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Dubowitz syndrome is a complex comprised of multiple, genetically distinct and phenotypically overlapping disorders.

Stewart DR, Pemov A, Johnston JJ, Sapp JC, Yeager M, He J, Boland JF, Burdett L, Brown C, Gatti RA, Alter BP, Biesecker LG, Savage SA - PLoS ONE (2014)

Bottom Line: Western blotting showed an absence of a ligase IV band in both siblings.In the third patient, array SNP genotyping revealed a de novo ∼ 3.89 Mb interstitial deletion at chromosome 17q24.2 (chr 17:62,068,463-65,963,102, hg18), which spanned the known Carney complex gene PRKAR1A.Our work suggests that, in addition to dyskeratosis congenita, LIG4 and 17q24.2 syndromes also feature shortened telomeres; to confirm this, telomere length testing should be considered in both disorders.

View Article: PubMed Central - PubMed

Affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, United States of America.

ABSTRACT
Dubowitz syndrome is a rare disorder characterized by multiple congenital anomalies, cognitive delay, growth failure, an immune defect, and an increased risk of blood dyscrasia and malignancy. There is considerable phenotypic variability, suggesting genetic heterogeneity. We clinically characterized and performed exome sequencing and high-density array SNP genotyping on three individuals with Dubowitz syndrome, including a pair of previously-described siblings (Patients 1 and 2, brother and sister) and an unpublished patient (Patient 3). Given the siblings' history of bone marrow abnormalities, we also evaluated telomere length and performed radiosensitivity assays. In the siblings, exome sequencing identified compound heterozygosity for a known rare nonsense substitution in the nuclear ligase gene LIG4 (rs104894419, NM_002312.3:c.2440C>T) that predicts p.Arg814X (MAF:0.0002) and an NM_002312.3:c.613delT variant that predicts a p.Ser205Leufs*29 frameshift. The frameshift mutation has not been reported in 1000 Genomes, ESP, or ClinSeq. These LIG4 mutations were previously reported in the sibling sister; her brother had not been previously tested. Western blotting showed an absence of a ligase IV band in both siblings. In the third patient, array SNP genotyping revealed a de novo ∼ 3.89 Mb interstitial deletion at chromosome 17q24.2 (chr 17:62,068,463-65,963,102, hg18), which spanned the known Carney complex gene PRKAR1A. In all three patients, a median lymphocyte telomere length of ≤ 1st centile was observed and radiosensitivity assays showed increased sensitivity to ionizing radiation. Our work suggests that, in addition to dyskeratosis congenita, LIG4 and 17q24.2 syndromes also feature shortened telomeres; to confirm this, telomere length testing should be considered in both disorders. Taken together, our work and other reports on Dubowitz syndrome, as currently recognized, suggest that it is not a unitary entity but instead a collection of phenotypically similar disorders. As a clinical entity, Dubowitz syndrome will need continual re-evaluation and re-definition as its constituent phenotypes are determined.

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Frontal view of Patient 3 at age 15 years.He was originally diagnosed with Dubowitz syndrome and was determined to harbor a 3.89 Mb deletion on chromosome 17q24.2. Dysmorphic features include bilateral upslanted palpebral fissures with apparent telecanthus, broad nasal bridge and a bulbous nose.
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pone-0098686-g003: Frontal view of Patient 3 at age 15 years.He was originally diagnosed with Dubowitz syndrome and was determined to harbor a 3.89 Mb deletion on chromosome 17q24.2. Dysmorphic features include bilateral upslanted palpebral fissures with apparent telecanthus, broad nasal bridge and a bulbous nose.

Mentions: He was initially evaluated at age 15 years at the NIH. His height was 142.5 cm (<3rd centile; 50th centile for 11 years), weight was 39.4 kg (<3rd centile; 50th centile for 11.5 years), and OFC was 54 cm (∼25th centile). He appeared anxious with near-continuous teeth grinding and unintelligible speech. There were bilaterally upslanted palpebral fissures with apparent telecanthus. His outer canthal distance was 9.5 cm, inner canthal distance 3.7 cm, inner pupillary distance 6.25 cm (∼90th centile). The palpebral fissures lengths were 2.9 cm (−1 standard deviation). His eyebrows were full with no arching or synophrys. He had a broad nasal bridge. He had a bulbous nose. There was freckling across his nose and under his eyes. His ears were normally formed but somewhat low-set and posteriorly rotated, with a length of 5.5 cm (−1.5 standard deviations); see Figures 3 and 4. Overall, his skin had the appearance of cutis marmorata telangiectasia congenita (Figure 5). Cardiopulmonary exam was normal. The abdominal exam was normal except for a left upper quadrant surgical scar and PEG tube scar. He was tanner IV with bilaterally descended testes and a sacral dimple. He had tapered fingers and a slight resting hand tremor. Third finger length bilaterally was 6 cm (<3rd centile; 50th centile for 8-year-old); right hand length was 14 cm (<3rd centile; 50th centile for 7.5 year old) and left hand length was 15 cm (<3rd centile; 50th centile for 9-year-old). He had bilateral 2–3 cutaneous toe syndactyly. Ophthalmology consultation showed mild intermittent exotropia. An abdominal ultrasound was unremarkable. At a chronological age of 14 years, 11 months, a bone age from the left hand and wrist showed ossification was consistent with the male standard of 17 years. A scoliosis series showed mild-to-moderate thoracic kyphosis. Cholesterol testing showed total cholesterol 216 mg/dL, triglycerides 375 mg/dL, HDL 35 mg/dL and LDL 106 mg/dL. A CBC showed WBC 13.85 K/µl, Hgb 14.9 g/dL, MCV 92.4 fL, platelets 267 K/µl.


