Immunodeficiency, Centromeric Region Instability, Facial Anomalies Syndrome 1

Kalyani Srinivas¹, Prajnya Ranganath², Palle Sreelekha³, Kalivela Santhimayee⁴, Shaik Mahin⁵ https://orcid.org/0000-0001-9695-4615

^1,3–5Department of Pediatrics, Institute of Women and Child Health, Niloufer Hospital, Hyderabad, Telangana, India

²Department of Medical Genetics, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India

Corresponding Author: Shaik Mahin, Department of Pediatrics, Institute of Women and Child Health, Niloufer Hospital, Hyderabad, Telangana, India, Phone: +91 7207235057, e-mail: skmahin04b1@gmail.com

Received on: 05 July 2022; Accepted on: 02 October 2022; Published on: 14 December 2023

ABSTRACT

The immunodeficiency, centromeric region instability, facial anomalies (ICF) syndrome is a rare autosomal recessive disease characterized by facial dysmorphism, immunoglobulin deficiency, and centromeric instability. We describe a 14-month-old female child with recurrent infections, facial anomalies, and psychomotor retardation. The child had recurrent admissions for fever, cough, and cold—7 times and required intensive care unit (ICU) stay for pneumonia twice at 4 and 9 months of age, urinary tract infection at 4 months of age, febrile seizures at 9 months of age, and left otitis media at 13 months of age. Serum immunoglobulin G (IgG), IgA, and IgM deficiency levels were low. Further evaluation for immunodeficiency revealed a homozygous variant in the deoxyribonucleic acid methyltransferase 3B (DNMT3B) gene at exon 22 c.2401T>C variant.

How to cite this article: Srinivas K, Ranganath P, Sreelekha P, et al. Immunodeficiency, Centromeric Region Instability, Facial Anomalies Syndrome 1. Pediatr Inf Dis 2023;5(4):129–131.

Source of support: Nil

Conflict of interest: None

Patient consent statement: The author(s) have obtained written informed consent from the patient’s parents/legal guardians for publication of the case report details and related images.

Keywords: Case report, Facial dysmorphism, Primary immune deficiency

INTRODUCTION

The immunodeficiency, centromeric region instability, facial anomalies syndrome (ICF) is a rare autosomal recessive disease. It has been documented in approximately 50 patients worldwide. The syndrome is defined by a combination of immunodeficiency (though B cells are present), facial anomalies, and centromeric instability.¹

Most common presenting symptoms are recurrent infections in early childhood. The syndrome manifests with a multitude of symptoms, such as mild facial dysmorphism, stunted growth, inadequate development, and impaired psychomotor abilities. Diminished levels of immunoglobulin G (IgG), IgE, IgM, and/or IgA in the serum are observed, although the specific subtype of immunoglobulin deficiency may vary.

The ICF syndrome is primarily caused by mutations in genes that are involved in deoxyribonucleic acid (DNA) methylation. The most common mutations are found in the DNA methyltransferase 3B (DNMT3B) gene, located on chromosome 20, giving rise to a subtype known as ICF1. In case of ICF2, the mutation takes place in the ZBTB24 gene located on chromosome 6. ZBTB24 acts as a transcription factor, performing regulatory functions in gene expression, and works in conjunction with DNMT3B to regulate DNA methylation. Notably, patients with ICF2 exhibit a phenotype that is similar to that of individuals with ICF1. The defining characteristic of ICF syndrome is the presence of a persistent attribute of restricted DNA hypomethylation. This phenomenon is frequently attributed to mutations found in one of the DNA methyltransferase genes, most notably DNMT3B.²

The treatment approach for ICF syndrome is primarily supportive and tailored to address the specific clinical and immunological challenges faced by each individual patient. One of the key interventions involves regular monthly infusions of immunoglobulins to manage the immunologic problems associated with the syndrome. This mechanism aids in counterbalancing the diminished levels of immunoglobulins (IgG, IgM, IgE, and/or IgA) typically detected in individuals affected by ICF syndrome.³

Allogeneic hematopoietic cell transplantation (HCT) in patients with severe disease corrects the immunodeficiency and improves growth.

