Skip to main content
SpringerLink
Log in

Prenatal diagnosis of Wolf–Hirschhorn syndrome: from ultrasound findings, diagnostic technology to genetic counseling

  • Maternal-Fetal Medicine
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

Wolf–Hirschhorn syndrome (WHS) is a contiguous gene syndrome due to terminal chromosome 4p deletions. We explored prenatal diagnosis of WHS by ultrasound as well as karyotype and single nucleotide polymorphism array (SNP array) to characterize the structural variants of WHS prenatally.

Methods

Ten prenatal cases of WHS were evaluated for the indication of the invasive testing, the ultrasound features, and cytogenetic and microarray results.

Results

Eight cases were diagnosed by karyotyping and SNP array, while two cases were detected only by SNP array. Combining our cases with 37 prenatal cases from the literature, the most common sonographic features were IUGR (97.7%) and typical facial appearance (82.9%). Other less common phenotypes included renal hypoplasia (36.2%), cardiac malformation (29.8%), cleft lip and palate (25.5%), cerebral abnormalities (25.5%), skeletal anomalies (21.3%), and increased nuchal translucency/nuchal fold thickness (NT/NF) (19%).

Conclusions

The most common intrauterine phenotypes of WHS were severe IUGR and typical facial appearance with other less consistent ultrasound findings. Noninvasive prenatal testing (NIPT) is one very promising screening tool for WHS. SNP array can improve diagnostic precision for detecting WHS, especially for the cryptic aberrations that cannot be identified by the traditional karyotyping. Ectopic kidney may be a previously unrecognized phenotype of WHS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Hirschhorn K, Cooper HL, Firschein IL (1965) Deletion of short arms of chromosome 4-5 in a child with defects of midline fusion. Humangenetik 1(5):479–482

    PubMed  CAS  Google Scholar 

  2. Wolf U, Reinwein H, Porsch R, Schroter R, Baitsch H (1965) Deficiency on the short arms of a chromosome No. 4. Humangenetik 1(5):397–413

    PubMed  CAS  Google Scholar 

  3. Maas NMC, Van Buggenhout G, Hannes F, Thienpont B, Sanlaville D, Kok K, Midro A, Andrieux J, Anderlid BM, Schoumans J, Hordijk R, Devriendt K, Fryns JP, Vermeesch JR (2008) Genotype-phenotype correlation in 21 patients with Wolf–Hirschhorn syndrome using high resolution array comparative genome hybridisation (CGH). J Med Genet 45(2):71–80

    Article  PubMed  CAS  Google Scholar 

  4. Zollino M, Murdolo M, Marangi G, Pecile V, Galasso C, Mazzanti L, Neri G (2008) On the nosology and pathogenesis of Wolf–Hirschhorn syndrome: genotype-phenotype correlation analysis of 80 patients and literature review. Am J Med Genet C Semin Med Genet 148C(4):257–269. https://doi.org/10.1002/ajmg.c.30190

    Article  PubMed  CAS  Google Scholar 

  5. Wright TJ, Ricke DO, Denison K, Abmayr S, Cotter PD, Hirschhorn K, Keinanen M, McDonald-McGinn D, Somer M, Spinner N, Yang-Feng T, Zackai E, Altherr MR (1997) A transcript map of the newly defined 165 kb Wolf–Hirschhorn syndrome critical region. Hum Mol Genet 6(2):317–324

    Article  PubMed  CAS  Google Scholar 

  6. Zollino M, Lecce R, Fischetto R, Murdolo M, Faravelli F, Selicorni A, Butte C, Memo L, Capovilla G, Neri G (2003) Mapping the Wolf–Hirschhorn syndrome phenotype outside the currently accepted WHS critical region and defining a new critical region, WHSCR-2. Am J Hum Genet 72(3):590–597. https://doi.org/10.1086/367925

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Battaglia A, Carey JC, Wright TJ (2001) Wolf–Hirschhorn (4p-) syndrome. Adv Pediatr 48:75–113

    PubMed  CAS  Google Scholar 

  8. Kohlschmidt N, Zielinski J, Brude E, Schafer D, Olert J, Hallermann C, Coerdt W, Arnemann J (2000) Prenatal diagnosis of a fetus with a cryptic translocation 4p;18p and Wolf–Hirschhorn syndrome (WHS). Prenat Diagn 20(2):152–155

