* National Center for Fetal Medicine, Department of Gynecology and Obstetrics, ^§Department of Pathology, Trondheim University Hospital, N-7006 Trondheim, Norway, Tel: 47-7-998-307; Fax 47-7-997-696.

Department of Obstetrics and Gynecology, Buskerud Central Hospital, N-3004 Drammen, Norway. ^£Department of Medical Genetics, City of Oslo, N-0315 Oslo 1, Norway

Synonyms: Rib gap defect-micrognathia, Smith-Theiler-Schachenmann-Syndrome.

Definition: Congenital disorder including severe micrognathia, usually as a part of Robin"s anomalad with glossoptosis and cleft palate, posterior rib defects of variable extent and severity, facultative cerebral disorders and other associated anomalies.

Prevalence: Rare. At least 39 cases described. Incidence not known. M1:F1 is likely.

Etiology: Sporadic, autosomal recessive, and autosomal dominant transmission described.

Pathogenesis: Unknown.

Associated anomalies: Hydrocephaly, glial heterotopia, microstomia, ventricular septal defect, polycystic kidneys of adult type, anal atresia, spinal defects such as meningocele, myelomeningocele, hemivertebrae and kyphoscoliosis, club foot, hypoplastic elbow, webbed neck, nuchal hygroma, single umbilical artery and polyhydramnios in the third trimester.

Differential diagnosis: Other syndromes with severe Robin"s anomalad or with defective rib development.

Prognosis: Dependent on the severity of the rib defects and Robin"s anomalad. High mortality in the neonatal period and in early infancy.

Recurrence risk: Sporadic, autosomal recessive, and dominant transmission described.

Management: No causal treatment. If thoracic development is adequate, with only few ribs affected, and moderate micrognathia, intensive care at delivery is recommended in order to treat respiratory distress. In cases of severe micrognathia and/or rib maldevelopment, pregnancy termination could be an option.

MESH Pierre-Robin-Syndrome; Ribs-abnormalities BDE 0138 MIM 117650 POS 3056 ICD9 759.8 CDC 759.870

Introduction

Pierre Robin (1867-1950) was a French dentist from Paris who, in 1923, described the symptom triad micrognathia, glossoptosis and cleft palate. This triad, called Robin anomalad (Pierre Robin syndrome, Robin sequence), is found both isolated or in association with other syndromes.

Cerebro-costo-mandibular syndrome is a rare developmental disorder involving especially the mandible, as a part of the Robin"s anomalad, and the ribs. Occasional central nervous defects or dysfunction has been found.

In 1966 Smith, Theiler and Schachenmann¹ described this syndrome for the first time in a newborn child with severe micrognathia, malformed tracheal cartilages, redundant skin - especially in the neck - and unusual posterior rib-gap defects. The first intrauterine diagnosis was made by X-ray examination in a pregnancy at risk in 1970 by McNicholl et al². The first intrauterine ultrasound description was published by Merlob et al³ in 1987, who found mild polyhydramnios and short, defective ribs in a 27-week-old  fetus, whose father also had cerebro-costo-mandibular syndrome. Familial cases, such as four affected children in two subsequent twin pregnancies, have been described4. At least 39 cases have been published.

We present the sonographic diagnosis of cerebro-costo-mandi­bular syndrome in a 17-week-old fetus at risk.

Case report

A 32-year-old G4P3 was referred from another hospital with cystic hygroma colli and suspected micrognathia in the 17th week of pregnancy.

She had Robin"s anomalad herself with micrognathia, glossoptosis and a cleft palate which had been surgically corrected in early childhood. She had no defects in the spine nor in the thoracic skeleton.

