Clin Genet 2010: 77: 266–272 Printed in Singapore. All rights reserved  2010 John Wiley & Sons A/S CLINICAL GENETICS doi: 10.1111/j.1399-0004.2009.01314.x Short Report Stüve–Wiedemann syndrome: long-term follow-up and genetic heterogeneity Jung C, Dagoneau N, Baujat G, Le Merrer M, David A, Di Rocco M, Hamel B, Mégarbané A, Superti-Furga A, Unger A, Munnich A, Cormier-Daire V. Stüve–Wiedemann syndrome: long-term follow-up and genetic heterogeneity. Clin Genet 2010: 77: 266–272.  John Wiley & Sons A/S, 2010 Stüve–Wiedemann syndrome (SWS, OMIM 601559) is a severe autosomal recessive condition caused by mutations in the leukemia inhibitory receptor (LIFR) gene. The main characteristic features are bowing of the long bones, neonatal respiratory distress, swallowing/sucking difficulties and dysautonomia symptoms including temperature instability often leading to death in the first years of life. We report here four patients with SWS who have survived beyond 36 months of age with no LIFR mutation. These patients have been compared with six unreported SWS survivors carrying null LIFR mutations. We provide evidence of clinical homogeneity of the syndrome in spite of the genetic heterogeneity. C Junga , N Dagoneaua , G Baujata , M Le Merrera , A Davidb , M Di Roccoc , B Hameld , A Mégarbanée , A Superti-Furgaf , S Ungerf , A Munnicha and V Cormier-Dairea a Department of Genetics, Université Paris Descartes, Paris, France, b Clinical Genetics Unit, Nantes Hospital, Nantes, France, c Second Unit of Pediatrics, Isituto G. Gaslini, Genoa, Italy, d Department of Human Genetics, Radboud University Nijmegen Medical Centre, The Netherlands, e Unité de Génétique Médicale, Université Saint Joseph, Beirut, Lebanon, and f Centre for Pediatrics and Adolescent Medicine, Freiburg University Hospital, Mathildenstr. 1, D-79106 Freiburg, Germany Key words: follow-up – genetic heterogeneity – LIFR – long-term – Stüve – Wiedemann syndrome Corresponding author: Valérie Cormier-Daire Department of Genetics, Université Paris Descartes, INSERM U781, AP-HP, Hôpital Necker Enfants Malades, Paris, France. Tel.: 33144495163; fax: 33144495150; e-mail: valerie.cormier-daire@inserm.fr Received 22 May 2009, revised and accepted for publication 31 August 2009 Stüve–Wiedemann syndrome (SWS, OMIM 601559) is a severe autosomal recessive condition characterized by bowing of the lower limbs with cortical thickening, wide metaphyses, abnormal trabecular pattern and camptodactyly (1–3). Additional features include dysautonomia symptoms with temperature instability, respiratory distress and sucking/swallowing difficulties in the first months of life. Evolution is fatal in most cases due to respiratory distress or unexplained episodes of hyperthermia. Survival beyond 1 year has been 266 previously reported in 12 children (4–13). The patients reported so far have growth retardation with short and bowed long bones, prominent joints, restricted joint mobility, severe spinal deformities, osteoporosis and spontaneous fractures. Respiratory symptoms and sucking/swallowing difficulties improve after a few months of life, whereas temperature instability persists in association with altered sweating, dental abnormalities, hyporeflexia and smooth tongue. Motor development is generally delayed but intelligence is normal. In Stüve Wiedemann syndrome: long follow-up 2004, Dagoneau et al. have identified null mutations in the leukemia inhibitory factor receptor (LIFR) in 19 SWS families (14). LIFR is located on 5p13.1 and codes for the gp190 (or LIFRβ) subunit of the LIF receptor. The LIF receptor is composed of the gp190, which specifically binds LIF and the gp130 subunit that is able to bind different IL-6 cytokines. Binding of LIF to the LIFR complex leads to activation of various signaling pathways including JAK/STAT3 pathway. We report here four cases of SWS survivors beyond 36 months of age with no LIFR mutation and a normal activation of JAK/STAT3 pathway following stimulation by LIF. These patients have been compared with six SWS survivors carrying null LIFR mutations. We provide evidence of clinical homogeneity of the syndrome in spite of genetic