American Journal of Medical Genetics 14115-123 (1983)

A New Short Rib Syndrome: Report of Two Cases

Frits A. Beerner, Leonard 0. Langer, Jr., Johanna M. Klep-de Pater, Anne M. Hernrnes, Jan 6. Bylsrna, Richard M. Pauli, Terry L. Myers, and Claude C. Haws 111

Clinical Genetics Center Utrecht (J. 6.6.) and Wilhelmina Kinderziekenhuis, State University, Utrecht (17 A. 6.); Developmental Disorders Clinic, De Ederhorst (J. M. K. -f.) and Department of Pediatrics, Juliana Ziekenhuis (A. M. H.), Ede, The Netherlands; Department of Radiology (L. 0. L., Jr.) and Departments of Pediatrics and Medical Genetics (R. M. P.), University of Wisconsin Center for Health Sciences and Medical School, Madison, Wisconsin; Department of Radiology, Johnson City Memorial Hospital (C. C. H. 111) and Departments of Pediatrics and Obstetrics and Gynecology, East Tennessee State University, Johnson City, Tennessee (l. L. M.)

We describe two unrelated malformed infants who died shortly after birth and who had multiple congenital anomalies including hydrops and ascites, facial abnormalities (with median cleft of the upper lip), narrow thorax, protuberant abdomen, and short, bowed limbs.

Postmortem radiographs showed very short ribs and disproportionately short long tubular bones; no metaphyseal abnormalities were present.

Comparison with earlier described short-ribkhort-rib-polydactyly syndromes suggest that the disorder present in our two cases is a new type of short-rib syndrome. One of our patients was born to a consanguineous couple; in a subsequent pregnancy, real-time ultrasonography in the second trimester showed that the female fetus had the same abnormalities as its sib. Diagnosis was con- firmed after elective abortion. This suggests that this short-rib syndrome may be an autosomal recessive disorder.

Key words: short-rib syndrome, autnsomal recessive inheritance, Majewski syndrome, polydac- tyly, short-rib polydactyly syndrome, neonatal death, dwarfism, malformation syn- drome, skeletal dysplasia

Received for publication December 11, 1981 ; revision received May 3, 1982.

Address reprint requests to Dr. Frits A. Beemer, Clinical Genetics Center, Utrecht, P.O. Box 18009, 3501 CA Utrecht, The Netherlands.

0148-7299/83/1401-0115$03.00@ 1983 Alan R. Liss, Ine.

116 Beemer et al

INTRODUCTION

Short ribs are present in many different short-limb dwarfing conditions, eg Jeune syndrome, Ellis-van Creveld syndrome, and thanatophoric dy splasia [Spranger et al, 1974al. In most of these the rib shortness, while it may be clinically significant, is less marked than in the recently delineated short rib/polydactyly (SRP) syndromes. In the latter, the severe thoracic dysplasia invariably leads to neonatal respiratory difficulties resulting in early death.

The SRP syndromes (type 1: Saldino-Noonan syndrome; type 2: Majewski syndrome; and type 3: Verma-Naumoff syndrome) have been reviewed by Spranger et a1 [1974a] and Yang et a1 [1980]. Besides short ribs, preaxial and/or postaxial polydactyly has been present in published patients with these disorders. We report two cases with a short-rib syndrome with clinical and radiologic characteristics reminiscent of SRP syndromes, but without polydactyly .

CLINICAL REPORTS Case 1

N was the first child of healthy, consanguineous parents (mother 19 and father 24 years old, respectively). Growth retardation was noted during the pregnancy (fetal size to gestational age discongruent by 4 wk).

Ultrasound examination at 30 wk gestation showed fetal abnormalities, inter- preted as an abdominal tumor and/or ascites. Delivery at 34 wk required forceps extraction. Birth weight was 2,930 gm, length 40 cm. The infant failed to breathe; in view of the multiple anomalies, ventilation was not assisted.