Her first and third children are healthy. The second child was delivered in 1987 by cesarean section after 32 weeks of pregnancy because of threatening asphyxia. Prenatally, Robin"s anomalad and extensive polyhydramnios had been diagnosed. Because of an extreme micrognathia and microstomia, it was impossible to intubate the child who subsequently died one hour after delivery. Necropsy showed micrognathia, glossoptosis, posterior cleft palate, hemivertebrae in the lower cervical spine, rudimentarily developed ribs, unilateral club foot, hypoplastic lungs, glial heterotopia in the basal leptomeninges of the cortex, and possibly a missing olfactory bulb. The karyotype was normal 46, XX.

In the current pregnancy, the biometry was appropriate for gestational age at 17 weeks (BPD 40 mm, mean abdominal diameter 37 mm, femur length 23 mm). The amniotic fluid was normal. The fetus had a 7 to 8 mm thick nuchal hygroma. The profile showed an extreme microretrognathia (fig. 1). Tangential sections of the mouth revealed  microstomia with a width of only 3 mm (fig. 2). The ears had a low position. The thorax was narrow and hypoplastic with complete lack of rib ossification, while the clavicle was well ossified (fig. 1, 3). The transverse section through the thorax showed a relatively large heart in a narrow thorax without detectable ribs (fig. 4). The right heart seemed to be larger than the left heart, but a structural defect could not be detected. The umbilical cord had only one artery. Cordocentesis and amniocentesis were performed. The karyotype was 46, XY, and the a-fetoprotein was 9,6 mg/ml (normal).

Figure 1: Sagittal section through the fetal head and chest reveals the extreme microretrognathia and the narrow thorax compared to the abdomen. The nose is small. The mouth is indicated by the curved arrow

Figure 2: Tangential section of the mouth, which actually is a transverse section through the base of the head (compare with figure 1). The distance between the corners of the mouth (open arrows) is only 3 mm.

Figure 3: Slightly para-sagittal section through the thorax (left side) and abdomen (right side). The aorta lies anterior to the spine. The clavicle (arrow) is well ossified in contrast to the narrow thoracic cage without rib ossification. The left lung is seen in the thorax.

Figure 4: Transverse section through the thorax, the left side of the fetus tilts to the right. The spine lies downwards. No ribs  can be identified. The heart fills half of the thorax. Its apex points upwards to the right in this figure. The right heart, especially the atrium, seems to be larger than the left heart.

The ultrasound findings were consistent with cerebro-costo-mandibular syndrome. The severity of the Robin"s anomalad and non-development of the ribs indicated a lethal condition. After termination of the pregnancy, the necropsy confirmed all ultrasound findings including a hypoplastic mandible and hypoplastic lungs. In addition, anal atresia and a small muscular ventricular septal defect were found.

Discussion

Embryology & pathogenesis

There is no pathogenetic concept which sufficiently explains the combination of Robin"s anomalad and rib defects. A defect in mesenchymal development has been discussed regarding cerebro-costo-mandibular syndrome. The clavicle has normal growth in cerebro-costo-mandibular syndrome (fig. 3). Its embryonic development differs from that of the ribs.

The mandible   

The embryologic development of the face is complicated5. The mandible and the palate develop from the mesectoderm. At Carnegie stage 11 (equivalent to 38 - 39 LMP-based days), while the anterior neuropore is still open, the mandibular arch already surrounds the degenerating oropharyngeal membrane caudally. Initirrounds the degenerating oropharuth grows as rapidly as the head. At stage 18 (58 - 60 LMP-based days) the maxillary and mandibular arch form the corners of the mouth. The further growth of the mouth is proportional to the rest of the body. If there is a deficient growth of the maxilla and mandible, the outer ear will not ascend dorso-cranially, resulting in low-set ears. Deficient mandibular growth will also disturb the normal development of the oral cavum, including the normal fusion of the posterior palate, leading to glossoptosis and subsequent cleft palate.

The ribs

The ribs originate from the paraxial mesoderm, which forms the segmental somites. These somites differentiate into the dorsolateral epithelial dermatomes, the epithelial myotomes, and a loose ventromedial tissue, the sclerotomes. The ribs develop from the processus ventralis of the thoracic sclerotomes and grow appositionally into the thoracic wall until the sternocostal joints6.

