591090
research-article2015
CPJXXX10.1177/0009922815591090Clinical PediatricsFriedman et al
Article
Post-childhood Presentation and Diagnosis of DiGeorge Syndrome
Clinical Pediatrics 1–6 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0009922815591090 cpj.sagepub.com
Nir Friedman, MD1, Shlomit Rienstein, MD,PHD2, Yonatan Yeshayahu, MD1,3, Doron Gothelf, MD,PHD4, and Raz Somech, MD,PHD1
Abstract Background and Objectives. The diversity of clinical presentations makes the diagnosis of DiGeorge syndrome (DGS) a diagnostic challenge. The objective of our study was to report the clinical presentation of DGS in the postchildhood period. Methods. A retrospective study, investigating patients diagnosed clinically and genetically with DGS at Sheba Medical Center during the period of 2010-2013. Post-childhood period was defined as age >10 years. Results. During the study period, 29 patients were diagnosed with DGS. Nine (31%) patients with DGS were diagnosed in their post-childhood period. The basis for clinical suspicion was diverse. However, once the suspicion was brought to attention, additional symptoms consistent with DGS were noted at up to 88% of patients who presented characteristic of facial features and developmental delay. Conclusion. Our research shows that diagnosing DGS patients in the post-childhood period is not uncommon. Characteristic facial features and developmental delay, although not leading presenting symptoms, are found very frequently in patients with DGS. Keywords diagnostic challenge, DiGeorge syndrome (DGS), Partial DGS, post-childhood period, 22q11deletion syndrome
Introduction DiGeorge syndrome (DGS), one of the 22q11deletion syndromes, is a group of signs and symptoms associated with defective development of the third and fourth pharyngeal pouch system. The syndrome is considered as the most common genomic deletion which leads to a clinical implication.1 Specific DNA sequence deletions of chromosome 22q11.2 are found in up to 90% of the patients. One classification of DGS is based on the level of immune function, a system that is affected in the syndrome. Patients are divided into 2 subtypes: Complete or Partial. Complete DGS is fatal during infancy unless identified and treated promptly. However, the majority of DGS patients belong to the Partial DGS group, which are diagnosed later in life based on typical clinical phenotypes.2 The spectrum of Partial DGS is wide with more than 180 different clinical features having been described. Not all features occur in 100% of affected individuals. There are limited records indicating the common age of diagnosis of partial DGS. Previous studies have shown two clusters of age; - during infancy/toddler and around the early school-age years.3-6 Health concerns per each group of patients change significantly. For example, the
predominant manifestation other than cardiac anomaly in infants and children is developmental delay, especially speech delay. Other clinical presentations are laryngotracheal and esophageal abnormalities, feeding difficulties, ocular anomalies, endocrine problems, renal abnormalities, and skeletal abnormalities.7-10 In adolescents and adults, DGS should be considered in individuals who present characteristic facial features, developmental delay, 1
Pediatric Department of B North and Immunology Service, Edmond and Lily Safra Children's Hospital, Jeffrey Modell Foundation Center, Sheba Medical Center, Tel Hashomer, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Israel 2 Cytogenetic Molecular Laboratory, the Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer 3 Pediatric Endocrinology Unit, Sheba Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Israel 4 The Behavioral Neurogenetics Center, Sheba Medical Center, Tel Hashomer, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Israel. Corresponding Author: Raz Somech, Pediatric Department of B North and Immunology Service, Edmond and Lily Safra Children Hospital, Sheba Medical Center, Tel Hashomer, 52621, Israel. Email: [email protected]
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palatal anomalies, hypernasal speech, and psychiatric problems. Compared with a large series of children with DGS, patients diagnosed after the childhood period had significantly lower rates of major cardiac anomalies and higher rates of palatal anomalies, mental disabilities, and psychiatric conditions. Interestingly, the most common findings in this age group were minor facial anomalies and hypernasal speech.11,12 In addition, there are many less frequent conditions associated with DGS, usually presenting later in life, including autoimmune cytopenias,13,14 arthritis and thyroid disease, allergic diseases,15 and even malignancies.16 In several cases, these atypical manifestations were the presenting symptom leading to the diagnosis of DGS.17,18 Once DGS is suspected beyond the childhood period, a few parameters for initial assessment and monitoring have been proposed.19 The diversity of clinical presentations makes the diagnosis of DGS, especially in the post-childhood period, a diagnostic challenge. Here we present DGS cases that were diagnosed in the post-childhood period, during a three year study. The primary objective of the clinical descriptions presented hereby is to raise the awareness of physicians to suspect DGS in the postchildhood period.
