Authors: Gokul Thimmarayan, MD - Marshfield Clinic, Marshfield, WI and
Destiny F. Chau, MD - Arkansas Children’s Hospital/University of Arkansas for Medical Sciences, Little Rock, AR.
A 1-week-old neonate with pulmonary atresia and ventricular septal defect undergoes a complete surgical repair. Postoperatively, the patient has persistent hypocalcemia and prolonged mechanical ventilation due to pneumonia. Subsequent workup demonstrates immunodeficiency. Which of the following syndromes is MOST LIKELY associated with this constellation of findings?
Correct!
Wrong!
Question of the Week 347
22q11.2 deletion syndrome is the most common chromosomal microdeletion disorder affecting 1:2000 to 1:6000 live births. The microdeletion leads to the maldevelopment of structures derived from the third and fourth pharyngeal arches. It is associated with parathyroid aplasia or hypoplasia resulting in hypocalcemia; hypoplasia of the thymus leading to immunodeficiency; and conotruncal anomalies such as tetralogy of Fallot, pulmonary atresia with ventricular septal defect, truncus arteriosus, interrupted aortic arch, and ventricular septal defect. It is also associated with palatal anomalies, facial dysmorphism, renal anomalies, speech and learning disabilities, and psychiatric illness. 22q11.2 deletion syndrome is a multisystem disorder with a heterogeneous presentation also known as DiGeorge syndrome, Velocardiofacial syndrome, and Conotruncal anomaly face syndrome.
Congenital heart disease (CHD) is the most common cause of mortality in 22q11.2 deletion syndrome. Patients often require multiple cardiac surgeries due to complex congenital heart disease. The postoperative course may be complicated by prolonged mechanical ventilation, inotropic support, and prolonged intensive care unit and hospital stays. Hypocalcemia from parathyroid hypoplasia can be associated with perioperative hemodynamic instability and postoperative seizures. The incidence of hypocalcemia is higher in those patients with CHD than those without CHD. Thymic hypoplasia is associated with T-cell deficiency resulting in an increased risk of recurrent and severe infections. Immunoglobulin (IgG, IgM, IgA) deficiency is seen in 10% of the patients with 22q11.2 deletion syndrome. Transfusion of blood products in IgA deficient patients could lead to a severe anaphylactic reaction. Irradiated and leukocyte-depleted blood products should be used to reduce the risk of infection and prevent transfusion-associated graft vs host disease due to the immunodeficient state. Craniofacial abnormalities such as micrognathia, retrognathia, and cleft palate could cause difficulty during endotracheal intubation. Of the syndromes listed in the answer choices, this patient’s findings of a conotruncal cardiac lesion, persistent hypocalcemia, and immunodeficiency are most consistent with 22q11.2 deletion syndrome. The other syndromes are briefly described below.
CHARGE syndrome is an acronym for the multisystem genetic conditions: Coloboma, Heart defects, Atresia of choanae, Retardation of growth and mental development, Genitourinary anomalies and Ear malformations/hearing loss. It occurs with an approximate frequency of 1:10,000 births. It is diagnosed clinically and confirmed by detection of a genetic mutation in the CHD7 gene on chromosome 8q12. Cardiac malformations are present in 75-85% of the patients. Conotruncal defects, atrioventriculoseptal defects, and aortic arch abnormalities are seen commonly in CHARGE syndrome.
Williams syndrome or Williams-Beuren syndrome (WS) is a multisystem disorder caused by the deletion of multiple genes in chromosome 7 including the elastin gene. Williams syndrome occurs in 1:7,500 to 10,000 births. Patients with WS have characteristic facial findings including flat nasal bridge, short upturned nose, periorbital puffiness, long philtrum and delicate chin. Smooth muscle cells in patients with WS produce a decreased amount of normal elastin resulting in an arterial media with many hypertrophied smooth muscle cells, thickening of the media of large arteries, and ultimately obstructive lesions. The most common lesion is supravalvular aortic stenosis that characteristically develops at the sinotubular junction. Stenosis can also occur in the pulmonary arteries, coronary arteries, aortic arch, descending aorta, renal arteries, and mesenteric arteries. Patients with Williams syndrome are known to have increased risk of sudden cardiac death, especially in the setting of sedation and anesthesia. This is mostly attributed to the presence of coronary artery stenosis and biventricular outflow tract obstruction. Hypertension, hypercalcemia, impaired growth and impaired cognition are other associated findings.