The clavicle     

The origin of the clavicle is different than that of the mandible and ribs. This may explain the fact that it is fully developed in this condition. The clavicle is part of the shoulder girdle. It originates during the sixth week (LMP-based) from mesenchymal condensations in the limb buds, which derive from the lateral (not the paraxial) mesoderm. During week eight, the mesenchymal model undergoes chondrofication to form hyaline cartilage. The clavicle initially develops by intramembraneous ossification and later by endochondral ossification with growth cartilage present at both ends of the bone. The clavicle begins to ossify before any other bone in the body⁷.

Diagnosis

Major findings

All cases with cerebro-costo-mandibular syndrome show micrognathia and rib defects.

Central nervous system

Central nervous system compromise, such as mental retardation, was found in 8 of 13 cases8. Besides mental retardation, central nervous system anomalies include hydrocephaly, heterotopic glial tissue in the leptomeninges, and possibly the absence of the olfactory bulb (our patient"s second child). Heterotopic glial tissue was also found in a patient described by Silverman et al9. Central nervous system involvement is not mandatory. It may often be present as mental retardation secondary to perinatal asphyxia, since severe micrognathia,  glossoptosis and thoracic defects lead to serious respiratory complications and asphyxia2,4,10. Hennekam8 found respiratory distress in 25 of 25 cases.

Ribs    

Rib compromise varies greatly. In some cases, only one rib is affected, while the opposite extreme, as demonstrated in our two cases, has only rudimentarily developed ribs.

Mandible         

Typically, the micrognathia is serious and is associated with posterior cleft palate and glossoptosis, which constitutes the classical Robin"s anomalad.

Associated anomalies

The spectrum of associated anomalies increases with the descriptions of new cases (Table 1). The following have been described: microstomia and low-set ears (both consequences of the micro- and retrognathia), nuchal hygroma, redundant skin or webbed neck, meningocele, myelomeningocele, hemivertebrae, kyphoscoliosis, hypoplasia of an elbow, club foot, anal atresia, polycystic kidneys of the adult type, ventricular septal defect, and single umbilical artery.     

Polyhydramnios is a known complication in pregnancies where fetal swallowing is impaired, and should be expected in cerebro-costo-mandibular syndrome^2,3,4. Our patient"s second pregnancy, where cerebro-costo-mandibular syndrome was present and which ended prematurely after 32 weeks of gestation, had marked polyhydramnios.  Premature delivery has been described several times3,8,11, all between 27 and 34 weeks, perhaps due to polyhydramnios.

Table 1: Associated anomalies

Karyotype

Chromosomal aberrations have never been found in the syndrome.

Risk of recurrence

Three types have been described:

Sporadic: The first case of cerebro-costo-mandibular syndrome was described in 1966. It occurred in a family with no previous appearance of any traits of this syndrome¹.

Autosomal recessive: In 1970, McNicholl et al reported three sibs with cerebro-costo-mandibular syndrome and assumed an autosomal recessive inheritance². The presence of the syndrome in all sibs of two subsequent twin pregnancies4 in a  couple with a negative family history was described in 1991.

Autosomal dominant: In 1981, Leroy et al recorded the first case of autosomal dominant inheritance11 of this syndrome in a mother and her two children with fully expressed cerebro-costo-mandibular syndrome.

This and other familial cases in the literature demonstrate the genetic heterogeneity of this rare syndrome with great variability and expressivity. Genetic counseling is necessary when cerebro-costo-mandibular syndrome occurs.

Differential diagnosis

Conditions with Robin"s anomalad        

Robin"s anomalad is frequently associated with other syndromes and may be found in: Acrofacial dysostosis (Nager), post-axial acrofacial dysostosis, mandibulofacial dysostosis, persistent left vena cava syndrome, Beckwith-Wiedemann syndrome, velo-cardio-facial syndrome, digito-palatal syndrome (Stevenson), oro-facio-digital syndrome, agnathia-holoprosencephaly, CHARGE-association, campomelic dysplasia, diastrophic dysmelia, spondylo-epiphysial dysplasia (congenital), hereditary progressive arthro-ophthalmo­pathy (Stickler), myotonic dystrophy (Curshmann-Steinert), fetal alcohol syndrome, and chromosomal aberrations (Table 2).

