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Aphallia as part of urorectal septum malformation sequence in an infant of a diabetic mother

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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. [1987] 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 [1997]. A
report of 13 cases of URSMS by Wheeler et al. [1997]
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
[1987] 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 [1993] 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. [1997]; 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. [1986] 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. Further investigation, in particular of the organ systems most
commonly affected, such as CNS, heart, and spine, is
indicated.
Aphallia and URSMS Due to Maternal Diabetes
ACKNOWLEDGMENTS
Karen W. Gripp is supported by the Howard Hughes
Medical Institute.
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