CASE DESCRIPTION

A 14-month-old female child born of third-degree consanguinity, full term with history of recurrent admissions for fever, cough, cold—7 times, and intensive care unit (ICU) stay twice at 4 and 9 months of age for pneumonia, urinary tract infection at 4 months of age, febrile seizures at 9 months of age, and left otitis media at 13 months of age. There was a family history of early neonatal deaths in two male siblings and one maternal male cousin.

At 13 months of age, a detailed assessment was conducted due to recurring infections. The results of immunological investigations demonstrated the presence of hypogammaglobulinemia, which is characterized by diminished levels of IgG and IgA in the serum. Flow cytometry analysis detected low levels of CD19, CD16, and CD56 cells. Child had facial dysmorphism—bilateral medial epicanthic folds and hypertelorism. She had borderline psychomotor developmental delay with a developmental quotient of 85% (Fig. 1).

Fig. 1: Image of patient

INVESTIGATIONS

Investigations include complete hemogram with an increased total leukocyte count of 19,600 with differential count—neutrophils 32%, lymphocytes 63%, monocytes 3%, eosinophils 2%; normal renal, and liver function tests. Thyroid profile was normal. All cultures, including blood and urine, were negative. Ultrasonography of the neck revealed multiple small-enlarged lymph nodes in neck, ultrasonography of the abdomen was normal.

The two-dimensional (2D) echo was normal.

Serum immunoglobulin analysis detected low levels of IgG at 203 mg/dL (700–1600), IgA at <10 mg/dL (70–400), and IgM at 6 mg/dL (40–230).

Lymphocyte subset analysis revealed low CD19⁺ (B cells) at 13.4% (16–35%) and low CD16⁺, CD56⁺ [natural killer (NK) cells] at 2% (3–15%). Dihydrorhodamine (DHR) assay was normal.

To identify potential disease-associated mutations in the patient, whole-exome sequencing was carried out for genetic testing purposes. This involved the comprehensive sequencing of the protein-coding regions of the genome. Remarkably, a homozygous variant was detected in the DNMT3B gene. This variant involves a T > C substitution, specifically at position c.2401 on exon 22 of the gene. Based on the observed phenotype and in silico predictions, this variant is classified as “likely pathogenic” and is considered to have a disease-causing impact.

Monthly intravenous immunoglobulin (IVIG) infusions were given to the child after the diagnosis of ICF was established.

The child improved with IVIG infusion and supportive treatment and is under regular monitoring and follow-up.

DISCUSSION

The ICF syndrome is an uncommon autosomal recessive disease. Since its initial description in the late 1970s, only around 50 patients have been reported worldwide. A characteristic feature observed in ICF patients is the hypomethylation of a small portion of the genome. This can be attributed to mutations in the DNMT3B gene, predominantly occurring as a homozygous mutation in some affected individuals, which encodes for the DNMT3B enzyme. DNA methylation plays a pivotal role in the regulation of gene expression, embryonic development, and the preservation of chromosomal stability. As a consequence, mutations in the DNMT3B gene that reduce its enzymatic activity lead to widespread DNA hypomethylation throughout the genome.

In a study conducted by Jin et al., global gene expression patterns were investigated in individuals afflicted with ICF syndrome. The analysis revealed changes in the expression of 778 genes, many of which are crucial for immune function, development, and neurogenesis. These findings are in line with the clinical manifestations observed in individuals with ICF syndrome, which include combined immunodeficiency, chromosomal pericentromeric anomalies, mild facial dysmorphism, and psychomotor retardation.

Through homozygosity mapping, the genetic locus for ICF syndrome was successfully identified and localized to the region 20q11-q13. The remarkable discovery from this study was the identification of frequent mutations in the DNMT3B gene among individuals with ICF syndrome. These mutations predominantly occur in the C-terminal region of the DNMT3B protein, which includes the catalytic domain. Notably, a significant number of these mutations are missense mutations, where a single nucleotide change leads to the incorporation of a different amino acid into the protein sequence.

These mutations in DNMT3B lead to a loss of DNA methyltransferase activity, which is the underlying cause of ICF syndrome. In your study, a homozygous variant was specifically identified in exon 22 of the DNMT3B gene, involving a nucleotide substitution from T to C at position c.2401.

