Aphallia as part of urorectal septum malformation sequence in an infant of a diabetic motherкод для вставкиСкачать
American Journal of Medical Genetics 82:363–367 (1999) Aphallia as Part of Urorectal Septum Malformation Sequence in an Infant of a Diabetic Mother Karen W. Gripp,1* Mason Barr, Jr.,2 George Anadiotis,1 Donna M. McDonald-McGinn,1 Stephen A. Zderic,3 and Elaine H. Zackai1 1 Division of Human Genetics and Molecular Biology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 2 Division of Pediatric Genetics, C. S. Mott Children’s Hospital, Ann Arbor, Michigan 3 Department of Urology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania A male patient with aphallia, anal stenosis, tetralogy of Fallot, multiple vertebral anomalies including sacral agenesis and central nervous system (CNS) malformations was born after a pregnancy complicated by poorly controlled maternal diabetes. Aphallia is an extremely rare abnormality and can be part of the urorectal septum malformation sequence (URSMS). While aphallia has not been reported in infants of diabetic mothers, urogenital malformations are known to occur with increased frequency. Two female products of pregnancies complicated by diabetes presented with multiple malformations including anal atresia and recto-vaginal fistula consistent with the diagnosis of URSMS. The three patients share CNS, cardiac, and vertebral anomalies, abnormalities secondary to abnormal blastogenesis and characteristic of diabetic embryopathy. URSMS is also caused by abnormal blastogenesis. Therefore, this particular malformation should be viewed in the context of the multiple blastogenetic abnormalities in the cases reported here. The overlap of findings of URSMS in our cases with other abnormalities of blastogenesis, such as VATER association or sacral agenesis is not surprising, as these associations are known to lack clear diagnostic boundaries. Am. J. Med. Genet. 82:363–367, 1999. © 1999 Wiley-Liss, Inc. KEY WORDS: a p h a l l i a ; b l a s t o g e n e t i c anomalies; diabetic embryopathy; urorectal septum malformation sequence Contract grant sponsor: Howard Hughes Medical Institute. *Correspondence to: Karen W. Gripp, M.D., Clinical Genetics Center, The Children’s Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, PA 19104–4399. Received 9 December 1997; Accepted 8 January 1998 © 1999 Wiley-Liss, Inc. INTRODUCTION A male infant with multiple congenital anomalies including aphallia was born after a pregnancy complicated by poorly controlled maternal diabetes. Aphallia is an extremely rare malformation and has not been reported previously in infants of diabetic mothers. However, urogenital malformations occur with increased frequency in infants of diabetic mothers. In addition, we report two female fetuses born to diabetic mothers, who showed urogenital abnormalities as part of multiple congenital abnormalities. These three cases share many findings in common, such as central nervous system (CNS), cardiac, and urogenital abnormalities. PATIENTS Patient 1 A male was delivered by cesarean section for breech presentation at 37 weeks of gestational age. He was born to a 25-year-old African-American primigravida and her nonconsanguineous partner. The pregnancy was complicated by maternal diabetes requiring insulin therapy for 2 years before conception. Diabetes control was reportedly poor despite prenatal care. There was no other reported prenatal exposure. Birth weight was 3.6 kg (>90th centile), length 49 cm (75th centile) and occipitofrontal circumference (OFC) 31.5 cm (10– 25th centile). Congenital anomalies noted postnatally included an arachnoid cyst superior to the tentorium and frontal pachygyria, tetralogy of Fallot, multiple vertebral anomalies with sacral agenesis (Fig. 1), aphallia (Fig. 2), vesico-rectal fistula, and anal stenosis. His karyotype was normal (46,XY, 500 band level). Patient 2 This female was delivered by cesarean section for fetal distress at 31 weeks gestational age to a 33-yearold Caucasian G2P0 mother. The pregnancy was complicated by diet-controlled gestational diabetes and by polyhydramnios noted at 30 weeks. Birthweight was 1.2 kg (10–25th centile), crown-to-rump length 23.5 cm, 364 Gripp et al. Fig. 1. Radiograph of Patient 1, showing