Ultrasound Obstet Gynecol 2011; 38: 553–558 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.8967 Stuve–Wiedemann syndrome: a skeletal dysplasia characterized by bowed long bones M. A. BEGAM*#, W. ALSAFI*#, G. N. BEKDACHE*, F. CHEDID†, L. AL-GAZALI‡ and H. M. MIRGHANI§ *OBYGN/Fetal Medicine Unit, Tawam Hospital, Al Ain, Abu Dhabi, United Arab Emirates; †Pediatrics, Tawam Hospital, Al Ain, Abu Dhabi, United Arab Emirates; ‡Pediatrics, UAE University, Al Ain, Abu Dhabi, United Arab Emirates; §OBGYN, UAE University, Al Ain, Abu Dhabi, United Arab Emirates K E Y W O R D S: outcome; prenatal diagnosis; Stuve–Wiedemann syndrome ABSTRACT Objective To describe the prenatal sonographic features of Stuve–Wiedemann syndrome (SWS). Methods A retrospective review of all cases of confirmed SWS during an 8-year period was conducted. Clinical and historical data and outcome of the pregnancies were noted. Fetal biometry, skeletal survey, amniotic fluid volume and associated anomalies were recorded. A sonographic algorithm was proposed to distinguish SWS from other bent bone disorders. Results In total, there were 10 cases, six of which were diagnosed prenatally. The main prenatal features of SWS were mild-to-moderate micromelia and bowing of the lower limb bones, affecting the tibia more than the femur. There was relative sparing of fibula and upper limb bones, with normal scapulae and clavicles. Camptodactyly was the main associated anomaly. All fetuses developed growth restriction in the late second trimester with oligohydramnios in half of the cases. These features could appear late in pregnancy. Although the thoracic dimensions were normal in the majority of fetuses, respiratory insufficiency, as a result of myotonia, was a leading cause for mortality. Conclusions It is possible to diagnose SWS prenatally. SWS is associated with high mortality during the first year of life, and those who survive have high morbidity. Copyright  2011 ISUOG. Published by John Wiley & Sons, Ltd. INTRODUCTION Stuve–Wiedemann syndrome (SWS; MIM 601 559) is an autosomal-recessive syndrome characterized by myotonia with mask-like face, skeletal dysplasia and intrauterine growth restriction (IUGR). Stuve and Wiedemann described the first case in 1971 in two sisters with an early lethal outcome1 . Because of the similar clinical and radiological features, SWS and Schwartz–Jampel syndrome type 2 are considered to be a single entity2,3 . The syndrome is characterized by short stature, bowing of extremities that affect the lower limbs more than the upper limbs, camptodactyly, respiratory distress/apneic spells and hyperthermic episodes frequently associated with feeding/swallowing difficulties. Other clinical findings are mask-like face, pursed mouth, hypoplastic midface, congenital contractures and muscular hypotonia. Associated malformations are rare. SWS is associated with a significant increase in neonatal mortality mainly because of respiratory insufficiency and malignant hyperthermia that is refractory to therapy4 . The rare survivors develop progressive scoliosis, spontaneous fractures, bowing of the lower limbs (with prominent joints), dysautonomia symptoms (including temperature instability, absent corneal and patellar reflexes and smooth tongue) and normal mental development5,6 . Dagoneau et al.7 identified that SWS is caused by mutations in the leukemia inhibitory factor receptor (LIFR) gene on chromosome 5p13. Several mutations in this gene were identified in 19 families affected with this syndrome. In families from the United Arab Emirates (UAE), an identical frameshift insertion (653 654T) was identified, indicating a founder effect in this region. Accurate antenatal diagnosis of SWS may prove difficult as the main prenatal feature, short and bowed long bones, is a common finding in many skeletal dysplasias. Hence, the very few prenatal reported cases were in patients with familial SWS8 – 10 . Correspondence to: Dr H. M. Mirghani, OBGYN, UAE University, Faculty of Medicine PO Box 17666, Al Ain, Abu Dhabi, United Arab Emirates (e-mail: hmirghani@uaeu.ac.ae) #Dr M. A. Begam and Dr W. Alsafi contributed equally to this manuscript. Accepted: 2 February 2011 Copyright  2011 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINAL PAPER 554 The aims of this study were to describe the sonographic features of SWS, and to identify features that may be helpful in the differential diagnosis with other skeletal dysplasias. The prenatal differentiation among this group of skeletal disorders is important in guiding clinical management. METHODS This was a retrospective study of cases seen in the Fetal Medicine Unit of Tawam Hospital, Al Ain District, UAE, over a period of 8 years from January 2002 to April 2010, with a confirmed postnatal diagnosis of SWS. The Fetal