RUBINSTEIN-TAYBI SYNDROME RUBINŠTAJN-TAJBI SINDROM. Sanja Šarac, Rade Milić, Tijana Kosanović, Momir Šarac

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1 RUBINSTEIN-TAYBI SYNDROME RUBINŠTAJN-TAJBI SINDROM Sanja Šarac, Rade Milić, Tijana Kosanović, Momir Šarac Sažetak: Rubinštajn-Tajbi sindrom (RTS) je retka genetska bolest koja se karakteriše postojanjem širokih palčeva, pljosnatim nosem, antimongoloidnim palpebralnim fisurama, mentalnom i motornom retardacijom, kardiovaskularnim i renalnim abnormalnostima. U radu smo prikazali slučaj 34-godišnje žene sa tipičnom prezentacijom bolesti. Postojala je teška kifoskolioza torakolumbalne kičme sa redukcijom anteroposteriornog dijametra grudnog koša i teškom restriktivnom bolešću pluća. Imala je tešku plućnu insuficijenciju, pućnu hipertenziju i ponavljane infekcije pluća. Od ostalih anomalija bili su prisutni atrijalni septum defekt, aneurizma atrijalnog septuma i kalkuloza bubrega. Tokom dve godine praćenja plućna funkcija opada a respiratorne infekcije postale su učestalije. Postavljena je indikacija za hirurški tretman deformiteta grudnog koša koji nije učinjen zbog rizika za opštu anesteziju i nepristanka porodice pacijentkinje. Ključne reči: Rubinštajn-Taybi sindrom, kifoskolioza, plućna insuficijencija INTRODUCTION In Rubinstein and Taybi first delineated a syndrome characterized by broad thumbs, broad toes, mental and motor retardation, cardiovascular and renal anomalies, a beaked nose and a downward slanting palpebral fissure. ( 1 ) Rubinstein-Taybi syndrome (RTS) is a rare syndrome with a frequency of 1 in to newborns. ( 2 ) Most of the typical RTS features as described by Hennekam. These features include a prominent nasal bridge, down-slanting palpebral fissures, a small mouth, low set ears, bilateral broad thumbs and great toes and growth retardation. ( 3 ) Although hirsutism is found in 75% of cases. Congenital heart defects (mainly patent ductus arteriosus, ventricular and atrial septal defect) were observed in 32% of patients. The characteristic craniofacial features are downslanting palpebral fissures, a columella extending below the nares, a highly arched palate, a 1 Rubinstein JH, Taybi H. Broad thumbs and toes and facial abnormalities. Am J Dis Child 1963;105: Kumar S, Suthar R, Panigrahi I, Marwaha RK. Rubinstein- Taybi syndrome: Clinical profile of 11 patients and review of literature. Indian J Hum Genet 2012;18(2): Hennekam RCM, Stevens CA, Van De Kamp JJP. Etiology and recurrence risk in Rubinstein-Taybi syndrome. Am J Med Genet 1990; 6: grimacing smile and talon cusps. ( 4 ) Other variable findings are obesity, coloboma, cataract, renal abnormalities and cryptorchidism. ( 5 ) The cause of the syndrome remains unknown. There were no clues for autosomal recessive or X- linked inheritance, nor a teratogenic cause. No consistent chromosome anomaly was found. An autosomal dominant mutation, either as submicroscopic chromosome deletion or duplication, or a point mutation seems the most likely explanation. RTS can be regarded as a microdeletion syndrome with a low rate of microdeletions, as only 4% to 25% of patients with RTS were found to have the CREB-binding protein gene (CREBBP) deletion on chromosome 16 p13.3 when using fluorescence in situ hybridization. ( 6 ),( 7 ) 4 Kumar S, Suthar R, Panigrahi I, Marwaha RK. Rubinstein- Taybi syndrome: Clinical profile of 11 patients and review of literature. Indian J Hum Genet 2012;18(2): Beets L, Rodrıguez-Fonseca C, Hennekam RC: Growth charts for individuals with Rubinstein Taybi syndrome.am J Med Genet A 2014; 164(9): Marzuillo P, Grandone A, Coppola R, Cozzolino D, Festa A, Messa F et al BMC Med Genet 2013; 23: Caglayan AO, Lechno S, Gumus H, Bartsch O, Fryns JP. A boy with classical Rubinstein-Taybi syndrome but no detectable mutation in the CREBBP and EP300 genes. Genet Couns 2011;22(4): ; 5 (1-2):

