Aphallia as Part of Urorectal Septum MalformationSequence in an Infant of a Diabetic Mother

Karen W. Gripp,1* Mason Barr, Jr.,2 George Anadiotis,1 Donna M. McDonald-McGinn,1Stephen A. Zderic,3 and Elaine H. Zackai1

1Division of Human Genetics and Molecular Biology, The Children’s Hospital of Philadelphia,Philadelphia, Pennsylvania

2Division of Pediatric Genetics, C. S. Mott Children’s Hospital, Ann Arbor, Michigan3Department of Urology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

A male patient with aphallia, anal stenosis,tetralogy of Fallot, multiple vertebralanomalies including sacral agenesis andcentral nervous system (CNS) malforma-tions was born after a pregnancy compli-cated by poorly controlled maternal diabe-tes. Aphallia is an extremely rare abnormal-ity and can be part of the urorectal septummalformation sequence (URSMS). Whileaphallia has not been reported in infants ofdiabetic mothers, urogenital malformationsare known to occur with increased fre-quency. Two female products of pregnan-cies complicated by diabetes presented withmultiple malformations including anal atre-sia and recto-vaginal fistula consistent withthe diagnosis of URSMS. The three patientsshare CNS, cardiac, and vertebral anoma-lies, abnormalities secondary to abnormalblastogenesis and characteristic of diabeticembryopathy. URSMS is also caused by ab-normal blastogenesis. Therefore, this par-ticular malformation should be viewed inthe context of the multiple blastogenetic ab-normalities in the cases reported here. Theoverlap of findings of URSMS in our caseswith other abnormalities of blastogenesis,such as VATER association or sacral agen-esis is not surprising, as these associationsare known to lack clear diagnostic bound-aries. 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 canomalies; diabetic embry-opathy; urorectal septummalformation sequence

INTRODUCTION

A male infant with multiple congenital anomaliesincluding aphallia was born after a pregnancy compli-cated by poorly controlled maternal diabetes. Aphalliais an extremely rare malformation and has not beenreported previously in infants of diabetic mothers.However, urogenital malformations occur with in-creased frequency in infants of diabetic mothers. Inaddition, we report two female fetuses born to diabeticmothers, who showed urogenital abnormalities as partof multiple congenital abnormalities. These three casesshare many findings in common, such as central ner-vous system (CNS), cardiac, and urogenital abnormali-ties.

PATIENTSPatient 1

A male was delivered by cesarean section for breechpresentation at 37 weeks of gestational age. He wasborn to a 25-year-old African-American primigravidaand her nonconsanguineous partner. The pregnancywas complicated by maternal diabetes requiring insu-lin therapy for 2 years before conception. Diabetes con-trol was reportedly poor despite prenatal care. Therewas no other reported prenatal exposure. Birth weightwas 3.6 kg (>90th centile), length 49 cm (75th centile)and occipitofrontal circumference (OFC) 31.5 cm (10–25th centile). Congenital anomalies noted postnatallyincluded an arachnoid cyst superior to the tentoriumand frontal pachygyria, tetralogy of Fallot, multiplevertebral anomalies with sacral agenesis (Fig. 1),aphallia (Fig. 2), vesico-rectal fistula, and anal steno-sis. His karyotype was normal (46,XY, 500 band level).

Patient 2

This female was delivered by cesarean section forfetal distress at 31 weeks gestational age to a 33-year-old Caucasian G2P0 mother. The pregnancy was com-plicated by diet-controlled gestational diabetes and bypolyhydramnios noted at 30 weeks. Birthweight was1.2 kg (10–25th centile), crown-to-rump length 23.5 cm,

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 CivicCenter Boulevard, Philadelphia, PA 19104–4399.

Received 9 December 1997; Accepted 8 January 1998

American Journal of Medical Genetics 82:363–367 (1999)

© 1999 Wiley-Liss, Inc.