Postmortem examination showed hydrops, large head, high bulging forehead, flat face (Fig. l) , epicanthal folds, flat, broad nasal bridge, short nose with broad alae, median cleft of the upper lip, cleft palate, apparently low-set ears, posteriorly rotated and dysplastic auricles with underdeveloped helices, and very small cavum conchae, short neck, short and narrow thorax with widely spaced, hypoplastic nip- ples, protuberant abdomen with small omphalocele. The genitals were ambiguous (Fig. 2) with small phallus and fused labioscrotal folds without palpable gonads. A right inguinal hernia was present. The limbs were short and fixed in external rotation; hands and feet were short and broad.

In addition there was a large amount of ascites, a high diaphragm, atelectatic lungs, open foramen ovale, ventricular septa1 defect, transposition of the great vessels, and a patent ductus Botalli. Liver and spleen were enlarged and edematous. Testes were located intra-abdominally .

Microscopic studies showed no further abnormalities except for marked inter- stitial fibrosis of lungs. Specifically, no renal abnormality was present. The infant had a normal 46,XY chromosome constitution.

The radiographic changes of this case and the next are considered to be qualitatively the same and quantitatively virtually the same allowing for the different gestational age and sex of the infants. They will therefore be described together below.

Case 2

S, a female, was born to a 27-year-old mother and 35-year-old father who were unrelated. This was the first child of the mother but the fifth of the father (he having

Short Rib Syndrome 117

Fig. 1. Whole body postmortem photograph of case 1. Fig. 2. Ambiguous genitalia of case 1.

had, in addition, two living offspring and twins who died neonatally due to extreme prematurity).

Pregnancy was complicated by severe polyhydramnios in the month before delivery at about 30 wk gestation. Birth weight was 2,450 gm and length 38.5 cm. Apgar scores were 3 at one and 5 min. Respiratory insufficiency caused death shortly after birth.

The infant had generalized edema (Fig. 3), large head, flat face, bilateral epicanthal folds, flat, broad nasal base, median cleft of the upper lip (without cleft palate), apparently low-set, extremely small, inrolled and edematous ears with small, nearly atretic canals, short neck with nuchal edema and considerable skin redundancy, short and extremely narrowed thorax, distended abdomen with demonstrable fluid wave, and 3-cm omphalocele. Except for edema, the genitalia were normal. Limbs were extremely short. Hands and feet were short and broad with marked brachydac- tyly but without poly- or syndactyly.

Postmortem evaluation confirmed the clinical observations and showed marked pulmonary hypoplasia and lack of mesenteric attachment of the colon. Heart, great vessels, kidneys, and ovaries were all normal.

The infant had an apparently normal 46,XX chromosome constitution.

RADIOLOGIC MANIFESTATIONS

The following changes were noted in both cases: 1) very short horizontal ribs with irregularity and widening of their anterior ends; 2) high position of the clavicles (owing to thoracic lordosis); 3) slightly small scapulae; 4) minimal retardation of vertebral body ossification and, secondary to this, larger than normal nonossified spaces between the bodies; 5 ) essentially normally shaped ilia with good ossification of the basilar portions (the iliac wings were somewhat small); 6) the long tubular bones were short, the femora were minimally bowed and the radius and ulna were

118 Beemer et al

Fig. 3 . Whole body postmortem photograph of case 2

markedly bowed, and tibiae were relatively normally tubulated and were longer than the fibulae; 7) no metaphyseal irregularity of the tubular bones was present; and 8) brachydactyly, but no polydactyly of the hands and feet [Figs. 4 and 5 (case 1), 6 and 7 (case 2)].

Postpartum radiographs of the sib of case 1, who was aborted at 21.4 wk gestation [Wladimiroff et al, 19811 showed very similar abnormalities, the most striking being short ribs, disproportionate short limb bones (but with less relative shortness than in the 30 and 34-week-old infants) (Fig. 8). No metaphyseal irregular- ity was present.