2 226 CASE REPORT Female patient, 34 years old, was admitted first time to our clinic in May She had symptoms and signs of respiratory infection and severe respiratory failure. She was the first of two children. Diagnosis RTS established in age of third. Parents were healthy and non-consanguineous. There was no significant family history. A physical examination showed dysmorphic features, such as a prominent nasal bridge, hypertelorism, down-slanting palpebral fissures, a small mouth, micrognathia, low set ears, sparse hair, severe kyphoscoliosis, bilateral broad thumbs and great toes (Figure 1,2), a central cyanosis, marked right thoracic rib prominence, right shoulder elevation, asymmetric scapulae, and pelvic obliquity. There was a systolic murmur heard on auscultation of the left sternal edge. Auscultation of the lungs revealed weakened respiratory sound, prolonged expirium bilaterally and diffuse fine endinspiratory crackles. The oxygen saturation frequently fell below 90%, especially during sleep. Loud snoring, excessive sweating and recurrent respiratory pause were also detected during sleep. She suffered from recurrent pulmonary and urinary infection. Severe deformity of chest and heart disease led to pulmonary hypertension, respiratory failure and recurrent pneumonia during two years. Ultrasound of heart revealed atrial septal defect and aneurism of interatrial septum. Chest X-ray and multi-slice computed tomography revealed high grade right convex kyphoscoliosis with deformity of other bone structures of the chest. (Figure 3, 4) She developed a severe thoracic scoliosis measuring 73 respectively. Her scoliosis was associated with thoracic hypokyphosis, causing a marked reduction in the anteroposterior diameter of her chest and consequent severe restrictive lung disease. Renal ultrasound showed large calculus in the right kidney, measuring almost 7 cm and occupying the lower half of the right renal pelvis and the adjacent calyces. Pulmonary infections are treated several times in hospital by combined antibiotic therapy, bronchodilators, mucolytics, oxygen therapy, Case report physical therapy and intensive symptomatic and supportive therapy. There was indication for surgical treatment of chest deformation but not implemented because of the high risk for general anesthesia and lack of consent of the patient's family. Lung function continued to deteriorate during two years and respiratory infections became more frequent. Patient had oxygen therapy at home, infections were treated in hospital conditions. Despite of treatment one of infections led to progression of lung failure and a fatal outcome of disease at age of 36. DISCUSSION RTS is a multiple congenital anomalies-mental retardation syndrome. There are several gene and chromosome abnormalities which associated with this disorder: microdeletion at 16p 13.3 region in the CREBBP in some patient, suggesting that deletion is the most probable cause of the syndrome. CREBBP is a transcription coactivator and functions as a potent histone acetyltransferase, both of which are essential to normal development. ( 8 ),( 9 ) Mutation of CREBBP is detected only in only 55% of disease cases. ( 10 ) Respiratory infections and complications from congenital heart disease are major causes of morbidity and mortality. Instability of the craniovertebral junction at C1-C2, hypoplasia of the dens and fusion of the cervical vertebrae are described as potentially life-threatening malformations. ( 11 ) Scoliosis can develop in RTS patients with the deformity deteriorating around the pubertal growth which can result in severe restrictive lung disease. ( 12 ),( 13 ) 9 Roelfsema JH, Peters DJM. Rubinstein- Taybisyndrome.Clinical and molecular overview. Expert Reviews in Molecular Medicine 2007; 9 (23): Clark JA, Turner ML, Howard L, Stanescu H, Kleta R, Kopp JB. Description of familial keloids in five pedigrees: Evidence for autosomal dominant inheritance and phenotypic heterogeneity.bmc Dermatol 2009; 9:8. 11 Wiley S, Swayne S, Rubinstein JH, Lanphear NE, Stevens CA. Rubinstein-Taybi syndrome medical guidelines. Am J Med Genet A 2003;119(2): Y. Tatora, N. Kawakami, T. Tsuji, K. Miyasaka, T. Ohara, A. Nohara. Rubinstein-Taybi syndrome with scoliosis. Scoliosis ; pp: ; 5 (1-2):