(<3rd centile), and OFC 29.5 cm (50–75th centile). Theinfant died at age 1 day due to pulmonary hypoplasia.Multiple congenital anomalies included hemifacial mi-crosomia with preauricular skin tags and mandibularhypoplasia, hypoplastic olfactory bulbs, absent rightlung, truncus arteriosus with atrial septal defect, ven-tricular septum defect, and right-sided descendingaorta, intestinal malrotation, anal atresia, recto-vaginal fistula, and hemiuterus with right vestigial fal-lopian tube. Skeletal abnormalities included sacralagenesis with hypoplastic pelvis, flexion contracturesof the hips and knees with inguinal and popliteal web-bing, tibial bowing and bilateral equinovarus positionof the feet (Fig. 3).

Patient 3

This female fetus was the product of a 19-week ges-tation. Her 26-year-old mother was diagnosed with dia-betes during the pregnancy and started insulin therapyat 6 weeks of gestation. Increased maternal seruma-feto protein level and abnormalities noted on ultra-sound led to the diagnosis of neural tube defect and thetermination of pregnancy. Weight was 139 g (1.1st cen-tile), crown-to-rump length 12.3 cm (0.02nd centile),

OFC 13.6 cm (0.8th centile), and brain weight 30.3 g(14th centile). Autopsy showed cleft palate, Dandy-Walker malformation, preductal coarctation of theaorta and right ventricular myocardial hyperplasia,single umbilical artery, recto-vaginal fistula with analatresia, bicornuate uterus, fused renal ectopia, myelo-meningocele at the T12 level and absence of vertebralstructures below L1, hypoplastic pelvis, and hypoplas-tic legs with popliteal webbing (Fig. 4).

DISCUSSION

The three cases have urogenital abnormalities, inthe females easily recognized as part of the spectrumseen in the urorectal septum malformation sequence(URSMS). Escobar et al. [1987] suggested the termURSMS for six female patients with urogenital malfor-mations consisting of ambiguous genitalia, absence ofurethral and vaginal openings, imperforate anus, vesi-couterorectal fistula, and Mullerian duct defects. Theyproposed that these malformations were secondary toincomplete division of the cloaca by a urorectal septumfailing to fuse with the cloacal membrane. This is as-sociated with persistence of the cloacal membrane re-sulting in absence of the urethral and vaginal openings

Fig. 1. Radiograph of Patient 1, showing scoliosis due to thoracic hemi-and butterfly vertebrae, sacral agenesis, and fusion of ribs 8 to 10 on theleft.

Fig. 2. Patient 1 with aphallia, normal scrotum, and suprapubic blad-der catheter.

364 Gripp et al.

and an imperforate anus. The presentation of URSMSin males has since been recognized in patients withurorectal communication and imperforate or anteriorlyplaced anus; it is often termed ‘‘cloacal extrophy vari-ant.’’ This malformation can occur with bifid, diminu-tive, and extremely rarely, absent phallus [Carr et al.,1994]. Five patients with aphallia and urethrorectalcommunication were reported by Hendren [1997]. Areport of 13 cases of URSMS by Wheeler et al. [1997]identified two males with aphallia. The cases reportedhere show findings typical for URSMS, in the maleaphallia, vesico-rectal fistula and anal stenosis, in thefemales anal atresia, recto-vaginal fistula, and abnor-mal uterus. While based on the definition by Escobar[1987] and subsequent reports URSMS can be clearlydiagnosed, it shows findings overlapping with other de-fects of blastogenesis, such as the anal atresia also seenin the VATER association. This illustrates the pointmade by Opitz [1993] that ‘‘the definition of individualassociation is potentially arbitrary, since associationshave no diagnostic boundaries, and, except for a clusterof highly correlated core anomalies, they overlap in alarge three-dimensional web with many similar enti-ties.’’ Of particular interest are three reports of identi-cal twins, two in males with aphallia and unaffectedco-twins [Koffler et al., 1978; Berry et al., 1984]. A fe-male presenting with absence of external genitalia,

anal atresia and bilateral renal agenesis was reportedby Klinger et al. [1997]; her co-twin was also unaf-fected. These cases are suggestive of a nongeneticcause, likely related to the blastogenetic process oftwinning [Opitz, 1993]. Furthermore, to our knowledgethere has been only one report of recurrence ofURSMS, affecting a mother and daughter [Mills andPergament, 1997]. As reproduction for patients withURSMS may be limited, the lack of affected parent-child pairs in the literature may not be surprising, evenif there is an underlying genetic or multifactorialcause. Further case reports and family studies will beneeded to clarify this question.

