RESEARCH ARTICLE
Stuve–Wiedemann Syndrome: Is it Underrecognized? ¨mer Gu¨ran,5 Ilke Ipek O ¨zahi,5 Go¨zde Yes¸il,1 Anne Sophie Lebre,2,3,4 Sofia Dos Santos,3 O Valeria Cormier Daire,2,3,4 and Tu¨lay Gu¨ran5* 1
Department of Medical Genetics, Bezmialem Vakif University of Medicine, Istanbul, Turkey Universite´ Paris Descartes; Sorbonne Paris Cite´, Insititut Imagine, Paris, France
2 3
Assistance Publique-Hoˆpitaux de Paris: Service de Ge´ne´tique, Hoˆpital Necker-Enfants Malades, 149, rue de Se`vres 75743, PARIS, C 15, France 4 INSERM U781, Hoˆpital Necker-Enfants Malades, 75015, Paris, France 5
Department of Pediatric Endocrinology, Marmara University, Istanbul, Turkey
Manuscript Received: 6 January 2014; Manuscript Accepted: 4 May 2014
Stuve–Wiedemann Syndrome (SWS) (OMIM #601559) is an autosomal recessive disorder characterized by skeletal changes, bowing of the lower limb, severe osteoporosis and joint contractures, episodic hyperthermia, frequent respiratory infections, feeding problems and high mortality in early life. It is caused by mutation in the leukemia inhibitory factor receptor gene (LIFR; 151443) on chromosome 5p13. We provide the clinical follow-up and molecular aspects of six new patients who carried the same novel mutation in the LIFR gene (p. Arg692X) and three patients carried a common haplotype at the LIFR locus supporting a founder effect in the Turkish population. The probable pathogenesis of the features is also discussed. Osseous findings in the presence of other abovementioned morbid conditions should raise the suspicion of SWS in neonates especially in Arabic and Eastern Mediterranean countries with high rate of consanguineous marriages like in Turkey. Severe osteoporosis, bone deformities, milias, leukocoria, inflammatory lesions on distal extremities, tongue biting behavior and oral ulcers could be more prominent features of the survivors beyond the neonatal period while respiratory and feeding problems are remitting. It is of crucial importance to diagnose such babies earlier in order to prevent extensive laboratory workup and to provide proper genetic counseling. Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article:
¨, Yes¸il G, Lebre AS, Santos SD, Gu¨ran O ¨ Ozahi II, Daire VC, Gu¨ran T. 2014. Stuve– Wiedemann syndrome: Is it underrecognized?. Am J Med Genet Part A 164A:2200–2205.
clinical and radiological findings and also in clinical course [Cormier-Daire et al., 1998]. There are distinct radiological findings such as congenital bowing of the long bones, which are typically short and thick with wide metaphysis and irregular striation. The clinical course is generally complicated by hyperthermic episodes, respiratory insufficiency as well as feeding and swallowing difficulties [Cormier-Daire et al., 1998]. SWS is related to high mortality even in neonatal period. The most frequent causes of death are respiratory insufficiency and malignant hyperthermia [Cormier-Daire et al., 1998; Al-Gazali et al., 2003]. This article presents the first Turkish cohort with typical features of SWS at birth and in older children along with some atypical and rare findings. We also aimed to identify a founder effect in the LIFR gene in Turkish population considering six new patients from the same institution.
Key words: Stuve–Wiedemann syndrome; LIFR; founder effect
INTRODUCTION Stuve–Wiedemann syndrome (SWS) (OMIM #601559) was first described by Stuve and Wiedemann in 1971 in two sisters [Stuve and Wiedemann, 1971]. Dagoneau et al. [2004] have mapped the disease to 5p13.1 and identified mutations in Leukemia inhibitor receptor (LIFR) gene. SWS is relatively common in the Arabic population with a prevalence of 0.5/10.000 births in the UAE [Al-Gazali et al., 2003a]. The disease is generally homogenous in
Ó 2014 Wiley Periodicals, Inc.
Correspondence to: Tulay Guran, M.D., Pediatric Endocrinology and Diabetes, Marmara University Hospital, Fevzi Cakmak Mh., Mimar Sinan Cd.No 41., 34899 Ustkaynarca, Pendik, Istanbul, Turkey. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 2 July 2014 DOI 10.1002/ajmg.a.36626
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YES¸IL ET AL.