Methods Patients This retrospective study investigated patients clinically and genetically diagnosed with DGS at Sheba Medical Center, Tel Hashomer during 2010-2013. Postchildhood period was defined as age ten years or older. Cases were investigated for their clinical phenotype, including age of diagnosis, presenting symptom at diagnosis or reason for DGS evaluation, and additional symptoms. The study was approved by the institutional review board of Sheba Medical Center, Tel Hashomer and conducted according to the Declaration of Helsinki.
Genetic Diagnosis The diagnosis of DGS was confirmed using fluorescence in situ hybridization (FISH). FISH for identification of the DiGeorge microdeletion was performed using DiGeorge Region Probe–LSI TUPLE 1 SpectrumOrange/ LSI ARSA SpectrumGreen (Vysis, Downers Grove, IL, USA) according to the manufacturer’s best practice instructions. Visualization was by Zeiss Axioscope fluorescent microscope and analysis was performed using an Applied Imaging System (Santa Clara, CA, USA).
Results General Description During the study period, 29 patients aged 0 to 57 years were diagnosed with DGS by FISH testing. Mean age of diagnosis was 8.6 ± 13.1 years (interquartile range 0-12 years). Nine DGS patients (31%) were diagnosed during the post-childhood period. Seven cases are described below in detail and two of the cases are presented only with age of diagnosis and gender because more data was unavailable. In addition, one patient whom we describe here in detail is a woman who has all the clinical phenotypes of DGS, including a descendant with DGS but refused to undergo FISH testing for identification. In total, our study population included total of 5 males and 5 females, age of post-childhood diagnosis ranged between 10 and 57 years, average age of diagnosis was 22 ± 14.7 years (interquartile range 11-28 years). Eight patients were diagnosed due to clinical suspicion and 2 were diagnosed after a family member with DGS was identified. Seven of the 8 patients had characteristic facial features and developmental delay. Other symptoms that were commonly seen were hypernasal speech (5 patients), attention deficit/hyperactive disorder (ADHD; 4 patients), palate pathology (4 patients), and psychiatric issues (3 patients). Table 1 summarizes age at diagnosis, main presenting features or reason for referral, and other associated symptoms that were documented during the evaluation.
Case Descriptions Patient 1. A girl aged 11 years 9 months, previously healthy, was admitted to our department after an episode of tonic-clonic convulsion for the first time in her life. The girl who attended a regular school was known to have ADHD and poor academic achievements. History of developmental and language delays and learning difficulties since early childhood were reported by her parents. Physical examination showed characteristic facial features and hypernasal speech. Laboratory studies showed severe hypocalcemia, hyperphosphatemia and an undetectable parathyroid hormone level, all consistent with hypoparathyroidism. Patient 2. A 31-year-old man was referred by a psychiatrist to our Genetic Behavior Clinic for evaluation after he was diagnosed with a brief psychotic disorder. Comprehensive medical history revealed poor academic achievements. In the previous few years he was unemployed after an outbreak of psoriatic arthritis, which left him disabled. His physical examination showed
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31 12, 9 28
11, 4 28
15, 2 10, 4
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Convulsion d/t hypocalcemia Brief psychotic episode Convulsions Firstborn son diagnosed with DGS Velopalatal Insufficiency Schizophrenia with a Additional symptoms Velopalatal Insufficiency Developmental delay, learning difficulties
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Abbreviations: DGS, DiGeorge syndrome; ADHD, attention deficit/hyperactivity disorder; OCD, obsessive compulsive disorder; VSD, ventricular septal defect.
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Age at Case Diagnosis Characteristic Facial Aberrant Right Descriptio (Years, Presenting Symptom at Features for Peer Developmental Hypernasal Cleft Palatal Pulmonary Subclavian Short Precocious Recurrent Patellar Feeding n Months) Diagnosis Review Delay ADHD OCD Epilepsy Speech Palate Insufficiency VSD Stenosis Artery Hypocalcemia Hypoparathyroidism Hyperthyroidism Stature Puberty Infections Thrombocytopenia Arthritis Dermatitis Dislocations Difficulties
Additional Symptoms
Table 1. Clinical Description of Patients With DGS Who Were Diagnosed During the Postchildhood Period.
