Holt-Oram Syndrome
Mr. Jophin Joseph
Department of Nursing and Midwifery, College of public health and medical Sciences, Jimma University, PO.Box:1104, Jimma, Ethiopia.
*Corresponding Author Email: jophinkjoseph@yahoo.co.in / jophinjoseph4@gmail.com
ABSTRACT:
"Heart-hand" syndrome is a broad category of diseases. The most common form is Holt-Oram syndrome (HOS) that occurs in approximately 1:100,000 live births. This review goes in to the details of wide spectrum of clinical characteristic, diagnosis and treatment of this rare syndrome. HOS is inherited in an autosomal dominant manner, a mutation in TBX5 gene located on chromosome 12 (12q24.1) is associated with variable phenotypes. This rare syndrome characterized by upper limb defects such as carpal bone defects, triphalangeal thumbs, hypoplasia or absence of the thumb and the radial ray are more frequent in addition to that this syndrome is associated with cardiac septal defects among these the most common congenital heart defect is the ostium secundum ASD, followed by the ventricular septal defect (VSD). The diagnosis was established on the base of clinical examination, radiological findings, and echocardiography. The management of individuals with HOS optimally involves a multidisciplinary team approach with specialists moreover, along with medical and surgical care genetic council is inevitable.
KEYWORDS: Holt-Oram syndrome, congenital heart malformation, Mutations, Upper limb deformity, anesthetic management, pollicization, Genetic counseling.
INTRODUCTION:
Holt-Oram syndrome, also called heart-hand syndrome, is an inherited disorder characterized by abnormalities of the upper limbs and heart. Holt and Oram first described this condition in 1960 in a 4-generation family with atrial septal defects and thumb abnormalities [1]. An abnormal carpal bone is present in all affected individuals and may be the only evidence of disease. Seventy-five percent of individuals with HOS have a congenital heart malformation [2], which can be life-threatening. The most common problem is a defect in the muscular wall (septum) that separates the right and left sides of the heart.
A hole in the septum between the upper chambers of the heart (atria) is called an atrial septal defect (ASD), and a hole in the septum between the lower chambers of the heart (ventricles) is called a ventricular septal defect (VSD). Some people with Holt-Oram syndrome have cardiac conduction disease, which is caused by abnormalities in the electrical system that coordinates contractions of the heart chambers. Individuals with Holt-Oram syndrome may have additional bone abnormalities including a missing thumb, a long thumb that looks like a finger, partial or complete absence of bones in the forearm, an underdeveloped bone of the upper arm, and abnormalities of the collar bone or shoulder blades. These skeletal abnormalities may affect one or both of the upper limbs [3].
Definition:
Holt–Oram syndrome is an autosomal dominant disorder that affects bones in the arms and hands (the upper limbs) and may also cause heart problems. The syndrome includes an absent radial bone in the arms, an atrial septal defect, and a first degree heart block [4].
Incidence:
1 in 10000 live births is affected [5]. More than 300 cases have been published reveling a wide spectrum of clinical signs [6]. Approximately 85% of cases are attributed to new mutations and it has no sexual predilection. Prognosis is generally good, but it depends on the severity of the cardiac malformations. In a 2014 report, the mean prevalence of HOS diagnosed prenatally or in the early years of life in European registries was 0.7 per 100,000 births or 1:135,615 births and it shows the regional variation in its prevalence [7]. In Hungary, the birth prevalence is 0.95 per 100,000 total births. About 350 cases have been reported worldwide. A report identified this syndrome in 4% of patients with radial longitudinal deficiency [8]. In a recent evaluation of medical conditions in 138 patients with radial longitudinal deficiency (RLD), 7 patients had Holt Oram syndrome, making it the fourth most common syndrome or association in patients with RLD [9].