While URSMS has not previously been reported inproducts of pregnancy of diabetic mothers, the overallincreased risk for malformations in infants of diabeticmother is well recognized. Among the most commonabnormalities are congenital heart defects [Cnat-tingius et al. 1994; Ferencz et al., 1990], central ner-vous system (CNS) malformations [Barr et al., 1983],vertebral anomalies [Lowy et al., 1986; Perrot et al.,1987], and renal malformations [Grix et al. 1982]. Theassociation of gestational diabetes with congenital mal-formations is less well established, but a recent reviewof all liveborn children delivered in Washington Statefrom 1984 to 1991 supports this possibility [Janssen etal., 1996]. While the direct mechanism or the mecha-

Fig. 3. Postmortem photographs of Patient 2, showing hemifacial microsomia with preauricular skin tags, hypoplastic pelvis, flexion contractures ofhips and knees, and bilateral equinovarus position of the feet (left), and lateral view with short neck, overfolded helix, preauricular skin tag, andmicrognathia (right).

Aphallia and URSMS Due to Maternal Diabetes 365

nisms by which maternal diabetes leads to the malfor-mations remains unclear, animal studies have shownthat hyperglycemia is not the only causal factor, asinsulin treatment failed to abolish the teratogenic po-tential of serum from diabetic rats [Wentzel and Eriks-son, 1996].

It is possible that a genetic predisposition towarddiabetes-induced abnormalities exists, because differ-ent substrains of rats have shown marked differencesin the occurrence of diabetes-induced malformations[Eriksson and Styrud, 1985]. An ultrasonographicstudy of human diabetic pregnancies documented anincreased frequency of early growth delay, particularlyin fetuses later found to have multiple malformations[Mølsted-Pedersen and Pedersen, 1985]. While thegrowth delay was noted at 7 weeks gestational age asno earlier studies were performed, it is likely that thegrowth delay was of earlier onset, because from em-bryological considerations it is known that the associ-ated anomalies were induced in weeks 3 to 7 [Mølsted-Pedersen and Pedersen, 1985; Mills et al., 1979].

Typical blastogenetic anomalies are induced duringthe first 4 weeks of embryogenesis, and these includethose anomalies commonly seen in infants of diabeticmothers [Opitz, 1993]. Lowy et al. [1986] reviewed con-genital malformations of babies of diabetic mothersand identified four patients with anomalies of the re-

productive tract. Three of those had additional kidneyand vertebral anomalies.

The three cases described here had multiple addi-tional malformations, including CNS and cardiac ab-normalities and sacral agenesis. These additional mal-formations are all common in infants of diabetic moth-ers, and all are of blastogenetic origin. Thus, theURSMS described in our patients, and possibly lesscharacteristic malformations of the urogenital tract ininfants of diabetic mothers reported previously, shouldbe considered in the context of the numerous associatedabnormalities. The URSMS appears to be one of theconsequences of disturbed blastogenesis in severely af-fected infants, rather than an isolated malformation.Therefore, the overlap between URSMS and other ab-normalities of blastogenesis, such as sacral agenesis orVATER, can be explained by a common origin, with theprecise presentation determined by the timing and spa-tial dimension of the insult.

In summary, while it is possible to make the diagno-sis of URSMS in infants of diabetic mothers, it is im-portant to view this malformation as part of the spec-trum of associations secondary to maternal diabetes,albeit at the severe end of this spectrum. Further in-vestigation, in particular of the organ systems mostcommonly affected, such as CNS, heart, and spine, isindicated.

Fig. 4. Postmortem photographs of Patient 3: anterior view demonstrating relative macrocephaly and hypoplastic lower limbs (left), and posteriorview with thoracic myelomeningocele and popliteal webbing (right).

366 Gripp et al.

ACKNOWLEDGMENTS

Karen W. Gripp is supported by the Howard HughesMedical Institute.

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