heterogeneity. Patients and methods Patients Ten patients (5 females and 5 males) have been included in this study. Criteria for inclusion were: (i) Criteria for inclusion were characteristic symptoms of SWS including bowed and short lower limbs, internal cortical thickening, wide metaphyses, dysautonomia symptoms. To accurately compare the clinical outcome of all the patients, we have focused our study only on patients who have survived beyond three years of age (age range: 3–14). Clinical data were collected on questionnaires focused on postnatal evolution. Molecular analysis LIFR sequence analysis has been performed as previously described (14). In the patients with no LIFR mutation, the phosphorylation of STAT3 in response to LIF has been tested in cultured skin fibroblasts using western blot analysis (14). The CRFL1 gene–responsible for Crisponi syndrome (CS) and cold-induced sweat syndrome type 1 (CISS1) which both share the same dysautonomia manifestations as SWS–has also been sequenced in the SWS patients with no LIFR mutation using primers as previously described (15). Results The clinical presentations of 10 cases of SWS survivors have been studied. Among them, six (cases 1–6) have LIFR mutations whereas the four others (cases 7–10) have no identified mutations. Moreover, in these four patients, a normal activation of the JAK/STAT3 pathway following LIF stimulation has been found (Figure 2) and no mutation in the CRLF1 gene has been identified. Follow-up duration extended from 36 months (patient 2) to 14 years (patient 1). Table 1 summarizes the nature of the mutations, sex, birth parameters and ethnic origin, whereas Table 2 summarizes bone manifestations and Table 3 the dysautonomia symptoms which are the cardinal features of the disorder. Bowing of the long bones was constant in all the patients even though it was not present at birth in case 1. This bowing was always present in the lower limbs but more variable for the upper limbs: only patients 6 and 7 had significant ulnar deviation. Camptodactyly, restricted joint mobility and/or club foot were observed in the two groups. Spontaneous fractures, joint effusions or instabilities, spinal deformations, and dental abnormalities were also occasionally reported in the two groups in the course of the disease. The severity of the growth retardation and of the spine deformities increased significantly with time. While recurrent episodes of unexplained fever are often mentioned in the neonatal period of SWS patients, few data are available on the long-term follow-up of the dysautonomia symptoms in SWS. All survivors reported here have had episodes of hyperthermia during the first year of life apart from patient 1. In almost all, episodes of hyperthermia associated with profuse sweating were persistent in the course of the disease with some trigger factors–emotion (case 1), ambient temperature increase (case 9) – and in two cases, repeated intense sweating was associated with disabling cutaneous milia (cases 1 and 4, Fig. 1). One patient (case 7) presented with access of decrease basal body temperature (35–36◦ C). Three LIFR-mutated patients (cases 1, 4 and 5) and three non-mutated patients (cases 7, 9 and 10) have presented severe neonatal respiratory distress. In four patients (cases 2, 4, 5 and 7), bronchospasm episodes have persisted, sometimes triggered by hot or cold temperatures (case 7). At birth, trismus was noted in four cases (1, 2, 4, 9), but gradually disappeared with time. Poor sucking and swallowing were consistently observed in the first months of life, requiring in some cases nasogastric tube or feeding gastrostomy. Beyond the age of 2, feeding difficulties resolved and no gastrointestinal dysmotility disorders were secondarily reported. Other symptoms like ocular–dry eyes (case 5), absence of corneal reflex (case 1), ptosis (case 3)–or stomatologic–smooth tongue (cases 1, 4, 5 and 7)–were also occasionally present in the two groups. 