Two new cases of Cumming syndrome confirming autosomal recessive inheritance

  • Published on
    06-Jun-2016

  • View
    213

  • Download
    0

Embed Size (px)

Transcript

  • Two New Cases of Cumming Syndrome ConfirmingAutosomal Recessive Inheritance

    M.J. Perez del Ro,1* J. Fernandez-Toral,2 B. Madrigal,1 M. Gonzalez-Gonzalez,1 P. Ablanedo,1 andA. Herrero11Department of Pathology, Central Hospital, University of Oviedo, Asturias, Spain2Department of Medicine, Central Hospital, University of Oviedo, Asturias, Spain

    We report on two stillborn sisters with gen-eralized hydrops, campomelia, cervical lym-phocele, and polycystic dysplasia of kidney,liver, and pancreas. This syndrome con-forms to that first described by Cumming etal. [Am. J. Med. Genet. 25:783790, 1986].This observation provides additional sup-port for the notion that this syndrome hasan autosomal recessive pattern of inheri-tance. Am. J. Med. Genet. 82:340343, 1999. 1999 Wiley-Liss, Inc.

    KEY WORDS: Cumming syndrome; campo-melia; polycystic dysplasia;cervical lymphocele; inheri-tance

    INTRODUCTION

    In 1986 Cumming et al. described a new syndromecomprising campomelia; polycystic dysplasia of kidney,liver, and pancreas; and cervical lymphocele in a still-born male infant born to consanguineous parents. Twoprevious brothers had macrocephaly and an undeter-mined pattern of malformations.

    In 1991 Urioste et al. reported on two new cases in apair of sisters. Autopsy showed a considerable numberof findings in common with the case reported by Cum-ming et al. [1986]. The presence of anomalies not pre-viously described was attributed to the variability ofthe clinical expression of the syndrome.

    We now report on two sisters born to young parentsof unknown consanguinity. The clinical and autopsyfindings were consistent with the diagnosis of Cum-ming syndrome.

    This case confirms the autosomal recessive inheri-tance of the syndrome.

    CLINICAL REPORTSCase 1

    A stillborn female was the product of an uncompli-cated pregnancy in a 24-year-old woman who deliveredat 36 weeks. The fetus had hydrops, clover-leaf skull,and a severely deformed face, with a considerableamount of redundant subcutaneous tissue, massivecervical edema, and microphthalmos; facial appear-ance was similar to that of a 40-day embryo. The chestwas narrow and the abdomen swollen with mild asci-tes. The limbs were short and bowed (Fig. 1). No genitalabnormalities were found. Examination of internal or-gans showed bilateral lung hypoplasia, enlarged kid-neys with a great number of cysts of various sizes incortex and medulla, and hepatomegaly. No other inter-nal alterations were seen. Histopathologic study of thekidneys showed numerous dilated cysts, lined by cuboi-dal flattened epithelium, some of them rounded by con-nective tissue. Scattered fetal glomeruli and scantprimitive ducts were found (Fig. 2). The liver showedexpanded portal spaces, with numerous and dilated bil-iar ducts, lined by cuboidal epithelium. The architec-ture of the pancreas was distorted, with marked fibro-sis and proliferating enlarged ducts, with scant acinarcomponent (Fig. 3). No changes were seen in the mi-croscopic study of bones, joints, or nervous system. Thekaryotype was 46,XX. Radiographic examination wasnot performed.

    The parents were informed of a probable increasedrecurrence risk, based on the interpretation of thesefindings as autosomal recessive hepato-renal polycys-tosis.

    Case 2

    A year later, after another uncomplicated pregnancy,which required a C-section at 31 weeks, another femalewas born who died within minutes. The fetus weighed6,300 g (>97th centile), and length was 57 cm (>97thcentile). The external appearance was similar to that ofher sister, with clover-leaf skull and abundant soft tis-sue in the occipital and facial region. The face wasasymmetric, with impossible definition of its parts, mi-

    *Correspondence to: M. Jose Perez del Ro, Plaza Del Callao1618, 40A, 15403 Ferrol (La Coruna), Spain.

    Received 7 August 1997; Accepted 1 October 1998

    American Journal of Medical Genetics 82:340343 (1999)

    1999 Wiley-Liss, Inc.

  • crophthalmia, cleft palate, and a protruding lower jaw.There was no well-developed nose, and ears weregrossly abnormal. Generalized hydrops was also pres-ent. The chest was narrow and the abdomen swollenwith ascites. The limbs were short and bowed, withoutsyndactyly. No genital abnormalities were seen (Fig.4). At autopsy, lungs were hypoplastic, and the kidneyswere enlarged, consisting of a large number of cystic

    formations with thin walls. An atrial septal defect, os-tium secundum type, was also present.

    Histopathologic study showed hepato-renal polycys-tic dysplasia. The pancreas could not be studied due toautolysis.

    The karyotype was 46,XX. Radiographic examina-tion was not performed.

    Fig. 1. Case 1, external appearance: hydrops, clover-leaf skull, swollenabdomen, and short and bowed extremities.

    Fig. 2. Case 1, renal dysplasia: numerous cystic spaces lined by flat-tened epithelium and scattered fetal glomeruli (arrows). H&E 100.

    Fig. 3. Case 1, pancreatic dysplasia: ductal proliferation and dilatation,fibrosis and loss of acinar tissue. H&E 250.

    Fig. 4. Case 2, similar external appearance to case 1: hydrops, clover-leaf skull, facial malformation, with protruding lower jaw and campomelia.

    Cumming Syndrome Inheritance 341

  • DISCUSSION

    The clinical picture described by Cumming et al.[1986] is that of a complex syndrome in which severalmalformations can be found, of which polycystic dys-plasia, campomelia and cervical lymphocele are themost important. Autosomal recessive inheritance waspreviously suggested and these cases present addi-tional evidence for that.