Cause:
Syndrome is inherited as an autosomal dominant trait that is completely penetrant. Mutations in the TBX5 (a member of the T-box gene family) with a gene locus at 12q24.1, has been linked to Holt Oram syndrome [10, 11]. The TBX5 gene plays a role in the development of the heart and upper limbs before birth; in particular, this gene appears to be important for the process that divides the developing heart into four chambers (cardiac septation), in addition to that it play a critical role in regulating the development of bones in the arm and hand. Mutations in this gene probably disrupt the development of the heart and upper limbs, leading to the characteristic features of Holt–Oram syndrome. In addition neither the genotype nor the location of the mutation determines the phenotype in Holt Oram syndrome[9]. The Molecular studies have demonstrated that mutations predicted to create null alleles cause substantial abnormalities in both the limbs and heart, and that missense mutations of TBX5 can produce distinct phenotypes. One class of missense mutations causes significant cardiac malformations but only minor skeletal abnormalities; others might cause extensive upper limb malformations but less significant cardiac abnormalities [12]. A systemic review found that with the proper examination, TBX5 mutations can be identified in more than 70% of patients with a clinical diagnosis of HOS [13].
The identification of the role of TBX5 in Holt-Oram syndrome suggests an important but as yet undefined role forTBX5 in human cardiac septation, isomerization, and upper limb development [14]. Recognizing that individuals who present with sporadic disease may transmit the disease to offspring is important. The pathophysiologic sequelae are a direct result of malformations of the heart and upper limbs. No contributory environmental factors are known [15].
Figure 1: Holt-Oram syndrome has an autosomal dominant pattern of inheritance.
Clinical Presentation:
Musculoskeletal defects:
A study investigates the distinguishing morphological characteristics of children with radial longitudinal deficiency (RLD) in Holt-Oram syndrome (HOS) exhibit that there was bilateral involvement in 84% of patients. The forearm was involved in 81% of the extremities and a shortened distal radius was the most commonly identified forearm anomaly (40%). Radioulnar synostosis was present in 15% of the extremities, all in the proximal forearms with reduced radial heads. Thumb aplasia was the most common type of classifiable thumb abnormality and occurred in 35% of involved thumbs. 27% percent of abnormal thumbs affected and 19% of involved thumbs had first-web syndactyly[16]. As per clinical aspects of HOS patients using data from EUROCAT (European Surveillance of Congenital Anomalies) registries shows that Thumb anomalies were reported in all cases. Agenesis/hypoplasia of radius was present in 49.2%, ulnar aplasia/hypoplasia in 24.6% and humerus hypoplasia/phocomelia in 42.6% of patients [7]. A case report by Aviña-Fierro J and Colonnelli-Barba G presents a patient with Holt-Oram syndrome associated with facial anomalies: hemifacial microsomia on the right side, forehead prominent and tall, hypertelorism, depressed nasal bridge, low set ears and micrognathia, this presentation broadens the clinical spectrum with delineation of facial dysmorphic features [17]. In an another case report describe clinical presentation in a male newborn baby who presented with thumb aplasia, forearm hypoplasia [18], moreover an 8-year-old-boy with short stature demonstrates congenital bilateral absence of a radial bone and thumbs [19]. Upper limbs are usually affected, although presence of foot anomalies in one affected individual, elaborates the role of atypical features in HOS differential diagnosis [20].
Fig 2: the baby was noted to have extra digit on the radial side of the right hand [21].
Upper limb deformity includes the following features:
· Always present but may be unilateral or bilateral
· Left-sided abnormalities often more severe than right arm or hand abnormalities
· Unequal arm lengths due to aplasia, hypoplasia, fusion, or anomalous development of the radial, carpal, and thenar bones.
· Abnormal forearm pronation and supination
· Triphalangeal or absent thumbs
· Possible abnormal opposition of thumb
· Possible sloping shoulders and restriction of shoulder joint movement
· Phocomelia
Cardiac defects:
The reported incidence ranges from 50-95% .The most common lesion is a secundum atrial septal defect (ASD)[22, 18]. Others include ventricular septal defect (VSD), atrioventricular (AV) block, pulmonic stenosis (including peripheral arterial), and mitral valve prolapse[22]. As per clinical aspects of HOS patients using data from EUROCAT (European Surveillance of Congenital Anomalies) registries shows congenital heart defects (CHD) were recorded in 78.7% of patients. Isolated septal defects were present in 54.2%, while 25% of patients had complex/severe CHD such as atrioventricular canal defects and tetralogy of Fallot [7, 23, 24, 25]. On the other hand an old study describes Atrial septal defect is the most cardiac abnormality (60.3% of 189 cases) occurring singly or in combination with other malformations. Thirty-three individuals (17.5%) of literature cases have more complex congenital malformations of the heart requiring complicated medical management and extensive cardiac surgery [26]. From the above two studies it can conclude that Approximately 15-25 % of patients have more complex cardiac malformations, which includes hypoplastic left heart syndrome[27], endocardial cushion defects, truncus arteriosus, Cardiac arrhythmias like paroxysmal atrial tachycardia, prolonged PR interval, wandering atrial pacemaker, atrial ectopic, AV block, and sinus bradycardia. Moreover, Syncope and sinus arrest have been reported. There was also rarely associated case reports of Holt-Oram syndrome with a double outlet right ventricle, patent ductus arteriosus (PDA) [28, 29] and multiple VSDs [22]. Pulmonary hypoplasia has occasionally been reported and can present with neonatal respiratory distress [30, 31] while Holt-Oram syndrome with aortopulmonary window has an extremely rare association [32]. Conduction heart disease may occur in the absence of structural anomaly.
