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

Douglas R Stewart,Meredith Yeager,Christina Brown,Leslie G Biesecker,Alexander Pemov,Jennifer J Johnston,Richard A Gatti,Sharon A Savage,Julie C Sapp,Blanche P Alter,Ji He,Joseph F Boland,Laurie Burdett,Ralf Krahe

doi:10.1371/journal.pone.0098686

Douglas R Stewart, Meredith Yeager + Show 12 more

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https://doi.org/10.1371/journal.pone.0098686

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Dubowitz syndrome, including a pair of previously-described siblings (Patients 1 and 2, brother and sister) and an unpublished patient (Patient 3).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

Highlights

Dubowitz syndrome was originally described in 1965 in a girl with intrauterine growth retardation (IUGR), eczema, short stature, failure to thrive, a high-pitched cry, presumed autosomal recessive inheritance and a distinctive facies, akin to Bloom and Seckel syndromes [1]
We report the genetic etiology of three individuals diagnosed clinically with Dubowitz syndrome
In addition to a Dubowitz syndrome diagnosis, the phenotypes of Patients 1 and 2 overlapped with the clinical spectrum of dyskeratosis congenita; an evaluation for this disorder prompted the discovery of markedly shortened telomere length [11] and abnormal colony survival and neutral comet assays, but no mutations in the known dyskeratosis congenita genes TERT, TERC, DKC1, TINF2, WRAP53, NOP10, NHP2, CRC1 or RTEL1

Summary

Introduction

Dubowitz syndrome was originally described in 1965 in a girl with intrauterine growth retardation (IUGR), eczema, short stature, failure to thrive, a high-pitched cry, presumed autosomal recessive inheritance and a distinctive facies (large, low set ears, retrognathia, ptosis, prominent nasal bridge), akin to Bloom and Seckel syndromes [1]. A 1996 review of 141 patients with Dubowitz syndrome by Tsukahara and Opitz defined the syndrome as one with multiple congenital anomalies, cognitive delay, growth failure, an immune defect (allergies and eczema), increased risk of blood dyscrasia (pancytopenia), hematologic malignancy and neuroblastoma [3] They speculated that the ‘‘extraordinarily broad’’ phenotypic variability might be due to a metabolic [4] or DNA repair defect. A fouryear-old girl with IUGR, microcephaly, poor feeding, ptosis, telecanthus, epicanthal folds, wide nasal bridge, low-set ears, developmental delay, and hoarse high-pitched voice had a ,2.7 Mb deletion on chromosome 14q32.33. These features overlapped with the 14q32.3 syndrome, which prompted the authors to speculate that the patient had a phenocopy of Dubowitz syndrome [7]. Yue [9] found compound heterozygous mutations in the nuclear ligase gene LIG4 in the sister from a pair of siblings previously reported with Dubowitz syndrome [2,10] who are investigated in this report (Patient 2)

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