CLINICAL REPORT Here we present six Turkish patients with genetically proven SWS. They were all diagnosed between 2009 and 2011 in Zeynep Kamil Maternity and Children’s Diseases Research and Training Hospital. Study was approved by local ethic committee of the institution and all families gave written consents for studies and scientific usage of the photos. The series included six cases from four unrelated families. Three of them died in early infancy. One of them died from a hyperthermic episode at 18 months and the other two from sudden infant death syndrome (SIDS) at 3 and 17 months. Longest survivors of the cohort are now 4.5 (Patient F1.1), 6 (Patient F2.2), and 2 (Patient F4.1) years old. All patients demonstrated typical findings of SWS however, they also presented with rarely described findings like inflammatory lesions at the tip of distal extremities and corneal opacity so-called to develop after a chickenpox infection [Al-Gazali et al., 2003, Jung
2201 et al., 2010] (Fig. 1). Table I compares the features of our patients in detail to those of previously reported cases [Al-Gazali et al., 2003]. Patients F1.1 and F2.1 were diagnosed retrospectively after the diagnoses of their siblings Patients F1.2 and F2.2, respectively. Patients F1.1, F2.1, F2.2, and F3.1 developed oxygen dependency due to recurrent respiratory infections and respiratory failure. All patients had a history of prolonged and repetitive hospital admissions before the final diagnosis of SWS due to respiratory failure, feeding and swallowing problems and bouts of fever spikes all of which necessitated extensive laboratory workup (lumbar punctures, bronchoscopy, repeated blood cultures, repeated sepsis screenings, urinary catheterizations for urine culture). Two of three survivors are now receiving prophylactic antibiotics and intravenous immunoglobulin (IVIG) therapy. Severe osteoporosis, growth retardation, and skeletal and joint deformities were consistently observed in older patients. Patients F1.1 and F4.1 are receiving physiotherapy because they are unable to walk due to deformed extremities. All the long-term survivors are
FIG. 1. Phenotypical features of our cohort with SWS are seen in Panel a and Panel b. Panel a demontrates camptodactyly and thin lip vermilion (a1), midface hypoplasia, deep-set eyes, frontal bossing (a2), hypotonia and tube feeding (a3), leukocoria/cataract and fair hair (a4), pursued lips and long philtrum (a5), microretrognatia, short neck, wide-set nipples (a6) of the patients, respectively (Patients F1.1, F1.2, F2.1, F2.2, F3, F4). Panel b shows severe skeletal deformities due to bowing of long bones and enlarged large joints and joint limitation (b1), camptodactyly and clubbing (b2), brachydactyly and clinodactyly with wrinkled skin (b3), oral apthtous lesions, smooth and damaged tongue, oligodontia and tooth decay (b4), inflammatory lesions at the distal extremities (b5, b6) and milia on skin (b7) of the patients (b1, b3, b6, b7 are from Patient F2.2; b2 is from Patient F1.2; b5 is from Patient F1.1). Panel c indicates internal cortical thickening and bowing of upper (c1) and lower (c2) leg bones; osteoporosis, healing fracture, destruction of femoral heads, diaphysial undertubulation and metaphyseal rarefaction (c3, c4); pulmonary infection (c4) and camptodactyly and wide methaphysis (c5) of the patients (c1 from Patient F4; c2 from Patient F1.2; c3 and c5 from Patient F2.2; c4 from Patient F1.1).
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AMERICAN JOURNAL OF MEDICAL GENETICS PART A
TABLE I. Clinical and Radiologic Features of the Patients With SWS Compared to Previous Data in Literature Al-Gazali et al. (2003)
Clinical findings Ancestral origin in Turkey Growth/development Oligohydramnios IUGR Short stature Head/face Sparse/fine/fair hair Frontal bossing Midface hypoplasia Retro/micrognathia Square face Low-set/prominent upper helix Short palpebra Deep-set eyes Leukoma/keratitis Broad base nose Anteverted nostrils Prominent columella Thin lip vermilion Large face Full cheeks Short neck Wide set nipples Pursed mouth Facial muscle contractions Milia Wrinkled skin Dental decay Respiratory Recurrent infection
F1.1 East
F1.2 East
F2.1 North
F2.2 North
F3 East
F4 East
þ
þ
þ
þ þ þ
þ þ þ þ þ þ þ þ þ þ þ þ þ þ
þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ NA
þ þ þ þ þ þ þ þ þ þ þ þ þ þ NA
þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ
þ þ þ þ þ þ þ þ þ þ þ NA
þ þ þ þ þ þ þ þ þ þ þ þ þ þ
þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ ND þ
þ
þ
þ
þ
þ
þ
Respiratory distress Neurological/dysautonomic Hyperthermia age of onset Hypotonia Early feeding difficulties Seizures Abundant saliva Excess/paradoxical sweating Poor temperature regulation Reduced pain Decreased lacrimation Absent corneal/patellar reflexes Smooth tongue Tongue ulcerations/bitting Encephalomalacia Skeletal Camptodactyly Brachydactyly Clubbing Ulnar deviation Contractures of large joints Spine involvement Broad pubic/ischiacdic bones Relatively short ilia Bowing of lower extremities Prominent enlarged joints Diaphyseal undertubulation Metaphyseal rarefaction Internal cortical thickening Destruction of femoral heads Fractures Osteoporosis
þ
þ
þ
þ (severe chicken pox pneumonia) þ
þ
þ
þ
Newborn þ þ þ þ þ þ þ þ
Newborn þ þ þ NA þ þ
Newborn þ þ þ þ þ þ þ þ þ
Newborn þ þ þ þ þ þ þ þ þ þ
Newborn þ þ þ þ þ þ þ þ þ þ
Newborn þ þ þ þ þ þ þ þ þ
þ þ þ ND þ þ þ þ þ þ þ ND
Bilateral þ þ þ Mild scoliosis
Bilateral
þ þ Ovoid vertebrae
þ þ þ þ Kyphosis, scoliosis
þ
þ
þ þ þ þ þ þ þ þ
þ þ þ þ þ þ
þ þ þ þ þ
þ þ þ þ þ þ þ Severe
þ þ þ þ þ
þ þ þ þ þ
þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ
NA, not applicable; ND, not documented.
YES¸IL ET AL.
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on calcium and vitamin D replacements and Patient F4.1 also receives oral alendronate treatment for severe bone pains and low bone mineral density (below 2 SD for age and sex corrected ranges). Patients F1.1 and F4.1 are under the surveillance for corrective osteotomies. Corneal transplantation is planned for bilateral keratitis for Patient F4.