Alagille syndrome is a rare autosomal dominant, multisystem disorder occurring in approximately 1:70,000 births. It is related to mutations in the JAG1 gene or the NOTCH2 gene. It is associated with a paucity of intrahepatic bile ducts leading to cholestasis and potential liver failure. Other abnormalities include cardiac anomalies such as peripheral pulmonary artery stenosis and tetralogy of Fallot; butterfly vertebrae; typical facial features such as prominent forehead, deep-set eyes with moderate hypertelorism, pointed chin, and straight nose with a bulbous tip; and vascular and renal anomalies.
References:
Yeoh TY, Scavonetto F, Hamlin RJ, Burkhart HM, Sprung J, Weingarten TN. Perioperative management of patients with DiGeorge syndrome undergoing cardiac surgery. J Cardiothorac Vasc Anesth. 2014; 28(4): 983-989.
Rayannavar A, Levitt Katz LE, Crowley TB, et al. Association of hypocalcemia with congenital heart disease in 22q11.2 deletion syndrome. Am J Med Genet A. 2018; 176(10): 2099-2103.
Davies EG. Immunodeficiency in DiGeorge Syndrome and Options for Treating Cases with Complete Athymia. Front Immunol. 2013; 4: 322.
National Institute of Health. National Center for Advancing Translational Sciences. Genetic and Rare diseases Information Center. 22q11.2 deletion syndrome. Last updated 2017 https://rarediseases.info.nih.gov/diseases/10299/22q112-deletion-syndrome Accessed October 25, 2021.
Hsu P, Ma A, Wilson M, et al. CHARGE syndrome: a review. J Paediatr Child Health. 2014; 50(7): 504-511.
Pober BR. Williams-Beuren syndrome. N Engl J Med. 2010; 362(3): 239-252.
Burch TM, McGowan FX, Kussman, BD, Powell AJ, DiNardo JA. Congenital Supravalvar Aortic Stenosis and Sudden Death Associated with Anesthesia: What’s the Mystery? Anesth Analg. 2008;107(6); 1848-1854.
Collins Ii RT, Collins MG, Schmitz ML, Hamrick JT. Peri-procedural risk stratification and management of patients with Williams syndrome. Congenit Heart Dis. 2017; 12(2): 133.
Saleh M, Kamath BM, Chitayat D. Alagille syndrome: clinical perspectives. Appl Clin Genet. 2016; 9: 75-82.
Congenital heart disease (CHD) is the most common cause of mortality in 22q11.2 deletion syndrome. Patients often require multiple cardiac surgeries due to complex congenital heart disease. The postoperative course may be complicated by prolonged mechanical ventilation, inotropic support, and prolonged intensive care unit and hospital stays. Hypocalcemia from parathyroid hypoplasia can be associated with perioperative hemodynamic instability and postoperative seizures. The incidence of hypocalcemia is higher in those patients with CHD than those without CHD. Thymic hypoplasia is associated with T-cell deficiency resulting in an increased risk of recurrent and severe infections. Immunoglobulin (IgG, IgM, IgA) deficiency is seen in 10% of the patients with 22q11.2 deletion syndrome. Transfusion of blood products in IgA deficient patients could lead to a severe anaphylactic reaction. Irradiated and leukocyte-depleted blood products should be used to reduce the risk of infection and prevent transfusion-associated graft vs host disease due to the immunodeficient state. Craniofacial abnormalities such as micrognathia, retrognathia, and cleft palate could cause difficulty during endotracheal intubation. Of the syndromes listed in the answer choices, this patient’s findings of a conotruncal cardiac lesion, persistent hypocalcemia, and immunodeficiency are most consistent with 22q11.2 deletion syndrome. The other syndromes are briefly described below.
