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Holt-Oram Syndrome Sunil Mhaske, Sandeep Mhaske Maharashtra
olt-Oram syndrome is rare congenital anomaly of the musculoskeletal and the cardiovascular systems. The prevalence of this syndrome is 1/1,00,000 population. The commonest findings are absent thumb and radius, atrial septal defect. Holt-Oram syndrome is also known as heart hand syndrome, cardiac limb syndrome, atrio-digital syndrome or ventriculo-radial syndrome. In this syndrome 75% of the cases have cardiovascular problem. The commonest cause of mortality and morbidity is cardiovascular malformation.
Case Summary An unbooked rural habitat multigravida of 31-32 weeks of gestational period was admitted to the labor room with pain in abdomen and bleeding per vaginum since three days. She was first treated by a private practitioner who referred her to the medical college for further management. According to her last menstrual period, her gestational age was 32 weeks and seven days. She had no antenatal check-up during this period. She had received two doses of TT injection. She had
family history of consanguineous marriages. She was G4P3L3. First three are living, full term normal deliveries. Out of three, two are female and one is male. These children donâ€™t have congenital abnormality. She had pain in abdomen which was colicky in nature associated with nausea and bleeding per vaginum. Bleeding was moderate, fresh blood, since three days. She also had one bout of unconsciousness. On examination, she was average built with moderate pallor, tachycardia bilateral pedal edema, BP was 170/110 mmHg. Rest all her vitals are normal. She received tablet nifedipine (10 mg) t.d.s. P/A - showed uterus of 32 weeks with good relaxation, and a fetus with cephalic presentation. Inspection of the vulva showed moderate bleeding. Per vaginum examination was not done due to excessive bleeding. USG showed live fetus of 32 weeks, severe oligohydramnios, cephalic presentation, placenta lying anteriorly with Grade 2 maturity. FHS 140/min. Motherâ€™s investigation revealed Hb 9 g, TLC - 5,400/mm3, ESR - 20 mm. Blood group Tridot
negative. LFT and RFT were normal. Urine showed traces of albumin. A male baby weighing 1.7 kg was delivered by lower segment cesarean section. Baby cried immediately after birth. His HR - 35/min, RR - 40/min. His color was pink, there was no cyanosis and reflexes were normal. Placenta and cord were normal. On inspection following abnormalities were found in the baby (Fig. 1): Absence of thumb on both sides Widely spaced eyes Low set ears Hypoplastic receding mandible Single palmar crease High arched palate.
Baby was given to the mother for feeding after two hours. Afterwards opinion of orthopedics, ENT and ophthalmology department was taken. Following investigations were done: X-ray of both wrist - AP and lateral view showed
X-ray of spine - hemivertebra (Fig. 2) X-ray of chest - normal USG abdomen and pelvis - absence of left
USG cranium - normal
We did the 2D Echo after 4th day, but it did not show any cardiac abnormality. The patient was discharged and advised follow-up after 15 days, but patient did not comeback.
Discussion Holt-Oram syndrome was discovered by Mary Holt
and Samul Oram in 1960. Clinical features of HoltOram syndrome vary depending upon the severity of cardiac and limb malformations.
Musculoskeletal Defects Upper limbs are usually affected. Although bilateral, the left side is more commonly affected. The most severe form is phocomelia with rudimentary limbs. Mildest forms include clinodactyly, limited supination and sloping shoulders. The most common defects include radial thumb anomalies ranging from absent thumbs to displaced duplicated or triphalangeal thumbs. Hypoplasia of the radius manifests as short deformed forearm. Sprengel deformity (upward displacement of the scapula) and hypoplasia of the shoulders and clavicles may also be present. Associated muscular hypoplasia involves the hypothenar, wrist extensor, supinator, biceps brachii and triceps brachii.
Heart Defects The reported incidence ranges from 50 to 95%. The most common lesion is a secundum atrial septal defect. Other lesions include ventricular septal defect, atrioventricular block (AV block), pulmonic stenosis and mitral valve prolapse. Approximately 17% of patient have more complex cardiac malformations, such as tetralogy of Fallot, hypoplastic left heart, endocardial cushion defect and truncus arteriosus. Cardiac arrhythmias including paroxysmal tachycardia, prolonged PR interval, wandering atrial pacemaker, atrial ectopics, AV block and sinus bradycardia may be present. According to Mglinets, a specific feature of the syndrome is a changes in the main palmar lines and their termination on the radial border of the
0. No abnormality on physical or radiological examination. 1. Minor abnormalities, including reduced thenar eminence, clinodactyly or hypoplasia of thumb. 2. Present arms and forearms, with one or more bones missing. 3. Phocomelia. Figure 1. Inspection of the body revealed findings suggestive of Holt-Oram syndrome.
