Monogenic diseases, a class of hereditary disorders caused by gene mutations, are diverse and have a profound impact. In the pediatric field, stem cell transplantation is emerging as a promising treatment for conditions such as inborn errors of immunity (IEI), very early-onset inflammatory bowel disease (VEO-IBD), and inherited metabolic diseases (IEM). At the 12th Lu Daopei Hematology Forum, Hematology Frontier invited Dr. Xiaowen Zhai from the National Children's Medical Center and Children's Hospital of Fudan University to provide an in-depth analysis of the current state of stem cell transplantation for pediatric monogenic diseases in China and discuss future research directions to advance the field.

Monogenic diseases, also known as Mendelian disorders, are genetic diseases caused by mutations in a single gene on a pair of alleles or homologous chromosomes. These diseases follow Mendel’s laws of inheritance, with clear hereditary patterns. According to available data, more than 8,000 types of human monogenic genetic disorders have been identified, with an overall incidence of about 1%. While a few monogenic disorders can be corrected and treated surgically, most result in death, disability, or deformities and lack effective treatments.

Although the incidence of monogenic diseases is relatively low, it is noteworthy that the carrier rate is relatively high. Research reports suggest that approximately 1 in 16 people may carry a gene for a monogenic disorder. Hence, genetic screening and prenatal diagnosis are particularly important for fetuses at high risk of hereditary diseases.

In the clinical research of pediatric monogenic disease treatments, Dr. Xiaowen Zhai discussed the application and development trends of stem cell transplantation in treating three major conditions: inborn errors of immunity (IEI), very early-onset inflammatory bowel disease (VEO-IBD), and inherited metabolic diseases (IEM).

1. Inborn Errors of Immunity (IEI)

Inborn errors of immunity (IEI) are a group of diseases primarily caused by single-gene mutations that lead to changes in the components and functions of immune cells and molecules. The prevalence of IEI continues to rise, and new mutations in these diseases are a key research focus in international immunology. Currently, the International Union of Immunological Societies (IUIS) classifies IEI into 10 categories (2022 edition): combined immunodeficiencies (CID), immunodeficiency syndromes with characteristic symptoms, antibody immunodeficiencies, immune dysregulation disorders, phagocyte defects, innate immunity deficiencies, autoinflammatory diseases, complement deficiencies, bone marrow failure disorders, and IEI phenocopies.

In 2021, the European Society for Blood and Marrow Transplantation (EBMT) and the European Society for Immunodeficiencies (ESID) issued guidelines on hematopoietic stem cell transplantation (HSCT) for treating severe combined immunodeficiency (SCID) and non-SCID IEI. SCID typically presents with severe infections and impaired immune function, and affected children often die within the first year of life.

A longitudinal study spanning 36 years (1982-2018) involving 902 SCID patients treated with HSCT found that the overall five-year survival rate (OS) was 72%-73% between 1982 and 2009, but improved to 87% between 2010 and 2018. The implementation of newborn screening significantly improved outcomes, with younger age at transplant and the absence of infection at the time of transplantation being the two main factors contributing to better prognosis. Early diagnosis and timely treatment are crucial in improving SCID outcomes.

Studies from the U.S. and Japan show 10-year OS rates of 74% and 67%, respectively, for SCID patients treated with HSCT, with better outcomes for younger patients, those without pre-transplant infections, reduced-intensity conditioning (RIC), and those with fully matched sibling donors (MSD). The EBMT study reported a two-year OS of 81.1%, with no significant differences in prognosis among ADA/X-SCID subtypes, transplant age, or conditioning regimens, although HLA-matched donors and infection-free pre-transplant status were associated with better outcomes.

For non-SCID IEI, not all patients achieve a cure through transplantation, with only some groups experiencing long-term benefits. Chronic granulomatous disease (CGD), a non-SCID IEI, is characterized by recurrent chronic infections, dysregulated inflammation leading to granuloma formation, and other inflammatory diseases. In Western countries, treatment typically focuses on anti-infective therapies rather than transplantation. However, due to the high cost of managing recurrent infections, China and many developing countries generally recommend transplantation. A study comparing 240 CGD patients who underwent HSCT with 151 who did not found improvements in infection, inflammation, and growth development after transplantation. A multicenter study in China reported a three-year OS of 87% for CGD patients post-transplant.

