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Cerebro-costo-mandibular syndrome with autosomal dominant inheritance
Volume 99 Number 3
B r i e f clinical and laboratory observations
44 1
Cerebro-costo-mandibular syndrome with autosomal dominant inheritance Jules G. Leroy M.D., Ph.D.,* Antwerp, Belgium, Erik A. Devos, M.D., Leon J. Vanden Bulcke, M.D., and Norbert S. Robbe M.D., Roeselare, Belgium
CHARACTERIZED by multiple posterior rib gaps and upper thorax deformity, by the R o b i n triad of micrognathia, cleft palate, a n d glossoptosis, a n d often by psychomotor r e t a r d a t i o n a n d growth deficiency, the cereb r o - c o s t o - m a n d i b u l a r s y n d r o m e has recently been reviewed in detail." ~ This c o m m u n i c a t i o n records the first u n q u e s t i o n a b l e instance of m o n o g e n i c d o m i n a n t inheritance of the syndrome. CASE REPORTS
Patient 1, a white boy, was born in 1971 by spontaneous vaginal delivery after 34 weeks' gestation and weighed 2,400 gm. He had severe respiratory distress and feeding difficulty, for which gavage feeding was necessary. When first evaluated at 7 months for poor weight gain and feeding problems, his length was 67 cm (twenty-fifth percentile), his head circumference 44 cm (twenty-fifth percentile), and his weight 5,500 gm ( < third percentile). In addition to severe laterolateral narrowing of the upper thorax with pectus carinatum and dorsal hyperkyphosis, the elements of the Robin triad were apparent. Radiologic studies confirmed the micrognathia and identified dorsal discontinuity of multiple ribs. When the soft palate was surgically closed at 29/,2 years, tracheal intubation was extremely difficult. At 4'7,~ years a conductive hearing loss of 40 dB was found for the low frequencies. At 86A~years the thoracic deformity had become less obvious clinically. His height was at and his weight below the third percentile, but his head circumference of 53 cm was above the fiftieth. His speech had developed slowly and was still indistinct. Although respiratory infections recurred frequently, mental development and grade school performance were adequate (Figure, a and c). Patient 2, a female infant, was born in 1973 at 30 weeks' gestation to the same mother as Patient 1 but by a different father, weighed 1,500 gin, and died two hours later because of intractable respiratory distress. The attending physician noticed severe micrognathia, cleft palate, and a narrow, deformed thoracic cage. Unfortunately, neither radiographic study nor postmortem examination was performed. Patient 3, born in 1949, was the mother of the previous two patients. She was 22 years of age when Patient 1 was first evaluated. Information on her infancy was unavailable. At the
From the Division of Medical Genetics', Antwerp University Medical School, and the Divisions of Pediatrics and Plastic Surgery, "H. Hart" General Hospital, Roselare. *Reprint address: Division of Medical Genetics, Antwerp University Medical School, B-2610 Wilrijk, Belgium. 0022-3476/81/090441 +03500.30/0 9 1981 The C. V. Mosby Co.
age of 5 years she underwent surgical repair of the cleft palate. Her microretrognathia was treated by plastic surgery with moderate cosmetic success but without improvement of her indistinct speech. Except for dorsal hyperkyphosis, anterior and lateral deformation of the thorax was clinically mild. Her height was 156 cm. Her head circumference and intelligence were normal. Radiographs of the thorax showed multiple, dorsally located costal anomalies, most of which had healed with large and irregular callus formation and downward angulation (Figure, b and d). Abbreviation used CCM: cerebro-costo-mandibular
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Patient 4, a white girl, born in 1969 and unrelated to the previous family, was first studied at the age of 2~/,~ years while hospitalized for plastic surgery of her cleft palate. It was learned in retrospect that throughout infancy she had needed treatment of respiratory distress and nasogastric tube feeding. At the time of the operation tracheotomy was required because endotracheal intubation proved impossible. Postoperatively paralysis of the soft palate was noticed. She weighed 9.5 kg (third percentile). Her height and head circumference Were 89 and 48 cm respectively (both measurements between tenth and twenty-fifth percentile). The upper thoracic deformity was grotesque, with extreme laterolateral narrowing and increased anteroposterior diameter, hyperkyphosis, and pectus carinatum. The Robin complex of malformations was complete and severely expressed. When seen again at 11%._, years she had indistinct speech but normal intelligence and school performance. No similar or related