Bone marrow transplantation in DiGeorge syndrome

A Hispanic infant girl with DiGeorge syndrome underwent successful bone marrow transplantation (BMT) at age 28 1/2 weeks. She had typical facies, a cardiac defect, hypoparathyroidism, severe T and B cell immunodeficiency, and low levels of facteur thymique serique (FTS). In vitro incubation of the peripheral blood lymphocytes with thymosin alpha 1 showed no increase in the number of T cells on two occasions. A fetal thymus for transplantation was not available, and further review of past experience with thymic cells or factors revealed inconsistent and incomplete responses. Because of the patient's worsening clinical and immunologic status, BMT was performed, with her histocompatible brother as donor. The patient has had a good clinical and immunologic response to BMT, with evidence of T cell engraftment, improved B cell function, and increased levels of serum FTS. This experience indicates that minimal thymic influence is necessary for successful BMT and that patients with DiGeorge syndrome with significant T cell deficiency may benefit from this treatment.     

The DiGeorge syndrome

This study describes clinical signs and symptoms in 16 patients with the DiGeorge syndrome (DGS). Diagnosed on the basis of typical facial stigmata, a broad spectrum of severity is seen with respect to congenital heart disease, hypoparathyroidism and immunologic parameters. A simple index of severity is introduced that clearly differentiates complete forms of the syndrome (cDGS) with poor prognosis from partial forms of the syndrome (pDGS). Of 13 pDGS patients, 12 are still living; 8 underwent corrective heart surgery without infectious complications. Moderate to severe mental retardation is seen in all pDGS patients. Due to the lack of thymus function, immunodeficiency is a result of cDGS, whereas immunoregulatory disturbances (hypergammaglobulinaemia, high titres of specific antibody production) prevail in pDGS patients.Abbreviations ABC-33 antigen-binding-capacity-33 - BSA bovine serum albumin - cDGS complete DiGeorge syndrome - CHD congenital heart disease - DGS DiGeorge syndrome - hPTH human parathyroid hormone - PBMC peripheral blood mononuclear cells - pDGS partial DiGeorge syndrome     

Asymmetric crying facies associated with congenital hypoparathyroidism and 22q11 deletion

Asymmetric crying facies is caused by congenital hypoplasia or agenesis of the depressor anguli oris muscle. Associations of this facial defect with major congenital anomalies have been reported, most commonly in the cardiovascular system and less frequently involving the genitourinary, musculoskeletal, cervicofacial, respiratory, and rarely, the endocrine system. CATCH 22 is a medical acronym for cardiac defects, abnormal facies, thymic hypoplasia, cleft palate and hypocalcemia and a variable deletion on chromosome 22q11. The deletion within chromosme region of 22q11 may occur in patients with dysmorphologic and cardiological syndromes: DiGeorge syndrome, velo-cardiofacial syndrome and conotruncal anomaly face syndrome. We report a newborn infant who had asymmetric crying facies associated with congenital hypoparathyroidism, severe neonatal hypocalcemia and tetralogy of Fallot. Genetic confirmation of chromosome 22q11 deletion was made.     

Partial DiGeorge syndrome with substantial cell-mediated immunity.

Results of studies on two male infants with incomplete expression of the DiGeorge syndrome are analyzed. Both infants demonstrated neonatal tetany with hypoparathyroidism, cardiovascular anomalies, and absence of a thymus shadow on roentgenographic examination. Some degree of cellular immunity was present in both infants, however, including normal in vitro responses to phytohemagglutinin, thus postponing attempts at thymus transplantation. Both infants died suddenly at home, one at age 7 1/2 weeks and the other at age 44 weeks. At autopsy, no thymus was found in one, and a 2x2-mm thymus was detected after extensive search in the other. These cases emphasize the need for repeated monitoring of all immunologic measurements in the partial DiGeorge syndrome, so that early therapeutic intervention can be undertaken.     

Esophageal atresia and tracheo-esophageal fistula associated with coarctation of the aorta,CHARGE association,and DiGeorge syndrome: a case report and literature review

CHARGE association and DiGeorge syndrome (DGS) rarely occur together and only eight cases have been reported in the English literature. Two were associated with esophageal atresia (EA) and severe congenital heart anomalies. We report a third case of EA with tracheoesophageal fistula (EA-TEF) associated with coarctation of the aorta (CoA), CHARGE association, and DGS. The challenge for management in this complicated case is the background DGS which influences surgical outcome because of Ca++ imbalance and immune deficiency that can be life-threatening and require bone marrow transplantation.     