For leukocyte adhesion deficiency (LAD), a retrospective analysis by EBMT showed a three-year OS of 83%, with 84% and 75% for type I and III, respectively. Matched sibling donors (10/10), related unrelated donors, and unrelated donors provided good survival outcomes. Children’s Hospital of Fudan University reported good outcomes in four out of five LAD-I patients who underwent cord blood transplantation.

The clinical manifestations of hyper IgE syndrome (HIES) include eczema-like skin lesions, recurrent respiratory infections, and significantly elevated blood IgE levels. HIES caused by DOCK8 mutations often leads to death from severe infections or malignancies. Allogeneic HSCT is currently the only curative treatment for HIES caused by DOCK8 mutations. HIES can be divided into autosomal dominant (AD-HIES) and autosomal recessive (AR-HIES), with AD-HIES caused by mutations in the STAT3 gene accounting for approximately 60%-70% of cases. A study from Children’s Hospital of Fudan University on HSCT for DOCK8-mutated HIES showed a significant reduction in eosinophils and IgE levels, with effective control of clinical symptoms.

2. Very Early-Onset Inflammatory Bowel Disease (VEO-IBD)

Research has confirmed that dozens of gene mutations are associated with the development of VEO-IBD, with the five most common being IL-10RA, XIAP, CYBB, IL-10RB, and LRBA. Conventional anti-inflammatory drugs, biologics, and surgery can provide partial relief for the disease; however, certain types of VEO-IBD can only be cured through stem cell transplantation. For example, for patients with less than 10% effectiveness from biologics, transplantation can significantly improve outcomes.

In 2015, Children’s Hospital of Fudan University performed China’s first successful umbilical cord blood transplantation for a patient with IL10R deficiency-related VEO-IBD. Subsequent comparisons between transplanted and non-transplanted patients showed that early HSCT, before the onset of lung infections, led to better outcomes. A study involving about 80 transplanted patients in China reported an OS of approximately 65%, while the survival rate for untreated patients was estimated to be only around 10%. HSCT offers a relatively optimistic future for these patients. Additionally, the Nomogram prediction model is being used to assess survival rates early in patient treatment.

3. Inherited Metabolic Diseases (IEM)

Inherited metabolic diseases (IMD), also known as inborn errors of metabolism (IEM), are primarily caused by enzyme deficiencies, which prevent the conversion of substrates into products. This leads to the accumulation of toxic substances upstream, depletion of essential compounds downstream, or abnormal alternative substrate metabolism. These diseases severely affect the lifespan and quality of life of affected children. HSCT has been shown to improve the prognosis of certain IEMs.

Mucopolysaccharidoses (MPS)

MPS is a type of IEM and lysosomal storage disorder (LSD) caused by enzyme deficiencies that prevent the complete degradation of acidic mucopolysaccharides, leading to their accumulation in tissues. This results in progressive multi-organ dysfunction, including developmental delays, skeletal disease, cardiopulmonary complications, and even early death.

In MPS IH (Hurler syndrome), donor leukocytes can provide normal enzymes to prevent early death and reduce multisystem disease. International studies have shown that early transplantation and better HLA-matched donors improve event-free survival (EFS), and umbilical cord blood is highly accessible. Retained cognitive function and younger age at transplant are key factors for post-transplant cognitive development, and normal IDUA levels post-transplant are associated with better prognosis across organ systems. Early referral for transplantation, non-carrier donors, and optimized conditioning regimens improve engraftment and long-term outcomes.

X-Linked Adrenoleukodystrophy (X-ALD)

ALD is an X-linked recessive disorder caused by ABCD1 gene mutations that lead to the accumulation of very long-chain fatty acids in the brain and adrenal glands. Clinical presentations vary, with seven subtypes classified by the Moser criteria, including childhood cerebral ALD and adolescent cerebral ALD.

