PRENATAL DIAGNOSISPrenat Diagn 2003; 23: 728730.Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/pd.672
Prenatal diagnosis of multiple pterygium syndromeassociated with Klinefelter syndromeArda Lembet1, Mesut Oktem1*, Zerrin Ylmaz2, Umit Kaya1 and Murat Derbent31Baskent University School of Medicine, Department of Obstetrics and Gynecology, Ankara, Turkey2Baskent University School of Medicine, Department of Medical Biology and Genetics, Ankara, Turkey3Baskent University School of Medicine, Department of Pediatrics, Ankara, Turkey
A nonlethal form of multiple pterygium syndrome (MPS) was diagnosed prenatally at 16 weeks of gestationwith associated Klinefelter syndrome in the same fetus. The ultrasound findings were cystic hygroma,hypertelorism, micrognathia, low-set ears, flexion contractures of upper and lower extremities and rocker-bottom foot. Genetic amniocentesis revealed a 47,XXY karyotype. After genetic counseling, the parents decidedto have a therapeutic abortion. We presented this case for the purpose of further describing the early ultrasoundfindings and clinical features of multiple pterygium syndromes. Also, what makes our patient unique is thecoincidental presence of Klinefelter syndrome with MPS. To our knowledge, this is the first case in the literaturein which a 47,XXY karyotype has been found in a fetus with multiple pterygium syndrome. The importanceof delineating the exact subtype of MPS and making a precise differential diagnosis becomes critical duringthe process of evaluation of patients with MPS. Copyright 2003 John Wiley & Sons, Ltd.KEY WORDS: multiple pterygium syndrome; Klinefelter syndrome; ultrasound; prenatal diagnosis
Bussiere originally described the multiple pterygiumsyndrome (MPS) in 1902 (Jones, 1997). In 1976, Gorlinet al. described an autosomal recessive disorder charac-terized by congenital arthrogryposis, skin webs (ptery-gia) across joints and unusual facies (Gorlin et al.,1976). This disorder was fully delineated as a distinctentity by Escobar et al. in 1978 and an alternative name,Escobar syndrome, was quoted by Smith (Escobar et al.,1978; Thompson et al., 1987). Although many caseshave been reported to be sporadic, in a few families, theinheritance may be dominant or recessive (Hall, 1997).The phenotypic features of MPS are extensive pterygiaacross the major joints, finger contractures, scoliosis, tal-ipes equinovarus, short stature, cleft palate, ptosis andmultiple minor facial anomalies (Rammer et al., 1988).The syndrome has been reported together with differentabnormalities (Derbent et al., 1992; Angle et al., 1997;Madhuri et al., 2001).
Klinefelter syndrome results from an aberration of sexchromosomes (47,XXY karyotype), which can be due toa non-disjunction during the early postzygotic mitoticdivisions or during the maternal or paternal meiosis(De la Chapelle, 1990).
In this paper, we report an MPS case, togetherwith Klinefelter syndrome, that has not been describedpreviously in the literature.
*Correspondence to: Mesut Oktem, Onur Sokak 38/9 06570,Maltepe, Ankara, Turkey. E-mail: email@example.com
A 23-year-old woman of gravida 6, para 2, (abortions3) was admitted to the hospital for routine prenatal careat 16 weeks of gestation. Her past obstetric history wassignificant and she had a missed abortion at 16 weeksof gestation 5 years previously. In a subsequent preg-nancy, she had a genetic amniocentesis, two weeks afterwhich an ultrasound evaluation revealed no fetal heartactivity and a medical abortion was performed. A yearlater, the patient conceived a third time and at 20 weeksof gestation multiple fetal anomalies consistent withMPS and KlippelTrenaunayWeber syndrome weredetected. However, prenatal care and delivery occurredin another center and we were unable to obtain docu-mentation. Subsequently, the patient gave birth to twofull-term healthy babies. Her medical and family his-tory were unremarkable except for a consanguineousmarriage.
