History
Cumming Syndrome History
In 1986 Cumming et al described a fetus affected by several anomalies: campomelia, cervical lymphocele, polysplenia, short intestines, and polycystic kidneys, liver, and pancreas. The parents were consanguineous, suggesting autosomal recessive transmission.
In 1991, Urioste reported two similar cases with cervical lymphocele, multicystic dysplastic kidneys, and campomelia. The first infant died after five minutes of life and the second after an hour of life. The parents came from the same village in Spain.
Tricoire et al in 1993 described what also seems to be a case of Cumming syndrome, as did Ades et al in 1994. Dibbern, in 1998, reported two cases. Also in 1998, Perez Del Rio et al described two sisters affected by hydrops, campomelia, and polycystic dysplasia of the kidneys, liver, and pancreas. Both sisters died shortly after birth. Ming et al (1997) reported another case with campomelia, visceral heterotaxy with polysplenia, and multicystic dysplastic kidney disease.
Reunion Island History
Reunion Island (Ile de la Reunion), France, is located in the Indian Ocean near Madagascar in the Mascareigne archipelago. It is a small volcanic island of about 720,000 inhabitants. It is over 2500 km2 with a mountain range whose highest peak is 3069 meters, the hook of Snows. The Portugese discovered the island in 1513. From the 17th to the 19th centuries, French immigration was supplemented by an influx of Africans, Chinese, Malays, and Indians from Malabar. Reunion Island was an important stopover on the East Indies trade route until the opening of the Suez Canal in 1869.
Reunion Island is nicknamed "the island of intensity;†it is a paradise of variety. Its volcano, "le piton de la Fournaise,†is one of the most active volcanoes worldwide. There are three isolated regions on the island, Mafate, Cilaos, and Salazy. They are surrounded by mountains. In these areas there are tiny villages with no roads; only foot travel is possible, leading to isolation and consequently a high incidence of consanguinity.
Our patient and her husband were from Mafate, one of these isolated regions.
Prevalence
According to Urioste et al, the prevalence of Cumming syndrome at birth is estimated to be 0.027:10,000 births. According to Lazebnick, Cumming syndrome affects male fetuses more often than female.
Etiology
Cumming syndrome is genetic. Autosomal recessive transmission seems likely, as all cases in the literature feature parental consanguinity. Our two cases seem to be the eleventh and twelfth cases of Cumming syndrome reported in the literature to date.
Pathogenesis
Exact pathogenesis of Cumming syndrome is unknown; the responsible gene has not yet been identified.
Sonographic findings
Cumming described specific findings: general edema, cervical hygroma, cleft palate; short limbs with bowing of lower-extremity long bones. Polysplenia, cecal atresia, and short intestines were also described by Ming. Ming et al also described a fetus with Cumming syndrome, tetramelic campomelia, and bilateral rocker-bottom feet.
In Cumming syndrome, the thorax is often narrow. Cardiac anomalies such as anomalous pulmonary venous return, persistent left superior vena cava, and dextrocardia may be seen. One of Ming's cases presented with two left-sided auricles, left ventricular hypoplasia, and left isomerism (polysplenia). In another case of Cumming syndrome, Ming described anomalous pulmonary lobulation.In our first case, the fetus had total visceral situs inversus.
Multicystic polycystic kidney disease is reported in all cases of Cumming syndrome. The polycystic hyperechogenic kidneys characteristic of Cumming syndrome are featured in other syndromes.
Implications for targeted examinations
Suspicion for Cumming syndrome is raised on visualization of the constellation of multicystic kidneys, bowed femurs, cardiac anomalies, visceral heterotaxy, and/or cervical hygroma. Fetal akaryotypia must be assessed, as it will be normal in cases of Cumming. Genetic consultation is indispensable.