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Clinical Pediatrics
Figure 1. Patient 2 fluorescence in situ hybridization (FISH) analysis demonstrating 22q11.2 deletion. FISH analysis for identification of the DiGeorge microdeletion using DiGeorge Region Probe (Red areas, white arrow) and control chromosome 22 probe outside the critical DiGeorge syndrome region (Green areas, white arrow). The figure demonstrates a patient with chromosome 22q11.2 deletion by binding of 22q11.2 probe to only one chromosome.
hypernasal speech, a relative cleft palate, and a known cardiac systolic murmur. FISH analysis revealed a chromosome 22q11.2 deletion (Figure 1). Patient 3. A boy aged 12 years 9 months was admitted to our department for evaluation of his uncontrolled seizure disorder. Comprehensive medical history revealed developmental delay, which included “slow” speech and hypotonia, febrile convulsions that later turned into epilepsy. He had episodes of hypocalcemia for which he occasionally received calcium supplements. Physical examination showed characteristic facial features, hypernasal speech, and a cardiac systolic murmur. Laboratory studies indicated hypocalcemia and hyperphosphatemia. Parathyroid hormone and vitamin D levels were both low. Ear, nose, and throat (ENT) evaluation demonstrated palatal insufficiency.
Patient 4. A 28-year-old woman gave birth in our medical center. Her child was prenatally diagnosed with truncus arteriosus and multicystic dysplastic right kidney. Postnatal genetic testing revealed chromosome 22q11.2 deletion. Comprehensive medical history of the mother revealed juvenile myoclonic epilepsy, thrombocytopenia, developmental delay, hyperthyroidism, and hypocalcemia. Physical examination showed characteristic facial features of DGS. She refused genetic testing. Patient 5. A girl, 11 years 4 months old, was referred to our outpatient clinic by an ENT specialist for further evaluation due to velopalatal insufficiency. Comprehensive medical history revealed ADHD, obsessivecompulsive disorder and a history of pulmonic stenosis. Physical examination showed hypernasal speech.
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Friedman et al Patient 6. A 25-year-old man diagnosed at age of 14 with schizophrenia. His psychiatrist revealed a history of ventricular septal defect, developmental delay, asthma, and multiple knee joint dislocation that were related to Ehlers-Danlos syndrome. Physical examination showed characteristic facial features and hypernasal speech. FISH test revealed a chromosome 22q11.2 deletion. After the diagnosis, his parents both carried out a genetic investigation as well. FISH testing revealed that his 57-year-old father also has a chromosome 22q11.2 deletion. Patient 7. A girl aged 15 years and 2 months was referred to our outpatient clinic by an ENT specialist for further evaluation due to velopalatal insufficiency. A comprehensive medical history revealed developmental delay, ADHD, history of ventricular septal defect, and recurrent infections and pneumonia. Physical examination showed some characteristic facial features and hypernasal speech. Patient 8. A girl, 10 years and 4 months old was referred to our outpatient clinic for further evaluation due to developmental delay and learning difficulties. Comprehensive medical history revealed feeding difficulties during infancy, aberrant right subclavian artery, and recurrent infections with pneumonia as a toddler, precocious puberty, short stature, and ADHD. Physical examination showed minor characteristic facial features of DGS.