In the presented case, ultrasound evaluation at16 weeks revealed nuchal edema (nuchal fold: 6.5 mm),rocker-bottom feet, flexion contractures of the upper andthe lower extremities, hypertelorism, micrognathia andlow-set ears. Detailed examination of the nuchal edemadid not show any extension of the upper body or necknor did it involve any septations. Chest circumferenceand thorax appeared normal with no signs of abnormalcervical curvature. Also, the amniotic fluid volume andgross fetal movements appeared normal. Amniocentesiswas performed at 16 weeks of gestation and a 47,XXYkaryotype (Klinefelter syndrome) was obtained. Aftergenetic counseling, a therapeutic abortion was performedat 18 weeks of gestation. Intracardiac fetal blood andskin samples confirmed the 47,XXY karyotype.
Copyright 2003 John Wiley & Sons, Ltd. Received: 6 November 2002Revised: 12 May 2003
Accepted: 19 May 2003
MULTIPLE PTERYGIUM SYNDROME COEXISTING WITH KLINEFELTER SYNDROME 729
Figure 1Picture of the fetus after abortion showing nuchal edema,low-set ears, micrognathia, pterygia involving the axillae, flex-ion deformities of the elbows, wrists, hips, knees and bilateralrocker-bottom feet
The autopsy report revealed multiple joint contrac-tures: adducted shoulders, flexion deformities of theelbows, wrists, hips, knees and bilateral rocker-bottomfeet. In addition, there were multiple pterygia involv-ing the major joints. A high arched palate was detectedalong with micrognathia, ptosis, low-set ears, hyper-telorism, long philtrum and a small nose. At the backof the neck, a cystic hygroma was present (Figure 1).Microscopic examination of hygromata and sections ofthe skin and deep soft tissues showed numerous widelydilated lymphatic channels. Macroscopically, placentaand umbilical cord were normal. X-ray findings showedscalp edema, molding of the head, soft-tissue swellingextending at the back of the neck and bilateral rocker-bottom feet.
Escobar syndrome, or multiple pterygium syndrome ischaracterized clinically by small stature, pterygia ofneck, axillae, antecubital, popliteal and intercrural areas;camptodactyly, syndactyly, equinovarus and/or rocker-bottom feet; cryptorchidism, absence of labia majora,scoliosis, kyphosis, fusion of vertebrae and/or fusedlaminae; rib anomalies and absent or dysplastic patella(Thompson et al., 1987). The pathogenesis of ptery-gia is unknown; however, a primary muscle, nerve orspinal cord defect may be the cause (Yokochi et al.,1985). After detection of the abnormalities, a thoroughultrasonographic differential diagnosis should includeother genetic syndromes such as arthrogryposis multi-plex, Cornelia de Lange, Neu-Laxova, Pena Shokeir,Roberts and Seckel syndromes. The differential diag-nosis of MPS should always include the popliteal ptery-gium syndrome that is characterized by cleft lip, lip pits,syngnathia and ankyloblepharon philiforme. Conversely,characteristics of the MPS such as pterygia of the neck,antecubital and axillary areas are not seen in poplitealpterygium syndrome (Derbent et al., 2001).
Our patient manifested many of the commonlydescribed features of patients with Escobar syndrome:
extremity pterygia, the classic facies of Escobar syn-drome, rocker-bottom feet and cystic hygroma of theneck. The lethal (h) type of MPS with a recessiveor X-linked heritability is important in the differen-tial diagnosis of fetal hydrops. This form of syndromepresents with intrauterine growth retardation, hydrops,early severe fatal akinesia sequence, generalized amy-oplasia, hypoplastic heart, hypoplastic lungs, lethal poly-hydramnios and intrauterine death in the second or thirdtrimester of pregnancy. Fetuses with the lethal type ofMPS generally die in the neonatal period as a result ofpulmonary hypoplasia. In the course of the pregnancy,some fetuses die early in utero before the third trimester,whereas some fetuses survive into the third trimesterwithout hydrops, then die at birth (Jones, 1997). Inthe lethal multiple pterygium syndrome (LMPS) clas-sification, both clinical findings and time of onset areimportant. Tolmie et al. reported on an X-linked patternof inheritance with broad ribs and clavicles as clinicalfindings (Tolmie et al., 1987). In our index case, thediagnosis was made prenatally and the fetus did not havehydrops at the time of diagnosis.