Cardiac involvement includes the following signs:
· Bradycardia
· Irregular pulse (ectopy)
· Irregular pulse that occurs irregularly (atrial fibrillation)
· Wide, fixed splitting of the second heart sound
· Pulmonary systolic flow murmur
· Holosystolic murmur (should raise consideration for a VSD)
A scoring system to assess severity has been recommended by Gall et al and modified by Gladstone and Sybert, as follows [33].
Scoring system to assess skeletal abnormalities in HOS;
· 0- No abnormality on physical or radiological examination
· 1- Minor abnormalities, including reduced thenar eminence, clinodactyly, or hypoplasia of the thumb
· 2- Present arms and forearms, with one or more bones missing
· 3- Phocomelia
Scoring system to assess cardiac abnormalities in HOS;
· 0- Asymptomatic, with no abnormal physical findings
· 1- Conduction defect
· 2- Structural heart abnormality that does not require surgery
· 3- Structural heart abnormality that requires surgery but is not life threatening
· 4- Potentially lethal malformation
Diagnosis:
The diagnosis of HOS is established in a proband with a preaxial radial ray anomaly and a personal or family history of cardiac septation and/or conduction defects. More than 70% of individuals who meet strict clinical diagnostic criteria have an identifiable heterozygous pathogenic variant in TBX5 [34].
In a case report of Holt-Oram syndrome describes the role of the neonatologist is to instruct the parents about the importance of early diagnosis and interdisciplinary approach [18].A registry-based study in Europe reveals that 30.8% were suspected prenatally, 55.4% at birth, 10.7% in the first week of life, and 3.1% in the first year of life. The prenatal detection rate was 39.2%, with no significant change over the study period, however in 55% of prenatally detected cases, parents decided to terminate pregnancy [7]. Another study concludes that the presence of radioulnar synostosis and syndactyly of the radial 2 digits in RLD should prompt the hand surgeon to obtain a cardiac evaluation and thorough search for upper limb abnormalities should be carried out and genetic testing for Holt-Oram syndrome should be discussed with the parents. [16, 35].
Patients may have a family history of cardiac and/or limb malformation. A report about family with three sons having HOS coincides the report of another family with two children having similar disease [36, 37] furthermore, a report of Japanese family with 2 affected individuals having the typical Holt-Oram syndrome phenotype, namely bilateral asymmetrical radial ray deformities and atrial septal defect [38]. Patients may present in infancy with obvious limb malformations and signs of cardiac failure secondary to ASD, VSD, or cardiac conduction disease.
Blood tests are required for molecular genetics in patients with Holt-Oram syndrome (HOS). Molecular genetic testing approaches can include single-gene testing and – if the phenotype includes features that are atypical for Holt-Oram syndrome – a multi-gene panel. Though rare, chromosome rearrangements involving 12q24 have been reported in individuals with Holt-Oram syndrome [15, 10].
· Single-gene testing. Sequence analysis of TBX5 is performed first followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
· A multi-gene panel that includes TBX5 and other genes of interest (based on Differential Diagnosis) may also be considered. Note: The genes included and sensitivity of multi-gene panels varies by laboratory and over time [34].