MOLECULAR ANALYSIS Blood samples were obtained from the probands and their parents. Sanger sequencing and haplotyping with microsatellite markers flanking the LIFR locus on chromosome 5 were performed using standard procedures.
RESULTS All patients carried a new homozygous substitution c.2074C>T (p. Arg692X) in LIFR exon 15. We therefore hypothesize a founder effect in the Turkish population. The affected children were expected to be homozygous by descent for the polymorphic microsatellites markers flanking the LIFR gene on chromosome 5. We found that three patients shared an identical haplotype for three markers over a 1.5 Mb region of chromosome 5 that spanned the LIFR locus (LIFR-CA, FYB-CA, and D5S418), suggesting a founder effect (Table II).
DISCUSSION In the present study, we characterized six new Turkish patients with SWS admitted to a single clinic within a period of 2 years. As to authors knowledge this is the only reported Turkish cohort with SWS so far. SWS is relatively common in the Arabic population with most cases being reported from Oman, Yemen, Sudan, and the United Arab Emirates (prevalence in the UAE is reported 0.5/10.000 births) [Al-Gazali et al., 2003]. An identical frameshift insertion (c.653_654insT) was identified in families from the UAE, suggesting a founder effect in this region [Dagoneau et al., 2004]. Our findings suggest that the condition is not rare in Turkey, as well. This high frequency might be addressed to highly inbred population in this region or a founder effect likewise in UAE [Tuncbilek and Koc, 1994; Al-Gazali et al., 1997; Dagoneau et al., 2004]. All the patients of our cohort were homozygous for the c.2074C>T (p.Arg692X) in LIFR gene. Up to date, LIFR gene was investigated in only two Turkish patients and c.2274_2275insT and c.1789C>T mutations were found [Dagoneau et al., 2004; Jung et al., 2010]. The families presented in this study are not related even not from the same region with an exception of Family 1 and Family 3 who were from same city located at the east of Turkey. The haplotype study suggests that the c.2074C>T mutation is likely a founder mutation in the Turkish population. We propose that SWS is
TABLE II. Genotypes of Patients Carrying the c.2074C>T (p.Arg692X) Mutation at the LIFR Locus Genetic markers D5S392 D5S406 D5S1953 D5S630 D5S416 D5S419 D5S426 SLC1A3 NIPBL-CA3 NIPBL-CA1 D5S2021 D5S1964 LIFR gene LIFR-CA FYB-CA D5S418 D5S822 D5S623 D5S664 D5S2068 D5S407 D5S2107 D5S1990 D5S647 D5S629
F4 99 166 254 251 284 216 197 275 260 143 109 120 c.2074C >T 242 221 203 238 149 121 247 107 182 232 132 249
F3 99 170 266 259 290 222 197 275 260 143 109 120 c.2074C >T 242 221 203 238 149 121 247 107 182 240 132 253
101 173 254 233 286 210 199 293 260 155 113 122 c.2074C >T 242 221 203 250 139 133 243 115 174 240 128 249
F2.1 101 177 260 233 290 212 199 293 260 155 113 122 c.2074C >T 242 221 203 250 139 133 243 115 174 240 136 249
91 173 254 235 284 210 181 277 258 145 109 122 c.2074 C >T 242 221 203 246 149 121 nd 107 182 224 134 249
101 177 262 239 284 212 197 277 258 145 109 122 c.2074C >T 242 221 203 246 149 121 nd 107 182 224 134 249
F1.1 91 173 260 239 284 220 191 nd 260 165 109 122 c.2074C >T 252 217 213 238 153 115 243 117 174 216 134 243
109 177 260 257 290 222 191 nd 260 165 109 122 c.2074C >T 252 217 213 238 153 131 243 117 176 220 134 243
Position (bp) on chromosome 5 302,140 4,994,043 7,658,252 9,560,963 16,719,995 26,658,466 34,762,796 36,672,033 36,768,767 36,987,946 37,817,527 37,859,401 38475065–38595507 38,610,452 39,228,010 40,015,767 50,511,131 52,285,454 54,973,521 55,624,208 55,994,743 58,149,805 60,975,052 66,247,150 68,295,376
nd, failure of the PCR amplification. Loci are listed according to their relative chromosomal position (top to bottom) according to Ensembl (GRCh37). Bold indicates common haplotypes.