Establishment of immunity against Epstein‐Barr virus infection in a patient with CHARGE/complete DiGeorge syndrome after peripheral blood lymphocyte transfusion

CHARGE syndrome is a rare congenital malformation syndrome which may share symptoms with DiGeorge syndrome. Complete DiGeorge syndrome (cDGS) is a severe form of DiGeorge syndrome, characterized by a CD3+ T‐cell count of <50/mm³ due to athymia, and is fatal without immunologic intervention. We performed peripheral blood lymphocyte transfusion (PBLT) from an HLA‐identical sibling without pretransplant conditioning in a CHARGE/cDGS patient with a novel CHD7 splice site mutation. Cyclosporine and short‐term methotrexate were used for graft versus host disease (GVHD) prophylaxis, and neither acute nor chronic GVHD was observed. After PBLT, T‐cell proliferative response to phytohemagglutinin and concanavalin A recovered, and intractable diarrhea improved. EBV infection, evidenced by a gradual increase in the viral genome copy number to a maximum of 2861 copies/μgDNA on day 42 after PBLT, resolved spontaneously. HLA A2402 restricted, EBV‐specific CTLs were detected from peripheral blood on day 148, and EBV seroconversion was observed on day 181. Thus, EBV‐specific immunity was successfully established by PBLT. Our results indicate that PBLT is a simple and effective therapy to reconstitute immune systems in CHARGE/DiGeorge syndrome.     

PARA-INFLUENZA PNEUMONIA IN DiGEORGE SYNDROME TWO YEARS AFTER THYMIC EPITHELIAL TRANSPLANTATION

Abstract. Beard, Lorraine J., Robertson, Evelyn F. and Thong, Y. H. (Department of Paediatrics, University of Adelaide and Department of Chemical Pathology, Adelaide Children's Hospital Inc.). Para-influenza pneumonia in DiGeorge syndrome two years after thymic epithelial transplantation. Acta Paediatr Scand 69:403, 1980.—A patient with DiGeorge syndrome developed pneumonia caused by para-influenza virus type 3 two years after immunological reconstitution with foetal thymic epithelium. There was a transient reduction of mitogen-induced lymphocyte transformation at the time of the pneumonia. Although she recovered from the pneumonia, bronchitis persisted and the virus could still be isolated from her pharyngeal secretions 3½ months later.     

Transient congenital hypoparathyroidism and 22q11 deletion

CATCH-22 syndrome represents a spectrum of abnormalities associated with microdeletions of chromosome 22q11. We report a patient with transient congenital hypoparathyroidism, with severe neonatal hypocalcemia and spontaneous resolution in infancy, tetralogy of Fallot and thymic hypoplasia. Genetic confirmation of chromosome 22q11 deletion was made. Newborns with congenital hypoparathyroidism need genetic analysis and examination for anomalies associated with CATCH-22 syndrome.     

22Q11 microdeletion syndrome: cardiorespiratory symptoms and fibrobronchoscopy

The 22q11 deletion syndrome is a frequent contiguous-gene deletion syndrome. This disorder has a broad spectrum of phenotypic manifestations. It includes various syndromes such as DiGeorge syndrome. The most frequent clinical manifestations are congenital cardiac defects, characteristic facies, palate malformations, hypoparathyroidism, immunodeficiency due to thymic hypoplasia, growth retardation, and behavioural and psychiatric problems. Among the symptoms observed, many patients suffer from respiratory insufficiency or failure. The origin is often multifactorial. Structural airway abnormalities are frequently found in this syndrome. In many of these patients the malformation is mild or non-existent, and remains asymptomatic. However, in some cases it can cause a severe respiratory insufficiency, being diagnosed when other disorders are ruled out. These cases illustrate the importance of early visualisation of the airway by fibrobronchoscopy in the management of the patient with 22q11 deletion syndrome who has recurrent respiratory difficulties.     

Unmasking of latent hypoparathyroidism in a child with partial DiGeorge syndrome by ethylenediaminetetraacetic acid infusion

DiGeorge syndrome is a rare congenital anomaly with a wide range of clinical manifestations. This syndrome is usually associated with hypocalcaemia resulting from primary hypoparathyroidism. We report here a case of an 8-year-old boy with partial DiGeorge syndrome who presented initially with neonatal hypocalcaemia, but was subsequently normocalcaemic. Latent hypoparathyroidism was unmasked by a diagnostic EDTA infusion resulting in hypocalcaemia without a parathyroid hormone response. We propose that EDTA infusions can be useful in the diagnosis of latent hypoparathyroidism in children.     