267 ? Dead Alive Alive Alive Alive F Yes 49 2995 Yes 40 3200 Yes 44 2430 35 Yes 48 2800 35 F Alive Alive Outcome BL, length at birth; BW, weight at birth; HC, head circumference at birth.; ?, unknown Alive Alive Yes 50 3500 37 Yes 47 2450 35 Yes 46 2200 33 Yes 44.5 3230 34.5 Yes 44 2510 Birth term BL (cm) BW (g) HC (cm) Alive 8 years 6 years 12 years 5.5 years M M M F 9 years F 6 years 36 months M Sex F 5.5 years 5 years M 1 brother death: day 2 No No Others features linked to the autonomic nervous system have been searched (16). Several patients had an altered perception of pain: increase in two cases (1 and 7) and decrease in three others (cases 4, 5 and 9). Patient 10 had hyporeflexia. At the age of nine, patient 4 was still incontinent during nighttime and presented sleep disturbance with multiple wakes per night. No cardiovascular/vasomotor troubles have been found, in particular neither headache, loss of consciousness, syncope or acrocyanosis nor orthostatic hypotension or arrhythmia have been reported. Holter ECG performed in three cases (cases 1, 2 and 7) were normal. Patient 2 had atrio septal defect while patient 5 developed pulmonary hypertension of unknown etiology. Motor development was mildly delayed for nine children and severely delayed for patient 10. Cognitive functions were normal in all and no attention deficit disorder, anxious troubles or learning disabilities have been reported. Discussion Age at the end of the follow-up 14 years Senegal 1 brother death 1mth No Affected sibs No 2 deaths (<1 year) No No No − − − c.1252C>T c.380 381insT − c.1252C>T c.2336G>T c.875T>C c.2434C>T c.1438-4A>G c.2434C>T LIFR Mutation c.756 757insT c.1789C>T c.756 757insT c.1789C>T No Holland France Italy France No Lebanon No German Turkey Yes ? (first cousin parents) Consanguinity Romania France No Ethnic origin Yes ? (first cousin parents) 7 6 5 4 3 2 1 Case Table 1. Mutation, ethnic origin and familial history of the 10 SWS patients studied 268 Yes No (first cousin parents) 8 9 10 Jung et al. SWS is a rare chondrodysplasia characterized by bowing of long bones and dysautonomia symptoms and was initially described as lethal during the first months of life. Long-term survivors have been reported in a few cases. In order to better define the clinical outcome of these patients, we report on 10 patients that have survived beyond three years of life. Bowing of limbs–genu valgum, retroversion of the neck of the femur, ulnar deviation–increases with age and often requires surgical orthopedic treatment. Severe scoliosis is consistently observed and certainly contributes to the small height of the patients. Spontaneous fractures and dislocation of the patellae or radial head are frequent. While respiratory and feeding difficulties reported in neonatal period resolve in the first years of life, temperature instability is mentioned in all cases. We have compared six SWS patients carrying LIFR mutations with four SWS patients with no LIFR mutations. We did not find any differences between the two groups in term of clinical outcome supporting the clinical homogeneity of SWS contrasting with the genetic heterogeneity. Twelve cases with prolonged survival have been published, the oldest being 16 years old (4–8, 10–13). To our knowledge the existence of LIFR mutations is documented for six of them (6–8, 10). It is possible that some of them do not carry LIFR mutations. In all the cases, clinical evolution of the patients described in our series is very similar to those described in the literature making this Table 2. Bone manifestations of the 10 SWS patients Case Lower limb bowing Camptodactyly 1 2 3 4 5 6 7 8 9 10 3 years Antenatal Neonatal Antenatal Neonatal Neonatal Antenatal Antenatal Neonatal Neonatal Yes Yes Yes Yes Yes No No Yes Yes − − Yes Yes Yes Yes Yes − Yes Yes Feet malposition No No No Yes Yes − Yes No No No Surgery : age and indication 10.5 years Genu valgum No No 5 years Genu valgum Yes ND 2 years camptodactyly ulnar deviation 2 years Dislocation of radial head; ulnar deviation yes Genu valgum No − Spontaneous fractures Yes 13 years No No No Yes <1 year old No Yes 2.5 years Yes <2 years No No Joint effusion Yes 13 years No No No No No No Joint instability Yes − Yes − − − − − − Yes Scoliosis 6 years Scoliosis 3 years Scoliosis ? No Lordosis ND No Scoliosis 3 years Scoliosis 18 m Yes