Hyper- IgE syndrome presenting with early life craniosynostosis in monozygotic twin sisters

To the Editor, Autosomal dominant pathogenic variants in signal transducer and activator of transcription 3 (STAT3; OMIM*102582) are implicated in both autosomal dominant hyperIgE syndrome (ADHIES; OMIM*147060) and autosomal dominant autoimmune disease, multisystem, infantileonset type 1 (ADMIO1; OMIM*615952). Gainoffunction variants (GoF) are described to be causative of ADMIO1, whereas dominant negative (DN) variants cause ADHIES.1,2 Indeed, recent articles have demonstrated that heterozygous lossoffunction (LoF) variants underlie ADHIES through a dominant negative effect rather than haploinsufficiency.3 ADHIES results in a syndrome with both hematopoietic and nonhematopoietic features, including a significant issue with bone remodeling.4 HIES can be caused by pathogenic variants in other genes such as IL6R, IL6ST, ZNF341, SPINK5, PGM3, CARD11, TGFBR1, TGRBR2, BCL11B, and ERBB21P.5 STAT3 is a signaling molecule acting downstream of many cytokine receptors. Aberrant transduction of these pathways explains the multisystem manifestations of the syndrome comprising skeletal and connective tissue abnormalities, dermatitis, autoimmunity disorders, pulmonary disease, vasculopathy, and immunodeficiency. Many of the immunological abnormalities, such as high IgE levels, low levels of inflammation, atopy, and recurrent staphylococcal infections, are due to impaired IL6 pathways, a proinflammatory cytokine crucial for Th17 and early stages of T follicular helper (Tfh) cell differentiation.6– 8 A deficiency in Th17, which releases antimicrobial peptides and produce the IL17 cytokine family, is implicated in Staphylococcus aureus, Candida, and gramnegative infections. Thus, decreased IL17 production may explain the predisposition to epithelial and lung infections as keratinocytes and bronchial epithelial cells require IL17A for antistaphylococcal βdefensin secretion.9 In addition, recurrent sinopulmonary infections in association with impaired connective tissue remodeling lead to pulmonary structural abnormalities.8,9 The most consistent laboratory finding in HIES is an elevated serumIgE level (2000– 100,000 IU/mL).9,10 Total immunoglobulin and white blood cell counts are usually normal, although common eosinophilia and relative neutropenia have been observed. Leukocytosis and acute phase reactants often fail to increase in response to infection.10,11 Current therapies include antistaphylococcal antibiotic prophylaxis together with antiseptic washes to prevent dermatological and pulmonary infections and antifungals to treat and prevent mucocutaneous Candida, while moldactive antifungals are considered when parenchymal lung disease is present to prevent aspergillosis.8 Patients with hypogammaglobulinemia and/or functional antibody deficiency or impaired memory immunity can benefit from immunoglobulin replacement therapy.9 Other treatments include Dupilumab, especially for atypical cutaneous manifestations or severe eczema.5,12 Hematopoietic stem cell transplantation also appears promising in immune reconstitution and pulmonary and dermatological symptoms; however, postsuccessful transplant, patients have continued to develop muscular skeletal complications (fractures, scoliosis).8 Craniosynostosis results from the premature closure of one or more sutures of the skull. Craniosynostosis can be nonsyndromic, when it is an isolated finding, or syndromic, i.e., associated with other signs such as anomalies of the face, skeleton, or nervous system and developmental delay. Craniosynostosis can be caused by pathogenic variants in the following genes: FGFR2, FGFR3, FGFR1, TWIST1, TCF12, ERF, ALPL, FBN1, SKI, and EFNB1. Half of the patients with craniosynostosis carry a de novo variant.13,14 Craniosynostosis has been described in some cases with ADHIES,15– 17 as well as Arnold Chiari type 1 malformation.15 Of note, craniosynostosis is more frequent in HIES caused by IL6ST pathogenic variants.18 Craniosynostosis and dental abnormalities are caused by a disturbance in a shared IL6, IL6R./IL11/IL11RA/glycoprotein gp130 (GP130)/STAT3– driven process. Sutural closure depends on the coordinated regulation of the apposition and resorption by osteoblasts and osteoclasts, respectively. Thus, STAT3 deficiency explains the premature, often prenatal fusion of some or several calvarial bones. As a result, the lack of space limits brain growth and the compensatory increase in other sutures causes skull deformation.19 We herein report two patients diagnosed at 5 years of age with ADHIES. Patients were monozygotic twin sisters born at 33 weeks without major complications after a bichorionic, triamniotic pregnancy following in vitro fertilization. Parents and the male triplet were healthy. The twin sisters presented in early infancy with recurrent otitis media with chronic middle ear effusion and pansynostosis presenting with raised intracranial pressure just before 4 years of age. Case 1 developed severe respiratory syncytial virus (RSV) bronchiolitis at 6 months requiring noninvasive ventilation (NIV) with


Hyper-IgE syndrome presenting with early life craniosynostosis in monozygotic twin sisters
To the Editor, Thus, decreased IL-17 production may explain the predisposition to epithelial and lung infections as keratinocytes and bronchial epithelial cells require IL-17A for antistaphylococcal β-defensin secretion. 9 In addition, recurrent sino-pulmonary infections in association with impaired connective tissue remodeling lead to pulmonary structural abnormalities. 8,9 The most consistent laboratory finding in HIES is an elevated serum-IgE level (2000-100,000 IU/mL). 9,10 Total immunoglobulin and white blood cell counts are usually normal, although common eosinophilia and relative neutropenia have been observed.