HSCT is currently the only curative and disease-controlling treatment available for ALD, preventing the progression of early-stage cerebral ALD. However, HSCT does not affect adrenal insufficiency or late-stage spinal cord disease, and late-stage cerebral ALD is considered a contraindication for HSCT due to the risk of disease progression post-transplant. Studies have reported that RIC and umbilical cord blood transplantation improve prognosis, with early transplantation offering more benefits and lower treatment-related mortality.

Globoid Cell Leukodystrophy (GLD)

GLD, also known as Krabbe disease, is caused by mutations in the GALC gene, resulting in a deficiency of galactocerebrosidase and the accumulation of galactocerebrosides and their derivatives in the nervous system, leading to demyelination and neurodegeneration. GLD is classified into early-onset and late-onset forms. Early-onset GLD typically presents within the first six months of life and progresses rapidly, with a median survival of only two years. HSCT provides the greatest therapeutic benefit for asymptomatic patients.

Research shows that transplanting early-onset patients within the first month of life improves prognosis for motor function, communication, and feeding. HSCT also extends the lifespan of late-onset Krabbe disease patients, with greater benefits for those who undergo transplantation before symptoms develop—an estimated 25-year survival rate of 72.5%. The median age of death for untreated patients is 6.72 years, with a projected 13% survival rate by age 11.

Metachromatic Leukodystrophy (MLD)

MLD is caused by mutations in the ARSA gene, leading to arylsulfatase A deficiency, which results in the accumulation of myelin components in the central and peripheral nervous systems, causing demyelination. The clinical manifestations depend on the level of residual enzyme activity. In late-infantile MLD, disease progression is rapid, with children often dying within 2 to 3 years. HSCT has been shown to be ineffective in preventing early disease progression. However, for juvenile and adult patients with early symptoms, HSCT is considered an appropriate treatment option, though peripheral nerve disease responds less well to HSCT.

A JAMA study reported better gross motor and language development and reduced MRI severity in children post-transplant. HSCT stabilizes disease in asymptomatic or early symptomatic patients, though there was no significant difference in OS between transplanted and non-transplanted patients.

Conclusion Stem cell transplantation has been shown to cure several pediatric monogenic disorders. Early diagnosis is crucial for monogenic diseases, as HSCT before organ damage occurs provides the greatest treatment benefits. By rebuilding the patient’s hematopoietic and immune systems, some patients can achieve complete symptom relief. Additionally, novel therapies show promise in treating certain monogenic diseases, offering new hope. As medical technology advances, more innovative treatment methods are expected to be developed to improve outcomes and enhance the quality of life for affected patients.

Dr. Xiaowen Zhai Ph.D. in Medicine, Chief Physician, Ph.D. Supervisor Vice President of Children’s Hospital of Fudan University, Head of Hematology Deputy Director of the National Pediatric and Pediatric Surgery Medical Quality Control Center Vice Chairperson of the National Health Commission’s Expert Committee on Childhood Leukemia Vice Chairperson of the China Maternal and Child Health Association’s Cord Blood Application Professional Committee Vice Chairperson of the Pediatric Committee of the Chinese Research Hospital Association Member of the Hematology Group of the Pediatrics Branch of the Chinese Medical Association Deputy Leader of the Hematology Group of the Pediatrics Branch of the Shanghai Medical Association Executive Director of the Shanghai Anti-Cancer Association Chairperson of the Quality Control Group of the Maternal and Child Health Standards Committee of the China Maternal and Child Health Association Chairperson of the Pediatric Research Group of the Internet Hospital Branch of the Chinese Research Hospital Association

Professor Zhai has led multiple national and provincial scientific research projects, including those funded by the National Natural Science Foundation and the National Key Research and Development Program. She has published over 100 papers as the first or corresponding author and has received several awards, including the Chinese Hospital Association’s Science and Technology Innovation Award, the Soong Ching Ling Pediatric Medicine Award, the Shanghai Medical Science and Technology Award, and the Shanghai Hospital Management Award.