DISCUSSION

The generally accepted subdivision of the short rib/polydactyly (SRP) group is principally based on the radiographic appearance of the bones [Spranger et al, 1974a,b; Yang et al, 19801. All are neonatally lethal autosomal recessive conditions. There is uncertainty whether SRP 1 (Saldino-Noonan syndrome) and SRP 3 (Verma- Naumoff syndrome) are separate entities or represent differences in ossification in the same genetic entity [Cherstvoy et al, 1980; Sillence, 19801. These two forms of SRP [Saldino and Noonan, 1972; Verma et al, 1975; Naumoff et al, 19771 are characterized by metaphyseal irregularity of the tubular bones. In view of the absence of metaphy- seal irregularity in our cases at 21.4, 30, and 34 wk gestation, these entities are not serious diagnostic possibilities and will not be discussed further. Part of the diagnostic criterion for the third entity, SRP 2 (Majewski syndrome), is the absence of such metaphyseal irregularity. This therefore remains a diagnostic possibility in our cases.

Short Rib Syndrome 119

Fig. 4. Postmortem AP radiograph of case 1. Fig. 5 . Postmortem lateral radiograph of case 1 . Fig. 6. AP radiograph of case 2. Fig. 7. Lateral radiograph of case 2.

120 Beemeretal

Fig. 8. Postmortem radiograph of the sibling of case 1 , aborted at 21.4 wk gestation.

It has been stated that polydactyly may be absent in otherwise typical examples of SRP 1 and SRP 3 [eg, Naumoff et al, 1977, case 2; Sillence, 19801. We have seen an example of this in SRP 3. Therefore the question arises whether our cases represent SRP 2 without polydactyly or are examples of a previously undescribed entity within the short rib skeletal dysplasia group. Rimoin [1981] has indicated that he had seen several SRP 2 cases and one case of SRP 1 without polydactyly. All were sporadic.

The initially proposed radiologic criteria for SRP 2 include the following skeletal changes: short horizontal ribs, polydactyly (pre- and post-axial), short tubular bones, disproportionately short tibiae, underossified phalanges, and the absence of metaphyseal irregularity or abnormalities of ossification in the basilar portions of the ilia. In a review article Cherstvoy et a1 [1980] included seven cases as examples of SRP 2. Of these, four met all of the above criteria [Majewski et al, 1971, case 1; Spranger et al, 1974a, case 1; Motegi et al, 1979, two sibs].

Further typical cases not listed in that article were reported by Bergstrom et al [1979] and Chen et al [1980]. The three remaining cases listed by Cherstvoy et a1 [1980] as examples of SRP 2 were either atypical in some regard or did not include radiographic documentation. The case of Sommer et a1 [1977] included no radio- graphic illustrations or description. Kozlowski et a1 [1977] reported a case in which the tibiae were longer than the fibulae and not tubulated. This case was also atyp- ical in that no midline cleft of the lip or palate was present-an anomaly present in the other cases. The third case, a term infant reported by Bidot-Lbpez et a1 [1978], showed less shortness of the ribs, preaxial polydactyly of feet only, and relative shortness of the tibiae in relation to the fibulae. While there was a “pseudocleft” of the lip, the abnormalities of the internal organs or genitalia usually present in some combination in typical cases of SRP 2 were absent.

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TABLE I. Comparison of Clinical Characteristics of Six Well-Documented Cases of SRP 2 (Majewski Syndrome) and the Two Cases of This Report*

Majewski Spranger Motegi et Motegi et Chen et et al et a1 al [1979] a1 [1979] Bergstrom a1 This report

Clinical sign [1971] [1974a] (case 1) (case 2) et al [I9791 [I9801 Case 1 Case 2

Short limbs Narrow thorax Polydacty ly Sy ndactyly Brachy dacty ly Median cleft lip

+ / - cleft palate Malformed ears Malformed tongue Hypoplastic larynx

+ + +

? ? +

? ?