Figure 3: Forearm and hand radiograph showing hypoplastic radius and triphalangeal thumb [39]
Figure 4: Chest radiograph showing boot-shaped heart and pulmonary oligemia [39]
Ø Ultrasonography: The antenatal Ultrasonography detects and correctly estimates the severity of the cardiac and skeletal expressions in HOS. Real-time ultrasound, with a detailed study of the fetal heart and skeletal system, can play a crucial role in the counselling of affected pregnant women [40]. In families with a parental Holt Oram syndrome, the diagnosis may have been suggested by prenatal ultrasound and confirmed after birth [9]. A rare case of familial Holt-Oram syndrome diagnosed sonographically at 18 weeks of gestation and the fetus had serious bilateral upper limb malformations, a ventricular septal defect and a type B interrupted aortic arch, while the mother had bilateral upper limb malformations only. This report concludes that a prenatal diagnosis of Holt-Oram syndrome in association with a type B interrupted aortic arch has not been reported in the English literature before [41]. Another case report from a woman with no family history of genetic diseases underwent prenatal sonography at 25 weeks revels the diagnosis of Holt- Oram syndrome [42], further more 3-D ultrasound has an important role in prenatal diagnosis of HOS, which is essential for proper genetic counseling [43]. Finally, two cases of perinatal ultrasound diagnosis of Holt-Oram syndrome characterized by significant right atrial enlargement [35].
Ø Magnetic resonance imaging (MRI) is helpful for delineating cardiac and skeletal involvement, but it may not be necessary in all cases. MRI may also be used to confirm muscular hypoplasia and to help distinguish the muscle involvement from those of any coexisting progressive neuromuscular disorders.
· Electrocardiography (ECG):
ECG reveals the features of the underlying heart defect. The most common defect, secundum atrial septal defect (ASD), usually demonstrates right atrial enlargement and right ventricular enlargement. Twenty-four hour Holter ECG reveals paroxysmal tachycardia, especially atrial tachycardia. Occasional sinus pauses or sinus arrest is found. This test is especially important in patients with a history of syncope.
Treatment:
Acute-stage of Holt-Oram syndrome treatment is directed at the cardiac manifestations. Care may be necessary with exacerbations of heart failure, for interventional procedures, or for surgical correction of heart disease. Administer medications as dictated by the heart disease. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physicians who diagnose and treat heart abnormalities (cardiologists), specialists who diagnose and treat skeletal abnormalities (orthopedists), and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment [34,44].
Medical care:
Regular follow-up is essential for both cardiac and skeletal conditions. The patient should be seen by orthopedic and occupational therapists, as well as by physiotherapists.
Ø Medications: The specific cardiac defect and its effects dictate appropriate therapy. For example, treatment of congestive heart failure may include diuretics, an ACE inhibitor, and digoxin. Iron supplements are appropriate in patients with cyanotic heart disease. Bacterial endocarditis prophylaxis is administered to patients with Holt-Oram syndrome (HOS) based on the specific cardiac condition. An isolated secundum atrial septal defect (ASD) does not require this treatment.
Surgical Care:
Holt oram syndrome patient require surgical care. The anesthetic implications include difficulty in catheterizing vessels, difficulty in tracheal intubation, lung ventilation, and problems with blood pressure (BP) monitoring. There is a potential susceptibility to arrhythmias, hemodynamic instability, and even cardiac arrest in the perioperative period [45, 46]. The peripheral venous access and arterial cannulation may be difficult in patients with significant limb abnormalities. Upper limb defects may make fixation of an appropriate size BP cuff difficult, and inaccurate pressures may be displayed by non-invasive monitors. Two of the Holt and Oram's original family had hypoplastic peripheral vessels which prevented cardiac catheterization [47] even though, the use of ultrasound-guided cannulation may improve success rate in such patients [48]. Another article reports safe and effective use of low dose sequential combined spinal and epidural anesthesia for caesarean section in a parturient with Holt-Oram syndrome and automatic implantable cardioverter defibrillator (AICD). Concerns with regards to anesthetic management include problems with vascular access, possible arrhythmias, the presence of an AICD, and the possibility of cardiovascular instability [49]. The key message is one should keep in mind that this syndrome has potential difficulties due to congenital cardiac problems like ASD, conduction blocks, and skeletal problems. The choice of regional anesthesia is superior technique when compared with general anesthesia due to lesser chances of sympathetic stimulation [50].