2204 relatively common in Arabic and Eastern Mediterranean population and might be under-recognized clinically. Dagoneau et al. [2004] demonstrated that null LIFR mutations abolishes the LIF mediated JAK-STAT3 signaling. Patients in our cohort presented with growth failure, especially the long-term survivors. This short stature can arise either from skeletal deformities and osteoporosis or as a direct consequence on ossification process [Ware et al., 2003]. As JAK–STAT pathway has also been linked to signaling of growth hormone further hormonal studies are required to address the relation between short stature and growth hormone deficiency in SWS [Ray et al., 1996]. While all the reported patients were carrying the same homozygous Arg692X mutation in LIFR, some phenotype variability was observed. However, the characteristic findings like bone deformities, hyperthermia, respiratory and feeding problems were rather consistent and homogenous. Three of six had died in early infancy. Survivors are now at the age of 2, 4.5 and 6 years. All patients had a common history of prolonged and repeated hospital admissions during neonatal period and early infancy because of feeding and respiratory problems and hyperthermias. Respiratory problems include respiratory insufficiency, pulmonary infections, and the necessity for artificial ventilation. These morbidities can be explained by swallowing deficits, microaspirations, hypotonia, and gastroeosophageal reflux. Impaired STAT3 pathway due to LIFR mutations may also explain the respiratory and mucocutaneous infections observed in our cohort. Autosomal dominant STAT3 mutations in humans are known to cause hyper-immunoglobulin E (IgE) syndrome. These patients share many common manifestations such as mucocutaneous infections, pneumonia, secondary bronchiectasis, dermatitis, facial dysmorphism, and osteopenia. These patients have been shown to improve with antibiotic and antifungal prophylaxis, and IgG infusions [Chandesris et al., 2012]. Long-term survivors of our cohort might have a better health status in relation with the prophylactic antibiotics and IgG infusions. Patients mainly suffered from hyperthermic episodes requiring intensive infectious work-up studies. They had recurrent viral infections especially pneumonia and their occasional complications, like as one of our patients developed bilateral keratitis after a chicken pox infection. Micro-aspiration may have a contributing effect on severe recurrent pneumonias on the other hand it is also important to carry out immune function tests to exclude other conditions that might be responsible for frequent and opportunistic infections. Since null LIFR mutations was shown to abolish the LIF mediated JAK-STAT3 signaling in SWS, proper functioning of this pathway is surely mandatory in order to avoid recurrent and opportunistic infections and their unexpected complications. Periodic ophthalmologic visits are important for such patients for corneal opacities and timely intervention. Bilateral cataract severely impairs quality of life of Patient F2.1 and he is now in line of corneal transplantation to save his sight. For corneal protection patients should be encouraged to use sunlight glasses. Skeletal findings also cause a major morbidity for the long-term survivors. For this reason multidisciplinary approach as well as supportive treatments like calcium and vitamin D replacements and oral bisphosphonate is required for the management of bone and joint deformities and severe osteoporosis in SWS [Mikelonis et al., 2014]. Rehabilitative care and orthopedic follow-up is also
AMERICAN JOURNAL OF MEDICAL GENETICS PART A essential. Histomorphometric abnormalities in osteoid tissues and importance of LIF-LIFR signaling in bone development have been shown previously. LIFR/ animals have decreased bone volume and increased osteoclast numbers [Ware et al., 2003]. Repetitive tongue biting is frequent condition observed in SWS patients that result in loss of tissue in tongue after dentition. This condition raises a suspicion for impaired pain sensation. Tsuda et al. [2011] stated that astrocyte proliferation regulated by JAK-STAT3 signaling participates in the maintenance of peripheral nerve injury-induced allodynia. Although these patients have near normal mental development such lesions in tongue may impair language development and social interaction. We observed this finding in all our patients after dentition. Oral and dental hygiene is especially important in those patients to prevent secondary infections. We have observed hyperthermia in newborn patients and in early infancy. Paradoxical sweating, on the other hand, was noticed in older patients that might account for the development of milia lesions in the skin. In addition, LIF is one of the neurotrophic cytokines, and has a role in survival and maintenance of motor neurons in brain stem and spinal cord [Li et al., 1995; Schweizer et al., 2002]. LIF also stimulates cholinergic differentiation in sympathetic neurons, induce choline acetyltransferase gene expression, and promote the survival of cholinergic neurons in vitro and in vivo [Dziennis and Habecker, 2003]. Thus dysautonomia like inappropriate sweating and hyperthermia in SWS may be attributed to these functions of LIF and therefore the STAT3 signaling, which is responsible for induction of the cholinergic and peptidic properties of sympathetic neurons. With the clinical description of a series of six Turkish SWS patients with the same mutations, we emphasize the spectrum of manifestations and the natural history of this rare disorder. An early diagnosis is crucial in order to prevent extensive laboratory workup to exclude infections and to take measures for respiratory complications and feeding/swallowing rehabilitation timely.
ACKNOWLEDGMENTS The authors are grateful to the families for their participation in our study over the course of laboratory studies.
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YES¸IL ET AL. Debre´ M, Le Bourgeois M, Gandemer V, Lambert N, Grandin V, Ndaga S, Jacques C, Harre C, Forveille M, Alyanakian MA, Durandy A, Bodemer C, Suarez F, Hermine O, Lortholary O, Casanova JL, Fischer A, Picard C. 2012. Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: Molecular, cellular, and clinical features from a French national survey. Medicine 91:1–19. Cormier-Daire V, Superti-Furga A, Munnich A, Lyonnet S, Rustin P, Delezoide AL, De Lonlay P, Giedion A, Maroteaux P, Le Merrer M. 1998. Clinical homogeneity of the Stuve–Wiedemann syndrome and overlap with the Schwartz-Jampel syndrome type 2. Am J Med Genet 78:146–149.
2205 Mikelonis D, Jorcyk CL, Tawara K, Oxford JT. 2014. Stuve–Wiedemann syndrome: LIFR and associated cytokines in clinical course and etiology. Orphanet J Rare Dis 9:34. doi: 10.1186/1750-1172-9-34 Ray DW, Ren SG, Melmed S. 1996. Leukemia inhibitory factor (LIF) stimulates proopiomelanocortin (POMC) expression in a corticotroph cell line. Role of STAT pathway. J Clin Invest 97: 1852–1859. Schweizer U, Gunnersen J, Karch C, Wiese S, Holtmann B, Takeda K, Akira S, Sendtner M. 2002. Conditional gene ablation of Stat3 reveals differential signaling requirements for survival of motoneurons during development and after nerve injury in the adult. J Cell Biol 156: 287–297.