A scoring system to assess cardiac abnormalities in Holt-Oram syndrome. 0. Asymptomatic, with no abnormal physical findings. 1. Conduction defect 2. Structural heart abnormality that doesnâ€™t require surgery. 3. Structural heart abnormality that requires surgery. 4. Potentially lethal malformations.
Pathophysiology Figure 2. X-ray of spine showing hemivertebra.
hand. Pulmonary hypoplasia has occasionally been reported and can present with neonatal respiratory distress.
A scoring system to assess severity has been recommended by Gall et al and modified by Gladstone and Sybert as follows. Scoring system to assess skeletal abnormalities in Holt-Oram syndrome.
Defective development of the embryonic radial ray (aplasia, hypoplasia, fusion) results in a widespectrum of phenotypes, including triphalangeal or absent thumb, foreshortened arms and phocomelia. The syndrome is associated with defective development of cardiac structures that results in atrial septal defect, most commonly, secundum type; heart block of varying degree or both. The responsible gene has been mapped to band 12q 24.1, which encodes the human transcription factor TBX-5. One of the recently added loci is c.373 G > A, with results in the missense mutation p.Gly125
Arg, a novel mutation. A cardiomelic developmental field has also been postulated to relate the genetic heterogeneity of Holt-Oram syndrome, to a cascade of molecules, including the brachyury, sonic hedgehog homolog, bone morphogenetic protein, retinoic acid receptor and transforming growth factor beta families.
Suggested Reading 1.
Basson CT, Bachinsky DR, Lin RC, Levi T, Elkin JA, Soults J, et al. Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet 1997;15(1):30-5. Basson CT, Huang T, Lin RC, Bachinsky DR, Weremowicz, S, Vaglio A, et al. Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations. Proc Nat Acad Sci USA 1999;96(6):2919 24. Borozdin W, Bravo-Ferrer Acosta AM, Seemanova E, Leipoldt M, Bamshad MJ, et al. Contiguous hemizygous deletion of TBX5, TBX3, and RBM19 resulting in a combined phenotype of Holt-Oram and ulnar-
mammary syndromes. Am J Med Genet A 2006;140A(17):1880 6. 4.
Braulke I, Herzog S, Thies U, Zoll B. HoltOram syndrome in four half-siblings with unaffected parents: brief clinical report. Clin Genet 1991;39(4):241-4.
Davies P. Obituary: S Oram, Brit Med J 1992;304:500.
Fryns JP, Bonnet D, De Smet L. Holt-Oram syndrome with associated postaxial and central polydactyly. Further evidence for genetic heterogeneity in the Holt-Oram syndrome. Genet Couns 1996;7(4):323-4.
Gruenauer-Kloevekorn C, Froster UG. HoltOram syndrome: a new mutation in the TBX5 gene in two unrelated families. Ann Genet 2003;46(1):19-23.
Hurst JA, Hall CM, Baraitser M. The Holt-Oram syndrome. J Med Genet 1991;28(6):406-10.
Kantaputra PN, Yamasaki K, Ishida T, Kishino T, Niikawa N. A dominantly inherited malformation syndrome with short stature, upper limb anomaly, minor craniofacial anomalies, and absence of TBX5 mutations: report of a Thai family. Am J Med Genet 2002;111(3):301 6.
Juvenile Dermatomyositis with Calcinosis Cutis Sibabratta Patnaik, Manas Ranjan Behera, Nirmal Kumar Mahakud, Ashwini Kumar Mohanty Bhubaneswar, Odisha
case of juvenile dermatomyositis ( JDM) with calcinosis cutis in a 6-year-old girl. She presented with irregular fever for last two months and difficulty in standing from sitting position for one and half months. She had pathognomonic heliotrope rashes on both eye lids, Gottron’s papules in proximal interphalangeal and metacarpophalangeal joints of both hands and papules on elbow, knee and ankle joints. She had elevated serum muscle enzyme levels and electromyogram was in favor of JDM. Magnetic resonance imaging (MRI) of muscles revealed hyperintense signals in bilateral gluteal muscles. Muscle biopsy from biceps was normal. Our patient developed calcinosis around elbow joint two months after starting treatment. She is now under steroids and showing signs of improvement. Key words: Juvenile dermatomyositis, heliotrope rashes, Gottron’s papule, proximal myopathy, MRI, calcinosis cutis
Case Report A 6-year-old girl presented with irregular fever for last two months and difficulty in standing from sitting position for one and half months. She had pruritic, erythematous rashes on face, trunk and extremities.