Ø Cardiac defects: Treatment for the heart defect includes the following:
o Appropriate surgical or nonsurgical correction of the heart defect is indicated and possible. A vast majority of atrial septal defects may be closed by trans-catheter methods. A case report of a one year and 6 months old female infant with truncus arteriosus (Collett-Edwards type II), peripheral pulmonary stenosis and Holt-Oram syndrome describe the radical correction under a cardiopulmonary bypass with deep hypothermia, PFO was closed directly. First of all, the pulmonary arteries were dissected from the aorta, the defect of the aorta was closed directly and VSD was closed with Dacron fabric patch. The reconstruction of the pulmonary arteries was performed with valved conduit which consisted of Dacron graft and 14 mm Björk-Shily valve. The post-operative course was uneventful [51].
o Palliative surgery, as indicated, if complete correction is not possible
London, a newborn baby born with a rare heart condition has made an amazing recovery after British doctors, in a pioneering surgery, used parts of a cow heart to save his life. Noa Gwilym Pritchard was born on February 10 this year with Holt-Oram syndrome, genetic diseases, characterized by abnormally developed bones in their upper limbs and often suffer with cardiac problems. Just days after being born, the baby was operated on at Alder Hey Hospital near Liverpool. The surgeons at the hospital repaired Noas heart with "both human and bovine parts" and his heart is now "near perfect," the Cambrian News reported. (http://indiatoday.intoday.in/story/baby-saved-after-doctors-fix-his-heart-with-parts-of-a-cow/1/513499.html).
Ø Musculoskeletal defects: The type of treatment of the clubhand in cases with HOS depends on (1) the age and (2) the pattern and degree of accompanying malformations of the upper limb. For patients with aplasia of the thumb or amputation of a rudimental one it is recommends pollicisation of the index finger to improve its function[52]. Treatment for musculoskeletal defects may include the following:
o Take adequate measures to prevent acquired deformities and to treat existing deformities.
o Surgical management of hand anomalies depends on the age, pattern, and degree of accompanying malformations of the upper limb.
o Pollicization to improve function of index finger is recommended for patients with aplasia of the thumb. This is also recommended following amputation of a rudimental thumb. Young patients that were treated with the pollicization, they are satisfied and use the neo-thumb like normal thumb [53].
Genetic counseling:
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with genetics professional.
HOS is inherited in an autosomal dominant manner. Approximately 85% of affected individuals have HOS as the result of a de novo pathogenic variant. Offspring of an affected individual are at a 50% risk of being affected. In pregnancies at 50% risk, detailed high-resolution prenatal ultrasound examination may detect upper-limb malformations and/or congenital heart malformations. Prenatal molecular genetic testing may be used to confirm a diagnosis if the TBX5 pathogenic variant has been identified in an affected relative [34].There are reported studies which insist the importance of genetic counselling [43,35,40].
CONCLUSION:
Holt-Oram syndrome is an autosomal dominant condition associated with skeletal malformations of the upper limbs, and congenital heart disease, which are often simple septal and conduction defects, less frequently complex CHDs. Prognosis in patients with Holt-Oram syndrome is dictated by the severity and type of cardiac and limb malformations. Because the most common defect in HOS is atrial septal defect (ASD), the prognosis is excellent. It essential to ensure family members are aware that this is an autosomal dominant disorder and that the chance is 50% that offspring of an affected individual will also have the disorder. Genetic counseling should be provided to all patients with HOS. Of probands, 60% to 70% have an affected parent, and 30% to 40% have a de novo mutation. Evaluation of both parents is recommended.
REFERENCES:
1. Holt M, Oram S. Familial heart disease with skeletal malformations. Br Heart J. 1960 Apr. 22:236- 42.
2. Deborah A McDermott et.al. Holt-Oram Syndrome. July 20, 2004; Last Update: October 8, 2015.
4. Skelley, Tao Le, Vikas Bhushan, Nathan William. First aid for the USMLE step 2 CK (8th ed.). New York: McGraw-Hill Medical. p. 357. ISBN 978-0-07-176137-6.
6. Torsten Bosserti et.al. Holt oram syndrome, Orphanet encyclopedia. http://www.orpha.net/data/patho/GB/uk-HOS.pdf.
9. Goldfarb CA, Wall LB. Holt-Oram syndrome. J Hand Surg Am. 2014 Aug; 39(8):1646-8. doi: 10.1016/j.jhsa. 2014.02.015. Epub 2014 Mar 20.