Discussion The currently proposed diagnostic criteria for DGS related to the Complete DGS subtype are based on reduced number of CD3+ T cells. However, the majority of DGS patients have Partial DGS resulting in diverse immune functions, and therefore, their diagnosis cannot be based on these criteria. The combination of variable clinical presentation and lack of appropriate diagnostic criteria makes partial DGS a diagnostic challenge, especially in the post-childhood period. A recent study conducted on 228 patients with DGS revealed a median age at diagnosis of 4 months with 71% of patients diagnosed before 2 years of age.20 In this study, the authors reported that the phenotype of adult patients with DGS was different from that of children and consists of mainly speech and language impairment, developmental delay, minor cardiac defects, recurrent infections, and facial features. In order to diagnose Partial DGS in this age group, physician should maintain a high index of suspicion in the presented clinical case as diagnosis may be challenging. Indeed, 31% of our patients who were
diagnosed with DGS during a period of 3 years were older than 10 years. The cases we reviewed had initially presented or sent for evaluation with several different clinical presentations, including convulsions (2), psychiatric problems (2), velopalatal insufficiency (2), genetic investigation due to a sibling diagnosed with DGS (1), and developmental delay (1). Interestingly, severe hypocalcemia leading to seizures was present at this advanced age, despite the fact that it was not causing any problems during early childhood or infancy. Furthermore, in each patient, there were additional features that raised the possible diagnosis of DGS. These symptoms were “hidden” and revealed themselves by the physicians through comprehensive medical history or physical examination. Among these associated symptoms, in the postchildhood period, our study shows that almost all of the patients had characteristic facial features (88%) and a history of developmental delay (88%). The typical characteristic facial features of patients with DGS include ocular hypertelorism, upslanting palpebral fissures, hooded eyelids, low set posteriorly rotated ears, widened area below nasal bridge, bulbous nose tip, micrognatia, short filtrum, high arched palate, bifid uvula, tapered fingers. The typical characteristics of developmental delay in DGS include motor and/or speech delays, learning disabilities, and mental retardation. We also found that our patients shared other common symptoms of DGS which are well described in medical references such as hypernasal speech, ADHD,21,22 palate pathology, and psychiatric issues.22 In addition, there are many less frequent conditions associated with DGS that were noted in our patients such as autoimmune cytopenias,13,14 arthritis, and thyroid disease.15 Clinical focus in DGS patients changes over time and requires constant reevaluation and adjustments, which makes early diagnosis of DGS important for appropriate intervention and multi-disciplinary care. This is because in DGS, like in the cases presented above, and in many other patients, the revealing symptom is only the “tip of the iceberg.” By making the diagnosis, we, as physicians, can offer the right treatment to the many disorders, clinical, and behavioral problems associated with this syndrome that were untreated or mistreated until that point. We can also provide the patient’s families an explanation to their child’s difficulties, which were unexplained up until then, as well as genetic counseling and investigation. In light of the above, patients with DGS need a long-term follow-up by a multidisciplinary team “tailored” to their own clinical and behavioral findings.19 In summary, diagnosing patients older than 10 years with DGS is not uncommon and description of such cases should raise the awareness among physicians to the late presentation and diagnosis of DGS.
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Author Contributions NF and RS designed the study. NF, YY, DG and RS gathered the data. SR did the genetic diagnosis. NF and RS wrote the paper. All the Authors agreed to publish this paper. All the authors vouch for the data and analysis.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Botto LD, May K, Fernhoff PM, et al. A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to the major birth defects in the population. Pediatrics. 2003;112:101-107. 2. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies representing PAGID (Pan American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. 1999;93:190-197. 3. McElhinney DB, McDonald-McGinn D, Zackai EH, Goldmuntz E. Cardiovascular anomalies in patients diagnosed with a chromosome 22q11 deletion beyond 6 months of age. Pediatrics. 2001;108(6):E104. 4. Del Carmen Montes C, Sturich A, Chaves A, et al. Clinical findings in 32 patients with 22qll.2 microdeletion attended in the city of Córdoba, Argentina. Arch Argent Pediatr. 2013;111:423-427. 5. Oskarsdóttir S, Vujic M, Fasth A. Incidence and prevalence of the 22q11 deletion syndrome: a population-based study in Western Sweden. Arch Dis Child. 2004;89: 148-151. 6. Devriendt K, Fryns JP, Mortier G, van Thienen MN, Keymolen K. The annual incidence of DiGeorge/velocardiofacial syndrome. J Med Genet. 1998;35:789-790. 7. Ryan AK, Goodship JA, Wilson DI, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet. 1997;34:798-804. 8. Emanuel BS, McDonald-Mcginn D, Saitta SC, Zackai EH. The 22q11.2 deletion syndrome. Adv Pediatr. 2001;48:39-73.
