias by dividing patients into 11 groups by morphological similarities in radiological study.

The objectives of the present survey were diagnostic confirmation of suspected cases of lethal perinatal osteochondrodysplasias; identification of unknown or rare syndromes; evaluation of methodology used in diagnostic definition, and to provide genetic counseling to the affected patient's families.

PATIENTS AND METHODS

Patient selection

Seventeen patients suspected of lethal osteochondrodysplasia were evaluated. The retrospective and prospective cases were selected from March 1992 to January 1994. Cases were selected from the Genetic Department's medical files and were tested by the Fetal Medicine Sector and Neonatal Unity. This work group is a referral center and assists a heterogeneous population. However, this sample is not a representative epidemiological study, because it is not possible to establish frequency and incidence rates from isolated samples. One case was referred by the Genetic Group at Federal University of Alagoas .

Clinical evaluation

Anamnesis were provided by the patients' mothers. Information concerned: identification, gynecological and obstetric antecedents, family history, genealogy and prenatal examinations. Patient evaluation was performed using clinical-genetical methodology through phenotypic description and anthropometry, a standard form for the malformed newborns.

Radiological study

Posterior-anterior and lateral whole body radiographs were performed in all cases. Specific body segments were X-rayed in some situations. Radiographs were studied by a genetics team who were assisted by a radiologist.

Anatomopathological study

Necropsy was performed in 15 cases. Phenotypic deviations and internal anomalies were identified by macroscopic examination. Microscopic study was performed on all tissue with special attention to bone tissue. Hematoxylin-eosin staining was routinely used. Other staining methods were used in some cases such as Masson's Trichrome, periodic acid-Schiff, and Alcian blue.

Classification of osteochondrodysplasias

Cases were classified using the International Classification of Chondrodysplasias, 1992. Three cases were not classified in that manner. Two were classified with Spranger's Classification of Lethal Osteochondrodysplasias (Spranger, 1989; Spranger and Maroteaux, 1991), and the other was not classified by either system.

Genetic counseling

Genetic counseling was provided after the study was concluded for each case. The objectives were to explain the diagnosis and establish the risk of recurrence for patients' parents.

RESULTS

Diagnosis

After the conclusion of the survey, the diagnosis was confirmed in 16 of the 17 cases evaluated (Table I).

Table I
- Internal organ anomalies and recurrence risk in 17 cases of lethal osteochondrodysplasias.

Diagnosis	Internal organ anomalies	Recurrence risk (%)
Achondrogenesis I A (Houston-Harris)	Pulmonary hypoplasia	25
Achondrogenesis I A (Houston-Harris)	Pulmonary hypoplasia	25
Atelosteogenesis type I	Pulmonary hypoplasia	<1
Blomstrand dysplasia	Pulmonary hypoplasia	25
Campomelic dysplasia	Pulmonary hypoplasia	25
Hypochondrogenesis	Pulmonary hypoplasia and biliary atresia	25
Langer-Saldino dysplasia	Pulmonary hypoplasia, dilatation of left lateral encephalic ventricle, left inguinal hernia	25
Langer-Saldino dysplasia	None	25
Langer-Saldino dysplasia	Pulmonary hypoplasia	25
Osteogenesis imperfecta type II A	Pericardic effusion	<1
Osteogenesis imperfecta type II A	None	<1
Osteogenesis imperfecta type II B	None	7.7
Short rib-polydactyly syndrome type III	Pulmonary hypoplasia, cardiac hypoplasia, bilateral pleural effusion, ascitis, kidney hypoplasia, congenital liver fibrosis	25
Thanatophoric dysplasia	Pulmonary hypoplasia	<1
Thanatophoric dysplasia	–	<1
Thanatophoric-like dysplasia, Glasgow type	–	25
Not defined	Pulmonary hypoplasia, pneumopericardium	25

Diagnostic methods

Clinical evaluation, through careful phenotypic description, indicated a diagnostic hypothesis for osteochondrodysplasia in 12 cases. They were: thanatophoric dysplasia (two cases), osteogenesis imperfecta (three cases), achondrogenesis group (five cases), short rib-polydactyly syndrome (one case) and campomelic dysplasia (one case). A definitive diagnosis was achieved through radiographic examination in all cases.

Necropsy was performed in 15 of the 17 cases. Macroscopic and microscopic examinations of organs and tissues almost always revealed cardiac and pulmonary anomalies. Histological study of osseous tissue was decisive in diagnosing Blomstrand dysplasia in which advanced skeletal maturity pattern was observed, and in atelosteogenesis in which the giant cells in the resting cartilage zone were decisive for classifying it in one of the atelosteogenesis groups.

Separately, the histological examination would not define the diagnosis in the other cases. Pulmonary hypoplasia was observed in 73% of necropsy cases (11/15). This data may also be seen in Table I.

Genetic counseling

Genetic counseling was performed in 14 cases. In these cases the risk of recurrence was established based on Mendelian inheritance patterns (Table I). Three families did not accept counseling in spite of several attempts.

DISCUSSION

Diagnostic methods

Clinical evaluation based on observation and careful phenotypic description was very important for establishing the diagnostic hypothesis for the 17 cases studied. Later, confirmation was possible in 11 cases.

Radiological study established the definitive diagnosis in agreement with the criteria of the International Classification of Osteochondrodysplasias (1992). These results are similar to those in published surveys (Foot et al., 1978; Seppänen, 1986). Xeroradiography is an excellent diagnostic method for tissues with little mineral content (e.g., fetal bones and soft tissues), producing images with better definition than traditional radiography in osteochondrodysplasias (Graham Jr. et al., 1984; Elejalde et al., 1985). Unfortunately, we do not have access to this method, since it is only used for mammographs in our hospital. We think that this method would be much more efficient than conventional radiography in extremely premature newborns.

