OBJECTIVE: To summarize the clinical features and management of two brothers affected with X-linked inhibitor of apoptosis protein (XIAP) deficiency. METHODS: This study retrospectively analyzed the clinical presentations, treatment, and follow-up of two brothers with XIAP deficiency diagnosed at Shanghai Children's Hospital in 2020, and summarized similar cases recorded in databases such as PubMed, Wanfang, Chinese Medical Association Journals, and WIP from January 2006 to November 2024. This study was approved by the Medical Ethics Committee of our hospital (Ethics No.: 2025R128-E01). RESULTS: Patient 1 was the younger brother, who presented at 8 years of age with growth retardation, folliculitis, erythema nodosum, and perineal abscess. Sequencing revealed that he has carried a hemizygous c.566T>C (p.Leu189Pro) variant of the XIAP gene, which was inherited from his mother. He was allergic to infliximab treatment and underwent allogeneic stem cell transplantation (HSCT) in January 2021. During a follow-up of 3 years and 10 months post-transplantation, he showed no gastrointestinal symptoms and had a good outcome. Patient 2 was the elder brother, who presented at 10 years and 6 months of age with growth retardation, rash, and anal fistula. Genetic testing revealed the same variant. He was treated with oral azathioprine but did not have regular follow-ups. At 14-years-and-6-months of age, he had developed severe gastrointestinal infection and hemophagocytic lymphohistiocytosis, which was alleviated after treatment with antibiotics, glucocorticoids, immunoglobulin, and rituximab. He is currently being prepared for HSCT. A total of 13 publications were retrieved, which involved 64 patients from 23 families, with 23 different variants identified. The main clinical manifestations included splenomegaly (34 cases, 53.1%), hemophagocytic lymphohistiocytosis (27 cases, 42.2%), and inflammatory bowel disease or colitis (20 cases, 31.8%). There were significant phenotypic differences among patients from the same family. Thirteen patients (20.3%) underwent HSCT, with a survival rate of 61.5%. CONCLUSION For male children with early onset, poor treatment response, especially those with unexplained splenomegaly and IBD-like symptoms, early genetic testing is recommended. HSCT is a safe and effective treatment for XIAP deficiency. For patients with developmental delay, early onset, and severe IBD phenotype, early transplantation is recommended.
Humans ; Male ; X-Linked Inhibitor of Apoptosis Protein/deficiency* ; Child ; Genetic Diseases, X-Linked/therapy* ; Phenotype ; Siblings ; Retrospective Studies ; Hematopoietic Stem Cell Transplantation

Allogeneic stem cell transplantation (allo-SCT) is currently the only curative option for patients with X-linked agammaglobulinemia (XLA). In this study, patient 1 aged 4 years who underwent allogeneic peripheral blood stem cell transplantation (allo-PBSCT) from HLA-mismatched unrelated donor; patient 2 aged 24 years (childhood onset) with primary cutaneous acral CD8 T cell lymphoma who underwent allo-PBSCT from haploidentical relative donor. Both were treated by reduced toxicity myeloablative conditioning with post-transplantation cyclophosphamide (PTCy), anti-thymocyte globulin (ATG), methotrexate (MTX) and cyclosporine (CsA) for graft-versus-host-disease (GVHD) prophylaxis. In patient 1, neutrophil and platelet engraftment were observed on day 11 post-transplantation; the donor chimerism dropped on day 90 post-transplantation, and recovered on day 150 with donor lymphocyte infusion (DLI). In patient 2, neutrophil and platelet engraftment were observed on days 20 and 87 post-transplantation respectively, with complete donor chimerism on day 30 post-transplantation. The serum levels of IgG, IgM and IgA and the percentage of CD19 B cells in peripheral blood of patients 1 and 2 returned to normal within 2 months and more than 1 year after transplantation respectively. There was no evidence of acute GVHD for the two patients. Patient 1 developed a limited type of skin chronic GVHD after DLI, which disappeared after anti-GVHD treatment. This is the first report of successful treatment for two XLA patients using PTCy with allo-PBSCT from HLA-mismatched unrelated donor or haploidentical donor, combining with improved conditioning, which expands the pool of eligible donors for patients with XLA.
Agammaglobulinemia ; therapy ; Genetic Diseases, X-Linked ; therapy ; Graft vs Host Disease ; HLA Antigens ; Hematopoietic Stem Cell Transplantation ; Humans ; Peripheral Blood Stem Cell Transplantation ; Treatment Outcome ; Unrelated Donors ; Young Adult

