Journal of Postgraduate Medicine Medknow Publications and Staff Society of Seth GS Medical College and KEM Hospital, Mumbai, India ISSN: 0022-3859 EISSN: 0972-2823 Vol. 46, Num. 4, 2000, pp. 268-271

Journal of Postgraduate Medicine, Vol. 46, No. 4, October-December, 2000, pp. 268-271

Case Report

Hosalkar HS, Shaw BA, Ceppi CL, Ng BC

Division of Paediatric Orthopaedics, The Valley Children's Hospital, Fresno, UCSF, 93638-8762, USA.
Address for Correspondence: Harish Hosalkar. MS, Dept. of Paediatric Orthopaedic Surgery, The Valley Children's Hospital Madera, California - 93638-8762, USA. E-mail: hosalkarharish@hotmail.com

Code Number: jp00090

Abstract:

Cerebro-costo-mandibular syndrome (CCMS) is a rare multiple congenital anomaly with a low survival rate. There are few reports of long-term survival in this condition. We describe the findings and management of a 9-year-old survivor of CCMS, outline the importance of early intervention and multidisciplinary team approach. The child presented in the neonatal period in respiratory distress with classical features of the syndrome. Aggressive initial respiratory management was later followed up with an integrated multidisciplinary team approach. He has been carefully followed up for nine years now, illustrating well, the course of the syndrome. (J Postgrad Med 2000: 46:268-271)

Key Words : Cerebro- costo- mandibular syndrome, micrognathia, posterior rib gap defects.

Cerebro-costo-mandibular syndrome (CCMS) is a rare, well-described congenital anomaly, but there is limited literature regarding long-term follow-up and survival in these cases.¹ We present the case of a 9-year-old boy with CCMS that illustrates well the natural course of the syndrome. We present this case to highlight features of a potentially debilitating syndrome, discuss role of early diagnosis and multidisciplinary team approach in management, and review the literature.

Case History

The patient was a Hispanic boy born of a non-consanguinous marriage at 37 weeks by normal delivery following an uncomplicated pregnancy. The birth weight was 2800 grams (10^th percentile), total body length was 49 centimeters (25^th percentile) and occipito- frontal- circumference was 35 centimeters (50^th percentile). Micrognathia, arched palate with a secondary cleft, and mild glossoptosis were noted at birth. Echoencephalogram done at the age of five weeks was essentially normal.

He had feeding problems in infancy, and suffered bronchopneumonia with respiratory distress at one month that necessitated a tracheostomy and feeding gastrostomy. Radiograph of the chest revealed a thoracic cage deformity and multiple rib gap defects (Figure 1). The child was stabilised and discharged at 3-months of age. The parents were explained the nature of the syndrome, the child's individual problems, emphasising on the need for aggressive respiratory management. The genetic heterogeneity of the condition, and the risks involved in future pregnancy, as well as the role of early prenatal diagnosis, was explained.

The child was managed on outpatient basis, and needed intermittent hospitalisation for respiratory infections, feeding tube problems, and occasional gastroenteritis and dehydration. Respiratory physiotherapy was continued on a regular basis. At the age of 6 years and 3 months his head circumference was 49 centimeters (5^th to 25^th percentile) height was 108 centimeters (5^th to 10^th percentile) and weight was 37.8 kilograms (5^th to 10^th percentile). Subsequently, the intensity as well as the frequency of his respiratory infections decreased (1to 2 episodes per year), and he had a normal psychomotor and speech development.

At 10 years of age (with a nine-year follow-up), he was a healthy boy with height of 134 centimeters (25^th percentile), weight of 27 centimeters (10^th to 25^th percentile), and head circumference of 52 centimeters (25^th percentile). He had a small chin, malar hypoplasia, multiple orthodontic problems with dental caries, and a narrow thorax flared inferiorly (figure 2). The pulmonary capacity was 55%. Audiologic evaluation revealed bilaterally impacted tympanic membranes and conductive hearing loss. He had a kyphoscoliotic deformity of the spine (figure 3). Radiographs revealed a 70° of thoracic kyphosis and a right thoracic scoliosis of 25°from T4 to T12 with a compensatory lumbar curve of 14° (figure 4). Imaging revealed a diastematomyelia without any bone spur or evidence of tethered cord. Further management essentially involved addressing individual problems with a multidisciplinary team approach, summarised in Table 1. He remained healthy and could attend regular school.

Surgical procedures performed on the patient during the course of management were as follows:

• Tracheostomy: Maintained for 7 years 6 months (from 1 month of age).
• Gastrostomy: Maintained for 7 years (from 1 month of age).
• Cleft palate repair: Performed at 8 years of age.
• Frenulectomy: Performed at 8 years of age
• Mandibular, oral and spinal surgeries are scheduled at later dates.

Discussion

Smith et al² in 1966 first referred to a developmental defect that included micrognathia and rib gap defects. It was subsequently labelled as CCMS in 1970 by McNicholl et al.¹ The incidence is almost the same in males and females.³ Review of the English literature, to the best of our knowledge reveals that this is the 57^th case described.^1,4,5 As far as survival more than ten years in CCMS is concerned the only report was by Van den Ende et al where they reported 5 cases, with ages ranging from 12 to 36 years.¹ Although most cases of CCMS reported are sporadic, there are 6 reported cases suggesting autosomal recessive inheritance.^1,5 and 5 reported cases of autosomal dominant inheritance.^1,6 Consanguinity has been reported twice.^1,7 In their case report of an unusually severe expression of CCMS Hennekam et al have hypothesised that mutations in goosecoid gene (mapped to chromosome 14q32.1 in humans) or Myf5 may have a causal role in CCMS.⁸ The exact pathogenesis of CCMS is unknown.