Medicine Unit at Tawam Hospital is the tertiary referral unit for the whole of the country. All babies with suspected SWS were examined by a neonatologist and a geneticist. The diagnosis of SWS was confirmed postnatally by clinical (mask-like face, pursed mouth, camptodactyly, congenital contractures, muscular hypotonia, respiratory distress/apneic spells and hyperthermic episodes associated with feeding/swallowing difficulties), radiological (bowing of the lower limbs more than the upper limbs, short, thick long bones with internal cortical thickening, wide metaphyses and an abnormal trabecular pattern)4 and molecular7 studies. All cases included in this study had the same founder mutation, the frameshift insertion in the LIFR gene. Analysis was performed by reviewing the prenatal ultrasound images and the charts of mothers and babies. Clinical and historical data, including family history and consanguinity, fetal biometry, details of the skeletal survey, amniotic fluid volume and associated anomalies were recorded. Thoracic size was determined from the thoracic circumference11 and the cardiothoracic ratio. The postnatal data and outcome of the pregnancies were noted. An algorithm was formulated based on the prenatal features to distinguish SWS from other bent skeletal disorders12 . Asymmetric IUGR was defined as an abdominal circumference and estimated fetal weight falling below the 10th percentile with normal head measurements13 . Begam et al. dysplasia, and the skeletal disorder was recognized postnatally. A prenatal diagnosis of SWS was made in 6/10 (60%) patients. Of these, four patients had a positive family history of SWS; however, in two patients the diagnosis was highly suspected in the absence of a previous affected child (Cases 8 and 9). In the remaining 4/10 (40%) cases, the diagnosis was entirely postnatal. Two were interpreted as IUGR, and the other two were recorded as nonlethal skeletal dysplasia with no definite antenatal diagnosis. These four cases constitute the false-negatives during the study period. No false-positives were encountered. The main prenatal ultrasound findings were mild-tomoderate micromelia and bowing of the lower limb bones, affecting the tibia more than the femur, with relative sparing of the fibula and the upper limb bones. Furthermore, the femora were symmetrically bowed with angulation between the proximal third and distal twothirds of the shaft, while the tibia was severely bowed (Figure 1). Other bones, such as the scapulae and the clavicles, were normal. The shortening and bowing of the femur was diagnosed during the second trimester in the majority of cases. However, in two fetuses (Cases 8 and 10), the femur was of normal length and shape at the mid-trimester scan and the abnormality was only evident in the third trimester (Table S1). The thoracic dimensions were normal in 7/10 (70%) fetuses. No measurements were recorded in the remaining RESULTS In total, there were 10 fetuses with a confirmed postnatal diagnosis of SWS. Their prenatal features and perinatal outcome are shown in detail in Table S1. The total number of deliveries during the study period in our hospital was 28 728. Hence, the birth prevalence of SWS in this highrisk referral group was 3.5/10 000 births. The main reason for referral was short, bowed long bones (Table S2). The mean (± SD) gestational age at the initial ultrasound examination was 23.8 (± 5.4) weeks. The presence of a skeletal abnormality was recognized prenatally in eight (80%) patients. In two (20%) patients the discrepancy between the femur length and gestational age was attributed to IUGR rather than to skeletal Copyright  2011 ISUOG. Published by John Wiley & Sons, Ltd. Figure 1 Ultrasound images of the lower limb bones in a fetus with Stuve–Wiedemann syndrome. (a) Femur showing angulation between proximal third and distal two-thirds of the shaft. (b) Tibia showing acute severe bowing. Ultrasound Obstet Gynecol 2011; 38: 553–558. Stuve–Wiedemann syndrome three cases; however, in one (10%) fetus the thorax was described as bell shaped. The associated anomalies were talipes in 2/10 (20%) fetuses and camptodactyly in 3/10 (30%) fetuses. One case was affected with tetralogy of Fallot. In the third trimester, there was a decline in growth in all fetuses. They developed signs of asymmetrical IUGR. Five (50%) cases were associated with oligohydramnios. The onset of oligohydramnios was variable, occurring between 28 and 36 weeks of gestation. However, Doppler ultrasound of the umbilical and middle cerebral arteries was normal. Table 1 summarizes the prenatal ultrasound features of SWS. All mothers, except one, reported normal fetal movements during the course of pregnancy. All neonates were born at term. Their birth weights were all below the 10th percentile, and