Patients with ICF syndrome, including those without identified mutations in DNMT3B, consistently exhibit hypomethylation in major DNA regions, specifically 1qh and 16qh (referred to as classical satellite 2 DNA), as well as 9qh (referred to as classical satellite 3 DNA), in various tissues and B-cell lines. Additionally, these individuals display chromosomal abnormalities at 1qh and 16qh in cells when stimulated by mitogens.

The DNMT3B mutations leading to reduced enzymatic activity have a significant impact on specific regions of heavily mutated DNA in individuals affected by ICF syndrome. Notably, the heterochromatin regions of chromosomes 1, 9, and 16 exhibit a higher frequency of hypermethylated regions compared to other genomic regions. Moreover, these chromosomes possess longer heterochromatin regions, making them more vulnerable to breakage.

The hypomethylation of heterochromatin regions contributes to chromosomal breaks and subsequent rejoining, resulting in the formation of multi-radial configurations with multiple p and q arms. Chromosomal abnormalities involving the 1qh and/or 16qh regions are considered characteristic features of ICF1 syndrome.

These specific chromosomal changes are highly characteristic of the disorder and are used as confirmatory diagnostic markers for ICF1. Detection of such abnormalities through cytogenetic or molecular genetic testing can help in definitively diagnosing ICF syndrome, especially ICF1 subtype, in patients with the clinical features associated with the condition. In individuals with ICF syndrome, even though B cells are present, immunodeficiency typically leads to severe recurrent infections, which commonly manifest in early childhood and often serve as the initial presenting symptom. Respiratory infections of a severe nature are nearly ubiquitous among ICF patients, while over half of them experience recurrent gastrointestinal infections. The extent of immunodeficiency varies among ICF patients, ranging from agammaglobulinemia to a mild reduction in immune response.

The majority of patients with ICF syndrome exhibit a deficient immune response characterized by low or undetectable levels of IgA, IgG, and/or IgM, although the specific nature of the immunodeficiency can vary.

The ICF syndrome is characterized by distinctive facial features, including a broad and flat nasal bridge, widely spaced eyes (hypertelorism), and the presence of epicanthic folds (as observed in our case). Less commonly, but still frequently associated with the syndrome, are micrognathia (a small jaw), low-set ears, and macroglossia.

Approximately one-third of patients present with mental retardation, while around one-fifth of patients exhibit neurologic defects. These neurologic defects manifest as delayed cognitive and motor development, along with psychomotor impairment characterized by an unsteady gait and decreased muscle tone (muscle hypotonia) (Table 1).

**Table 1:** Comparison between a typical ICF 1 syndrome and our hospital case
Typical ICF1 syndrome	Features seen in our child
Immunodeficiency—recurrent infections in early childhood with variable immunoglobulin deficiency	Immunodeficiency-recurrent infections in early childhood with IgG, IgA, and IgM immunoglobulin deficiency
Majority have mutation in DNMT3B gene	A homozygous variant was identified in the DNMT3B gene which was a T > C substitution at position c.2401 on exon 22
The typical facial features are a broad flat nasal bridge, hypertelorism (very widely spaced eyes), and epicanthic folds	Facial dysmorphism features in this child were bilateral medial epicanthic folds and hypertelorism
Mental retardation and neurologic defects have been seen in about one-third and one-fifth of the patients, respectively, and include slow cognitive and motor development and psychomotor impairment (ataxic gait and muscle hypotonia)	Borderline psychomotor developmental delay with a developmental quotient of 85%

Opportunistic infections or pulmonary infections are commonly cited as the primary causes of mortality in individuals with ICF syndrome. Children who experience gastrointestinal complications leading to persistent diarrhea and failure to thrive generally have a bleak prognosis. However, in instances where combined-type immunodeficiency is absent, the overall clinical trajectory tends to be more favorable.

ORCID

Shaik Mahin https://orcid.org/0000-0001-9695-4615

REFERENCES

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2. Bemanian MH, Arshi S, Nabavi M, et al. Immunodeficiency, centromeric region instability, and facial anomalies syndrome (ICF) in a boy with variable clinical and immunological presentations. Iran J Allergy Asthma Immunol 2021;20(2):249–254. DOI: 10.18502/ijaai.v20i2.6058

3. Kamae C, Imai K, Kato T, et al. Clinical and immunological characterization of ICF syndrome in Japan. J Clin Immunol 2018;38(8):927–937. DOI: 10.1007/s10875-018-0559-y

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