scoliosis due to thoracic hemiand butterfly vertebrae, sacral agenesis, and fusion of ribs 8 to 10 on the left. (<3rd centile), and OFC 29.5 cm (50–75th centile). The infant died at age 1 day due to pulmonary hypoplasia. Multiple congenital anomalies included hemifacial microsomia with preauricular skin tags and mandibular hypoplasia, hypoplastic olfactory bulbs, absent right lung, truncus arteriosus with atrial septal defect, ventricular septum defect, and right-sided descending aorta, intestinal malrotation, anal atresia, rectovaginal fistula, and hemiuterus with right vestigial fallopian tube. Skeletal abnormalities included sacral agenesis with hypoplastic pelvis, flexion contractures of the hips and knees with inguinal and popliteal webbing, tibial bowing and bilateral equinovarus position of the feet (Fig. 3). Patient 3 This female fetus was the product of a 19-week gestation. Her 26-year-old mother was diagnosed with diabetes during the pregnancy and started insulin therapy at 6 weeks of gestation. Increased maternal serum ␣-feto protein level and abnormalities noted on ultrasound led to the diagnosis of neural tube defect and the termination of pregnancy. Weight was 139 g (1.1st centile), crown-to-rump length 12.3 cm (0.02nd centile), Fig. 2. Patient 1 with aphallia, normal scrotum, and suprapubic bladder catheter. OFC 13.6 cm (0.8th centile), and brain weight 30.3 g (14th centile). Autopsy showed cleft palate, DandyWalker malformation, preductal coarctation of the aorta and right ventricular myocardial hyperplasia, single umbilical artery, recto-vaginal fistula with anal atresia, bicornuate uterus, fused renal ectopia, myelomeningocele at the T12 level and absence of vertebral structures below L1, hypoplastic pelvis, and hypoplastic legs with popliteal webbing (Fig. 4). DISCUSSION The three cases have urogenital abnormalities, in the females easily recognized as part of the spectrum seen in the urorectal septum malformation sequence (URSMS). Escobar et al.  suggested the term URSMS for six female patients with urogenital malformations consisting of ambiguous genitalia, absence of urethral and vaginal openings, imperforate anus, vesicouterorectal fistula, and Müllerian duct defects. They proposed that these malformations were secondary to incomplete division of the cloaca by a urorectal septum failing to fuse with the cloacal membrane. This is associated with persistence of the cloacal membrane resulting in absence of the urethral and vaginal openings Aphallia and URSMS Due to Maternal Diabetes 365 Fig. 3. Postmortem photographs of Patient 2, showing hemifacial microsomia with preauricular skin tags, hypoplastic pelvis, flexion contractures of hips and knees, and bilateral equinovarus position of the feet (left), and lateral view with short neck, overfolded helix, preauricular skin tag, and micrognathia (right). and an imperforate anus. The presentation of URSMS in males has since been recognized in patients with urorectal communication and imperforate or anteriorly placed anus; it is often termed ‘‘cloacal extrophy variant.’’ This malformation can occur with bifid, diminutive, and extremely rarely, absent phallus [Carr et al., 1994]. Five patients with aphallia and urethrorectal communication were reported by Hendren . A report of 13 cases of URSMS by Wheeler et al.  identified two males with aphallia. The cases reported here show findings typical for URSMS, in the male aphallia, vesico-rectal fistula and anal stenosis, in the females anal atresia, recto-vaginal fistula, and abnormal uterus. While based on the definition by Escobar  and subsequent reports URSMS can be clearly diagnosed, it shows findings overlapping with other defects of blastogenesis, such as the anal atresia also seen in the VATER association. This illustrates the point made by Opitz  that ‘‘the definition of individual association is potentially arbitrary, since associations have no diagnostic boundaries, and, except for a cluster of highly correlated core anomalies, they overlap in a large three-dimensional web with many similar entities.’’ Of particular interest are three reports of identical twins, two in males with aphallia and unaffected co-twins [Koffler et al., 1978; Berry et al., 1984]. A female presenting with absence of external genitalia, anal atresia and bilateral renal agenesis was reported by Klinger et al. ; her co-twin was also unaffected. These cases are suggestive of a nongenetic cause, likely related to the blastogenetic process of twinning [Opitz, 1993]. Furthermore, to our knowledge there has been only one report of recurrence of URSMS, affecting a mother and daughter [Mills and Pergament, 1997]. As reproduction for patients with URSMS may be limited, the lack of affected parentchild pairs in the literature may not be surprising, even if there is an underlying genetic or multifactorial cause. Further case reports and family studies will be needed to clarify this question. While URSMS has not previously been reported in products of pregnancy of diabetic mothers, the overall increased risk for malformations in infants of diabetic mother is well recognized. Among the most common abnormalities are congenital heart defects [Cnattingius et al. 1994; Ferencz et al., 1990], central nervous system (CNS) malformations [Barr et al., 1983], vertebral anomalies [Lowy et al., 1986; Perrot et al., 1987], and renal malformations [Grix et al. 1982]. The association of gestational diabetes with congenital malformations is less well established, but a recent review of all liveborn children delivered in Washington State from 1984 to 1991 supports this possibility [Janssen et al., 1996]. While the direct mechanism or the mecha- 366 Gripp et al. Fig. 4. Postmortem photographs of Patient 3: anterior view demonstrating relative macrocephaly and hypoplastic lower limbs (left), and posterior view with thoracic myelomeningocele and popliteal webbing (right). nisms by which maternal diabetes leads to the malformations remains unclear, animal studies have shown that hyperglycemia is not the only causal factor, as insulin treatment failed to abolish the teratogenic potential of serum from diabetic rats [Wentzel and Eriksson, 1996]. It is possible that a genetic predisposition toward diabetes-induced abnormalities exists, because different substrains of rats have shown marked differences in the occurrence of diabetes-induced malformations [Eriksson and Styrud, 1985]. An ultrasonographic study of human diabetic pregnancies documented an increased frequency of early growth delay, particularly in fetuses later found to have multiple malformations [Mølsted-Pedersen and Pedersen, 1985]. While the growth delay was noted at 7 weeks gestational age as no earlier studies were performed, it is likely that the growth delay was of earlier onset, because from embryological considerations it is known that the associated anomalies were induced in weeks 3 to 7 [MølstedPedersen and Pedersen, 1985; Mills et al., 1979]. Typical blastogenetic anomalies are induced during the first 4 weeks of embryogenesis, and these include those anomalies commonly seen in infants of diabetic mothers [Opitz, 1993]. Lowy et al.  reviewed congenital malformations of babies of diabetic mothers and identified four patients with anomalies of the re- productive tract. Three of those had additional kidney and vertebral anomalies. The three cases described here had multiple additional malformations, including CNS and cardiac abnormalities and sacral agenesis. These additional malformations are all common in infants of diabetic mothers, and all are of blastogenetic origin. Thus, the URSMS described in our patients, and possibly less characteristic malformations of the urogenital tract in infants of diabetic mothers reported previously, should be considered in the context of the numerous associated abnormalities. The URSMS appears to be one of the consequences of disturbed blastogenesis in severely affected infants, rather than an isolated malformation. Therefore, the overlap between URSMS and other abnormalities of blastogenesis, such as sacral agenesis or VATER, can be explained by a common origin, with the precise presentation determined by the timing and spatial dimension of the insult. In summary, while it is possible to make the diagnosis of URSMS in infants of diabetic mothers, it is important to view this malformation as part of the spectrum of associations secondary to maternal diabetes, albeit at the severe end of this spectrum. 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