3 Pulmonary hypertension can be induced by a patent ductus arteriosus or different types of congenital heart disease within RTS. These patients can also have upper airway obstruction during sleep due to hypotonia, obesity and the susceptible anatomy of the oropharynx and airway (small nasal passages, retrognathia, micrognathia, hypertrophy of the tonsils and adenoids). ( 14 ) Hypoxia is a contributive factor of pulmonary hypertension. Pulmonary vasoconstriction induced by repeated hypoxia may cause pulmonary vascular remodeling, which may become irreversible. ( 15 ),( 16 ) Kidney anomalies are common (hydronephrosis, duplications, vesicoureteral reflux, urinary tract infections, nephrolithiasis and nephrotic syndrome). Anesthesia may be dangerous in these patients. According to theliterature, sometimes patients with RTS may develope complications (e.g. respiratory distress and/or irregular heartbeats, cardiac arrythmias) associated with a muscle relaxant like succinylcholine and general anesthesia. ( 17 ) Any situations requiring the administration of anesthesia or succinlycholine (e.g. surgical procedures) should be closely monitored by skilled professionals. ( 18 ),( 19 ) deformity and restrictive pulmonary disease with numerous complications. Timely surgical treatment is an option to stabilize the chest area and avoid respiratory complications developing as the kyphoscoliosis progresses despite of potential risk of general anesthesia. In advanced syndrome with irreversible changes supportive treatment including continuous oxygenation, noninvasive ventilation is an option. CONCLUSION RTS is a rare genetic condition which landmark is kyphoscoliosis, often progressive during the adolescent growth. It can produce severe thoracic 13 Bounakis N, Karampalis C, Sharp H, Tsirikos AI. Surgical treatment of scoliosis in Rubinstein-Taybi syndrome type 2. J Med Case Rep 2015;9: Ramar K, Caples SM. Vascular changes, cardiovascular disease and obstructive sleep apnea. Future Cardiol 2011;7: Golbin JM, Somers VK, Caples SM. Obstructive sleep apnea, cardiovascular disease, and pulmonary hypertension. Proc Am ThoracSoc 2008;5: Ramar K, Caples SM. Vascular changes, cardiovascular disease and obstructive sleep apnea. Future Cardiol2011;7: Cheon-Hee Park,Kyung Hee Park, Bo-Yoon Choi. Korean J Anesthesiol 2012; 63(6): Stirt JA. Succinylcholine in Rubinstein-Taybi syndrome. Anesthesiology 1982; 57: Dearlove OR, Perkins R. Anaesthesia in an adult with Rubinstein-Taybi syndrome. Br J Anaesth 2002;90:399. Figure 1. Hand and foot in RTS. Broad thumb and broadened terminal phalanges. 2015; 5 (1-2):

4 Case report Figure 2. Typical facial appearance in RTS. Thick and arched eyebrows with long eyelashes, downslanted palpebral fissures, low handing columella and hypoplastic maxilla. (with the permission of the patient s family) Figure 4. Multi-slice computed tomography of chest. Thoracolumbar spinal kyphoscoliosis with the curve towards the right. The curvature angle of 73 degrees. There was no sign of bone fractures. Figure 3. Chest X-ray. Severe kyphoscoliosis of thoracolumbar spine. There is complete deformation of bone structures of the chest. Mineral intensity opacification paravertebral is large calculus in the right kidney ; 5 (1-2):

5 Summary : Rubinstein-Taybi syndrome (RTS) is rare genetic disease characterized by broad thumbs, broad toes, beaked nose, downward slanting palpebral fissure, mental and motor retardation, cardiovascular and renal abnormalities. We reported the case 34 year old woman with typical presentation of the disease. She developed a severe double thoracolumbar kyphoscoliosis, which was associated with reduction in the anteroposterior diameter of the chest and consequent severe restrictive lung disease. She had a pulmonary insufficiency, pulmonary hypertension and suffered from recurrent pulmonary infection. She also had atrial septal defect, aneurism of interatrial septum and nephrolithiasis. Lung function continues to deteriorate during two years and respiratory infections became more frequent. There was indication for surgical treatment of chest deformation but not implemented because of the high risk for general anesthesia and lack of consent of the patient's family. Key words: Rubinstein-Taybi syndrome, kyphoscoliosis, pulmonary insufficiency Sanja Šarac Klinika za pulmologiju VMA, Beograd sanja_sarac@yahoo.com 2015; 5 (1-2):