CHARGE association with neuroblastoma

The CHARGE association, choanal arresia or coloboma with multiple anomalies, is rare. A newborn boy with CHARGE association was referred to our hospital because of bilateral choanal atresia. Additionally, he had left renal aplasia, one of the anomalies associated with this syndrome. A right suprarenal neuroblastoma (stage IV) was diagnosed when the patient was 5 months old. At operation, great care was taken not to injure the right kidney, and resection of the primary tumor as well as radical dissection of the right renal hilar and para-aortic lymph nodes were performed without difficulty. The patient received postoperative chemotherapy with vincristine, cyclophosphamide, and adriamycin for 2 years and is alive without recurrence 5 years after the operation. No report of the CHARGE association with a malignancy has appeared in the literature. The relationship between the CHARGE association and malignant tumors is still obscure, so that further study is necessary to define it.     

Maldescent of the Thymus: 34 Necropsy and 10 Surgical Cases, Including 7 Thymuses Medial to the Mandible

Among 3236 pediatric necropsies over 23 years, abnormal position of thymic tissue was recorded in 34 cases. Cardiac anomalies, predominantly those seen in DiGeorge syndrome, were present in 24; 3 had noncardiac anomalies only, 4 had other diseases, and 3 were sudden infant deaths. Mediastinal thymic tissue was absent in 22 cases, small or unilateral in 7, and normal in 5. The maldescended thymic tissue was unilateral in 18, bilateral in 11, and multiple on one or both sides in 5. It was situated near the thyroid gland in 19, lower in the neck in 6, and higher in 9, including 7 medial to the submandibular salivary gland and 1 at the base of the skull. The maldescended tissue approached the size of a normal lobe of thymus in eight and was 2.4 to 0.1 cm in the remainder. Over the same period, in only two cases was no thymic tissue found. Among 68,000 surgical specimens over 40 years, there were 10 cases of ectopic thymus in the neck, including 1 cutaneous and 4 cystic. This frequency of thymic tissue in the neck may explain why lymphoid tissues are sometimes relatively normal in cases of absent mediastinal thymus and behooves a search in the submandibular salivary gland region and higher before diagnosing thymic agenesis.     

The pattern of cardiovascular malformation in the CHARGE association

Congenital heart disease occurred in 64% of patients with the CHARGE (coloboma, heart disease, choanal atresia, retardation of postnatal growth and mental development, genitalia hypoplasia, and ear anomalies) association (55% of 67 previously described patients and 100% of 16 new patients). Of those with congenital heart disease, 42% had conotruncal anomalies (tetralogy of Fallot, double-outlet right ventricle, truncus arteriosus), and 36% had aortic arch anomalies (vascular ring, aberrant subclavian artery, interrupted aortic arch). This striking pattern of cardiovascular malformations is similar to that found in the DiGeorge sequence.     

HDR Syndrome (Hypoparathyroidism,Sensorineural Deafness and Renal Disease) Accompanied by Hirschsprung Disease

Background

HDR syndrome (hypoparathyroidism, sensorineural deafness and renal disease) is an autosomal dominant condition, defined by the triad hypoparathyroidism, renal dysplasia and hearing loss. Hirschsprung (HSCR) disease is a variable congenital absence of ganglion cells of the enteric nervous system resulting in degrees of functional bowel obstruction. Rarer chromosomal anomalies are reported in combination with Hirschsprung disease like DiGeorge syndrome, mosaic trisomy 8, XXY chromosomal constitution, partial duplication of chromosome 2q, tetrasomy 9p, and 20p deletion.

Case Presentation

Here, we describe an 8 year-old girl with HDR syndrome accompanied by Hirschsprung disease. Although the association of Hirschsprung disease with chromosomal anomalies has been reported, according to our knowledge, this is the first report of associated HSCR with HDR syndrome.     

Role of rare cases in deciphering the mechanisms of congenital anomalies: CHARGE syndrome research

In this review, our work on CHARGE syndrome will be used to exemplify the role of rare cases in birth defects research. The analysis of 29 cases with mutations of CHD7, the causative gene for CHARGE syndrome, clarified the relative importance of the cardinal features, including facial nerve palsy and facial asymmetry. Concurrently, in situ hybridization using chick embryos studies were performed to delineate the expression pattern of Chd7. The Chd7-positive regions in the chick embryos and the anatomical defects commonly seen in patients with CHARGE syndrome were well correlated: expression in the optic placode corresponded with defects such as coloboma, neural tube with mental retardation, and otic placode with ear abnormalities. The correlation between expression in the branchial arches and nasal placode with the clinical symptoms of CHARGE syndrome, however, became apparent when we encountered two unique CHARGE syndrome patients: one with a DiGeorge syndrome phenotype and the other with a Kallman syndrome phenotype. A unifying hypothesis that could explain both the DiGeorge syndrome phenotype and the Kallman syndrome phenotype in patients with CHARGE syndrome may be that the mutation in CHD7 is likely to exert its effect in the common branch of the two pathways of neural crest cells. As exemplified in CHARGE syndrome research, rare cases play a critical role in deciphering the mechanisms of human development. Close collaboration among animal researchers, epidemiologists and clinicians hopefully will enhance and maximize the scientific value of rare cases.     