9. Choi JH, Shin YL, Kim GH, et al. Endocrine manifestations of chromosome 22q11.2 microdeletion syndrome. Horn Res. 2005;63:294-299. 10. Devriendt K, Swillen A, Fryns JP, Proesmans W, Gewillig M. Renal and urological tract malformations caused by a 22q11 deletion. J Med Genet. 1996;33:349. 11. Bassett AS, Chow EW, Husted J, et al. Clinical features of 78 adults with 22q11 deletion syndrome. Am J Med Genet A. 2005;138:307-313. 12. Cohen E, Chow EW, Weksberg R, Bassett AS. Phenotype of adults with the 22q11 deletion syndrome: a review. Am J Med Genet A. 1999;86:359-365. 13. Gennery AR, Barge D, O’sullivan JJ, Flood TJ, Abinun M, Cant AJ. Antibody deficiency and autoimmunity in 22q11.2 deletion syndrome. Arch Dis Child. 2002;86: 422-425. 14. Bruno B, Barbier C, Lambilliotte A, Rey C, Turck D. Auto-immune pancytopenia in a child with DiGeorge syndrome. Eur J Pediatr. 2002;161:390-392. 15. Staple L, Andrews T, Mcdonald-Mcginn D, Zackai E, Sullivan KE. Allergies in patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardial syndrome) and patients with chronic granulomatous disease. Pediatr Allergy Immumol. 2005;16:226-230. 16. McDonald-McGinn DM, Reilly A, Wallgren-Pettersson C, et al. Malignancy in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Am J Med Genet A. 2006;140:906-909. 17. Davies JK, Telfer P, Cavenagh JD, Foot N, Neat M. Autoimmune cytopenias in the 22q11.2 deletion. Clin Lab Haematol. 2003;25:195-197. 18. DePiero AD, Lourie EM, Berman BW, Robin NH, Zinn AB, Hostoffer RW. Recurrent immune cytopenias in two patients with DiGeorge/velocardiofacial syndrome. J Pediatr. 1997;131:484-486. 19. Bassett AS, McDonald-McGinn DM, Devriendt K, et al. Practical guidelines for managing patients with 22q11.2 deletion syndrome. J Pediatr. 2011;159:332-339. 20. Cancrini C, Puliafito P, Digilio MC, et al. Clinical features and follow-up in patients with 22q11.2 deletion syndrome. J Pediatr. 2014;164:1475-1480.e2. 21. Antshel KM, Hendricks K, Shprintzen R, et al. The longitudinal course of attention deficit/hyperactivity disorder in velo-cardio-facial syndrome. J Pediatr. 2013;163: 187-193. 22. Schneider M, Debbané M, Bassett AS, et al. Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome. Am J Psychiatry. 2014;171:627-639.
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research-article2015
CPJXXX10.1177/0009922815591090Clinical PediatricsFriedman et al
Article
Post-childhood Presentation and Diagnosis of DiGeorge Syndrome
Clinical Pediatrics 1–6 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0009922815591090 cpj.sagepub.com
Nir Friedman, MD1, Shlomit Rienstein, MD,PHD2, Yonatan Yeshayahu, MD1,3, Doron Gothelf, MD,PHD4, and Raz Somech, MD,PHD1
Abstract Background and Objectives. The diversity of clinical presentations makes the diagnosis of DiGeorge syndrome (DGS) a diagnostic challenge. The objective of our study was to report the clinical presentation of DGS in the postchildhood period. Methods. A retrospective study, investigating patients diagnosed clinically and genetically with DGS at Sheba Medical Center during the period of 2010-2013. Post-childhood period was defined as age >10 years. Results. During the study period, 29 patients were diagnosed with DGS. Nine (31%) patients with DGS were diagnosed in their post-childhood period. The basis for clinical suspicion was diverse. However, once the suspicion was brought to attention, additional symptoms consistent with DGS were noted at up to 88% of patients who presented characteristic of facial features and developmental delay. Conclusion. Our research shows that diagnosing DGS patients in the post-childhood period is not uncommon. Characteristic facial features and developmental delay, although not leading presenting symptoms, are found very frequently in patients with DGS. Keywords diagnostic challenge, DiGeorge syndrome (DGS), Partial DGS, post-childhood period, 22q11deletion syndrome
Introduction DiGeorge syndrome (DGS), one of the 22q11deletion syndromes, is a group of signs and symptoms associated with defective development of the third and fourth pharyngeal pouch system. The syndrome is considered as the most common genomic deletion which leads to a clinical implication.1 Specific DNA sequence deletions of chromosome 22q11.2 are found in up to 90% of the patients. One classification of DGS is based on the level of immune function, a system that is affected in the syndrome. Patients are divided into 2 subtypes: Complete or Partial. Complete DGS is fatal during infancy unless identified and treated promptly. However, the majority of DGS patients belong to the Partial DGS group, which are diagnosed later in life based on typical clinical phenotypes.2 The spectrum of Partial DGS is wide with more than 180 different clinical features having been described. Not all features occur in 100% of affected individuals. There are limited records indicating the common age of diagnosis of partial DGS. Previous studies have shown two clusters of age; - during infancy/toddler and around the early school-age years.3-6 Health concerns per each group of patients change significantly. For example, the