Differential diagnosis
Cumming syndrome can be differentiated from several osteochondrodysplasias:
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Campomelic dysplasia is the most important osteochondrodysplasia to rule out. It is characterized by scapular and iliac wing dysplasia, and especially by curved bowed lower-extremity long bones. A narrow, bell-shaped thorax may be seen. Most infants die of pulmonary hypoplasia in early infancy. 50% of campomelic dysplasia cases are phenotypic females with a 46, XY karyotype. All cases present with an irregularity of the SOX-9 gene. Campomelic dysplasia does not usually present with multicystic dysplastic kidney disease. It can be differentiated from Cumming syndrome because in campomelic dysplasia, all of the lower-extremity long bones are curved, whereas in Cumming syndrome, only the femurs are affected.
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Osteogenesis imperfecta type II and type III are eliminated in the differential because the long bones are always shortened, and fractures as well as various healing bony calluses present.
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Kyphomelic dysplasia or diastrophic dysplasia, hypophosphatasia, and Larsen syndrome: These are easily eliminated from the differential, as none present with renal anomalies.
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Stuve-Wiedemann syndrome (which often features renal, pancreatic, and hepatic dysplasia) is excluded because of absence of campomelia.
Prognosis
Cumming syndrome prognosis is directly linked to the severity of renal dysfunction, as well as to the developmental beginnings of renal dysplasia in the pregnancy. The prognosis also depends on associated cardiac anomalies and thoracic hypoplasia. Among all the cases we researched in the literature, we found no infant with Cumming syndrome who survived the immediate postnatal period.
Conclusion
Prenatal discovery of Cumming syndrome is difficult for two reasons: Cumming syndrome is extremely rare; and second, because of phenotypic likenesses, Cumming syndrome is frequently confused with campomelic dysplasia, as demonstrated by Watiker et all (2005). Mutation SOX-9 is pathognomonic for Cumming syndrome. Campomelic dysplasia is usually sporadic with rare autosomal dominant transmission, whereas Cumming syndrome has autosomal recessive transmission with a recidivism risk of 25% in the same family.
Upon suspicion of Cumming syndrome, in particular in the same family, it is advisable to recommend medical interruption of pregnancy. If the patient wishes to continue pregnancy, amniocentesis (or cordocentesis, if there is not enough amniotic fluid) and renal biopsy in utero may be recommended.
References
1. | Lazebnik N, Bellinger MF, Ferguson JE, Hogge JS, Hogge WA. Insights into the pathogenesis and natural history of fetuses with multicystic dysplastic kidney disease. Prenat Diagn 1999; 19:418-23. |
2. | Rizzo N, Gabrielli S, Pilu G, Perolo A, Cacciari A, Domini R, Bovicelli L. Prenatal diagnosis an dobstetrical managment of multicystic dysplastic kidney disease. Prenat DFDiagn 1987, 7:109-18. |
3. | Inyard P, Chitty L. Dysplastic and polycystic kidneys: diagnsois, associations and management. Prental Diagn 2001; 21:924-35. |
4. | Perez del Rio MJ, Fernandez-Toral J, Marigal B, Gonzalez-Gonzalez M, Ablanedo P, Herrero A. Two new cases of Cumming syndromee confirming autosomal recessive inheritance. Am J Med Genet 1999; 82; 340-3. |
5. | Dibbern KM, Graham JM, Lachman RS, Wilcox WR. Cumming Syndrome: report of two additional cases. Pediatr radiol. 1998 Oct; 28(10):798-801. |
6. | Ming JE, McDonald-McGinn DM, Markowitz RI, Ruchelli E, Zackai EH. Heterotaxia in a fetus with campomelia, cervical lymphocele, polysplenia and multicystic dysplastic kidneys: Expanding the phenotype of Cumming Syndromee. Am J Med Gen 1997; 73:419-24. |
7. | Urioste M, Arroyo A, Martinez-Frias ML. Campomelia, polycystic dysplasia and cervical lymphocele in two Sibs. Am J Med Gen 1991; 41:475-7. |
8. | Watiker V, Barroso I, Schafer AJ, Scherer G, Wilcox WR, Lachman RS. Differentiating campomelic dysplasia from Cumming Syndromee. Am J Med gen 2005; 135A:110-2. |
9. | Cumming WA, Ohlsson A, Ali A. Campomelia, cervical lymphocele, polycystic dysplasia, short gut, polysplenia. Am. J. Med. Genet. 25:783-790, 1986. |