Yes Yes − Yes Yes No Spinal deformation; age Months poor dentition; loss of teeth Height (DS) Bone age Scoliosis 11 years Yes 3.5 years Yes − Yes −1.5DS −4DS −4.2DS −3DS −2DS −2DS −2DS <−2DS −3DS <−4DS − − − Normal Normal Normal −2DS − Normal − 269 Stüve Wiedemann syndrome: long follow-up Yes Restricted limb extension 270 ND, non-documented; Nl, normal. a The frequency of the temperature instability episodes has been determined by the referring physician: +, rare (1/month); ++, frequent (1/ week); + + +, very frequent. ND, non documented;Nl, normal. Yes Yes No + ND − ND Nl Yes Yes Yes +++ Yes ++ Diminished ND Yes Yes No + No − ND ND Yes Yes Yes +++ Yes +++ Increased ND Yes Yes Yes ++ Yes ++ ND ND Yes Yes Yes ND Yes ND Diminished Nl Yes Yes Yes +++ Yes +++ Diminished ND Yes Yes Yes ++ Yes +++ Nl Nl Yes Yes No ++ No − Nl Nl ND Yes No + Yes +++ Increased Absent Hyperthermia from birth to one year Hyperthermia >1 year Hypothermia Frequency of the episodes Profuse sweating Frequency of profuse sweating Perception of pain Corneal reflex 1 Case Table 3. Dysautonomia symptoms in the 10 SWS patientsa 2 3 4 5 6 7 8 9 10 Jung et al. syndrome a homogeneous clinical entity. Followup beyond adulthood will permit to better define the range of the clinical manifestations, especially the dysautonomia symptoms. Precise role of LIFR in skeletogenesis is still unknown but its functional implication has been studied in vitro and in vivo. The bones of lifr-/mice have larger and more numerous osteoclasts leading to severe osteopenia and abnormal trabecular pattern (17, 18). A recent study confirms the role of LIFR in osteoclastogenesis regulation using a Fra2 −/− mouse model (19). These data are consistent with the reduction of bone density and the bone matrix remodeling observed in SWS patients (2). The knowledge of the exact role of LIFR in skeletogenesis may allow the improvement of the management of SWS patients and prolongation of their lifespan. Dysautonomia symptoms observed in SWS are very similar to those observed in Crisponi syndrome (CS) which is distinct from SWS by the absence of bone manifestations (15, 20, 21). Common features are episodes of hyperthermia, camptodactyly, feeding difficulties and scoliosis. However, CS is also characterized by hypertonia, dysmorphic features and psychomotor retardation, features not observed in SWS. The rare descriptions of cold sweat induced syndrome (CISS, 22) probably correspond to CS survivors. Manifestations described in CISS children and adults include profuse sweating triggered by cold, inability to fully extend their elbow, nasal voice, kyphoscoliosis and sometimes feeding difficulties. Mutations in CRLF1 (cytokine receptor-like factor 1) have been identified in both CS and CISS (15, 21, 23). CRFL1 forms a heterodimer with CLCF1 (cardiotrophin-like cytokine factor 1) and competes with CNTF (ciliary neurotrophic factor) for binding to CNTFR (ciliary neurotrophic factor receptor 1) complex, composed by IL6ST (gp130), LIFR and CNTFR. The binding between this heterodimer and its receptor induces JAK/STAT3 pathway signaling. Both lifr-/- and cntfr-/- mice die during neonatal period with severe neuronal defects (24, 25). Because of the functional link between LIFR and CNTF/CNTFR pathways and the overlap between SWS and CS/CISS, all the patients with no LIFR mutation from our study have been tested for CRFL1 and the activation of the JAK/STAT3 pathway by LIF has been checked. The normality of these analyses suggests the implication of other gene (s) in SWS, presumably also involved in the binding of IL6type cytokines to their specific receptor leading to the activation of the JAK/STAT3 pathway. Ongoing studies in the LIFR non-mutated SWS families Stüve Wiedemann syndrome: long follow-up Fig. 1. Clinical and radiological manifestations in patients 1 and 6. Patient 1: (a) general habitus; (b) cutaneous milia; (c) lower limb X-rays at 9 years old. Note the major deformation of the lower limbs with genu valgum, wide metaphyses and abnormal trabecular pattern. Patient 6: (d) and (e) lower limb X-rays at five years of age. 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