Leukocytosis and acute phase reactants often fail to increase in response to infection. 10,11 Current therapies include antistaphylococcal antibiotic prophylaxis together with antiseptic washes to prevent dermatological and pulmonary infections and antifungals to treat and prevent mucocutaneous Candida, while mold-active antifungals are considered when parenchymal lung disease is present to prevent aspergillosis. 8 Patients with hypogammaglobulinemia and/or functional antibody deficiency or impaired memory immunity can benefit from immunoglobulin replacement therapy. 9 Other treatments include Dupilumab, especially for atypical cutaneous manifestations or severe eczema. 5,12 Hematopoietic stem cell transplantation also appears promising in immune reconstitution and pulmonary and dermatological symptoms; however, postsuccessful transplant, patients have continued to develop muscular skeletal complications (fractures, scoliosis). 8 Craniosynostosis results from the premature closure of one or more sutures of the skull. Craniosynostosis can be nonsyndromic, when it is an isolated finding, or syndromic, i.e., associated with other signs such as anomalies of the face, skeleton, or nervous system and developmental delay. Craniosynostosis can be caused by pathogenic variants in the following genes: FGFR2, FGFR3, FGFR1, TWIST1, TCF12, ERF, ALPL, FBN1, SKI, and EFNB1. Half of the patients with craniosynostosis carry a de novo variant. 13,14 Craniosynostosis has been described in some cases with AD-HIES, [15][16][17] as well as Arnold Chiari type 1 malformation. 15 Of note, craniosynostosis is more frequent in HIES caused by IL6ST pathogenic variants. 18 Craniosynostosis and dental abnormalities are caused by a disturbance in a shared IL-6, IL6R./IL-11/IL-11RA/glycoprotein gp130 (GP130)/STAT3-driven process. Sutural closure depends on the coordinated regulation of the apposition and resorption by osteoblasts and osteoclasts, respectively. Thus, STAT3 deficiency explains the premature, often prenatal fusion of some or several calvarial bones.
As a result, the lack of space limits brain growth and the compensatory increase in other sutures causes skull deformation. 19 We herein report two patients diagnosed at 5 years of age with AD-HIES. Patients were monozygotic twin sisters born at 33 weeks without major complications after a bichorionic, triamniotic pregnancy following in vitro fertilization. Parents and the male triplet were healthy. The twin sisters presented in early infancy with recurrent otitis media with chronic middle ear effusion and pansynostosis presenting with raised intra-cranial pressure just before  Table 1).
A few weeks after the end of antibiotic treatment for the pulmonary abscess, she had a relapse of pneumonia in the same place, which was treated with oral rifampicine and ciprofloxacin. However, 2 weeks later, she developed a varicella pneumonia and was therefore treated with intravenous ciprofloxacin, rifampicin, and acyclovir. During the same period, she continued to have left ear secretions with a culture positive for Candida albicans and Stenotrophomona.
Case 2 was hospitalized in the intensive care unit at 6 months of age for severe RSV bronchiolitis requiring NIV with continuous positive airway pressure for 3 days. She also had acute pyelonephritis caused by Escherichia coli, treated with 7 days of antibiotics. At 1 year, she had bronchitis. Then, she presented with recurrent otitis media, with a range of bacterial and candida species isolated. She benefited from the insertion of grommets at 3 years and 7 months. At 2 years, she presented with a first episode of pneumonia, which was treated with oral antibiotics. At almost 4 years, she had retrocardiac pneumonia, which was treated with oral antibiotics. She also had recurrent conjunctivitis and identification of papilloedema at 3 years and 9 months, with imaging showing craniosynostosis (see (DHR) and lymphocyte proliferation tests were normal (see Table 1).
Genetic analyses were initiated. , which can also be observed in STAT3 gain-of-function variants. 21 According to the NIH HIES scoring system (https://bsolomon. us/app/hies-score/), 22,23 the two sisters had a score of, respectively, 31 and 34 points (see Table 2), making the diagnosis of HIES very likely.