Dagoneau H, Scheffer D, Huber C, Al-Gazali LI. 2004. Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve–Wiedemann/ Schwartz-Jampel type 2 syndrome. Am J Hum Genet 74:298–305.
Stuve A, Wiedemann HR. 1971. Congenital bowing of the long bones in two sisters. Lancet 2:495.
Dziennis S, Habecker BA. 2003. Cytokine suppression of dopamine-betahydroxylase by extracellular signal-regulated kinase-dependent and independent pathways. J Biol Chem 278:15897–15904.
Tsuda M, Kohro Y, Yano T, Tsujikawa T, Kitano J, Tozaki-Saitoh H, Koyanagi S, Ohdo S, Ji RR, Salter MW, Inoue K. 2011. JAK-STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats. Brain 134:1127–1139.
Jung C, Dagoneau N, Baujat G, Le Merrer M, David A, Di Rocco M, Hamel B, Me´garbane´ A, Superti-Furga A, Unger S, Munnich A, Cormier-Daire V. 2010. Stuve–Wiedemann syndrome: Long-term follow-up and genetic heterogeneity. Clin Genet 77:266–272.
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Li M, Sendtner M, Smith A. 1995. Essential function of LIF receptor in motor neurons. Nature 378:724–727.
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Stuve–Wiedemann Syndrome: Is it Underrecognized? ¨mer Gu¨ran,5 Ilke Ipek O ¨zahi,5 Go¨zde Yes¸il,1 Anne Sophie Lebre,2,3,4 Sofia Dos Santos,3 O Valeria Cormier Daire,2,3,4 and Tu¨lay Gu¨ran5* 1
Department of Medical Genetics, Bezmialem Vakif University of Medicine, Istanbul, Turkey Universite´ Paris Descartes; Sorbonne Paris Cite´, Insititut Imagine, Paris, France
2 3
Assistance Publique-Hoˆpitaux de Paris: Service de Ge´ne´tique, Hoˆpital Necker-Enfants Malades, 149, rue de Se`vres 75743, PARIS, C 15, France 4 INSERM U781, Hoˆpital Necker-Enfants Malades, 75015, Paris, France 5
Department of Pediatric Endocrinology, Marmara University, Istanbul, Turkey
Manuscript Received: 6 January 2014; Manuscript Accepted: 4 May 2014
Stuve–Wiedemann Syndrome (SWS) (OMIM #601559) is an autosomal recessive disorder characterized by skeletal changes, bowing of the lower limb, severe osteoporosis and joint contractures, episodic hyperthermia, frequent respiratory infections, feeding problems and high mortality in early life. It is caused by mutation in the leukemia inhibitory factor receptor gene (LIFR; 151443) on chromosome 5p13. We provide the clinical follow-up and molecular aspects of six new patients who carried the same novel mutation in the LIFR gene (p. Arg692X) and three patients carried a common haplotype at the LIFR locus supporting a founder effect in the Turkish population. The probable pathogenesis of the features is also discussed. Osseous findings in the presence of other abovementioned morbid conditions should raise the suspicion of SWS in neonates especially in Arabic and Eastern Mediterranean countries with high rate of consanguineous marriages like in Turkey. Severe osteoporosis, bone deformities, milias, leukocoria, inflammatory lesions on distal extremities, tongue biting behavior and oral ulcers could be more prominent features of the survivors beyond the neonatal period while respiratory and feeding problems are remitting. It is of crucial importance to diagnose such babies earlier in order to prevent extensive laboratory workup and to provide proper genetic counseling. Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article:
¨, Yes¸il G, Lebre AS, Santos SD, Gu¨ran O ¨ Ozahi II, Daire VC, Gu¨ran T. 2014. Stuve– Wiedemann syndrome: Is it underrecognized?. Am J Med Genet Part A 164A:2200–2205.
clinical and radiological findings and also in clinical course [Cormier-Daire et al., 1998]. There are distinct radiological findings such as congenital bowing of the long bones, which are typically short and thick with wide metaphysis and irregular striation. The clinical course is generally complicated by hyperthermic episodes, respiratory insufficiency as well as feeding and swallowing difficulties [Cormier-Daire et al., 1998]. SWS is related to high mortality even in neonatal period. The most frequent causes of death are respiratory insufficiency and malignant hyperthermia [Cormier-Daire et al., 1998; Al-Gazali et al., 2003]. This article presents the first Turkish cohort with typical features of SWS at birth and in older children along with some atypical and rare findings. We also aimed to identify a founder effect in the LIFR gene in Turkish population considering six new patients from the same institution.
Key words: Stuve–Wiedemann syndrome; LIFR; founder effect
INTRODUCTION Stuve–Wiedemann syndrome (SWS) (OMIM #601559) was first described by Stuve and Wiedemann in 1971 in two sisters [Stuve and Wiedemann, 1971]. Dagoneau et al. [2004] have mapped the disease to 5p13.1 and identified mutations in Leukemia inhibitor receptor (LIFR) gene. SWS is relatively common in the Arabic population with a prevalence of 0.5/10.000 births in the UAE [Al-Gazali et al., 2003a]. The disease is generally homogenous in
Ó 2014 Wiley Periodicals, Inc.