10. Li QY, Newbury-Ecob RA, Terrett JA, et al. (January 1997). "Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family". Nat. Genet.15 (1): 21–9. doi:10.1038/ng0197-21. PMID 8988164.
11. Basson CT, Bachinsky DR, Lin RC, et al. (January 1997). "Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome". Nat. Genet. 15(1): 30–5. doi:10.1038/ng0197-30. PMID 8988165.
16. Wall LB, et.al. Defining Features of the Upper Extremity in Holt-Oram Syndrome. J Hand Surg Am. 2015 Sep; 40(9):1764-8. doi: 10.1016/j.jhsa.2015.06.102. Epub 2015 Aug 1.
17. Aviña-Fierro JA, Colonnelli-Barba G. Holt-Oram syndrome associated with facial anomalies. A case report. Rev Med Inst Mex Seguro Soc. 2010 Nov-Dec; 48(6):657-9.
18. Zakanj Z. Holt-Oram syndrome; the importance of early diagnosis and interdisciplinary approach. A case report. Lijec Vjesn. 2013 Jan-Feb; 135(1-2):12-4.
20. Garavelli L, et.al. Holt Oram syndrome associated with anomalies of the feet. Am J Med Genet A. 2008 May 1; 146A (9):1185-9. doi: 10.1002/ajmg.a.32170.
22. http://emedicine.medscape.com/article/889716-clinical#b4
23. J. Bohm, W. Heinritz, A. Craig, et al. Functional analysis of the novel TBX5c.1333 delC mutation resulting in an extended TBX5 protein . BMC Med. Genet., 9 (2008), p. 88http://dx.doi.org/10.1186/1471-2350-9-88.
24. Baban A, Pitto L, et.al. Holt-Oram syndrome with intermediate atrioventricular canal defect, and aortic coarctation: functional characterization of a de novo TBX5 mutation. Am J Med Genet A. 2014 Jun; 164A (6):1419-24. doi: 10.1002/ajmg.a.36459. Epub 2014 Mar 24.
25. Kumar V, Agrawal V, Jain D, Shankar O. Tetralogy of Fallot with Holt-Oram syndrome. Indian Heart J. 2012 Jan-Feb;64(1):95-8. doi: 10.1016/S0019-4832(12)60021-2. Epub 2012 Mar 26.
26. Sletten LJ, Pierpont M E.Variation in severity of cardiac disease in Holt-Oram syndrome. Am J Med Genet. 1996 Oct 16; 65(2):128-32.
27. Ekure EN, Okoromah CN, Briggs E, Ajenifuja OA. Holt-Oram syndrome with hypoplastic left heart syndrome in an African child. Niger Postgrad Med J. 2004 Sep; 11(3):190-2.
28. Singh B1, Kariyappa M, Vijayalakshmi IB, Nanjappa MC. Holt-oram syndrome associated with double outlet right ventricle: A rare association. Ann Pediatr Cardiol. 2013 Jan; 6(1):90-2. doi: 10.4103/0974-2069.107245.
29. Sinha R, Nema C. Rare cardiac defect in Holt-Oram syndrome. Cardiovasc J Afr. 2012 Mar 12;23(2):e3-4. doi: 10.5830/CVJA-2011-017.
30. Seng YR, Su YN, Lu FL, et al. Holt-Oram syndrome with right lung agenesis caused by a de novo mutation in the TBX5 gene. Am J Med Genet A. 2007 May 1. 143A (9):1012-4.
31. Smets K, Mortier G, Zecic A. Perinatal/neonatal case presentation: unexpected severe respiratory insufficiency in a newborn with Holt-Oram Syndrome. J Perinatol. 2005 Nov. 25(11):745-6.
32. Srinivas SK, Balekundri VI, Manjunath CN. Holt-Oram syndrome with aortopulmonary window--a rare association. Cardiol Young. 2014 Oct; 24(5):947-9. doi: 10.1017/S1047951113001844. Epub 2013 Oct 14.
33. Venugopalan Poothirikovil. Medicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Cardiology Holt-Oram Syndrome. MBBS, MD, FRCP (Glasg), FRCPCH Consulting Staff, Department of Child Health University, Hospital of Hartlepool, UK.