She was treated for malaria and enteric fever elsewhere and was referred to our hospital as the symptoms did not improve. Her anthropometric measures were normal for age. She had shiny erythematous papules on proximal interphalangeal joints, metacarpophalangeal joints, elbow, knee and ankle joints of both side suggestive of Gottron’s papule. There were erythematous rashes on face and bridge of nose along with violaceous rashes on both eye lids consistent with heliotrope rashes. There was weakness of proximal muscles of legs with positive Gower sign. There was no neurodeficit and deep tendon jerks were normal.
Investigations Result showed a normal hemogram, ESR was 70 in first hour, rheumatoid factor, ANA, LE cell phenomena were negative, CRP level was elevated (>0.6 mg/dl). CPK was 72 u/l (21-215), ALT = 63 (normal 3-65), AST = 48 (15-37), lactate dehydrogenase (LDH) = 379 (100-190). Electromyogram revealed denervation along with myopathic changes characteristic of juvenile dermatomyositis ( JDM). Magnetic resonance imaging (MRI) of muscles revealed patchy hyperintense signals in bilateral
Figure 1. Heliotrope rashes. Figure 4. MRI of muscles showing patchy hyperintensesignals in bilateral gluteal region.
gluteus maximus muscles (Fig. 4). Muscle biopsy from biceps was normal.
Diagnosis and Treatment
Figure 2. Gottronâ€™s papules on hand.
She was diagnosed as a case of juvenile dermatomyositis and treated with oral prednisolone 2 mg/kg/day. Follow-up after three weeks showed improvement in muscle power and decrease in rashes with resumption of normal day-to-day activity. However, at second follow-up, two months after starting treatment, she had an ulceration around left elbow joint with whitish discharge, which was diagnosed as calcinosis cutis.
Figure 3. Calcinosis cutis in elbow joint.
JDM is a rare autoimmune vasculopathy of childhood that preferentially affects dermal and muscular vessels. By definition, the onset of JDM is prior to the age of 18, whereas, the average onset is in the 7th to 8th year of life, with a slight preference for the female
Casebook of gender.1 The disorder is rare, with a prevalence of 1-3.2 cases/million in children.2 While the etiology of JDM remains unclear, the working hypothesis is that, this involves environmental triggers, immune dysfunction and specific tissue responses (in particular those of muscle, skin and small vessel endothelium) in genetically susceptible individuals. Environmental factors such as bacterial and viral infections (Group A Î˛-hemolytic streptococci, Enterovirus, Coxsackie virus) and exposure to UV light have to be considered as important trigger factors. Anecdotal reports of JDM onset after exposure to drugs, biological therapies, vaccines also exist.3 At present, the most widely used set of criteria remain those defined by Bohan and Peter in 1975,4 which require the presence of one of the characteristic rashes, combined with three of the following features, for definite JDM: Symmetric proximal muscle weakness, raised serum muscle enzymes (which may include creatine kinase (CK), transaminases, LDH and aldolase) and abnormal findings on muscle biopsy and electromyography (EMG). The presence of the rash with two of these features make a diagnosis of probable JDM. These criteria, now over 30 years old, no longer reflect modern diagnostic investigation of suspected cases of JDM. Although MRI findings are not part of the Bohan and Peter criteria, MRI is now widely used to detect typical inflammatory changes in proximal muscles, and quantification of such changes has been shown to correlate with disease activity. Myopathy, mostly affecting the proximal muscles, is present in about 95% of dermatomyositis cases.5 In the international consensus survey of the diagnostic criteria for JDM, MRI was appreciated as one of