Correspondence to: Tulay Guran, M.D., Pediatric Endocrinology and Diabetes, Marmara University Hospital, Fevzi Cakmak Mh., Mimar Sinan Cd.No 41., 34899 Ustkaynarca, Pendik, Istanbul, Turkey. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 2 July 2014 DOI 10.1002/ajmg.a.36626
2200
YES¸IL ET AL.
CLINICAL REPORT Here we present six Turkish patients with genetically proven SWS. They were all diagnosed between 2009 and 2011 in Zeynep Kamil Maternity and Children’s Diseases Research and Training Hospital. Study was approved by local ethic committee of the institution and all families gave written consents for studies and scientific usage of the photos. The series included six cases from four unrelated families. Three of them died in early infancy. One of them died from a hyperthermic episode at 18 months and the other two from sudden infant death syndrome (SIDS) at 3 and 17 months. Longest survivors of the cohort are now 4.5 (Patient F1.1), 6 (Patient F2.2), and 2 (Patient F4.1) years old. All patients demonstrated typical findings of SWS however, they also presented with rarely described findings like inflammatory lesions at the tip of distal extremities and corneal opacity so-called to develop after a chickenpox infection [Al-Gazali et al., 2003, Jung
2201 et al., 2010] (Fig. 1). Table I compares the features of our patients in detail to those of previously reported cases [Al-Gazali et al., 2003]. Patients F1.1 and F2.1 were diagnosed retrospectively after the diagnoses of their siblings Patients F1.2 and F2.2, respectively. Patients F1.1, F2.1, F2.2, and F3.1 developed oxygen dependency due to recurrent respiratory infections and respiratory failure. All patients had a history of prolonged and repetitive hospital admissions before the final diagnosis of SWS due to respiratory failure, feeding and swallowing problems and bouts of fever spikes all of which necessitated extensive laboratory workup (lumbar punctures, bronchoscopy, repeated blood cultures, repeated sepsis screenings, urinary catheterizations for urine culture). Two of three survivors are now receiving prophylactic antibiotics and intravenous immunoglobulin (IVIG) therapy. Severe osteoporosis, growth retardation, and skeletal and joint deformities were consistently observed in older patients. Patients F1.1 and F4.1 are receiving physiotherapy because they are unable to walk due to deformed extremities. All the long-term survivors are
FIG. 1. Phenotypical features of our cohort with SWS are seen in Panel a and Panel b. Panel a demontrates camptodactyly and thin lip vermilion (a1), midface hypoplasia, deep-set eyes, frontal bossing (a2), hypotonia and tube feeding (a3), leukocoria/cataract and fair hair (a4), pursued lips and long philtrum (a5), microretrognatia, short neck, wide-set nipples (a6) of the patients, respectively (Patients F1.1, F1.2, F2.1, F2.2, F3, F4). Panel b shows severe skeletal deformities due to bowing of long bones and enlarged large joints and joint limitation (b1), camptodactyly and clubbing (b2), brachydactyly and clinodactyly with wrinkled skin (b3), oral apthtous lesions, smooth and damaged tongue, oligodontia and tooth decay (b4), inflammatory lesions at the distal extremities (b5, b6) and milia on skin (b7) of the patients (b1, b3, b6, b7 are from Patient F2.2; b2 is from Patient F1.2; b5 is from Patient F1.1). Panel c indicates internal cortical thickening and bowing of upper (c1) and lower (c2) leg bones; osteoporosis, healing fracture, destruction of femoral heads, diaphysial undertubulation and metaphyseal rarefaction (c3, c4); pulmonary infection (c4) and camptodactyly and wide methaphysis (c5) of the patients (c1 from Patient F4; c2 from Patient F1.2; c3 and c5 from Patient F2.2; c4 from Patient F1.1).
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AMERICAN JOURNAL OF MEDICAL GENETICS PART A
TABLE I. Clinical and Radiologic Features of the Patients With SWS Compared to Previous Data in Literature Al-Gazali et al. (2003)
Clinical findings Ancestral origin in Turkey Growth/development Oligohydramnios IUGR Short stature Head/face Sparse/fine/fair hair Frontal bossing Midface hypoplasia Retro/micrognathia Square face Low-set/prominent upper helix Short palpebra Deep-set eyes Leukoma/keratitis Broad base nose Anteverted nostrils Prominent columella Thin lip vermilion Large face Full cheeks Short neck Wide set nipples Pursed mouth Facial muscle contractions Milia Wrinkled skin Dental decay Respiratory Recurrent infection
F1.1 East
F1.2 East
F2.1 North
F2.2 North
F3 East
F4 East
þ
þ
þ
þ þ þ
þ þ þ þ þ þ þ þ þ þ þ þ þ þ
þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ NA
þ þ þ þ þ þ þ þ þ þ þ þ þ þ NA
þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ
þ þ þ þ þ þ þ þ þ þ þ NA
þ þ þ þ þ þ þ þ þ þ þ þ þ þ
þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ ND þ
þ
þ
þ
þ
þ
þ
Respiratory distress Neurological/dysautonomic Hyperthermia age of onset Hypotonia Early feeding difficulties Seizures Abundant saliva Excess/paradoxical sweating Poor temperature regulation Reduced pain Decreased lacrimation Absent corneal/patellar reflexes Smooth tongue Tongue ulcerations/bitting Encephalomalacia Skeletal Camptodactyly Brachydactyly Clubbing Ulnar deviation Contractures of large joints Spine involvement Broad pubic/ischiacdic bones Relatively short ilia Bowing of lower extremities Prominent enlarged joints Diaphyseal undertubulation Metaphyseal rarefaction Internal cortical thickening Destruction of femoral heads Fractures Osteoporosis
þ
þ
þ
þ (severe chicken pox pneumonia) þ
þ
þ
þ
Newborn þ þ þ þ þ þ þ þ
Newborn þ þ þ NA þ þ
Newborn þ þ þ þ þ þ þ þ þ
Newborn þ þ þ þ þ þ þ þ þ þ
Newborn þ þ þ þ þ þ þ þ þ þ
Newborn þ þ þ þ þ þ þ þ þ
þ þ þ ND þ þ þ þ þ þ þ ND
Bilateral þ þ þ Mild scoliosis
Bilateral
þ þ Ovoid vertebrae
þ þ þ þ Kyphosis, scoliosis
þ
þ
þ þ þ þ þ þ þ þ
þ þ þ þ þ þ
þ þ þ þ þ
þ þ þ þ þ þ þ Severe
þ þ þ þ þ
þ þ þ þ þ
þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ
NA, not applicable; ND, not documented.
