A novel mutation in a family with DNA ligase IV deficiency syndrome

Abstract

DNA ligase IV deficiency syndrome (LIG4 syndrome) is a rare autosomal recessive disorder characterized by microcephaly, growth retardation, low birth weight, dysmorphic facial findings, immunodeficiency, pancytopenia, and radiosensitivity due to impaired repair of DNA double-strand breaks by non-homologous end-joining. Herein, we report two siblings with LIG4 syndrome with a novel mutation. One of the siblings, who had normocellular marrow, had autologous reconstitution after initial non-myeloablative conditioning and underwent successful second hematopoietic stem cell transplantation after conditioning with busulfan, cyclophosphamide, and anti-thymocyte globulin. Our findings indicate that transplantation with myeloablative conditioning can be used successfully in LIG4 syndrome patients.

Novel compound heterozygous DNA ligase IV mutations in an adolescent with a slowly-progressing radiosensitive-severe combined immunodeficiency

“…However, his clinical profile was milder than predicted, in that there was only a mild infection without hematological malignancies, and pancytopenia advanced only after 17 years of age. The findings that our patient had already shown hypocellular bone marrow at the first visit (Fig 1, C) and progressed to pancytopenia and hypogammaglobulinemia over one year (Table 1) There have been eight reports of cases with LIG4 syndrome that received HSCT [13,14,27,[30][31][32].…”

“…However, there have recently been reports of successful HSCT in cases with LIG4 syndrome [14,27,31,32]. Among four successful cases, two cases were treated some months after…”

“…In this case, immunodeficiency was milder than in our case. In a recent report of a 10-year-old case, HSCT was performed twice from an HLA-matched father donor due to autologous reconstitution [32]. In this case, the LIG4 mutation caused a p.588delK variant at the border of the enzymatic domain, which retained ligase activity and caused no lethal infections.…”

Dubowitz Syndrome Is a Complex Comprised of Multiple, Genetically Distinct and Phenotypically Overlapping Disorders

“…Most patients with LIG4 mutations had dysmorphic features (“Seckel-like” facies, epicanthal folds, up- or down-slanted palpebral fissures), IUGR, microcephaly, short stature and developmental delay, although not all [23], [29], [31]. In older patients, endocrine problems were common: hypogonadism, hypothyroidism, amenorrhea, and diabetes (Table S5).…”

Two hits in one: whole genome sequencing unveils LIG4 syndrome and urofacial syndrome in a case report of a child with complex phenotype

“…After this first leukemia patient, several other patients have been identified with LIG4 deficiency and lymphoproliferation or lymphoid malignancies: EBV associated B cell lymphoma in two patients [6, 7] and acute T cell leukemia in another patient [8]. Two additional series of patients have been shown to exhibit developmental delay and microcephaly along with mild degrees of immunodeficiency [6, 8–10] and SCID, respectively [7, 11–13]. Recently Murray et al [14] updated these published 15 cases with an additional report of 10 LIG4 deficient cases from 9 families all sharing a similar phenotype (extreme growth retardation, microcephaly and mild immunodeficiency) and genotype (recurrence of p.R278H mutation in heterozygosity with a second variable mutation).…”