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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with Dubowitz syndrome, including a pair of previously-described siblings (Patients 1 and 2, brother and sister) and an unpublished patient (Patient 3).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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Related in: MedlinePlus

Frontal view of Patient 1 at age 41 years.He was originally diagnosed with Dubowitz syndrome (Opitz et al, 1973; Walters and Desposito, 1985). This is the first published photograph of this seminal patient. Exome sequencing identified compound heterozygote mutations in LIG4, confirming the formal diagnosis of LIG4 syndrome. Dysmorphic features include microcephaly (<3rd centile), bilateral downslanted palpebral fissures, low anterior hairline, and a long tubular nose with prominent bulbar tip.
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pone-0098686-g001: Frontal view of Patient 1 at age 41 years.He was originally diagnosed with Dubowitz syndrome (Opitz et al, 1973; Walters and Desposito, 1985). This is the first published photograph of this seminal patient. Exome sequencing identified compound heterozygote mutations in LIG4, confirming the formal diagnosis of LIG4 syndrome. Dysmorphic features include microcephaly (<3rd centile), bilateral downslanted palpebral fissures, low anterior hairline, and a long tubular nose with prominent bulbar tip.

Mentions: At age 41 years, Patient 1′s height was 157.2 cm (<5th centile), weight was 74.1 kg (BMI 29 m/kg2), and his OFC was 52 cm (<3rd centile, corrected for gender and height). He was a white male with an eunuchoid appearance, central obesity, a full head of graying hair, low anterior/posterior hairlines, and a clockwise hair whorl at the vertex. His ears were somewhat low-set and small (ear length 5.0 cm, <−2.0 SD) with no pits, tags or unusual rotation. There were bilaterally downslanted palpebral fissures; palpebral fissure length was 3.0 cm (normal). His interpupillary distance was 5.3 cm (3rd–25th centile). There were neither ptosis nor epicanthal folds. His nose was long and somewhat tubular with a prominent bulb at the tip, and a high nasal bridge. He had a small mouth (Figures 1 and 2). Cardiopulmonary exam was normal. He had inverted nipples bilaterally and gynecomastia. His abdomen was obese with striae and a small midline umbilical hernia. His hands were short with tapered fingers; his nails appeared normal. There was mild 2–3 cutaneous syndactyly bilaterally. The hand and foot lengths were all <3rd centile: right hand (15.5 cm), left hand (16.0 cm), right palm (9.0 cm), left palm (9.5 cm), right middle finger (6.5 cm), left middle finger (6.5 cm), right foot (22 cm) and left foot (22 cm). There were small (<5 ml) bilaterally descended testes, a small-uncorrected hypospadias and a micropenis. He was Tanner stage V. Neurologic exam was unremarkable except for diminished reflexes bilaterally.


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 1 at age 41 years.He was originally diagnosed with Dubowitz syndrome (Opitz et al, 1973; Walters and Desposito, 1985). This is the first published photograph of this seminal patient. Exome sequencing identified compound heterozygote mutations in LIG4, confirming the formal diagnosis of LIG4 syndrome. Dysmorphic features include microcephaly (<3rd centile), bilateral downslanted palpebral fissures, low anterior hairline, and a long tubular nose with prominent bulbar tip.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0098686-g001: Frontal view of Patient 1 at age 41 years.He was originally diagnosed with Dubowitz syndrome (Opitz et al, 1973; Walters and Desposito, 1985). This is the first published photograph of this seminal patient. Exome sequencing identified compound heterozygote mutations in LIG4, confirming the formal diagnosis of LIG4 syndrome. Dysmorphic features include microcephaly (<3rd centile), bilateral downslanted palpebral fissures, low anterior hairline, and a long tubular nose with prominent bulbar tip.
Mentions: At age 41 years, Patient 1′s height was 157.2 cm (<5th centile), weight was 74.1 kg (BMI 29 m/kg2), and his OFC was 52 cm (<3rd centile, corrected for gender and height). He was a white male with an eunuchoid appearance, central obesity, a full head of graying hair, low anterior/posterior hairlines, and a clockwise hair whorl at the vertex. His ears were somewhat low-set and small (ear length 5.0 cm, <−2.0 SD) with no pits, tags or unusual rotation. There were bilaterally downslanted palpebral fissures; palpebral fissure length was 3.0 cm (normal). His interpupillary distance was 5.3 cm (3rd–25th centile). There were neither ptosis nor epicanthal folds. His nose was long and somewhat tubular with a prominent bulb at the tip, and a high nasal bridge. He had a small mouth (Figures 1 and 2). Cardiopulmonary exam was normal. He had inverted nipples bilaterally and gynecomastia. His abdomen was obese with striae and a small midline umbilical hernia. His hands were short with tapered fingers; his nails appeared normal. There was mild 2–3 cutaneous syndactyly bilaterally. The hand and foot lengths were all <3rd centile: right hand (15.5 cm), left hand (16.0 cm), right palm (9.0 cm), left palm (9.5 cm), right middle finger (6.5 cm), left middle finger (6.5 cm), right foot (22 cm) and left foot (22 cm). There were small (<5 ml) bilaterally descended testes, a small-uncorrected hypospadias and a micropenis. He was Tanner stage V. Neurologic exam was unremarkable except for diminished reflexes bilaterally.

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