This research investigated the clinical features of immunodeficiency disease and the features of the mutation of its pathogenic genes. All 7 patients were boys aged 5 months to 4 years and 6 months and had a history of recurrent respiratory infection and pneumonia, low levels of IgM and IgG, and abnormal absolute values or percentages of lymphocyte subsets. High-throughput sequencing showed c.1684C>T mutations in the BTK gene in patient 1 and IVS8+2T>C splice site mutations in the BTK gene in patient 2. Both of these mutations came from their mothers. Patients 3, 4, and 5 had mutations in the IL2RG gene, i.e., c.298C>T, IVS3-2A>G, and c.164T>A, among which c.164T>A mutations had not been reported. Patient 6 had c.204C>G mutations in the RAG2 gene. Patient 7 had complex heterozygous mutations of c.913C>T and c.824G>A in the RAG2 gene, which came from his father and mother, respectively. Patients with immunodeficiency disease have abnormal immunological indices, and high-throughput sequencing helps to make a definite diagnosis.
Agammaglobulinaemia Tyrosine Kinase ; Agammaglobulinemia ; genetics ; Child, Preschool ; Computational Biology ; DNA-Binding Proteins ; genetics ; Genetic Diseases, X-Linked ; genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Immunologic Deficiency Syndromes ; genetics ; therapy ; Infant ; Interleukin Receptor Common gamma Subunit ; genetics ; Male ; Mutation ; Nuclear Proteins ; genetics ; Protein-Tyrosine Kinases ; genetics

In addition to hearing impairment, syndromic hearing impairment is often accompanied by disorders of urinary, skeletal, muscular, nervous, and ocular systems. Genetic factors have shown to play an important role in the pathogenesis of deafness. Mutations of X-linked genes may cause syndromic hearing impairment. Gene mapping, linkage analysis and next-generation sequencing may facilitate delineation of the pathogenesis of X-linked syndromic hearing impairment. This article reviews recent progress in molecular genetic research on X-linked syndromic hearing impairment, which may shed light for the diagnosis and treatment of these diseases.
Genetic Diseases, X-Linked ; genetics ; Genetic Research ; Hearing Loss ; diagnosis ; genetics ; therapy ; Humans ; Molecular Biology

OBJECTIVETo analyze the clinical and molecular characteristics of patients with X-linked thrombocytopenia (XLT) and their responsiveness to treatment with various doses of corticosteroids or intravenous immunoglobulin (IVIG) separately.

METHODData from 15 XLT patients who were hospitalized in Children's Hospital Affiliated to Chongqing Medical University from March 2010 to July 2014 were analyzed retrospectively, including clinical manifestations, scores, peripheral blood, immunological functions, responses to IVIG and steroid treatment with various doses and duration.

RESULTAll 15 XLT patients met the inclusion criteria and showed microthrombocytopenia with or without mild-to-moderate eczema or minor infections. Platelet counts ranged from (8-80) × 10⁹/L. The platelet volume value ranged between 5.6 and 10.9 fl (normal range: 9.4-12.5 fl). Raised serum IgG was found in 5 cases, while low serum IgG was found in 2 cases. WAS gene analysis revealed missense mutations in 14 patients, including 4 hotspots (V75M, R86C, R86H, R86L) and 1 novel mutation (Y107C). Flow cytometer analysis of 13 patients showed various amounts of WAS protein (WASP) expression, 2 patients had normal amounts of WASP expression, 5 had reduced amounts, and 6 had absent WASP expression. Their responses to individual steroid and IVIG treatment with various doses and duration were also reviewed. Fourteen patients who were misdiagnosed as immune thrombocytopenic purpura at first received 28 courses of steroids and (or) 47 courses of IVIG treatment. The post-treatment platelet counts of 1 000-2 000 mg/(kg × d) IVIG(25 courses) at 2-7 d and 8-14 d time points were (60 ± 10) × 10⁹/L and (41 ± 7) × 10⁹/L, which indicate a significantly better responsiveness than those by [(31 ± 7) × 10⁹/L, (21 ± 2) × 10⁹/L] of 400-500 mg/(kg·d) IVIG(22 courses) (Z = -4.419, -1.592;P = 0.002,0.011). However, there were no significant differences between the responsiveness of 3 doses [1-2 mg/(kg·d)(8 courses), 3-6 mg/(kg·d) (11 courses) and 20-30 mg/(kg × d)(9 courses)] of steroids (F = 0.387,0.252;P = 0.980,0.761) at 2-7 d and 8-14 d time points. The platelet counts gradually decreased to the primary level at 15-30 d after any doses of steroids and (or) IVIG treatment. The effective rate of 1 000-2 000 mg/(kg × d) IVIG treatment was 18/25, which was significantly higher than that (2/22) of 400-500 mg/(kg × d) (χ² = 9.836, P = 0.008). The effective rate of 20-30 mg/(kg × d) steroids treatment (7/9) was relatively higher than 1-2 mg/(kg × d) (4/8) and 3-6 mg/(kg × d) (6/11) with no significant difference (χ⁹ = 3.235, P = 0.581). After the treatment with steroids and /or IVIG 14 cases with hemorrhage were all improved.

CONCLUSIONThe clinical characteristics of X-linked thrombocytopenia were microthrombocytopenia with or without mild-to-moderate eczema or minor infections. WAS gene and WASP analysis were diagnostic methods. There were no significant differences between the responsiveness of 3 doses of steroids; 1 000-2 000 mg/(kg·d) IVIG had a significantly better responsiveness. However, IVIG and steroids with any dose and duration may only transiently increase peripheral platelet level of XLT patients.