Dubowitz syndrome is a complex comprised of multiple, genetically distinct and phenotypically overlapping disorders.

Stewart DR, Pemov A, Johnston JJ, Sapp JC, Yeager M, He J, Boland JF, Burdett L, Brown C, Gatti RA, Alter BP, Biesecker LG, Savage SA - PLoS ONE (2014)

Frontal view of Patient 3 at age 15 years.He was originally diagnosed with Dubowitz syndrome and was determined to harbor a 3.89 Mb deletion on chromosome 17q24.2. Dysmorphic features include bilateral upslanted palpebral fissures with apparent telecanthus, broad nasal bridge and a bulbous nose.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4043752&req=5

pone-0098686-g003: Frontal view of Patient 3 at age 15 years.He was originally diagnosed with Dubowitz syndrome and was determined to harbor a 3.89 Mb deletion on chromosome 17q24.2. Dysmorphic features include bilateral upslanted palpebral fissures with apparent telecanthus, broad nasal bridge and a bulbous nose.
Mentions: He was initially evaluated at age 15 years at the NIH. His height was 142.5 cm (<3rd centile; 50th centile for 11 years), weight was 39.4 kg (<3rd centile; 50th centile for 11.5 years), and OFC was 54 cm (∼25th centile). He appeared anxious with near-continuous teeth grinding and unintelligible speech. There were bilaterally upslanted palpebral fissures with apparent telecanthus. His outer canthal distance was 9.5 cm, inner canthal distance 3.7 cm, inner pupillary distance 6.25 cm (∼90th centile). The palpebral fissures lengths were 2.9 cm (−1 standard deviation). His eyebrows were full with no arching or synophrys. He had a broad nasal bridge. He had a bulbous nose. There was freckling across his nose and under his eyes. His ears were normally formed but somewhat low-set and posteriorly rotated, with a length of 5.5 cm (−1.5 standard deviations); see Figures 3 and 4. Overall, his skin had the appearance of cutis marmorata telangiectasia congenita (Figure 5). Cardiopulmonary exam was normal. The abdominal exam was normal except for a left upper quadrant surgical scar and PEG tube scar. He was tanner IV with bilaterally descended testes and a sacral dimple. He had tapered fingers and a slight resting hand tremor. Third finger length bilaterally was 6 cm (<3rd centile; 50th centile for 8-year-old); right hand length was 14 cm (<3rd centile; 50th centile for 7.5 year old) and left hand length was 15 cm (<3rd centile; 50th centile for 9-year-old). He had bilateral 2–3 cutaneous toe syndactyly. Ophthalmology consultation showed mild intermittent exotropia. An abdominal ultrasound was unremarkable. At a chronological age of 14 years, 11 months, a bone age from the left hand and wrist showed ossification was consistent with the male standard of 17 years. A scoliosis series showed mild-to-moderate thoracic kyphosis. Cholesterol testing showed total cholesterol 216 mg/dL, triglycerides 375 mg/dL, HDL 35 mg/dL and LDL 106 mg/dL. A CBC showed WBC 13.85 K/µl, Hgb 14.9 g/dL, MCV 92.4 fL, platelets 267 K/µl.

Bottom Line: Western blotting showed an absence of a ligase IV band in both siblings.In the third patient, array SNP genotyping revealed a de novo ∼ 3.89 Mb interstitial deletion at chromosome 17q24.2 (chr 17:62,068,463-65,963,102, hg18), which spanned the known Carney complex gene PRKAR1A.Our work suggests that, in addition to dyskeratosis congenita, LIG4 and 17q24.2 syndromes also feature shortened telomeres; to confirm this, telomere length testing should be considered in both disorders.

View Article: PubMed Central - PubMed

Affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, United States of America.

ABSTRACT
Dubowitz syndrome is a rare disorder characterized by multiple congenital anomalies, cognitive delay, growth failure, an immune defect, and an increased risk of blood dyscrasia and malignancy. There is considerable phenotypic variability, suggesting genetic heterogeneity. We clinically characterized and performed exome sequencing and high-density array SNP genotyping on three individuals with Dubowitz syndrome, including a pair of previously-described siblings (Patients 1 and 2, brother and sister) and an unpublished patient (Patient 3). Given the siblings' history of bone marrow abnormalities, we also evaluated telomere length and performed radiosensitivity assays. In the siblings, exome sequencing identified compound heterozygosity for a known rare nonsense substitution in the nuclear ligase gene LIG4 (rs104894419, NM_002312.3:c.2440C>T) that predicts p.Arg814X (MAF:0.0002) and an NM_002312.3:c.613delT variant that predicts a p.Ser205Leufs*29 frameshift. The frameshift mutation has not been reported in 1000 Genomes, ESP, or ClinSeq. These LIG4 mutations were previously reported in the sibling sister; her brother had not been previously tested. Western blotting showed an absence of a ligase IV band in both siblings. In the third patient, array SNP genotyping revealed a de novo ∼ 3.89 Mb interstitial deletion at chromosome 17q24.2 (chr 17:62,068,463-65,963,102, hg18), which spanned the known Carney complex gene PRKAR1A. In all three patients, a median lymphocyte telomere length of ≤ 1st centile was observed and radiosensitivity assays showed increased sensitivity to ionizing radiation. Our work suggests that, in addition to dyskeratosis congenita, LIG4 and 17q24.2 syndromes also feature shortened telomeres; to confirm this, telomere length testing should be considered in both disorders. Taken together, our work and other reports on Dubowitz syndrome, as currently recognized, suggest that it is not a unitary entity but instead a collection of phenotypically similar disorders. As a clinical entity, Dubowitz syndrome will need continual re-evaluation and re-definition as its constituent phenotypes are determined.

Show MeSH
Related in: MedlinePlus