The majority of individuals with Escobar syndromebecome ambulatory and have normal intelligence. Nearly6% of patients who have respiratory problems may havesignificant morbidity or death in the first year of life.
The respiratory problems include pneumonia, episodesof dsypnea or apnea, presumably secondary to the lor-dosis, and small chest size. As time passes, the pterygiamay lead to fixed contractures. For all these reasons,it is important to decide the type of MPS prenatallyin order to decide the fate of the pregnancy. In ourpatient, the absence of hydrops fetalis, small chest andany other severe skeletal deformation helped us rule outthe lethal type of the syndrome. The pedigree of theprobands family suggested autosomal recessive inheri-tance. The obstetric history of the mother also includedanother MPS phenotype fetus with multiple abnormali-ties, which confirmed our conclusion. We informed thepatient about the outcome and stated that the conditionmay become worse as the individual enters puberty. Theparents were informed about the prognosis for normalintelligence, but that the condition may become worseat puberty, and that intensive physiotherapy and correc-tive surgery might be traumatic for both the patient andthe family (Hall, 1997; Benacerraf, 1998).
Another point that is interesting to our case is thatthe fetus had associated Klinefelter syndrome. Kline-felter syndrome is a sex chromosome abnormality withan incidence of 1 in 1000 male live births. Nearlyhalf of Klinefelter cases result from paternal meiosis Ierrors, usually due to pseudoautosomal region Xp/Yprecombination failure. When the error is maternal, itis the result of meiosis I or meiosis II. It can also bea postzygotic mitotic error. Maternal age is increasedin meiosis I errors (Nussbaum et al., 2001). Differentphenotypic abnormalities and X-linked diseases coex-isting with Klinefelter syndrome have been reported(Zeitoun et al., 1997; Armbruster-Moraes et al., 1999;Fryns et al., 1996). However, we have not found anypatient with MPS who presented together with Kline-felter syndrome in the literature. We regarded the case
Copyright 2003 John Wiley & Sons, Ltd. Prenat Diagn 2003; 23: 728730.
730 A. LEMBET ET AL.
in the base of X-inactivation. The fetus did not havehydrops but might have had the lethal-type MPS, withthe process of lyonization causing inactivation of anexcess of mutation-bearing X chromosomes, thus pre-venting the lethal phenotype. Froster et al. proposed aprotocol for fetuses with LMPS (Froster et al., 1997);however, our case had two X chromosomes instead ofone, and X-inactivation should also be taken into accountin such cases.
XY gonadal dysgenesis has been reported with MPSpreviously (Angle et al., 1997). They concluded thatan X-linked or autosomal gene involved in sex deter-mination might be involved in the childs phenotype.Pashayan et al. reported a 47,XXY/48,XXXY mosaicwith MPS, which is probably similar to our fetus(Pashayan et al., 1973).
The association of these two conditions is probablyrandom. At this point, the importance of prenatal follow-up and prenatal genetic diagnosis is obvious. It isdifficult to distinguish between lethal and nonlethal MPSprenatally. Since the syndrome has a heterogeneouscharacter and the patient had a consanguineous marriage,we informed the patients of both the autosomal and theX-linked inheritance patterns of the syndrome during thecounseling session.
Advances in ultrasonography lead to the prenataldescription of many rare syndromes and malformations.We managed to detect malformations such as microg-nathia, low-set ears, hypertelorism, cystic hygroma colliand rocker-bottom feet sonographically. The early prena-tal diagnosis and management of this case were possibleusing ultrasonography by experienced sonographers.
A multidisciplinary approach in prenatal assessmentmay help to clarify difficult diagnostic problems and maybe of direct benefit to the pregnant patient.
Although MPS is a rare condition, increased aware-ness may bring more cases to light. Prenatal managementof this case may be helpful to physicians to further guidedecision-making.
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Copyright 2003 John Wiley & Sons, Ltd. Prenat Diagn 2003; 23: 728730.