An infant with X-linked anhidrotic ectodermal dysplasia with immunodeficiency presenting with Pneumocystis pneumonia: A case report.

Pneumocystis jirovecii pneumonia associated with primary immunodeficiency should be considered in infants with slowly progressing cyanosis, even without fever or respiratory symptoms. Genetic counseling is crucial for incontinentia pigmenti families in advance of pregnancy because lethal infections can occur before the diagnosis of X-linked anhidrotic ectodermal dysplasia with immunodeficiency.

Case Report: Analysis of Preserved Umbilical Cord Clarified X-Linked Anhidrotic Ectodermal Dysplasia With Immunodeficiency in Deceased, Undiagnosed Uncles.

Family history is one key in diagnosing inborn errors of immunity (IEI); however, disease status is difficult to determine in deceased relatives. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is one of the hyper IgM syndromes that is caused by a hypomorphic variant in the nuclear factor kappa beta essential modulator. We identified a novel IKBKG variant in a 7-month-old boy with pneumococcal rib osteomyelitis and later found that his mother has incontinentia pigmenti. Genetic analysis of preserved umbilical cords revealed the same variant in two of his deceased maternal uncles. Analysis of preserved umbilical cord tissue from deceased relatives can provide important information for diagnosing IEI in their descendants.

Recurrent fever, bulging fontanelle and elevated white blood cell / 中华实用儿科临床杂志

This patient presented with fever,seizure and bulging fontanelle when he was 6-month-old.According to the investigations,white blood cell (WBC),erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) increased significantly,and Streptococcus Pneumonia grew in both blood and cerebrospinal fluid (CSF).He responded to standard antibiotic treatment poorly even it lasted long enough.At the same time,the inflammation seemed to be over-activated,the WBC level was still elevated,high fever continued.Thus they thought of primary immunodeficiency and sent blood sample for gene panel testing (Sanger sequencing) but got negative result.At last,they added steroid together with anti-tuberculosis drug therapy,his temperature as well as the intracranial pressure became better ever since.At the age of 1 year and 1 month,he got another Streptococcus Pneumonia meningitis,while he was still on anti-tuberculosis drug therapy and tapering off steroid.At this time,he presented with coarse hair,hypohidrosis and delayed eruption of teeth,which strongly indicated Anhidrotic Ectodermal Dysplasia with Immunodeficiency (EDA-ID).NEMO is the most common gene responsible for EDA-ID and locates on X chromosome.It has a pseudogene named IKBKGP which locates downstream of NEMO.IKBKGP and NEMO share 3-10 exons with the homology of 99.8％,which makes it difficult to find out most real mutations within NEMO with Sanger sequencing.Then they performed PCR with the primer starting upstream of the shared exons.Finally,they found out the pathogenic mutation [c.505G ＞ C(p.A169P)] of NEMO,which has been reported.This finding led us to make the right diagnosis as well as the proper treatment and the prognosis for this patient.

NEMO Links Nuclear Factor-κB to Human Diseases.

The nuclear factor (NF)-κB essential modulator (NEMO) is a key regulator in NF-κB-mediated signaling. By transmitting extracellular or intracellular signals, NEMO can control NF-κB-regulated genes. NEMO dysfunction is associated with inherited diseases such as incontinentia pigmenti (IP), ectodermal dysplasia, anhidrotic, with immunodeficiency (EDA-ID), and some cancers. We focus on molecular studies, human case reports, and mouse models emphasizing the significance of NEMO molecular interactions and modifications in health and diseases. This knowledge opens new opportunities to engineer suitable drugs that may putatively target precise NEMO functions attributable to various diseases, while leaving other functions intact, and eliminating cytotoxicity. Indeed, with the advent of novel gene editing tools such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas)9, treating some inherited diseases may in the long run, become a reality.

Immunodeficiency in Two Female Patients with Incontinentia Pigmenti with Heterozygous NEMO Mutation Diagnosed by LPS Unresponsiveness.

PURPOSE: Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) is caused by mutations in the NF-κB essential modulator (NEMO) or NF-κB inhibitor, alpha (IKBA) genes. A heterozygous NEMO mutation causes incontinentia pigmenti (IP) in females, while a hemizygous hypomorphic mutation of NEMO causes EDA-ID in males. In general, immunodeficiency is not shown in IP patients. Here, we investigated two female patients with IP and immunodeficiency. METHODS: The patients were initially suspected to have IRAK4 deficiency and Mendelian susceptibility to mycobacterial disease, respectively, because of recurrent pneumonia with delayed umbilical cord detachment or disseminated mycobacterial infectious disease. We measured tumor necrosis factor (TNF)-α production and performed mutation screening. RESULTS: The TNF-α production from lipopolysaccharide (LPS)-stimulated CD14-positive cells was partially defective in both female patients. A genetic analysis showed them to carry the heterozygous NEMO mutations c.1167_1168insC or c.1192C>T. Although NEMO mutations in IP patients are typically eliminated by X-inactivation skewing, an analysis of cDNA obtained from the somatic cells of the patients showed the persistence of these mutations in peripheral blood mononuclear cells and peripheral granulocytes. A NF-κB reporter gene analysis using NEMO-deficient HEK293 cells showed the loss of NF-κB activity in these NEMO mutants, while the NF-κB protein expression levels by the NEMO mutants were consistent with those of wild-type NEMO. CONCLUSIONS: The delayed skewing of the mutant allele may be responsible for the observed innate immune defect in these patients. The detection of LPS unresponsiveness is suitable for identifying female IP patients with immunodeficiency.