+ + + + + + + + + + + + + +

- - - -

+ + + + - -

- and/or epiglottis

ascites

abdomen

? + + + Hydrops and/or + + Protuberant + + + + + + +

- -

-

+ + - - - Omphalocele - - - Malrotated intestine + ? ? ? + ? - +

+ + + Renal cystic -

Cardiovascular + ? ?

Abnormal genitalia

- - + -

dysplasia

anomalies

Female + Male + + + +

+ - - - -

- - -

* + , present; - , absent; ?, indeterminate.

Table I summarizes the manifestations of the six well-documented cases of SRP 2 and compares these with the clinical and pathological abnormalities of the two cases described here.

There are no clinical traits that are both constant in SRP 2 and exclusive of other short rib/polydactyly syndromes. Midline clefts of the lip with or without cleft of palate are characteristic of SRP 2, but similar abnormalities have been described in SRP 1 [Gordon and Brown, 1976; Leroy, 19781 and SRP 3 [Naumoff et al, 1977, case 11. And while cystic renal abnormalities are common, at least two of the well- documented cases [Majewski et al, 1971; Bergstrom et al, 19791 did not have such abnormalities. All of the other clinical nonskeletal changes are either inconstant even within this small group of cases and/or overlap with changes frequently described in SRP 1 and SRP 3.

Therefore while the two cases reported here share most of the manifestations of SRP 2 (including, incidentally, omphalocele, which has been described in this disorder [Majewski et al, 1971, case 3]), the characteristics are insufficiently specific to define whether these two cases are within or outside of the nosologic confines of SRP 2.

The skeletal abnormalities of our cases do differ from those seven published typical and atypical examples of SRP 2 in several respects. There is no polydactlyly. There is no relative shortness of tibiae in relation to fibulae. Both of these bones are short, as are the other long tubular bones, but normally tubulated. Bowing of the

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radius and ulna is present in all three cases. Single examples of this have been seen in SRP 1 and 3, but not in a typical case of SRP 2. It is our opinion that at least until more data are available these cases should be considered a separate entity from SFW 2. While this nosologic question cannot be resolved conclusively in the absence of specific biochemical markers or adequate numbers of cases for meaningful statistical analysis, the morphologic traits noted seem to support this distinction. Furthermore, recurrence without polydactyly in the aborted sib of case 1 argues against this absent feature simply reflecting variable expression of SRP 2. The apparent distinguishing skeletal changes therefore allow separation of SRP 2 and the entity described here using the same logic responsible for the current separation of SRP 1 and SRP 3 in the SRP cases with metaphyseal irregularity. Either the patients reported here are indeed examples of a new multiple congenital anomalies (MCA) syndrome, or eventually they will be subsumed into a more clearly defined short-rib syndromes classification; the occurrence of consanguinity and of a second affected sib in one of the families support autosomal recessive inheritance.

ACKNOWLEDGMENTS

The authors are indebted to Dr. R.J. Gorlin, Department of Oral Pathology, University of Minnesota, Minneapolis, and Dr. F. Majewski, Institut fiir Humange- netik und Anthropologie, Universitat Diisseldorf, Federal Republic of Germany, for their valuable comments. Thanks are due to Dr. J. Dorst, Johns Hopkins Hospital, who referred case 2, Dr. P.P.G. Kramer, Department of Radiodiagnosis, Wilhelmina Children’s Hospital, for comments on the radiographic findings, and Dr. J. Wladi- miroff, Department of Obstetrics and Gynecology, Erasmus University, Rotterdam, for permission to use the radiograph of the sib of case 1. We also thank Ms. M. de Jong for secretarial help, Mr. J. Olson for expert photographic processing, and Ms. R. Lebovitz for aiding in the literature research.

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Edited by John M. Opitz