the most important diagnostic methods to be added to the revised criteria.6 Approximately 50% of children present with rash as their initial symptom and 25% present with weakness as their first symptom.7 Early diagnosis is often hampered by the nonspecific nature of the initial signs of JDM, such as fatigue, fever, weight loss, irritability, myalgia and arthralgia. Identification of characteristic skin lesions may help establish an early diagnosis. Typical cutaneous lesions include a characteristic periorbital heliotrope rash (present in more than two-thirds of patients), facial malar rash, Gottron papules (livid scaly plaques on the extensor surface of joints), and nailfold changes that may present as periungual infarcts.5 Calcinosis is common in JDM.3 Our patient developed calcinosis around elbow joint, two months after starting treatment. Blood tests to measure specific markers of muscle inflammation should be ordered including CK, LDH, aldolase, ALT and AST. Because muscle inflammation is patchy, EMG and muscle biopsy is not always diagnostic. MRI scans have become more widely used and can be helpful in choosing the correct muscle biopsy site.8 The course of the disease is difficult to predict, but is known to have a long course with remissions and exacerbations or, in some cases, a chronic course with a severe debilitating morbidity. Systemic glucocorticosteroids are the mainstay of therapy; they are administered orally (upto 2 mg/kg/day of prednisolone) or as intravenous pulses (usually 30 mg/kg/day of methylprednisolone) Therapy is continued until there is improvement of clinical and laboratory parameters.6 The incidence of calcinosis is decreasing but, for some patients, it remains a debilitating and disfiguring
problem. Many treatments have been tried, including diltiazem, aluminum hydroxide, probenecid, bisphosphonates and local corticosteroid injections, amongst others. No treatment has been proven to be effective. Calcinosis in many patients tends to regress over time (often years).9
Therapeutic Options Dermatomyositis3
Pachman LM, Lipton R, Ramsey-Goldman R, Shamiyeh E, Abbott K, Mendez EP, et al. History of infection before the onset of juvenile dermatomyositis: results from the National Institute of Arthritis and Musculoskeletal and Skin Diseases Research Registry. Arthritis Rheum 2005;53(2):16672.
Callen JP. Collagen vascular diseases. J Am Dermatol 2004;51(3):427-39.
Wedderburn LR, Rider LG. Juvenile dermatomyositis: new developments in pathogenesis, assessment and treatment. Best Pract Res Clin Rheumatol 2009;23(5):665-78.
Bohan A, Peter JB. Polymyositis and dermatomyositis. N Eng J Med 1975;292:344-7.
Schmieder A, Von Komorowski G, Peitsch WK, Goerdt S, Goebeler M. Juvenile dermatomyositis in an 8-year-old boy. Dermatol Online J 2009;15(6):3.
Brown VE, Pilkington CA, Feldman BM, Davidson JE; Network for Juvenile Dermatomyositis, Paediatric Rheumatology European Society (PReS). An international consensus survey of the diagnostic criteria for juvenile dermatomyositis (JDM). Rheumatology (Oxford) 2006;45(8):990-3.
Feldman BM, Rider LG, Reed AM, Pachman LM. Juvenile dermatomyositis and other idiopathic inflammatory myopathies of childhood. Lancet 2008;371:2201-12.
Schneider M, Murphy K. J Pediatr Health Care 2011; 25(1):38-43.
Stringer E, Feldman BM. Advances in the treatment of juvenile dermatomyositis. Curr Opin Rheumatol 2006;18(5):503-6.
Prednisolone, intravenous methylprednisolone, methotrexate are used as first-line therapy and adjunctive therapies to these are hydroxychloroquine, physical therapy, photoprotective measures, topical therapies for skin rashes, calcium and vitamin D for bone protection. Second-line therapies include intravenous gammaglobulin, cyclosporine, azathioprine, while third-line therapies include cyclophosphamide, mycophenolate mofetil, tacrolimus, rituximab and antitumor necrosis factor Îą-agents. Combinations of the above agents as first-line therapies are among those most often used in the initial treatment of JDM, whereas secondand third-line therapies are most often used in the treatment of refractory patients, patients considered to have severe features, or patients with unacceptable medication toxicities.
Summary JDM is a very rare autoimmune disorder characterized by skin changes like Gottronâ€™s papule and heliotrope rashes along with proximal myopathy. MRI is helpful in demonstrating muscle edema and choosing the site of muscle biopsy. The disease has along course with remissions and exacerbations. Steroid therapy is the cornerstone in the management of JDM.