the mean birth weight was 2446 (± 222) g. Their immediate postnatal course was generally good with normal Apgar scores at 1, 5 and 10 min (Table S1). The infants soon presented with features typical of SWS with an unstable course that resulted in the death of four (40%) babies. The age at death ranged between 2 days and 8 months. Five infants survived beyond 1 year of age and one was alive at 8 years of age. Postnatal genetic investigation showed that all fetuses had an identical frameshift insertion in the LIFR gene. Table 1 Prenatal ultrasound features of Stuve–Wiedemann syndrome (SWS) Prenatal ultrasound features of SWS Mild-to-moderate micromelia Bowing of lower limb bones (tibia > femur) Relative sparing of fibula and upper limb bones Normal scapulae and clavicles Camptodactyly and talipes Normal thorax IUGR with normal Doppler findings Oligohydramnios IUGR, intrauterine growth restriction. 555 DISCUSSION In this study, we report on the largest prenatal series of SWS. The diagnosis of SWS is mainly postnatal, guided by clinical and radiological findings. The syndrome is well documented in the pediatric literature1 – 6 . To our knowledge, there are only four prenatal cases of SWS reported in the literature8,10,14 , mainly in patients with a family history of an affected child. In the absence of a family history, SWS poses a diagnostic dilemma14 because the main sonographic feature of SWS, short bowed long bones, is shared by many skeletal dysplasias. Interestingly, in two of our patients (Cases 8 and 9) the diagnosis was suspected prenatally despite a negative family history. This can be attributed to the following: SWS is relatively common in the UAE (the reported prevalence of SWS in the UAE is about 0.5/10 000 births owing to the high prevalence of consanguineous marriages15,16 ); early involvement of the geneticist; and increasing suspicion by the perinatal team. The prevalence of SWS in our study was 3.5/10 000 births. This is much higher than the previously reported 0.5/10 000 and might be because our unit is the main referral center for fetal pathology in the country. In this study, a similar pattern of mild-to-moderate micromelia and bowing of the lower limb bones was seen among the affected fetuses (Tables 1 and S1, Figure 1). In addition, SWS is characterized by the presence of sonographically detectable anomalies, namely talipes and camptodactyly (hyperextension of the index finger with occasional involvement of the 5th digit and constant flexion of the other fingers; Figure 2). Camptodactyly is a prenatal feature of SWS1,8,9,14 . However, antenatal detection was possible in only one third of our cases (Table S1). This might be because of a low suspicion rate in the earlier part of the study (Cases 1–4) and the presence of oligohydramnios. A normal mid-trimester scan does not exclude the possibility of SWS. In all cases, fetal biometry in the third trimester suggested IUGR (Table S1). Hence, the short femur could Figure 2 (a) Three-dimensional reconstructed view of a fetus with camptodactyly (hyperextension of index finger). (b) Two-dimensional view of a fetus with camptodactyly (hyperextension of index and little fingers). (c) Postnatal image of the same case as that shown in (b) with camptodactyly. Copyright  2011 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2011; 38: 553–558. Begam et al. 556 Campomelia with mild-to-moderate micromelia (look for pattern of long bone findings and associated anomalies) Cumming syndrome: cervical lymphocele, polycystic kidneys, short gut, polysplenia, AR inheritance Antley–Bixler syndrome: hypoplastic scapulae, radio humeral synostosis, craniosynostosis, AR inheritance Bowed tibiae > femora (specific pattern of bowing), sparing of upper limb bones CMPD: hypoplastic fibula and scapula, macrocephaly, hydrocephalus, hydronephrosis, 11 pairs of ribs, facial features, sex reversal in male patients, narrow thorax, AD inheritance, SOX9 mutations26 SWS: camptodactyly, normal scapula, fibula, oligohydramnios with normal Doppler, normal thorax, AR inheritance, LIFR gene mutation Rhizomelic shortening, more apparent in lower limbs Kyphomelic dysplasia: symmetric femora, narrow thorax, AR inheritance, gene unknown FH-UFS: usually asymmetric femora, cleft palate, hypoplastic fibulae, genitourinary anomalies, sporadic, diabetic mothers Diastrophic dysplasia: upper and lower limbs, hand deformities (Hitch-hiker thumb), spine anomalies, joint contractures, DTDST gene mutations32, AR inheritance Figure 3 Algorithm to distinguish Stuve–Wiedemann syndrome (SWS) from other bent-bone disorders. AD, autosomal dominant; AR, autosomal recessive; CMPD, campomelic dysplasia (always consider a moderately severe form of osteogenesis imperfecta in the differential diagnosis20 ); DTDST, diastrophic