An anatomopathological study was performed in about 90% of the cases and demonstrated that most of the internal anomalies were cardiac and pulmonary. Pulmonary hypoplasia was detected in 70% of the cases in which necropsy was performed. Therefore, pulmonary hypoplasia was the cause of death in all living newborns. It was observed that a histopathological study could show a nosologic diagnosis in most situations, but with low specificity. However, in this sample, bone fragment examination was decisive in confirming the diagnosis of cases 5 and 17.

Genetic counseling

Genetic counseling was performed in 14 of 17 cases.

In syndromes in which the inheritance pattern was defined as dominant autosomal, a low risk of recurrence was established, as in two cases of thanatophoric dysplasia. In case 17 the diagnostic definition was decisive for establishing the risk of recurrence. While atelosteogenesis type I is probably a dominant autosomal, because all described cases are sporadic, type II is considered a recessive autosomal disorder. Therefore a low risk of recurrence was established, because the case was sporadic, and there was no parental consanguinity.

Risk of recurrence was established in about 75% of cases. Autosomal recessive inheritance is well defined for campomelic dysplasia, achondrogenesis I A, and short rib-polydactyly type III syndrome. For Blomstrand dysplasia (case 5), in spite of few published cases, there is a strong indication of autosomal recessive etiology, because in the two cases previously published, there was parental consanguinity (Blomstrand et al., 1985; Spranger and Maroteaux, 1991; Young et al., 1993). There were parental consanguinity and repetition in sibship in our case. These observations support the proposed inheritance patterns. Thanatophoric-like dysplasia Glasgow type (case 11) is considered an autosomal recessive disorder based on many reports (Connor et al., 1985; Maroteaux et al., 1988). In case 15, although there was no specific type definition, the nosologic diagnosis of osteochondrodysplasia was established. Thus, the risk of recurrence was 25% due to parental consanguinity.

The spondyloepiphyseal dysplasia congenital group has classically been referred to as autosomal recessive disorders, but the last edition of the International Classification of Osteochondrodysplasias characterized this group as an autosomal dominant disease (International Working Group on Constitutional Diseases of Bone, 1992). This fact is explained by an increase in the number of publications where the molecular aspects of osteochondrodysplasias were considered. Defects in the synthesis and functioning of collagen type II have been related to the pathogenesis of this "family" syndrome. Mutations in the Col2A1 gene have been present in the heterozygotic form, which explains the autosomal dominant pattern in the cases studied (Eyre et al., 1986; Horton et al., 1987; Godfrey and Hollister, 1988; Horton et al., 1989; Lee et al., 1989; Murray et al., 1989; Vissing et al., 1989; Tiller et al., 1990; Ramesar and Beighton, 1992; Lachman et al., 1992; Cole, 1993; Horton, 1993; Rimoin and Lachman, 1993). In congenital spondyloepiphyseal dysplasia group (cases 2, 3, 7, and 14) parental consanguinity was present only in one case (case 14 - hypochondrogenesis).

Genetic counseling for osteogenesis imperfecta families is controversial as well. Sillence et al. (1984), in a classical publication, analyzed several genealogies and concluded that the inheritance pattern is probably autosomal recessive in lethal cases (type II). However, with many works demonstrating heterozygotic mutations on Col1A1 and Col1A2 genes in infants affected by lethal forms of osteogenesis imperfecta, this concept has changed (Young et al., 1987; Thompson et al., 1987; Willing et al., 1988; Daw et al., 1990; Byers et al., 1991). Thus, those affected by osteogenesis imperfecta type II A are carriers of dominant collagen type I gene mutation, and random occurrence of affected individuals in the same sibship could be explained by germinative cell line mosaicism (Young et al., 1987; Byers et al., 1988). Osteogenesis imperfecta type II B is genetically heterogeneous. It can show autosomal recessive or autosomal dominant inheritance patterns. The empirical risk for this situation is 7.7% when no parental consanguinity exists and up to 25% when the parents are consanguineous (Thompson et al., 1987). Recurrence risks are indicated in Table I. Eleven families had high risks (25%), indicative of autosomal recessive inheritance. In accordance to this, the consanguinity rate in the whole sample was high (37.5%).

ACKNOWLEDGMENTS

This study was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). Publication supported by FAPESP.

RESUMO

Foram avaliados 17 pacientes com suspeita diagnóstica de osteocondrodisplasias letais. O diagnóstico definitivo foi estabelecido através da avaliação clínica, estudo radiológico e pela necropsia. Foi também procedido o aconselhamento genético aos familiares dos afetados. Houve confirmação diagnóstica específica em 16 casos. Em todos, o diagnóstico nosológico foi clinicamente suspeitado. O método mais eficiente para a determinação diagnóstica foi, contudo, o estudo radiológico do esqueleto. Isto corrobora a orientação da Classificação Internacional das Osteocondrodisplasias (International Working Group on Constitutional Disease of Bone, 1992) ao adotar o critério radiológico como o mais relevante na classificação deste grupo sindrômico. O estudo anatomopatológico, além de detectar anomalias internas, foi eficiente, através do estudo do fragmento ósseo, identificando alterações na placa epifisária de crescimento, porém com baixa especificidade, na maioria das vezes. Este método, por outro lado, foi decisivo na diferenciação diagnóstica de dois casos.

(Received March 24, 1997)

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Publication Dates

• Publication in this collection
  06 Jan 1999
• Date of issue
  June 1998

History

• Received
  24 Mar 1997