Most cases of CCMS show severe micrognathia, glossoptosis, palatal anomalies, and posterior rib defects that are diagnostic for the syndrome. The rib lesions are bilateral, present in all newborns, may not be symmetric, and usually involve the fourth and fifth pairs. They develop into pseudarthrosis over time.^1,3 Smith et al postulated that the rib defects represent lack of fusion of the posterior ossified parts of the ribs (which originate from the somites) with the anterior part (which originates from the lateral plate mesoderm).² Cartilage or bone abnormalities may be found in other areas like trachea, elbow and hip.³ Feeding and speech difficulties are common, as also is mental retardation (seen in almost half of the cases), failure to thrive and conductive hearing loss (seen in about 10 % of cases).^3,9 The developmental anomalies in our case with the estimated percentage of those described in literature¹ are given in Table 2.

Although cerebral involvement was thought to be a part of the syndrome, several authors suggest that mental retardation is secondary to hypoxia in the neonatal period. Microcephaly, that presents in about 15% to 40 % cases, could also be explained on this basis, and is not essential for diagnosis.^1,10 CCMS patients are also prone for other congenital anomalies^5,11 which include ventricular septal defects, polycystic kidneys, porencephaly, hydrancepaly, meningocele and meningomyelocele. Musculoskeletal anomalies occasionally include clinodactyly, sacral fusion, flask shaped pelvis, and hypoplasia of the humerus, sternum, clavicles, and pubic rami.^9,11 Progressive congenital kyphosis with progressive spinal cord compression can occur, necessitating neural decompression, fusion and stabilisation with instrumentation.¹² Radiographic features in CCMS include the demonstration of costo-vertebral rib defects, and micrognathia that help in the diagnostic work-up. Associated findings may necessitate computed tomography or magnetic resonance imaging. Prenatal ultrasonic diagnosis of CCMS has been described and findings include increased foetal nuchal translucency¹³ with features of combined orofacial and chest maldevelopment.⁴

Management includes intensive care for improving respiratory function, preventing feeding difficulties and recurrent infections. Operative intervention may be required for musculoskeletal, palatal or hearing problems, and other associated anomalies. Multidisciplinary integrated approach is the main essence of management. Plotz et al¹⁰ reported a mortality rate of as high as 56% in CCMS. It is mainly attributed to early respiratory problems and difficulties in intubation (in view of associated tracheal anomalies), leading to respiratory insufficiency. Cerebral involvement is usually related to hypoxia, and hence early recognition and intervention is extremely important in improving the prognosis. Development is quite satisfactory once the initial respiratory problems are overcome.¹ Longevity is thus related to early intervention and addressing major anomalies. Prenatal ultrasonic diagnosis of CCMS plays a key role and should be advocated in genetic counselling.^4,13

Clinicians should recognise that CCMS could lead to significant problems early in neonatal period and infancy leading to mortality. Initial respiratory insult and hypoxia can lead to secondary cerebral involvement. Early aggressive intervention and multidisciplinary long term management forms the mainstay of treatment. Prenatal ultrasonographic diagnosis and genetic counselling play an important role.

References

1. Van den Ende JJ, Schrander-Stumpel C, Rupprecht E, Meinecke P, Maroteaux P, de Die-Smulders C, et al. The cerebro-costo-mandibular syndrome: seven patients and review of the literature. Clin Dysmorphol 1998;7:87-95.
2. 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 1966; 69:799-803.
3. Silverman FN. Birth Defects Encyclopedia. In: Buyse ML, editor. Cerebro-costo-mandibular syndrome. Philadelphia: Blackwell scientific publications; 1990. pp301-302.
4. Megier P, Ayeva-Derman M, Esperandieu O, Aubry MC, Couly G, Desroches A. Prenatal ultrasonographic diagnosis of the cerebro-costo-mandibular syndrome: case report and review of the literature. Prenat Diagn 1998;18:1294-1299.
5. Kirk EP, Arbuckle S, Ramm PL, Ades LC. Severe micrognathia, cleft palate, absent olfactory tract, and abnormal rib development: cerebro-costo-mandibular syndrome or a new syndrome? Am J Med Genet 1999;84:120-124.
6. Leroy JG, Devos EA, Vanden Bulcke LJ, Robbe NS. Cerebro-costo-mandibular syndrome with autosomal dominant inheritance. J Pediatr 1981;99:441-443.
7. Clarke EA, Nguyen VD. Cerebro-costo-mandibular syndrome with consanguinity. Pediatr Radiol 1985;15:264-266.
8. Hennekam RC, Goldschmeding R. Complete absence of rib ossification, micrognathia and ear anomalies: extreme expression of cerebro-costo-mandibular syndrome? Eur J Hum Genet 1998;6:71-74.
9. Tachibana K, Yamamoto Y, Osaki E, Kuroki Y. Cerebro-costo-mandibular syndrome. A case report and review of literature. Hum Genet 1980;54:283-286.
10. Plotz FB, van Essen AJ, Bosschaart AN, Bos AP. Cerebro-costo-mandibular syndrome. Am J Med Genet 1996;62:286-292.
11. Smith KG, Sekar KC. Cerebro-costo-mandibular syndrome: case report and review of literature. Clin Pediatr 1985;24:223-235.
12. Philips MF, Dormans J, Drummond D, Schut L, Sutton LN. Progressive congenital kyphosis: report of five cases and review of the literature. Pediatr Neurosurg 1997;26:130-143.
13. Ibba RM, Corda A, Zoppi MA, Floris M, Todde P, Monni G. Cerebro-costo-mandibular syndrome: early sonographic prenatal diagnosis. Ultrasound Obstet Gynecol 1997;10:142-144.

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