35. Paladini D, Tiesi M, Buffi D, Tuo G, Marasini M. Unexplained right atrial enlargement may be a sign of Holt-Oram syndrome in the fetus. Ultrasound Obstet Gynecol. 2014 Apr; 43(4):475-6. doi: 10.1002/uog.13238. Epub 2014 Mar 3.
36. Bossert T, Walther T, Gummert J, Hubald R, Kostelka M, Mohr FW. Cardiac malformations associated with the Holt-Oram syndrome--report on a family and review of the literature. Thorac Cardiovasc Surg. 2002 Oct; 50(5):312-4.
37. Frota Filho JD, Pereira W, et.al. Holt-Oram syndrome revisited. Two patients in the same family. Arq Bras Cardiol. 1999 Nov; 73(5):429-34.
38. Kimura M , Kikuchi A, Ichinoi N, Kure S.Novel TBX5 duplication in a Japanese family with Holt-Oram syndrome. Pediatr Cardiol. 2015 Jan; 36(1):244-7. doi: 10.1007/s00246-014-1028-x. Epub 2014 Oct 2.
39. Tidake A1, Gangurde P, Shaikh Z, Mahajan A. Tetralogy of Fallot with Holt-Oram syndrome: case report and review. Clin Res Cardiol. 2015 Sep; 104(9):790-3. doi: 10.1007/s00392-015-0858-8. Epub 2015 Apr 23.
40. Muller LM, De Jong G, Van Heerden KM. The antenatal ultra-sonographic detection of the Holt-Oram syndrome. S Afr Med J. 1985 Aug 31; 68(5):313-5.
41. Law KM, Tse KT. Prenatal sonographic diagnosis of familial Holt- Oram syndrome associated with type B interrupted aortic arch. Hong Kong Med J. 2008 Aug; 14(4):317-20.
44. https://rarediseases.org/rare-diseases/holt-oram-syndrome/
45. Girish BN, Rajesh S, Somasekharam P, Kumar P. Anesthetic management of emergency cesarean section in a patient with Holt Oram syndrome. J Anaesthesiol Clin Pharmacol 2010; 26:541-3.
46. Ajmer Singh, Vikrant S Pathania, Samir Girotra, Krishna S Iyer . Anesthetic implications in Holt-Oram Syndrome. Year: 2013 Volume: 16 Issue: 2 Page: 157-158.
47. Holt M, Oram S. Familial heart disease with skeletal malformations. Br Heart J 1960; 22:236-42.
48. Hosokawa K, Shime N, Kato Y, Hashimoto S. A randomized trial of ultrasound image-based skin surface marking versus real-time ultrasound-guided internal jugular vein catheterization in infants. Anesthesiology 2007; 107:720-4.
49. Kanniah SK .Caesarean delivery in a parturient with Holt-Oram syndrome and implantable cardioverter defibrillator: anesthetic considerations. Arch Gynecol Obstet. 2009 Jul; 280(1):111-3. doi: 10.1007/s00404-008-0854-6. Epub 2008 Nov 27.
50. Akshaya N. Shetti, et.al. Anesthetic management of a patient with Holt-Oram syndrome undergoing right radial head excision. Anesth Essays Res. 2014 Jan-Apr; 8(1): 83–85.doi: 10.4103/0259-1162.128917.
51. Koishizawa T, Hayashi N, Tadokoro M, et al. A case report of the radical correction of a truncus arteriosus and peripheral pulmonary stenosis in association with Holt-Oram syndrome. Kyobu Geka. 1995 Feb; 48(2):133-6.
52. Weber M, Wenz W, van Riel A, Kaufmann A, Graf J. The Holt-Oram syndrome. Review of the literature and current orthopedic treatment concepts. Z Orthop Ihre Grenzgeb. 1997 Jul-Aug; 135(4):368-75.
53. Vaienti L, et.al. The pollicization of the index finger in the aplasia of the thumb. Pediatr Med Chir. 2009 Nov-Dec; 31(6):258-61.
Received on 06.01.2016 Modified on 27.01.2016
Accepted on 23.02.2016 © A&V Publications all right reserved
Asian J. Nur. Edu. and Research.2017; 7(1): 126-132.
DOI: 10.5958/2349-2996.2017.00026.X