Addison’s Disease Presenting Initially as Bronchial Asthma in a Child T Sathish Kumar, Sam Ebenazar, J Julius Xavier Scott Tamil Nadu
two-year-old boy who was admitted as bronchial asthma and eventually diagnosed to have Addison’s disease is presented here. Addison’s disease presenting initially as bronchial asthma is a rare occurrence. We report this case to alert physicians caring for children with asthma that in the presence of hyperpigmentation in a child with wheezing, Addison’s disease should be entertained as a possible association. Key words: Bronchial asthma, Addison’s disease
Case Report A two-year-old boy presented to us with acute exacerbation of wheezing. He reportedly had recurrent episodes of wheezing since two months of age. He is the third child born to consanguineous parents. His birth weight was 2.5 kg. He was noticed to have dark complexion since infancy but this was not taken notice of as significant by his parents. His development was normal and he was adequately immunized for age. He was hospitalized thrice in the past for wheezing and needed treatment with intravenous fluids, oxygen, antibiotics, bronchodilators and steroids. He never had any recurrent episodes of vomiting or symptoms of shock.
On examination, his weight was 11 kg and height was 81 cms. His blood pressure was 90/70 mmHg. He had generalized hyperpigmentation. Rest of the systemic examination was within normal limits. Investigations revealed – hemoglobin 11 g%, total count 11,600/cu.mm, differential count N 68%, L 25%, B 4%, E 3%. Serum sodium was 143 mmol/l, potassium was 3.6 mmol/l and creatinine was 0.4 mg%. His random blood sugar was 129 mg%. His chest radiograph was normal and Mantoux test was negative at 48 hours. Initially he was diagnosed and managed as bronchial asthma, but in view of generalized hyperpigmentation, Addison’s disease was considered as a possibility and he was evaluated for this. Serum cortisol at 8 AM and 11 PM were <1 µg%. His serum 17-hydroxyprogesterone was <5 ng/ml, dehydroepiandrosterone sulfate was 10.4 µg%, plasma renin activity was 0.5 ng/ml/hour. His serum cortisol showed no rise after administering intravenous tetracosactrin 250 µg, with 30 and 60 minute values remaining <1 µg%. He was started on oral hydrocortisone 10 mg three times a day for a week, and then tapered to 10 mg
in morning and 5 mg in evening. With steroid replacement therapy, his pigmentation lessened and he had no further recurrence of asthmatic attacks. He is doing well on follow up.
Discussion Addison’s disease with initial presentation as bronchial asthma had rarely been reported in children.1 Green et al and Harris et al reported that there was a possible relationship between Addison’s disease and asthma.2,3 In most of the cases, both these symptoms appeared together but in a few cases, clinical features of Addison’s disease were absent.4 In a retrospective survey of 481 patients with Addison’s disease, 27 were described as having allergic disease.5 In our case, the parents noticed that the child’s wheezing attacks and skin pigmentation developed simultaneously but yet it was not taken as significant and evaluated in the previous admissions. Glucocorticoids are involved in modulation of β-adrenoreceptor density and responsiveness.6 In the steroid-deficient state, β-adrenergic receptors of bronchi decrease in number or lose responsiveness to catecholamines presenting clinically with wheeze. A favorable response in asthma to steroid therapy will also support this fact. Asthma may be an uncommon presenting sign of Addison’s disease because a child developing
adrenal failure needs to be just on the threshold of bronchoconstriction for the latter to occur before other features of Addison’s disease. We report this case to alert physicians caring for children with asthma that in the presence of hyperpigmentation in a child with wheezing, Addison’s disease should be entertained as a possible association.
Saraclar Y, Turktas I, Adalioglu G, Tuncer A. Bronchial asthma with Addison’s disease. Respiration 1993;60:241-2.
Green M, Lim KH. Bronchial asthma with Addison’s disease. Lancet 1971;1:1159-62.
Harris PW, Collins JV. Bronchial asthma with Addison’s disease. Lancet 1971;1:1349-50.
Sanerkin NG, El-Shaboury AH. Chronic adrenalitis with bronchial asthma. Lancet 1965;7:468-70.
Carryer HM, Sherrick DW, Gastineau CF. Occurrence of allergic disease inpatients with adrenal cortical hypofunction. J Am Med Assoc 1960;172:1356-60.
Reinhardt D. Adrenoreceptors and the lung: their role in health and disease. Eur J Pediatr 1989;148:286-93.