American Journal of Medical Genetics 99:54 ±58 (2001)
Caudal Dysplasia Sequence With Penile Enlargement: Case Report and a Potential Pathogenic Hypothesis Imad R. Makhoul,1* Ayala Aviram-Goldring,2 Tamar Paperna,3 Polo Sujov,1 Shlomit Rienstein,2 Tatiana Smolkin,1 Monica Epelman,4 and Ruth Gershoni-Baruch3 1
Department of Neonatology, Rambam Medical Center, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel 2 Genetic Institute, Sheba Medical Center, Tel-Hashomer, Israel 3 Department of Medical Genetics, Rambam Medical Center, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel 4 Department of Radiology, Rambam Medical Center, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
The clinical spectrum of caudal dysplasia sequence (CDS) is noted for its diversity. The origin of CDS remains unknown, though poorly controlled gestational diabetes has been implicated in some cases. Here we describe the case of a newborn with CDS associated with penile enlargement (PE). The main anomalies included anal atresia, agenesis of the kidneys and of the sacrococcygeal vertebrae, dysgenesis of lumbar vertebrae, and bilateral cryptorchidism. Penile enlargement (7 cm), a rather unusual ®nding, has so far not been reported in association with CDS. Chromosomal analysis failed, and the neonate died 30 min after birth. Comparative genomic hybridization analysis using stored DNA showed a balanced normal male DNA content, which negates chromosomal losses or gains as a cause of CDS and/or PE. PE due to virilizing-type adrenal hyperplasia, caused by common mutations in the genes encoding for the adrenal enzymes 21-hydroxylase and 11-hydroxylase, was ruled out. We report on a previously unpublished case of the coexistence of PE and severe CDS and propose a possible pathogenetic hypothesis of this association. # 2001 Wiley-Liss, Inc. KEY WORDS: caudal dysplasia; comparative genomic hybridization; penile enlargement; adrenal hyperlasia *Correspondence to: Imad R. Makhoul, Department of Neonatology, Rambam Medical Center, Bat-Galim, Haifa 31096, Israel. E-mail:
[email protected] Received 17 May 2000; Accepted 1 November 2000 Published online 16 January 2001
ß 2001 Wiley-Liss, Inc.
INTRODUCTION Caudal dysplasia sequence (CDS), formerly termed caudal regression syndrome or caudal regression malformation sequence, has some overlap with sirenomelia, which is an extreme degree of abnormal differentiation of the caudal developmental ®eld. Several authors have proposed that sirenomelia is produced by an early vascular alteration, ``vitelline artery steal,'' with diversion of blood from embryonal caudal structures [Talamo et al., 1982; Stevenson et al., 1986]. This results in varying degrees of agenesis of caudal organs, including vertebrae, the spinal cord, abdominal organs, pelvic organs, umbilical arteries, genitalia, and lower extremities. In the most severely affected individuals, the prognosis is poor. CDS generally is considered a variation of sirenomelia, but its precise origin is unknown. There is also signi®cant clinical overlap between CDS and the VATER complex (vertebral defects, anal atresia, tracheoesophageal ®stula with esophageal atresia, and radial and renal anomalies). One percent of infants of mothers with poorly controlled diabetes have CDS, and at least 15% of all CDS cases occur in infants of diabetic mothers [Stewart and Stoll, 1979; Fuhrmann et al., 1983]. Herein we describe the case of a newborn with severe CDS who also had penile enlargement (PE), and we discuss the possibility of an association between CDS and PE. SUBJECT AND METHODS Clinical Report A 33-week gestational age, 1,740-g premature neonate was born to healthy and unrelated parents of Jewish-Moroccan origin. Prenatal ultrasonography showed severe oligohydramnios and fetal malforma-
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Fig. 1.
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Small hypoplastic thorax.
tions (small chest and suspected agenesis of thekidneys). There was no evidence of maternal diabetes. At birth, the following ®ndings were noted: Potter face; a hypoplastic thorax (Fig. 1); limb-positioning ¯exion contractures with fully developed legs; imperforate anus, ¯attening of the buttocks, and a shallow intergluteal cleft (Fig. 2); a single umbilical artery; and bilateral cryptorchidism and penile enlargement (Fig. 3) (stretched penile length 7 cm; normal penile length in a 33-week gestational age neonate 2±3.5 cm) [Feldman and Smith, 1975]. The urethral opening looked normal, but probing of the urethra was not done, because the parents did not consent to further examinations. The head circumference was normal. There were no audible heart murmurs and no structural limb anomalies. The neonate experienced severe respiratory failure, required substantial mechanical ventilation, and died at 30 min of age. The parents declined postmortem examination. Radiologic studies showed severe hypoplasia of the lungs and thorax (bell-shaped) (Fig. 4); agenesis of the sacrococcygeal vertebrae, abnormal L3 vertebra, and partial fusion of L4-5 vertebrae (Fig. 4); and agenesis of the kidneys and malpositioned adrenals, as evidenced by an abdominal sonogram. A brain sonogram showed normal results. Blood was obtained for a chromosomal study, but no cells could be cultured for analysis. For this reason, comparative genomic hybridization (CGH) was performed on stored DNA. Cytogenetic and DNA Studies
Comparative Genomic Hybridization. CGH was done as described previously, with minor modi®cations [Kallioniemi et al., 1992, 1994; du Manoir et al., 1993]. Reference and test DNA samples were labeled in
Fig. 2. Imperforate anus, ¯attening of buttocks, and a shallow intergluteal cleft.
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Fig. 3.
Bilateral cryptorchidism and penile enlargement (7 cm).
spectrum red and spectrum green, respectively, as a standard nick translation reaction (CGH nick translation kit, Vysis). DNA samples were hybridized to metaphase spreads of healthy male individuals. Chromosomes were counterstained with DAPI and embedded in antifade solution (Vectashield). CGH slides were evaluated with Zeiss Axiophot/Axioscope microscopes equipped with epi¯uorescence connected to a charge-coupled device camera controlled by custom computer image analysis systems (ISIS, MetaSystems, Altlusheim, Cytovision). CGH analysis was done by choosing 10±15 metaphases for image analysis, with high ¯uorescence intensity of uniform hybridization. Mean ratio pro®les for each chromosome were determined after data from all analyzed metaphases had been combined. Chromosomal gains were de®ned as having a green-to-red ratio > 1.20, and chromosomal losses were de®ned as having a green-to-red ratio
