Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) with multiple vascular complications misdiagnosed as Dubowitz syndrome

Dieks, Jana-Katharina; Baumer, Alessandra; Wilichowski, Ekkehard; Rauch, Anita; Sigler, Matthias

doi:10.1007/s00431-014-2368-5

Cited by 16 publications

(16 citation statements)

References 7 publications

(12 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Single gene disorders were identified in 14 individuals from nine families. Autosomal recessive mutations were identified in NSUN2 , LIG4 , BRCA1, UBE3B, RNU4ATAC, and PCNT1 (Dieks, Baumer, Wilichowski, Rauch, & Sigler, ; Kariminejad et al, ; Krøigård et al, ; Martinez et al, ; Sawyer et al, ; Table ). Autosomal dominant de novo mutations were reported in ACTB and STAT3 (Beitzke et al, ; Johnston et al, ; Table ).…”

Section: Resultsmentioning

confidence: 99%

“…Growth hormone treatment was reported in five cases of DS with a beneficial response reported in three individuals (Dentici, Mingarelli, & Dallapiccola, ; Giordano et al, ; Hirano et al, ; Oguz, Ozgen, & Erdem, ). Of the individuals with length/height less than −4.5 SD , primordial dwarfism (1/8) or another underlying syndromic presentation (2/8) was ultimately found to be responsible (Dieks et al, ; Sawyer et al, ).…”

Section: Resultsmentioning

confidence: 99%

“…There are two reports of patients or families initially suspect to have DS (Hansen et al, ; Seeburger, Rastan, & Mohr, ) that were later molecularly confirmed to have classic Microcephalic Osteodysplastic Primordial Dwarfism (MOPD) type 2 and atypical MOPD type 1, respectively (Dieks et al, ; Krøigård et al, ). Given that microcephaly is a common defining feature in DS, it is certainly likely that other patients diagnosed with DS, particularly those with significant microcephaly and or overall growth impairment may have mutations in these genes, or in other genes known to cause primordial dwarfism (Alkuraya, ).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Clinical and genetic heterogeneity in Dubowitz syndrome: Implications for diagnosis, management and further research

2018

View full text Add to dashboard Cite

Dubowitz syndrome was described in 1965 as a recognizable syndrome characterized by microcephaly, short stature, eczema, mild developmental delays, and an increased risk of malignancy. Since its original description, there have been over 200 reported cases though no single gene has been identified to explain a significant proportion of affected individuals. Since the last definitive review of Dubowitz syndrome in 1996, there have been 63 individuals with a clinical, or suspected, diagnosis of Dubowitz syndrome reported in 51 publications. These individuals show a markedly wide spectrum with respect to growth, facial gestalt, psychomotor development, and risk of malignancy; genetic causes were identified in 33% (21/63). Seven individuals had deleterious copy number variants, in particular deletions at 14q32 and 17q24 were reported and showed overlap with the Dubowitz phenotype. Several cases were shown to have single gene disorders that included de novo or biallelic pathogenic variants in several genes including NSUN2 and LIG4 frequently identified by next‐generation sequencing methods. It appears that the inability to identify a single gene responsible for Dubowitz syndrome reflects its extreme clinical and genetic heterogeneity. However, detailed phenotyping combined with careful grouping of subsets of unsolved cases and in conjunction with data‐sharing will identify novel disease genes responsible for additional cases. In the interim, for those clinically diagnosed with a Dubowitz phenotype, we recommend assessment by a Medical Geneticist, a microarray and, if available, clinical or research based genome‐wide sequencing. Management suggestions, including decisions regarding malignancy screening in select patients will be discussed.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Clinical and genetic heterogeneity in Dubowitz syndrome: Implications for diagnosis, management and further research

2018

View full text Add to dashboard Cite

show abstract

“…Up to now, based on Human Gene Mutation Database (HGMD) ( www.hgmd.cf.ac.uk/ ), 53 different pathogenic variants causing MOPD II have been reported. These pathogenic variants are depicted in Figure 3A ( 6 , 12 – 14 , 26 , 28 – 35 ). In addition, all variants identified in the PCNT gene are summarized in Table S1 .…”

Section: Discussionmentioning

confidence: 99%

“…Majewski et al also categorized MOPD to into three distinct types (MOPD I, II, III), whereas type I and III are now known as a same disorder. MOPD Type II (OMIM: 210720) is the most common type, inherited in an autosomal recessive mode (6,7). The clinical abnormalities associated with MOPD II include fetal growth restriction, microcephaly, post-natal growth retardation, skeletal dysplasia, and disproportionate face (7,8).…”

Section: Introductionmentioning

confidence: 99%

A Novel PCNT Frame Shift Variant (c.7511delA) Causing Osteodysplastic Primordial Dwarfism of Majewski Type 2 (MOPD II)

et al. 2020

View full text Add to dashboard Cite

Background: Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is an autosomal recessive and skeletal disorder included wide spectrum of clinical abnormalities such as fetal growth restriction, disproportionate face, microcephaly, post-natal growth retardation, adult height under 100 cm, abnormal skin pigmentation, insulin resistance, and susceptibility to cerebrovascular and hematologic abnormalities. Due to heterogeneous feature of MOPDs diseases and common clinical features among the different subtypes, mutation analysis can be considered as fundamental in the accurate diagnosis and confirmation of the MOPD II disease. Some studies revealed that, variants of gene encoding Pericentrin protein, PCNT, were associated with MOPD II. Methods: We performed whole exome sequencing based on the next generation sequencing (Illumina platform), to perform correct diagnosis in a 17-year-old girl with an unknown disease who was referred to the Diabetes Research Center in Yazd, Iran. The clinical features of the patient were short stature, generalized brachydactyly, gradual deterioration of brain functioning, menstrual irregularity, clitoromegaly, acanthosis nigricans, diabetes mellitus, hyperinsulinemia, insulin resistance, and dyslipidemia. Accordingly, her parents were also first cousin with no background disease. After identifying the novel variant, it was confirmed in the proband and her family using bi-directional Sanger sequencing, and its pathogenicity was also checked by different online tools. Results: Our study revealed a novel frame-shift variant in PCNT gene (c.7511delA, p.K2504Sfs * 27), which causes premature termination of Pericentrin protein. The result disclosed that, the proband was affected by MOPD II disease. In addition, the Sanger sequencing confirmed the novel homozygote variant in the proband and heterozygote one in her parents, and the extended family perfectly segregated among them. Online tools such as Varsome and MutationTaster also showed a high level of pathogenicity for the variant identified. Dehghan Tezerjani et al. Novel PCNT Variant in MOPD II Conclusion: A novel variant was identified in the proband and her extended family, which emphasized the importance of PCNT gene mutations analysis in the screening and accurate identification of MOPD II disease, especially in prenatal diagnosis.

show abstract

Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome

Dyment¹,

O’Donnell-Luria²,

Agrawal³

et al. 2020

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a “Dubowitz‐like” condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome‐wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy‐number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next‐generation sequencing. Overall, the DubS‐like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.

show abstract

Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) with multiple vascular complications misdiagnosed as Dubowitz syndrome

Cited by 16 publications

References 7 publications

Clinical and genetic heterogeneity in Dubowitz syndrome: Implications for diagnosis, management and further research

Clinical and genetic heterogeneity in Dubowitz syndrome: Implications for diagnosis, management and further research

A Novel PCNT Frame Shift Variant (c.7511delA) Causing Osteodysplastic Primordial Dwarfism of Majewski Type 2 (MOPD II)

Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome

Contact Info

Product

Resources

About