YES¸IL ET AL.
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on calcium and vitamin D replacements and Patient F4.1 also receives oral alendronate treatment for severe bone pains and low bone mineral density (below 2 SD for age and sex corrected ranges). Patients F1.1 and F4.1 are under the surveillance for corrective osteotomies. Corneal transplantation is planned for bilateral keratitis for Patient F4.
MOLECULAR ANALYSIS Blood samples were obtained from the probands and their parents. Sanger sequencing and haplotyping with microsatellite markers flanking the LIFR locus on chromosome 5 were performed using standard procedures.
RESULTS All patients carried a new homozygous substitution c.2074C>T (p. Arg692X) in LIFR exon 15. We therefore hypothesize a founder effect in the Turkish population. The affected children were expected to be homozygous by descent for the polymorphic microsatellites markers flanking the LIFR gene on chromosome 5. We found that three patients shared an identical haplotype for three markers over a 1.5 Mb region of chromosome 5 that spanned the LIFR locus (LIFR-CA, FYB-CA, and D5S418), suggesting a founder effect (Table II).
DISCUSSION In the present study, we characterized six new Turkish patients with SWS admitted to a single clinic within a period of 2 years. As to authors knowledge this is the only reported Turkish cohort with SWS so far. SWS is relatively common in the Arabic population with most cases being reported from Oman, Yemen, Sudan, and the United Arab Emirates (prevalence in the UAE is reported 0.5/10.000 births) [Al-Gazali et al., 2003]. An identical frameshift insertion (c.653_654insT) was identified in families from the UAE, suggesting a founder effect in this region [Dagoneau et al., 2004]. Our findings suggest that the condition is not rare in Turkey, as well. This high frequency might be addressed to highly inbred population in this region or a founder effect likewise in UAE [Tuncbilek and Koc, 1994; Al-Gazali et al., 1997; Dagoneau et al., 2004]. All the patients of our cohort were homozygous for the c.2074C>T (p.Arg692X) in LIFR gene. Up to date, LIFR gene was investigated in only two Turkish patients and c.2274_2275insT and c.1789C>T mutations were found [Dagoneau et al., 2004; Jung et al., 2010]. The families presented in this study are not related even not from the same region with an exception of Family 1 and Family 3 who were from same city located at the east of Turkey. The haplotype study suggests that the c.2074C>T mutation is likely a founder mutation in the Turkish population. We propose that SWS is
TABLE II. Genotypes of Patients Carrying the c.2074C>T (p.Arg692X) Mutation at the LIFR Locus Genetic markers D5S392 D5S406 D5S1953 D5S630 D5S416 D5S419 D5S426 SLC1A3 NIPBL-CA3 NIPBL-CA1 D5S2021 D5S1964 LIFR gene LIFR-CA FYB-CA D5S418 D5S822 D5S623 D5S664 D5S2068 D5S407 D5S2107 D5S1990 D5S647 D5S629
F4 99 166 254 251 284 216 197 275 260 143 109 120 c.2074C >T 242 221 203 238 149 121 247 107 182 232 132 249
F3 99 170 266 259 290 222 197 275 260 143 109 120 c.2074C >T 242 221 203 238 149 121 247 107 182 240 132 253
101 173 254 233 286 210 199 293 260 155 113 122 c.2074C >T 242 221 203 250 139 133 243 115 174 240 128 249
F2.1 101 177 260 233 290 212 199 293 260 155 113 122 c.2074C >T 242 221 203 250 139 133 243 115 174 240 136 249
91 173 254 235 284 210 181 277 258 145 109 122 c.2074 C >T 242 221 203 246 149 121 nd 107 182 224 134 249
101 177 262 239 284 212 197 277 258 145 109 122 c.2074C >T 242 221 203 246 149 121 nd 107 182 224 134 249
F1.1 91 173 260 239 284 220 191 nd 260 165 109 122 c.2074C >T 252 217 213 238 153 115 243 117 174 216 134 243
109 177 260 257 290 222 191 nd 260 165 109 122 c.2074C >T 252 217 213 238 153 131 243 117 176 220 134 243
Position (bp) on chromosome 5 302,140 4,994,043 7,658,252 9,560,963 16,719,995 26,658,466 34,762,796 36,672,033 36,768,767 36,987,946 37,817,527 37,859,401 38475065–38595507 38,610,452 39,228,010 40,015,767 50,511,131 52,285,454 54,973,521 55,624,208 55,994,743 58,149,805 60,975,052 66,247,150 68,295,376
nd, failure of the PCR amplification. Loci are listed according to their relative chromosomal position (top to bottom) according to Ensembl (GRCh37). Bold indicates common haplotypes.