    The second description in the literature was made byUrioste et al. [1991] who described two Spanish sisterswho presented several findings of those already men-tioned by Cumming et al. [1986]. No other cases werefound in an exhaustive bibliographic review (Compre-hensive Medline January 1985June 1997).

    Our cases have nine and eight findings, respectively,of those described by Cumming et al. [1986] (Table I),including those suggested as major criteria for the di-agnosis of the syndrome. However, no bowel or cerebralmalformations were found.

    All cases described were stillborn or died within min-utes after birth. Differential diagnosis with other non-immunological causes of hydrops fetalis [Stephenson etal.,1994], such as Turner syndrome, Noonan syndrome,Roberts syndrome, and trisomy 13 is important andshould be considered.

    Nosological questions could also arise with someforms of dwarfism with short limbs and hydrops. Cum-ming et al. [1986] described short and bowed longbones, with defects in the mineralization of the secondthoracic vertebra. Urioste et al. [1991] described bowedlong bones without osteopenia, small bell-shaped chest,and thin and malformed ribs. Unfortunately, no radio-logic studies were performed in our cases, but the bonehistology was normal.

    The campomelic syndrome should also be consideredin the differential diagnosis. Although this entity isquite variable [Houston et al., 1983], it also presentsconstant skeletal anomalies, such as talipes equino-

    varus, in addition to vascular abnormalities [Rodrguezet al., 1993] and possible sex reversal. Furthermore,the typical polycystic dysplasia of Cumming syndromewas never described in campomelic syndrome.

    Other complex syndromes [Ade`s et al., 1994] cancombine several findings of Cumming syndrome. Thus,Ivemark et al. [1959] and others [Bernstein et al., 1987,Neuhaus et al., 1996, Torra et al., 1996] described acombination of renal, pancreatic, and liver dysplasiawith autosomal recessive inheritance. Involvement ofother organs, and the lack of campomelia and externalmalformations of Cumming syndrome, can exclude therenal-hepatic-pancreatic dysplasia syndrome. Someauthors [Torra et al., 1996] propose that dysplasiacould be a nonspecific final common pathway of re-sponse of affected organs to a variety of disturbances,including those caused by mutations in different genes;it could even constitute a widespread spectrum of dis-ease [Neuhaus et al., 1996], with changeable manifes-tations.

    REFERENCES

    Ade`s LC, Clapton WK, Morphett A, Morris LL, Haan EA. 1994. Polydac-tyly, campomelia, ambiguous genitalia, cystic dysplastic kidneys, andcerebral malformation in a fetus of consanguineous parents: a newmultiple malformation syndrome, or a severe form of oral-facial-digitalsyndrome type IV? Am J Med Genet 49:211217.

    Bernstein J, Chandra M, Creswell J, Kahn E, Malouf NN, McVicar M,Weinberg AG, Wybel RE. 1987. Renal-hepatic-pancreatic dysplasia: asyndrome reconsidered. Am J Med Genet 26:391403.

    Cumming WA, Ohlsson A, Ali A. 1986. Brief clinical report: campomelia,cervical lymphocele, polycystic dysplasia, short gut, polysplenia. Am JMed Genet 25:783790.

    Houston CS, Opitz JM, Spranger JW, Macpherson RI, Reed MH,Gilbert E, Herrman J, Schinzel A. 1983. The campomelic syn-drome: review, report of 17 cases, and follow-up on the currently17-year-old boy first reported by Maroteaux et al. in 1971. Am J MedGenet 15:328.

    TABLE I. Clinical and Autopsy Findings in Cumming Syndrome*

    Cumminget al.[1986]

    Uriosteet al. (1)[1991]

    Uriosteet al. (2)[1991]

    Presentcase 1

    Presentcase 2

    Sex M F F F FParenteral consanguineity + Karyotype 46,XY ? 46,XX 46,XX 46,XXCampomelia + + + + +Cervical lymphocele + + + + +Hydrops + + + + +Renal dysplasia + + + + +Pancreatic dysplasia + + + ?Liver dysplasia + + + +Short gut + Polysplenia + Cecal atresia + Lung hypoplasia + + +Craniofacial deformity + + + + +Narrow chest + + + + +Cleft palate + Arrihnencephaly + Oligohydramnios + Syndactyly + +

    *? 4 Unknown; M 4 Male; F 4 Female.

    342 Perez del Ro et al.

  • Ivemark BI, Oldfelt V, Zetterstrom R. 1959. Familial dysplasia of kidneys,liver and pancreas. A probably genetically determined syndrome. ActaPaediatr Scan 48:111.

    Neuhaus TJ, Sennhauser F, Briner J, Van Damme B, Leumann EP. 1996.Renal-hepatic-pancreatic dysplasia: an autosomal recessive disorderwith renal and hepatic failure. Eur J Pediatr 155:791795.

    Rodrguez JI. 1993. Vascular anomalies in campomelic syndrome. Am JMed Genet 46:185192.

    Stephenson T, Zuccollo J, Mohajer M. 1994. Diagnosis and managementof non-immune hydrops in the newborn. Arch Dis Childhood 70:151154.

    Torra R, Alos L, Ramos J, Estivill X. 1996. Renal-hepatic-pancreatic dys-plasia: an autosomal recessive malformation. J Med Genet 33:409412.

    Urioste M, Arroyo A, Martnez-Fras ML. 1991. Campomelia, polycysticdysplasia, and cervical lymphocele in two sibs. Am J Med Genet 41:475477.

    Cumming Syndrome Inheritance 343

Recommended

View more >