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P1-96 LigaseIV deficiency syndrome as a cause of...
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ESPE 2015 Poster presented at: 91-P1 Anna Grandone DOI: 10.3252/pso.eu.54espe.2015 Growth Ligase IV deficiency syndrome as a cause of microcephalic primordial dwarfism in dizygotic twins Microcephalic primordial dwarfism (MPD) is a group of rare genetic disorders defined by severe restriction of both pre- and postnatal growth of weight (W), length (L), and particularly head circumference (HC). We report the genetic origin of MPD in dizygotic twins. Next generation exome sequencing, followed by targeted bioinformatics analysis of 19 genes known to be implicated in MPD, was performed in the affected boy. Familial segregation of the identified causative variants was done by Sanger sequencing. Dizygotic twins (a girl and a boy) were born from non-consanguineous healthy parents of normal height. Two older siblings of 4 and 2 years of age were healthy. Harmonious intrauterine growth restriction of both twins was noted starting in the 4 th month of pregnancy and Extensive work-up showed hypogammaglobulinemia and neutropenia. Gonadotropic axis exploration at mini-puberty in the boy showed slightly elevated FSH (7mU/l), normal LH and testosterone and slightly decreased AMH values (122pmol/l), potentially suggesting Sertoli cell insufficiency. Thyroid function tests, growth factors, brain MRI and skeletal x-rays were normal. P1-96 Introduction Method Case report & Results Discussion References: • Murray et al, Extreme growth failure is a common presentation of ligase IV deficiency. Hum Mutat. 2014 Jan;35(1):76-85. • Murray et al, Mutations in the NHEJ Component XRCC4 Cause primordial dwarfism, Am J of Hum Genet, 2015 Mar 5;96(3):412-24. • IJspeert et al, Clinical spectrum of LIG4 deficiency is broadened with severe dysmaturity, primordial dwarfism, and neurological abnormalities. Hum Mutat. 2013 Dec;34(12):1611-4. • van der Burg et al, A new type of radiosensitive T-B-NK+ severe combined immunodeficiency caused by a LIG4 mutation. J Clin Invest. 2006 Jan;116(1):137-45. • O'Driscoll et al, DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell. 2001 Dec;8(6):1175-85. Céline M Girardin 1 , Emmanuelle Ranza 3 , Mirjam Dirlewanger 1 , Philippe Klee 1 , Marianne Caflisch 2 , , Armand Bottani 3 , Valerie M Schwitzgebel 1 1 Pediatric Endocrinology and Diabetology, 2 Department of Pediatrics, 3 Department of Genetic Medicine, University Hospitals of Geneva, Switzerland. Authors have no conflict of interest Lans et al. Epigenetics & Chromatin 2012 Figure 1. Growth parameters at birth. Birth 36 1/7 Boy SD Girl SD Weight (g) 1530 -3.1 1490 -3.1 Length (cm) 41.5 -3.2 40 -3.9 Head circumference (cm) 28 -3.7 26.7 -4.4 Conclusion Ligase IV deficiency syndrome has to be considered in the differential diagnosis of patients with MPD, especially if associated with immune and hematological anomalies. The defect in the NHEJ DNA repair pathway is responsible for a constitutive hypersensitivity to ionizing radiations and a possible increased risk of cancer. Early diagnosis (and avoidance of non strictly indicated Xray imaging) is thus important, as it makes long-term follow-up mandatory. Figure 3. A: Schematic of the LIG4 gene. B: Position of the mutated loci. C: Genotype-phenotype correlation according to Murray et al, Human Mutation, 2013. p.(Leu774Pro) Figure 2. Weight, Length and Head circumference charts of both twins. Figure 4. DNA double-strand breaks repair : NHEJ pathway Both twins developed feeding difficulties and were hospitalized at the age of 5 months to investigate their growth failure. W, L and HC were well below -2SD (Fig. 2). Examination showed alert and non sick-looking babies with a similar round face, thin lips and a high-pitched voice. Penile length in the boy was 1 cm. Enteral nutrition through gastrostomy allowed weight gain and some statural catch-up growth (Fig 2). was confirmed at birth (Fig. 1). Genetic investigations revealed normal blood standard karyotype and array-CGH (180K). Exome sequencing of 19 candidate genes known to be implicated in MPD showed compound heterozygous mutations of LIG4 (chromosome 13) in both twins (Fig.3B) : - c.2321T>C, p.(Leu774Pro): previously undescribed “late” missense mutation. - c.2440C>T, p.(Arg814*): recurrent common “late” truncating mutation. The parents were heterozygous carriers of one of the respective mutations. Ligase IV is an enzyme of the nonhomologous end- joining (NHEJ) pathway which is implicated in the repair of DNA double-strand breaks (Fig. 4). Complexing with XLF and XRCC4 proteins, it joins DNA ends. Both of the mutated loci are located in the XRCC4 binding domain (Fig. 3). Ligase IV is also implicated in the V(D)J recombination of T and B cells, leading to the highly diverse repertoire of immunoglobulins and T cell receptors. To date, 28 cases of ligase IV deficiency have been reported. Major clinical features are: severe prenatal and postnatal growth restriction (W, L and HC), possible severe immunodeficiency, bone marrow failure and radiation hypersensitivity leading potentially to lympho-reticular malignancies. Other inconstant characteristics include feeding difficulties and hypergonadotropic hypogonadism which was reported in two girls who had reached age of puberty. Murray et al. established a genotype / phenotype correlation based on the combination and position of the causative mutations (Fig 3C). A B C
Transcript of P1-96 LigaseIV deficiency syndrome as a cause of...