malformation syndrome has been observed in her family. DISCUSSION T h e paucity of examples of familial cases has m a d e recognition of the m o d e of i n h e r i t a n c e of C C M difficult?' ~ T h e observation of the fully expressed s y n d r o m e in a m o t h e r a n d her two children strongly indicates a u t o s o m a l d o m i n a n t i n h e r i t a n c e in this family, but m a y s u p p o r t the possibility of genetic heterogeneity within C C M , or alternatively of a u t o s o m a l d o m i n a n t i n h e r i t a n c e with variable expressivity a n d / o r n o n p e n e t r a n c e in the few familial cases :~ ~ a n d in at least some of the sporadic ones i. 2 Mild expression of the heterozygous genotype m a y explain the mere occurrence of cleft palate in a n affected males infant's father, in w h o m i n f o r m a t i o n o n a chest r a d i o g r a p h is not available:'; because of this example of m a l e - t o - m a l e transmission, X-linked d o m i n a n t inheri-
442
Brief clinical and laboratory observations
The Journal of Pediatrics September 1981
Figure. a, Lateral view ofproband (Patient 1) at 9%~ years; thoracic detbrmity is no longer striking when seen frontally. b, Lateral photograph of proband's mother. Micrognathia 13as improved following plastic surgery, c, Radiograph of proband's thoracic cage at 6'Y,~ years, Multiple dorsal rib gaps are readily apparent, d, Thoracic radiograph of the mother. Only a few rib gaps remain, most having been healed by large callus formation. tance of C C M is ruled out. A single report of three affected siblings with clinically and radiologically normal parents 4 forms the basis for the current hypothesis of autosomal recessive inheritance. It remains possible, however, that in one of these parents C C M was nonpenetrant, and thus even this type of familial occurrence does not rule out autosomal dominant transmission.
The many sporadic cases in the literature 12 may be caused by new mutations, but some may be isolated because of nonpenetrance in family members. F r o m adolescence on, ascertainment o f C C M is probably incomplete because in more mildly affected patients with the Robin triad, congenital thoracic abnormalities may not be suspected clinically. Moreover, they are not looked
Volume 99 Number 3
for carefully in parents if autosomal recessive inheritance is assumed. The mother in the present family i s t h e only reported adult with fully expressed CCM known to have borne affected children. Even her thoracic deformity is clinically mild when compared to the severe roentgenographic anomalies. She offers a rare opportunity to observe partial healing of the rib discontinuities by bone remodeling and callus formation? The thoracic deformity in her son and in Patient 4 has also clinically improved now that they approach puberty. The three surviving patients presented here are remarkable for two additional reasons: (1) They have definitely indistinct speech, a feature which has not been pointed out before 1 and is probably related in part to the immobile soft palate and the pharyngolaryngeal malformation, and in part to moderate conductive hearing loss, documented in Patient 1 but clinically inapparent in the others. (2) Our patients with slightly small stature have a normal head circumference and are intellectually normal. In patients with longer survival normal psychomotor development has been rather exceptional; microcephaly and gross anatomic and histologic brain abnormalities have been documented? The observation of typical patients without mental handicap may indicate that microcephaly, mental
Brief clinical and laboratory observations
443
deficiency, and even cerebral anomalies are not inherent features of CCM but the frequent consequence of neonatal respiratory distress. A chest radiograph is mandatory in all neonates with the Robin anomaly,' since it may establish the diagnosis of CCM. Early adequate treatment of respiratory difficulties is likely to contribute to reducing the morbidity of CCM. Extending the recommendation of a chest radiograph to the patients' parents may be contributory to its prevention. REFERENCES
1. Silverman FN, Strefling AM, Stevenson DK, and Lazarus J: Cerebro-costo-mandibular syndrome, J PEDIATR97:406, 1980. 2. Tachibana K, Yamamoto Y, Osaki E, and Kuroki Y: Cerebrocosto-mandibular syndrome. A case report and ~zview of the literature, Hum Genet 54:283, 1980. 3. Miller KE, Allen RP, and Davis WS: Rib gap defects with micrognathia. The cerebro-costo-mandibular syndrome-a Pierre Robin-like syndrome with rib dysplasia, AJR 114:253, 1972. 4. McNicholl G, Egan-Mitchell B, Murray JP, et al: Cerebrocosto-mandibular syndrome. A new familial developmental disorder, Arch Dis Child 45:421, 1970.