Conditions with rib anomalies   

Whenever a narrow thorax is found, syndromes with costal maldevelopment should be considered for differential diagnosis. Besides different forms of dwarfism, short-rib-polydactyly syndromes Types I—III and Jeune syndrome  should be considered.

Table 2: Differential diagnoses of micrognathia 

• Acrofacial dysostosis (Nager syndrome)

• Postaxial acrofacial dysostosis 

• Mandibulofacial dysostosis

• Velo-cardio-facial syndrome 

• Digito-palatal syndrome (Stevenson syndrome) 

• Oro-facio-digital syndrome 

• Agnathia-holopronsencephaly

• CHARGE-association

• Campomelic dysplasia 

• Diastrophic dysplasia 

• Spondylo-epiphysial dysplasia

• Hereditary progressive arthro-ophthalmopathy (Stickler syndrome)

• Myotonic dystrophy (Curshmann-Steinert syndrome)

• Fetal alcohol syndrome

• Aneuploidies

Prognosis & management

In Hennekam"s summary8 of 29 reported cases, 14 of 29 children (50%) died before the first year. Silverman et al⁹ generally characterized the prognosis as poor, both for survival and intellectual status. The prognosis depends on the degree of  Robin"s anomalad and of the extent of rib maldevelopment. Respiratory distress is the main perinatal complication, both because of the glossoptosis and the thoracic malformation. Readiness for intensive care at delivery is necessary. When severe micrognathia or serious costal maldevelopment is detected, termination of the pregnancy should be an option.

References

1. Smith DW, Theiler K, Schachenmann G. Rib-gap defect with micrognathia, malformed tracheal cartilages, and redundant skin: A new pattern of defective development. J Pediatr 69:799-803, 1966.

2. McNicholl B, Egan-Mitchell B, Murray JP, et al: Cerebro-costo-mandibular syndrome—a new familial developmental disorder. Arch Dis Child 45:421-24, 1970.

3. Merlob P, Schonfeld A, Grunebaum M, et al: Autosomal dominant cerebro-costo-mandibular syndrome: ultrasonographic and clinical findings. Am J Med Genet 26:195-202, 1987.

4. Drossou-Agakidou V, Andreou A, Soubassi-Griva V, et al: Cerebro-costo-mandibular syndrome in four sibs, two pairs of twins. J Med Genet 28:704-7, 1991.

5. Hinrichsen KV. Gesichtsentwicklung. In: Hinrichsen KV (ed). Humanembryologie. Berlin: Springer Verlag 650-91, 1990.

6. Christ B, Jacob HJ, Jacob M. Experimentelle Untersuchungen zur Entwicklung der Rumpfwand beim Hühnerembryo. Basel, Experiential 30:1449-51, 1974.

7. Moore KL. The skeletal system. In: The developing human, clinically oriented embryology. Philadelphia, WB Saunders 334-49, 1988.

8. HelphilphilphilphilphilphilphilphiWAR, et al: The cerebro-costo-mandibular syndrome: third report of familial occurrence. Clin Genet 28:118-21, 1985.

9. Silverman FN, Strefling AM, Stevenson DK, et al: Cerebro-costo-mandibular syndrome. J Pediatr 97:406-16, 1980.

10. Trautman MS, Schelley SL, Stevenson DK: Cerebro-costo-mandibular syndrome: a familial case consistent with autosomal recessive inheritance. J Pediatr 107:990-1, 1985.

11. Leroy JG, Devos EA, Vanden Bulcke LJ, et al: Cerebro-costo-mandibular syndrome with autosomal dominant inheritance. J Pediatr 99:441-3, 1981.