2204 relatively common in Arabic and Eastern Mediterranean population and might be under-recognized clinically. Dagoneau et al. [2004] demonstrated that null LIFR mutations abolishes the LIF mediated JAK-STAT3 signaling. Patients in our cohort presented with growth failure, especially the long-term survivors. This short stature can arise either from skeletal deformities and osteoporosis or as a direct consequence on ossification process [Ware et al., 2003]. As JAK–STAT pathway has also been linked to signaling of growth hormone further hormonal studies are required to address the relation between short stature and growth hormone deficiency in SWS [Ray et al., 1996]. While all the reported patients were carrying the same homozygous Arg692X mutation in LIFR, some phenotype variability was observed. However, the characteristic findings like bone deformities, hyperthermia, respiratory and feeding problems were rather consistent and homogenous. Three of six had died in early infancy. Survivors are now at the age of 2, 4.5 and 6 years. All patients had a common history of prolonged and repeated hospital admissions during neonatal period and early infancy because of feeding and respiratory problems and hyperthermias. Respiratory problems include respiratory insufficiency, pulmonary infections, and the necessity for artificial ventilation. These morbidities can be explained by swallowing deficits, microaspirations, hypotonia, and gastroeosophageal reflux. Impaired STAT3 pathway due to LIFR mutations may also explain the respiratory and mucocutaneous infections observed in our cohort. Autosomal dominant STAT3 mutations in humans are known to cause hyper-immunoglobulin E (IgE) syndrome. These patients share many common manifestations such as mucocutaneous infections, pneumonia, secondary bronchiectasis, dermatitis, facial dysmorphism, and osteopenia. These patients have been shown to improve with antibiotic and antifungal prophylaxis, and IgG infusions [Chandesris et al., 2012]. Long-term survivors of our cohort might have a better health status in relation with the prophylactic antibiotics and IgG infusions. Patients mainly suffered from hyperthermic episodes requiring intensive infectious work-up studies. They had recurrent viral infections especially pneumonia and their occasional complications, like as one of our patients developed bilateral keratitis after a chicken pox infection. Micro-aspiration may have a contributing effect on severe recurrent pneumonias on the other hand it is also important to carry out immune function tests to exclude other conditions that might be responsible for frequent and opportunistic infections. Since null LIFR mutations was shown to abolish the LIF mediated JAK-STAT3 signaling in SWS, proper functioning of this pathway is surely mandatory in order to avoid recurrent and opportunistic infections and their unexpected complications. Periodic ophthalmologic visits are important for such patients for corneal opacities and timely intervention. Bilateral cataract severely impairs quality of life of Patient F2.1 and he is now in line of corneal transplantation to save his sight. For corneal protection patients should be encouraged to use sunlight glasses. Skeletal findings also cause a major morbidity for the long-term survivors. For this reason multidisciplinary approach as well as supportive treatments like calcium and vitamin D replacements and oral bisphosphonate is required for the management of bone and joint deformities and severe osteoporosis in SWS [Mikelonis et al., 2014]. Rehabilitative care and orthopedic follow-up is also
AMERICAN JOURNAL OF MEDICAL GENETICS PART A essential. Histomorphometric abnormalities in osteoid tissues and importance of LIF-LIFR signaling in bone development have been shown previously. LIFR/ animals have decreased bone volume and increased osteoclast numbers [Ware et al., 2003]. Repetitive tongue biting is frequent condition observed in SWS patients that result in loss of tissue in tongue after dentition. This condition raises a suspicion for impaired pain sensation. Tsuda et al. [2011] stated that astrocyte proliferation regulated by JAK-STAT3 signaling participates in the maintenance of peripheral nerve injury-induced allodynia. Although these patients have near normal mental development such lesions in tongue may impair language development and social interaction. We observed this finding in all our patients after dentition. Oral and dental hygiene is especially important in those patients to prevent secondary infections. We have observed hyperthermia in newborn patients and in early infancy. Paradoxical sweating, on the other hand, was noticed in older patients that might account for the development of milia lesions in the skin. In addition, LIF is one of the neurotrophic cytokines, and has a role in survival and maintenance of motor neurons in brain stem and spinal cord [Li et al., 1995; Schweizer et al., 2002]. LIF also stimulates cholinergic differentiation in sympathetic neurons, induce choline acetyltransferase gene expression, and promote the survival of cholinergic neurons in vitro and in vivo [Dziennis and Habecker, 2003]. Thus dysautonomia like inappropriate sweating and hyperthermia in SWS may be attributed to these functions of LIF and therefore the STAT3 signaling, which is responsible for induction of the cholinergic and peptidic properties of sympathetic neurons. With the clinical description of a series of six Turkish SWS patients with the same mutations, we emphasize the spectrum of manifestations and the natural history of this rare disorder. An early diagnosis is crucial in order to prevent extensive laboratory workup to exclude infections and to take measures for respiratory complications and feeding/swallowing rehabilitation timely.
ACKNOWLEDGMENTS The authors are grateful to the families for their participation in our study over the course of laboratory studies.
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