dysplasia sulfate transporter; FH-UFS, femoral hypoplasia unusual facies syndrome; LIFR, leukemia inhibitory factor receptor7 ; SWS, Stuve–Wiedemann syndrome. be misinterpreted as IUGR (Cases 6 and 7). However, the normal umbilical artery Doppler result would suggest causes other than uteroplacental insufficiency. The association of oligohydramnios might confuse the clinical picture. Oligohydramnios seems to be a common association with SWS (Table S1) and has been reported by others14 . In cases with skeletal dysplasia, the thoracic dimensions are considered as a predictor of lethality11 . In our series, the majority (70%) had normal thoracic dimensions (Table S1). Nevertheless, they all presented with a varied degree of respiratory insufficiency, which was a major contributing factor to their mortality. It seems that the respiratory distress and apneic spells associated with SWS are probably secondary to myotonia rather than to pulmonary hypoplasia. This should be considered during the prenatal counseling. In the Revised International Nosology and Classification of Genetic Disorders of Bone – 200612 , SWS has been classified under the bent skeletal dysplasias along with campomelic dysplasia (CMPD), Cumming syndrome and kyphomelic dysplasia17 . Alternative diagnostic considerations in the setting of bowed femora and Copyright  2011 ISUOG. Published by John Wiley & Sons, Ltd. mild-to-moderate micromelia would be Antley–Bixler syndrome, femoral hypoplasia-unusual facies syndrome (FH-UFS), osteogenesis imperfecta (OI) and diastrophic dysplasia18 – 21 . They can be diagnosed easily at birth based on clinical and radiological findings. The prenatal distinction is important for early diagnosis22 , selection of appropriate molecular tests23 , prediction of lethality, management and genetic counseling24 . Prenatally, it is possible to narrow the differential diagnosis utilizing a skeletal survey, the pattern of long bones and associated anomalies18 . We propose a sonographic algorithm to distinguish SWS from other bent skeletal disorders with a similar presentation (Figure 3). From our observations, the long bone abnormalities seen in SWS have also been reported in CMPD25 . In the past, SWS was frequently mistaken for CMPD until it finally emerged as a separate entity4,14 . CMPD, unlike SWS, is associated with a variety of skeletal and nonskeletal anomalies25 (Figure 3). Furthermore, the identification of a molecular basis for CMPD (SOX9 mutations)26 and SWS (LIFR mutations)7 has contributed to a better delineation of this group of syndromes. Ultrasound Obstet Gynecol 2011; 38: 553–558. Stuve–Wiedemann syndrome All cases studied in this series had an identical frameshift insertion in the LIFR gene. The exact frequency of this mutation in the UAE population is unknown but it seems to be quite high, especially among certain tribes in whom the disease is common. Therefore, identification of the founder mutation is very useful in this population. Several null mutations in the LIFR gene have been implicated in SWS in other parts of the world7 . The features of OI in the moderately severe forms of the condition overlap with those of CMPD as emphasized by Sanders et al.20 . The lower limbs are most severely affected in type 2B-3 OI, showing pronounced tibial bowing, mimicking CMPD20 . The lethality of the skeletal dysplasia will guide clinical management24 . CMPD is frequently lethal with few reported survivors27 . While Maroteaux reported a mean survival of only 2 months in SWS patients28 , others reported patients surviving infancy5,6 . In our series, all deaths occurred in the infantile period (Table S1). Although it is difficult to infer solid prognostic factors from small numbers, we observed that severe early involvement of long bones (Cases 1 and 2) and early onset of severe oligohydramnios (Case 8) could suggest poor outcome in SWS. Despite the occasional lethal neonatal problems, kyphomelic dysplasia, FHUFS and diastrophic dysplasia are compatible with a probably normal life expectancy29 – 32 . The prognosis of Cumming and Antley–Bixler syndromes will depend on the associated anomalies33,34 . In summary, it is possible to suspect and to distinguish SWS prenatally (Table 1). The availability of molecular diagnosis further strengthens the diagnosis. SWS should be considered in the antenatal workup of short and bowed long bones. 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SUPPORTING INFORMATION ON THE INTERNET The following supporting information may be found in the online version of this article: Table S1 Prenatal features and perinatal outcome of 10 fetuses with Stuve–Wiedemann syndrome. Table S2 Indications for referral to fetal medicine unit. Copyright  2011 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2011; 38: 553–558.