ESPE
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Poster presented at:
91-P1Anna Grandone DOI: 10.3252/pso.eu.54espe.2015
Growth
Ligase IV deficiency syndrome as a cause of microcephalic primordial dwarfism in dizygotic twins
Microcephalic primordial dwarfism (MPD) is a group of raregenetic disorders defined by severe restriction of both pre- andpostnatal growth of weight (W), length (L), and particularly headcircumference (HC).We report the genetic origin of MPD in dizygotic twins.
Next generation exome sequencing, followed by targetedbioinformatics analysis of 19 genes known to be implicated inMPD, was performed in the affected boy. Familial segregation ofthe identified causative variants was done by Sanger sequencing.
Dizygotic twins (a girl and a boy) were bornfrom non-consanguineous healthy parentsof normal height. Two older siblings of 4and 2 years of age were healthy.Harmonious intrauterine growthrestriction of both twins was noted startingin the 4th month of pregnancy and
Extensive work-up showed hypogammaglobulinemia and neutropenia.Gonadotropic axis exploration at mini-puberty in the boy showed slightly elevatedFSH (7mU/l), normal LH and testosterone and slightly decreased AMH values(122pmol/l), potentially suggesting Sertoli cell insufficiency. Thyroid function tests,growth factors, brain MRI and skeletal x-rays were normal.
P1-96
Introduction Method
Case report & Results
Discussion
References:• Murray et al, Extreme growth failure is a common presentation of ligase IV deficiency. Hum Mutat. 2014 Jan;35(1):76-85.• Murray et al, Mutations in the NHEJ Component XRCC4 Cause primordial dwarfism, Am J of Hum Genet, 2015 Mar 5;96(3):412-24.• IJspeert et al, Clinical spectrum of LIG4 deficiency is broadened with severe dysmaturity, primordial dwarfism, and neurologicalabnormalities. Hum Mutat. 2013 Dec;34(12):1611-4.
• van der Burg et al, A new type of radiosensitive T-B-NK+ severe combined immunodeficiency caused by a LIG4 mutation. J ClinInvest. 2006 Jan;116(1):137-45. • O'Driscoll et al, DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell. 2001 Dec;8(6):1175-85.
Céline M Girardin1, Emmanuelle Ranza3, Mirjam Dirlewanger1, Philippe Klee1, Marianne Caflisch2, , Armand Bottani3, Valerie M Schwitzgebel11Pediatric Endocrinology and Diabetology, 2 Department of Pediatrics, 3Department of Genetic Medicine, University Hospitals of Geneva, Switzerland.
Authors have no conflict of interest
Lans et al. Epigenetics & Chromatin 2012
Figure 1. Growth parameters at birth.Birth 36 1/7 Boy SD Girl SD
Weight (g) 1530 -3.1 1490 -3.1
Length (cm) 41.5 -3.2 40 -3.9
Head circumference (cm) 28 -3.7 26.7 -4.4
ConclusionLigase IV deficiency syndrome has to be considered in the differential diagnosis of patients with MPD, especially if associatedwith immune and hematological anomalies. The defect in the NHEJ DNA repair pathway is responsible for a constitutivehypersensitivity to ionizing radiations and a possible increased risk of cancer. Early diagnosis (and avoidance of non strictlyindicated Xray imaging) is thus important, as it makes long-term follow-up mandatory.
Figure 3. A: Schematic of the LIG4 gene. B: Position of the mutated loci. C: Genotype-phenotype correlation according to Murray et al, Human Mutation, 2013.
p.(Leu774Pro)
Figure 2. Weight, Length and Head circumference charts of both twins.
Figure 4. DNA double-strandbreaks repair : NHEJ pathway
Both twins developed feeding difficulties and were hospitalized at the age of 5months to investigate their growth failure. W, L and HC were well below -2SD (Fig.2). Examination showed alert and non sick-looking babies with a similar round face,thin lips and a high-pitched voice. Penile length in the boy was 1 cm. Enteral nutritionthrough gastrostomy allowed weight gain and some statural catch-up growth (Fig 2).
was confirmed at birth (Fig. 1).
Genetic investigations revealed normal blood standard karyotype and array-CGH (180K). Exome sequencing of 19 candidate genes known to be implicated in MPD showed compound heterozygous mutations of LIG4 (chromosome 13) in both twins (Fig.3B) : - c.2321T>C, p.(Leu774Pro): previously undescribed “late” missense mutation.- c.2440C>T, p.(Arg814*): recurrent common “late” truncating mutation.The parents were heterozygous carriers of one of the respective mutations.
Ligase IV is an enzyme of the nonhomologous end-joining (NHEJ) pathway which is implicated in the repair ofDNA double-strand breaks (Fig. 4). Complexing with XLFand XRCC4 proteins, it joins DNA ends. Both of the mutatedloci are located in the XRCC4 binding domain (Fig. 3).Ligase IV is also implicated in the V(D)J recombination of Tand B cells, leading to the highly diverse repertoire ofimmunoglobulins and T cell receptors.To date, 28 cases of ligase IV deficiency have beenreported. Major clinical features are: severe prenatal andpostnatal growth restriction (W, L and HC), possible severeimmunodeficiency, bone marrow failure and radiationhypersensitivity leading potentially to lympho-reticularmalignancies. Other inconstant characteristics includefeeding difficulties and hypergonadotropic hypogonadismwhich was reported in two girls who had reached age ofpuberty. Murray et al. established a genotype / phenotypecorrelation based on the combination and position of thecausative mutations (Fig 3C).
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