B r i e f clinical and laboratory observations
44 1
Cerebro-costo-mandibular syndrome with autosomal dominant inheritance Jules G. Leroy M.D., Ph.D.,* Antwerp, Belgium, Erik A. Devos, M.D., Leon J. Vanden Bulcke, M.D., and Norbert S. Robbe M.D., Roeselare, Belgium
CHARACTERIZED by multiple posterior rib gaps and upper thorax deformity, by the R o b i n triad of micrognathia, cleft palate, a n d glossoptosis, a n d often by psychomotor r e t a r d a t i o n a n d growth deficiency, the cereb r o - c o s t o - m a n d i b u l a r s y n d r o m e has recently been reviewed in detail." ~ This c o m m u n i c a t i o n records the first u n q u e s t i o n a b l e instance of m o n o g e n i c d o m i n a n t inheritance of the syndrome. CASE REPORTS
Patient 1, a white boy, was born in 1971 by spontaneous vaginal delivery after 34 weeks' gestation and weighed 2,400 gm. He had severe respiratory distress and feeding difficulty, for which gavage feeding was necessary. When first evaluated at 7 months for poor weight gain and feeding problems, his length was 67 cm (twenty-fifth percentile), his head circumference 44 cm (twenty-fifth percentile), and his weight 5,500 gm ( < third percentile). In addition to severe laterolateral narrowing of the upper thorax with pectus carinatum and dorsal hyperkyphosis, the elements of the Robin triad were apparent. Radiologic studies confirmed the micrognathia and identified dorsal discontinuity of multiple ribs. When the soft palate was surgically closed at 29/,2 years, tracheal intubation was extremely difficult. At 4'7,~ years a conductive hearing loss of 40 dB was found for the low frequencies. At 86A~years the thoracic deformity had become less obvious clinically. His height was at and his weight below the third percentile, but his head circumference of 53 cm was above the fiftieth. His speech had developed slowly and was still indistinct. Although respiratory infections recurred frequently, mental development and grade school performance were adequate (Figure, a and c). Patient 2, a female infant, was born in 1973 at 30 weeks' gestation to the same mother as Patient 1 but by a different father, weighed 1,500 gin, and died two hours later because of intractable respiratory distress. The attending physician noticed severe micrognathia, cleft palate, and a narrow, deformed thoracic cage. Unfortunately, neither radiographic study nor postmortem examination was performed. Patient 3, born in 1949, was the mother of the previous two patients. She was 22 years of age when Patient 1 was first evaluated. Information on her infancy was unavailable. At the
From the Division of Medical Genetics', Antwerp University Medical School, and the Divisions of Pediatrics and Plastic Surgery, "H. Hart" General Hospital, Roselare. *Reprint address: Division of Medical Genetics, Antwerp University Medical School, B-2610 Wilrijk, Belgium. 0022-3476/81/090441 +03500.30/0 9 1981 The C. V. Mosby Co.
age of 5 years she underwent surgical repair of the cleft palate. Her microretrognathia was treated by plastic surgery with moderate cosmetic success but without improvement of her indistinct speech. Except for dorsal hyperkyphosis, anterior and lateral deformation of the thorax was clinically mild. Her height was 156 cm. Her head circumference and intelligence were normal. Radiographs of the thorax showed multiple, dorsally located costal anomalies, most of which had healed with large and irregular callus formation and downward angulation (Figure, b and d). Abbreviation used CCM: cerebro-costo-mandibular
[
Patient 4, a white girl, born in 1969 and unrelated to the previous family, was first studied at the age of 2~/,~ years while hospitalized for plastic surgery of her cleft palate. It was learned in retrospect that throughout infancy she had needed treatment of respiratory distress and nasogastric tube feeding. At the time of the operation tracheotomy was required because endotracheal intubation proved impossible. Postoperatively paralysis of the soft palate was noticed. She weighed 9.5 kg (third percentile). Her height and head circumference Were 89 and 48 cm respectively (both measurements between tenth and twenty-fifth percentile). The upper thoracic deformity was grotesque, with extreme laterolateral narrowing and increased anteroposterior diameter, hyperkyphosis, and pectus carinatum. The Robin complex of malformations was complete and severely expressed. When seen again at 11%._, years she had indistinct speech but normal intelligence and school performance. No similar or related malformation syndrome has been observed in her family. DISCUSSION T h e paucity of examples of familial