predominant manifestation other than cardiac anomaly in infants and children is developmental delay, especially speech delay. Other clinical presentations are laryngotracheal and esophageal abnormalities, feeding difficulties, ocular anomalies, endocrine problems, renal abnormalities, and skeletal abnormalities.7-10 In adolescents and adults, DGS should be considered in individuals who present characteristic facial features, developmental delay, 1
Pediatric Department of B North and Immunology Service, Edmond and Lily Safra Children's Hospital, Jeffrey Modell Foundation Center, Sheba Medical Center, Tel Hashomer, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Israel 2 Cytogenetic Molecular Laboratory, the Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer 3 Pediatric Endocrinology Unit, Sheba Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Israel 4 The Behavioral Neurogenetics Center, Sheba Medical Center, Tel Hashomer, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Israel. Corresponding Author: Raz Somech, Pediatric Department of B North and Immunology Service, Edmond and Lily Safra Children Hospital, Sheba Medical Center, Tel Hashomer, 52621, Israel. Email: [email protected]
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palatal anomalies, hypernasal speech, and psychiatric problems. Compared with a large series of children with DGS, patients diagnosed after the childhood period had significantly lower rates of major cardiac anomalies and higher rates of palatal anomalies, mental disabilities, and psychiatric conditions. Interestingly, the most common findings in this age group were minor facial anomalies and hypernasal speech.11,12 In addition, there are many less frequent conditions associated with DGS, usually presenting later in life, including autoimmune cytopenias,13,14 arthritis and thyroid disease, allergic diseases,15 and even malignancies.16 In several cases, these atypical manifestations were the presenting symptom leading to the diagnosis of DGS.17,18 Once DGS is suspected beyond the childhood period, a few parameters for initial assessment and monitoring have been proposed.19 The diversity of clinical presentations makes the diagnosis of DGS, especially in the post-childhood period, a diagnostic challenge. Here we present DGS cases that were diagnosed in the post-childhood period, during a three year study. The primary objective of the clinical descriptions presented hereby is to raise the awareness of physicians to suspect DGS in the postchildhood period.
Methods Patients This retrospective study investigated patients clinically and genetically diagnosed with DGS at Sheba Medical Center, Tel Hashomer during 2010-2013. Postchildhood period was defined as age ten years or older. Cases were investigated for their clinical phenotype, including age of diagnosis, presenting symptom at diagnosis or reason for DGS evaluation, and additional symptoms. The study was approved by the institutional review board of Sheba Medical Center, Tel Hashomer and conducted according to the Declaration of Helsinki.
Genetic Diagnosis The diagnosis of DGS was confirmed using fluorescence in situ hybridization (FISH). FISH for identification of the DiGeorge microdeletion was performed using DiGeorge Region Probe–LSI TUPLE 1 SpectrumOrange/ LSI ARSA SpectrumGreen (Vysis, Downers Grove, IL, USA) according to the manufacturer’s best practice instructions. Visualization was by Zeiss Axioscope fluorescent microscope and analysis was performed using an Applied Imaging System (Santa Clara, CA, USA).
Results General Description During the study period, 29 patients aged 0 to 57 years were diagnosed with DGS by FISH testing. Mean age of diagnosis was 8.6 ± 13.1 years (interquartile range 0-12 years). Nine DGS patients (31%) were diagnosed during the post-childhood period. Seven cases are described below in detail and two of the cases are presented only with age of diagnosis and gender because more data was unavailable. In addition, one patient whom we describe here in detail is a woman who has all the clinical phenotypes of DGS, including a descendant with DGS but refused to undergo FISH testing for identification. In total, our study population included total of 5 males and 5 females, age of post-childhood diagnosis ranged between 10 and 57 years, average age of diagnosis was 22 ± 14.7 years (interquartile range 11-28 years). Eight patients were diagnosed due to clinical suspicion and 2 were diagnosed after a family member with DGS was identified. Seven of the 8 patients had characteristic facial features and developmental delay. Other symptoms that were commonly seen were hypernasal speech (5 patients), attention deficit/hyperactive disorder (ADHD; 4 patients), palate pathology (4 patients), and psychiatric issues (3 patients). Table 1 summarizes age at diagnosis, main presenting features or reason for referral, and other associated symptoms that were documented during the evaluation.