Microdeletion of 22q11 (CATCH 22) in children with conotruncal heart defect and extracardiac malformations

CATCH 22 is a medical acronym for cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcemia, and a variable deletion on chromosome 22q11. The deletion within the chromosome region of 22q11 may occur in patients with dysmorphologic and cardiological syndromes: DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS), and conotruncal anomaly face syndrome (CAFS). In this study, using N25 (D22S75) DiGeorge chromosome region probe. fluorescence in situ hybridization (FISH) analyses were performed on 32 patients with congenital heart diseases. Twenty-nine of 32 patients had conotruncal heart disease. A 22q11 deletion was detected in two patients (6.9%) of the 29 patients with conotruncal heart disease. One of our 22qdel (+) patients had unilateral facial nerve palsy. Although it is not a frequent finding, unilateral facial nerve palsy will be included among the symptoms of CATCH 22 syndrome. After careful clinical evaluation of patients with conotruncal cardiac anomalies, only syndromic cases should be screened for this deletion.     

Noonan's and DiGeorge syndromes with monosomy 22q11.

A boy with the dysmorphic features of Noonan's syndrome and pulmonary valve stenosis who had evidence of hypoparathyroidism and abnormal T lymphocyte numbers in the neonatal period is reported. He had a normal karyotype but molecular analysis revealed a submicroscopic deletion within chromosome 22q11, the region deleted in DiGeorge syndrome. Thus this child has both Noonan's syndrome and DiGeorge syndrome; 22q11 is a candidate region for a gene defective in Noonan's syndrome.     

Noonan's and DiGeorge syndromes with monosomy 22q11

A boy with the dysmorphic features of Noonan's syndrome and pulmonary valve stenosis who had evidence of hypoparathyroidism and abnormal T lymphocyte numbers in the neonatal period is reported. He had a normal karyotype but molecular analysis revealed a submicroscopic deletion within chromosome 22q11, the region deleted in DiGeorge syndrome. Thus this child has both Noonan's syndrome and DiGeorge syndrome; 22q11 is a candidate region for a gene defective in Noonan's syndrome.     

DiGeorge syndrome with hypogammaglobulinaemia: a patient with excess suppressor T cell activity treated with fetal thymus transplantation

A male infant with DiGeorge syndrome had hypogammaglobulinaemia with a normal number of B cells. CD3(+) T cells were reduced and the CD4(+)/CD8(+) ratio was reversed. Proliferative responses of T cells to mitogens and to allogeneic cells were low. The pokeweed mitogen (PWM)-induced B cell differentiation assay revealed a higher than normal suppressor T cell activity. This suggests that some T cells had differentiated into functionally mature cells resulting in an imbalance of regulatory T cell functions and that excess suppressor activity might play a role in hypogammaglobulinaemia. Fetal thymus transplantation improved both cellular and humoral immunity. The patient's susceptibility to viral and bacterial infections, proliferative response of T cells and serum Ig concentration returned to normal. The excess suppressor activity seen before transplantation disappeared. Hypocalcaemia did not improve. These results show that fetal thymus transplantation was effective not only in reconstituting cellular immunity but also in normalizing the imbalance of regulatory T cell functions in this patient with DiGeorge syndrome.Abbreviations MNC mononuclear cells - ConA concanavalin A - PHA phytohaemagglutinin P - PWM pokeweed mitogen - ³H-TdR tritiated thymidine - PBL peripheral blood lymphocytes     

T-cell immunodeficiency in CHARGE syndrome

CHARGE syndrome comprises coloboma of the eye, heart defects, choanal atresia, growth and developmental retardation, genitourinary anomalies and ear and hearing defects. The association between CHARGE syndrome and T-cell immunodeficiency is recognized, but has not been reported widely in the literature. We report four patients meeting the diagnostic criteria for CHARGE syndrome, who had moderate or severe T-cell lymphopenia complicated by infections. The patients presented in Leicester, UK, between 2000 and 2007. All patients were negative for 22q11.2 deletions by FISH analysis, but mutations in the CHD7 gene were identified in three patients in whom the analysis was performed. Our cases indicate that patients with CHARGE syndrome may have a spectrum of T-cell immune deficiency, and that this association may be more common than has previously been appreciated. We recommend that all patients diagnosed with CHARGE syndrome should have lymphocyte subsets evaluated as part of their initial investigation.
Conclusion: Thymic hypoplasia should be included in the clinical features associated with CHARGE syndrome. All patients with CHARGE syndrome should have lymphocyte subset analysis performed, to exclude T-cell immunodeficiency.