CHARGE syndrome is an acronym for the multisystem genetic conditions: Coloboma, Heart defects, Atresia of choanae, Retardation of growth and mental development, Genitourinary anomalies and Ear malformations/hearing loss. It occurs with an approximate frequency of 1:10,000 births. It is diagnosed clinically and confirmed by detection of a genetic mutation in the CHD7 gene on chromosome 8q12. Cardiac malformations are present in 75-85% of the patients. Conotruncal defects, atrioventriculoseptal defects, and aortic arch abnormalities are seen commonly in CHARGE syndrome.
Williams syndrome or Williams-Beuren syndrome (WS) is a multisystem disorder caused by the deletion of multiple genes in chromosome 7 including the elastin gene. Williams syndrome occurs in 1:7,500 to 10,000 births. Patients with WS have characteristic facial findings including flat nasal bridge, short upturned nose, periorbital puffiness, long philtrum and delicate chin. Smooth muscle cells in patients with WS produce a decreased amount of normal elastin resulting in an arterial media with many hypertrophied smooth muscle cells, thickening of the media of large arteries, and ultimately obstructive lesions. The most common lesion is supravalvular aortic stenosis that characteristically develops at the sinotubular junction. Stenosis can also occur in the pulmonary arteries, coronary arteries, aortic arch, descending aorta, renal arteries, and mesenteric arteries. Patients with Williams syndrome are known to have increased risk of sudden cardiac death, especially in the setting of sedation and anesthesia. This is mostly attributed to the presence of coronary artery stenosis and biventricular outflow tract obstruction. Hypertension, hypercalcemia, impaired growth and impaired cognition are other associated findings.
Alagille syndrome is a rare autosomal dominant, multisystem disorder occurring in approximately 1:70,000 births. It is related to mutations in the JAG1 gene or the NOTCH2 gene. It is associated with a paucity of intrahepatic bile ducts leading to cholestasis and potential liver failure. Other abnormalities include cardiac anomalies such as peripheral pulmonary artery stenosis and tetralogy of Fallot; butterfly vertebrae; typical facial features such as prominent forehead, deep-set eyes with moderate hypertelorism, pointed chin, and straight nose with a bulbous tip; and vascular and renal anomalies.
References:
Yeoh TY, Scavonetto F, Hamlin RJ, Burkhart HM, Sprung J, Weingarten TN. Perioperative management of patients with DiGeorge syndrome undergoing cardiac surgery. J Cardiothorac Vasc Anesth. 2014; 28(4): 983-989.
Rayannavar A, Levitt Katz LE, Crowley TB, et al. Association of hypocalcemia with congenital heart disease in 22q11.2 deletion syndrome. Am J Med Genet A. 2018; 176(10): 2099-2103.
Davies EG. Immunodeficiency in DiGeorge Syndrome and Options for Treating Cases with Complete Athymia. Front Immunol. 2013; 4: 322.
National Institute of Health. National Center for Advancing Translational Sciences. Genetic and Rare diseases Information Center. 22q11.2 deletion syndrome. Last updated 2017 https://rarediseases.info.nih.gov/diseases/10299/22q112-deletion-syndrome Accessed October 25, 2021.
Hsu P, Ma A, Wilson M, et al. CHARGE syndrome: a review. J Paediatr Child Health. 2014; 50(7): 504-511.
Pober BR. Williams-Beuren syndrome. N Engl J Med. 2010; 362(3): 239-252.
Burch TM, McGowan FX, Kussman, BD, Powell AJ, DiNardo JA. Congenital Supravalvar Aortic Stenosis and Sudden Death Associated with Anesthesia: What’s the Mystery? Anesth Analg. 2008;107(6); 1848-1854.
Collins Ii RT, Collins MG, Schmitz ML, Hamrick JT. Peri-procedural risk stratification and management of patients with Williams syndrome. Congenit Heart Dis. 2017; 12(2): 133.
Saleh M, Kamath BM, Chitayat D. Alagille syndrome: clinical perspectives. Appl Clin Genet. 2016; 9: 75-82.