Case Descriptions Patient 1. A girl aged 11 years 9 months, previously healthy, was admitted to our department after an episode of tonic-clonic convulsion for the first time in her life. The girl who attended a regular school was known to have ADHD and poor academic achievements. History of developmental and language delays and learning difficulties since early childhood were reported by her parents. Physical examination showed characteristic facial features and hypernasal speech. Laboratory studies showed severe hypocalcemia, hyperphosphatemia and an undetectable parathyroid hormone level, all consistent with hypoparathyroidism. Patient 2. A 31-year-old man was referred by a psychiatrist to our Genetic Behavior Clinic for evaluation after he was diagnosed with a brief psychotic disorder. Comprehensive medical history revealed poor academic achievements. In the previous few years he was unemployed after an outbreak of psoriatic arthritis, which left him disabled. His physical examination showed
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Convulsion d/t hypocalcemia Brief psychotic episode Convulsions Firstborn son diagnosed with DGS Velopalatal Insufficiency Schizophrenia with a Additional symptoms Velopalatal Insufficiency Developmental delay, learning difficulties
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Abbreviations: DGS, DiGeorge syndrome; ADHD, attention deficit/hyperactivity disorder; OCD, obsessive compulsive disorder; VSD, ventricular septal defect.
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Age at Case Diagnosis Characteristic Facial Aberrant Right Descriptio (Years, Presenting Symptom at Features for Peer Developmental Hypernasal Cleft Palatal Pulmonary Subclavian Short Precocious Recurrent Patellar Feeding n Months) Diagnosis Review Delay ADHD OCD Epilepsy Speech Palate Insufficiency VSD Stenosis Artery Hypocalcemia Hypoparathyroidism Hyperthyroidism Stature Puberty Infections Thrombocytopenia Arthritis Dermatitis Dislocations Difficulties
Additional Symptoms
Table 1. Clinical Description of Patients With DGS Who Were Diagnosed During the Postchildhood Period.
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Clinical Pediatrics
Figure 1. Patient 2 fluorescence in situ hybridization (FISH) analysis demonstrating 22q11.2 deletion. FISH analysis for identification of the DiGeorge microdeletion using DiGeorge Region Probe (Red areas, white arrow) and control chromosome 22 probe outside the critical DiGeorge syndrome region (Green areas, white arrow). The figure demonstrates a patient with chromosome 22q11.2 deletion by binding of 22q11.2 probe to only one chromosome.
hypernasal speech, a relative cleft palate, and a known cardiac systolic murmur. FISH analysis revealed a chromosome 22q11.2 deletion (Figure 1). Patient 3. A boy aged 12 years 9 months was admitted to our department for evaluation of his uncontrolled seizure disorder. Comprehensive medical history revealed developmental delay, which included “slow” speech and hypotonia, febrile convulsions that later turned into epilepsy. He had episodes of hypocalcemia for which he occasionally received calcium supplements. Physical examination showed characteristic facial features, hypernasal speech, and a cardiac systolic murmur. Laboratory studies indicated hypocalcemia and hyperphosphatemia. Parathyroid hormone and vitamin D levels were both low. Ear, nose, and throat (ENT) evaluation demonstrated palatal insufficiency.
Patient 4. A 28-year-old woman gave birth in our medical center. Her child was prenatally diagnosed with truncus arteriosus and multicystic dysplastic right kidney. Postnatal genetic testing revealed chromosome 22q11.2 deletion. Comprehensive medical history of the mother revealed juvenile myoclonic epilepsy, thrombocytopenia, developmental delay, hyperthyroidism, and hypocalcemia. Physical examination showed characteristic facial features of DGS. She refused genetic testing. Patient 5. A girl, 11 years 4 months old, was referred to our outpatient clinic by an ENT specialist for further evaluation due to velopalatal insufficiency. Comprehensive medical history revealed ADHD, obsessivecompulsive disorder and a history of pulmonic stenosis. Physical examination showed hypernasal speech.