Adrenal Cortex Hormones ; administration & dosage ; Child ; Genetic Diseases, X-Linked ; drug therapy ; Humans ; Immunoglobulins, Intravenous ; administration & dosage ; Platelet Count ; statistics & numerical data ; Retrospective Studies ; Thrombocytopenia ; drug therapy ; Treatment Outcome

Congenital adrenal insufficiency is caused by specific genetic mutations. Early suspicion and definite diagnosis are crucial because the disease can precipitate a life-threatening hypovolemic shock without prompt treatment. This study was designed to understand the clinical manifestations including growth patterns and to find the usefulness of ACTH stimulation test. Sixteen patients with confirmed genotyping were subdivided into three groups according to the genetic study results: congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH, n=11), congenital lipoid adrenal hyperplasia (n=3) and X-linked adrenal hypoplasia congenita (n=2). Bone age advancement was prominent in patients with CAH especially after 60 months of chronologic age (n=6, 67%). They were diagnosed in older ages in group with bone age advancement (P<0.05). Comorbid conditions such as obesity, mental retardation, and central precocious puberty were also prominent in this group. In conclusion, this study showed the importance of understanding the clinical symptoms as well as genetic analysis for early diagnosis and management of congenital adrenal insufficiency. ACTH stimulation test played an important role to support the diagnosis and serum 17-hydroxyprogesterone levels were significantly elevated in all of the CAH patients. The test will be important for monitoring growth and puberty during follow up of patients with congenital adrenal insufficiency.
17-alpha-Hydroxyprogesterone/blood ; 46, XY Disorders of Sex Development/drug therapy/*genetics ; Adolescent ; Adrenal Hyperplasia, Congenital/drug therapy/*genetics ; Adrenal Insufficiency/*congenital/diagnosis/drug therapy/genetics ; Adrenocorticotropic Hormone/*metabolism ; Bone Development/genetics ; Child ; Child, Preschool ; DAX-1 Orphan Nuclear Receptor/genetics ; Female ; Genetic Diseases, X-Linked/drug therapy/*genetics ; Genotype ; Glucocorticoids/therapeutic use ; Humans ; Intellectual Disability/complications ; Male ; Mineralocorticoids/therapeutic use ; Obesity/complications ; Phosphoproteins/genetics ; Puberty, Precocious/complications ; Retrospective Studies ; Steroid 21-Hydroxylase/genetics

PURPOSE: X-linked agammaglobulinemia (XLA) is a humoral immunodeficiency disease caused by a mutation in the Bruton tyrosine kinase (BTK) gene resulting in defective B cell differentiation. Because it is a relatively rare disorder, it is difficult for clinicians to have a comprehensive understanding of XLA due to a lack of exposure to the disease. Clinical presentations of patients with XLA were analyzed and discussed to improve care plans. MATERIALS AND METHODS: During a 20 year period, from January 1987 to June 2006, a total of 19 patients were diagnosed as XLA in the Department of Pediatrics at Severance Hospital, Seoul, Korea. A retrospective analysis of the clinical presentations of those patients was performed. RESULTS: The mean age of the XLA patients included in the study was 4.89 years, with a range of 6 months to 13 years. Twelve patients were diagnosed before age 5, while the other 7 patients were diagnosed after age 5. Recurrent infections observed in the patients included pneumonia, acute otitis media, septic arthritis, skin infection, sepsis, sinusitis, acute gastroenteritis, cervical lymphadenitis, epididymitis, meningitis, osteomyelitis, urinary tract infection and encephalitis. Frequency of admissions was variable from 0 to 12 times, depending on the time at which immunoglobulin therapy was started. Six cases had family histories positive for XLA. BTK gene mutations were found in 8 cases. CONCLUSION: The overall prognosis of XLA is good as long as patients are diagnosed and treated early with regular intra venous gamma globulin therapy before the sequelae of recurrent infections appear.
Adolescent ; Agammaglobulinemia/complications/*diagnosis/drug therapy/genetics ; Child ; Child, Preschool ; Genetic Diseases, X-Linked/enzymology/genetics/pathology ; *Hospitals ; Humans ; Infant ; Male ; Protein-Tyrosine Kinases/genetics/metabolism ; Retrospective Studies ; Time Factors

Glycerol kinase deficiency (GKD), a rare X-linked recessive disorder, is classified into two types: isolated and complex. Complex GKD is an Xp21 contiguous gene deletion involving the glycerol kinase locus together with the adrenal hypoplasia congenita (AHC) or Duchenne muscular dystrophy (DMD) loci or both. Its clinical features depend on the involved loci. GKD can be confirmed by an elevated urinary glycerol concentration tested by gas chromatography mass spectrometry (GC/MS). The three cases reported here were all male, presenting symptoms from neonatal period. The predominant clinical profile was characterized by hypoadrenocorticism, glyceroluria and Duchenne muscular dystrophy. After receiving a low fat diet and glucocorticoid replacement, they improved with relieved symptoms of hypoadrenocorticism. But they had significant developmental delays and myasthenia. In the follow-up two of them died of adrenal crisis.
Adrenal Insufficiency ; diagnosis ; Diagnosis, Differential ; Genetic Diseases, X-Linked ; diagnosis ; therapy ; Glycerol ; urine ; Glycerol Kinase ; deficiency ; Humans ; Infant ; Male