cases has m a d e recognition of the m o d e of i n h e r i t a n c e of C C M difficult?' ~ T h e observation of the fully expressed s y n d r o m e in a m o t h e r a n d her two children strongly indicates a u t o s o m a l d o m i n a n t i n h e r i t a n c e in this family, but m a y s u p p o r t the possibility of genetic heterogeneity within C C M , or alternatively of a u t o s o m a l d o m i n a n t i n h e r i t a n c e with variable expressivity a n d / o r n o n p e n e t r a n c e in the few familial cases :~ ~ a n d in at least some of the sporadic ones i. 2 Mild expression of the heterozygous genotype m a y explain the mere occurrence of cleft palate in a n affected males infant's father, in w h o m i n f o r m a t i o n o n a chest r a d i o g r a p h is not available:'; because of this example of m a l e - t o - m a l e transmission, X-linked d o m i n a n t inheri-
442
Brief clinical and laboratory observations
The Journal of Pediatrics September 1981
Figure. a, Lateral view ofproband (Patient 1) at 9%~ years; thoracic detbrmity is no longer striking when seen frontally. b, Lateral photograph of proband's mother. Micrognathia 13as improved following plastic surgery, c, Radiograph of proband's thoracic cage at 6'Y,~ years, Multiple dorsal rib gaps are readily apparent, d, Thoracic radiograph of the mother. Only a few rib gaps remain, most having been healed by large callus formation. tance of C C M is ruled out. A single report of three affected siblings with clinically and radiologically normal parents 4 forms the basis for the current hypothesis of autosomal recessive inheritance. It remains possible, however, that in one of these parents C C M was nonpenetrant, and thus even this type of familial occurrence does not rule out autosomal dominant transmission.
The many sporadic cases in the literature 12 may be caused by new mutations, but some may be isolated because of nonpenetrance in family members. F r o m adolescence on, ascertainment o f C C M is probably incomplete because in more mildly affected patients with the Robin triad, congenital thoracic abnormalities may not be suspected clinically. Moreover, they are not looked
Volume 99 Number 3
for carefully in parents if autosomal recessive inheritance is assumed. The mother in the present family i s t h e only reported adult with fully expressed CCM known to have borne affected children. Even her thoracic deformity is clinically mild when compared to the severe roentgenographic anomalies. She offers a rare opportunity to observe partial healing of the rib discontinuities by bone remodeling and callus formation? The thoracic deformity in her son and in Patient 4 has also clinically improved now that they approach puberty. The three surviving patients presented here are remarkable for two additional reasons: (1) They have definitely indistinct speech, a feature which has not been pointed out before 1 and is probably related in part to the immobile soft palate and the pharyngolaryngeal malformation, and in part to moderate conductive hearing loss, documented in Patient 1 but clinically inapparent in the others. (2) Our patients with slightly small stature have a normal head circumference and are intellectually normal. In patients with longer survival normal psychomotor development has been rather exceptional; microcephaly and gross anatomic and histologic brain abnormalities have been documented? The observation of typical patients without mental handicap may indicate that microcephaly, mental
Brief clinical and laboratory observations
443
deficiency, and even cerebral anomalies are not inherent features of CCM but the frequent consequence of neonatal respiratory distress. A chest radiograph is mandatory in all neonates with the Robin anomaly,' since it may establish the diagnosis of CCM. Early adequate treatment of respiratory difficulties is likely to contribute to reducing the morbidity of CCM. Extending the recommendation of a chest radiograph to the patients' parents may be contributory to its prevention. REFERENCES
1. Silverman FN, Strefling AM, Stevenson DK, and Lazarus J: Cerebro-costo-mandibular syndrome, J PEDIATR97:406, 1980. 2. Tachibana K, Yamamoto Y, Osaki E, and Kuroki Y: Cerebrocosto-mandibular syndrome. A case report and ~zview of the literature, Hum Genet 54:283, 1980. 3. Miller KE, Allen RP, and Davis WS: Rib gap defects with micrognathia. The cerebro-costo-mandibular syndrome-a Pierre Robin-like syndrome with rib dysplasia, AJR 114:253, 1972. 4. McNicholl G, Egan-Mitchell B, Murray JP, et al: Cerebrocosto-mandibular syndrome. A new familial developmental disorder, Arch Dis Child 45:421, 1970.