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Friedman et al Patient 6. A 25-year-old man diagnosed at age of 14 with schizophrenia. His psychiatrist revealed a history of ventricular septal defect, developmental delay, asthma, and multiple knee joint dislocation that were related to Ehlers-Danlos syndrome. Physical examination showed characteristic facial features and hypernasal speech. FISH test revealed a chromosome 22q11.2 deletion. After the diagnosis, his parents both carried out a genetic investigation as well. FISH testing revealed that his 57-year-old father also has a chromosome 22q11.2 deletion. Patient 7. A girl aged 15 years and 2 months was referred to our outpatient clinic by an ENT specialist for further evaluation due to velopalatal insufficiency. A comprehensive medical history revealed developmental delay, ADHD, history of ventricular septal defect, and recurrent infections and pneumonia. Physical examination showed some characteristic facial features and hypernasal speech. Patient 8. A girl, 10 years and 4 months old was referred to our outpatient clinic for further evaluation due to developmental delay and learning difficulties. Comprehensive medical history revealed feeding difficulties during infancy, aberrant right subclavian artery, and recurrent infections with pneumonia as a toddler, precocious puberty, short stature, and ADHD. Physical examination showed minor characteristic facial features of DGS.
Discussion The currently proposed diagnostic criteria for DGS related to the Complete DGS subtype are based on reduced number of CD3+ T cells. However, the majority of DGS patients have Partial DGS resulting in diverse immune functions, and therefore, their diagnosis cannot be based on these criteria. The combination of variable clinical presentation and lack of appropriate diagnostic criteria makes partial DGS a diagnostic challenge, especially in the post-childhood period. A recent study conducted on 228 patients with DGS revealed a median age at diagnosis of 4 months with 71% of patients diagnosed before 2 years of age.20 In this study, the authors reported that the phenotype of adult patients with DGS was different from that of children and consists of mainly speech and language impairment, developmental delay, minor cardiac defects, recurrent infections, and facial features. In order to diagnose Partial DGS in this age group, physician should maintain a high index of suspicion in the presented clinical case as diagnosis may be challenging. Indeed, 31% of our patients who were
diagnosed with DGS during a period of 3 years were older than 10 years. The cases we reviewed had initially presented or sent for evaluation with several different clinical presentations, including convulsions (2), psychiatric problems (2), velopalatal insufficiency (2), genetic investigation due to a sibling diagnosed with DGS (1), and developmental delay (1). Interestingly, severe hypocalcemia leading to seizures was present at this advanced age, despite the fact that it was not causing any problems during early childhood or infancy. Furthermore, in each patient, there were additional features that raised the possible diagnosis of DGS. These symptoms were “hidden” and revealed themselves by the physicians through comprehensive medical history or physical examination. Among these associated symptoms, in the postchildhood period, our study shows that almost all of the patients had characteristic facial features (88%) and a history of developmental delay (88%). The typical characteristic facial features of patients with DGS include ocular hypertelorism, upslanting palpebral fissures, hooded eyelids, low set posteriorly rotated ears, widened area below nasal bridge, bulbous nose tip, micrognatia, short filtrum, high arched palate, bifid uvula, tapered fingers. The typical characteristics of developmental delay in DGS include motor and/or speech delays, learning disabilities, and mental retardation. We also found that our patients shared other common symptoms of DGS which are well described in medical references such as hypernasal speech, ADHD,21,22 palate pathology, and psychiatric issues.22 In addition, there are many less frequent conditions associated with DGS that were noted in our patients such as autoimmune cytopenias,13,14 arthritis, and thyroid disease.15 Clinical focus in DGS patients changes over time and requires constant reevaluation and adjustments, which makes early diagnosis of DGS important for appropriate intervention and multi-disciplinary care. This is because in DGS, like in the cases presented above, and in many other patients, the revealing symptom is only the “tip of the iceberg.” By making the diagnosis, we, as physicians, can offer the right treatment to the many disorders, clinical, and behavioral problems associated with this syndrome that were untreated or mistreated until that point. We can also provide the patient’s families an explanation to their child’s difficulties, which were unexplained up until then, as well as genetic counseling and investigation. In light of the above, patients with DGS need a long-term follow-up by a multidisciplinary team “tailored” to their own clinical and behavioral findings.19 In summary, diagnosing patients older than 10 years with DGS is not uncommon and description of such cases should raise the awareness among physicians to the late presentation and diagnosis of DGS.
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Clinical Pediatrics
Author Contributions NF and RS designed the study. NF, YY, DG and RS gathered the data. SR did the genetic diagnosis. NF and RS wrote the paper. All the Authors agreed to publish this paper. All the authors vouch for the data and analysis.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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