    Article  PubMed  CAS  Google Scholar 

  9. Levaillant JM, Touboul C, Sinico M, Vergnaud A, Serero S, Druart L, Blondeau JR, Abd Alsamad I, Haddad B, Gerard-Blanluet M (2005) Prenatal forehead edema in 4p- deletion: the ‘Greek warrior helmet’ profile revisited. Prenat Diagn 25(12):1150–1155. https://doi.org/10.1002/pd.1246

    Article  PubMed  CAS  Google Scholar 

  10. Aslan H, Karaca N, Basaran S, Ermis H, Ceylan Y (2003) Prenatal diagnosis of Wolf–Hirschhorn syndrome (4p-) in association with congenital hypospadias and foot deformity. BMC Pregnancy Childbirth 3(1):1

    Article  PubMed  PubMed Central  Google Scholar 

  11. Tachdjian G, Fondacci C, Tapia S, Huten Y, Blot P, Nessmann C (1992) The Wolf–Hirschhorn syndrome in fetuses. Clin Genet 42(6):281–287

    Article  PubMed  CAS  Google Scholar 

  12. Verloes A, Schaaps JP, Herens C, Soyeur D, Hustin J, Dodinval P (1991) Prenatal diagnosis of cystic hygroma and chorioangioma in the Wolf–Hirschhorn syndrome. Prenat Diagn 11(2):129–132

    Article  PubMed  CAS  Google Scholar 

  13. Ikonomou T, Antsaklis P, Daskalakis G, Sindos M, Papantoniou N, Kosmaidou Z, Antsaklis A (2013) Prenatal diagnosis of Wolf–Hirschhorn syndrome: ultrasonography and genetics. J Mater Fetal Neonatal Med 26(9):941–942. https://doi.org/10.3109/14767058.2013.765855

    Article  Google Scholar 

  14. Debost-Legrand A, Goumy C, Laurichesse-Delmas H, Dechelotte P, Beaufrere AM, Lemery D, Francannet C, Gallot D (2013) Prenatal ultrasound findings observed in the Wolf–Hirschhorn syndrome: data from the registry of congenital malformations in Auvergne. Birth Defects Res A Clin Mol Teratol 97(12):806–811. https://doi.org/10.1002/bdra.23194

    Article  PubMed  CAS  Google Scholar 

  15. Bi W, Cheung SW, Breman AM, Bacino CA (2016) 4p16.3 microdeletions and microduplications detected by chromosomal microarray analysis: new insights into mechanisms and critical regions. Am J Med Genet. https://doi.org/10.1002/ajmg.a.37796

    Article  PubMed  Google Scholar 

  16. von Elten K, Sawyer T, Lentz-Kapua S, Kanis A, Studer M (2013) A case of Wolf–Hirschhorn syndrome and hypoplastic left heart syndrome. Pediatr Cardiol 34(5):1244–1246. https://doi.org/10.1007/s00246-012-0367-8

    Article  Google Scholar 

  17. Tautz J, Veenma D, Eussen B, Joosen L, Poddighe P, Tibboel D, de Klein A, Schaible T (2010) Congenital diaphragmatic hernia and a complex heart defect in association with Wolf–Hirschhorn syndrome. Am J Med Genet A 152A(11):2891–2894. https://doi.org/10.1002/ajmg.a.33660

    Article  PubMed  Google Scholar 

  18. South ST, Hannes F, Fisch GS, Vermeesch JR, Zollino M (2008) Pathogenic significance of deletions distal to the currently described Wolf–Hirschhorn syndrome critical regions on 4p16.3. Am J Med Genet C Semin Med Genet 148C(4):270–274. https://doi.org/10.1002/ajmg.c.30188

    Article  PubMed  CAS  Google Scholar 

  19. Battaglia A, Carey JC, South ST, Wright TJ (2002–2015) Wolf–Hirschhorn syndrome. GeneReviews ([Internet] [updated 2015 Aug 20])

  20. Rowe LR, Lee JY, Rector L, Kaminsky EB, Brothman AR, Martin CL, South ST (2009) U-type exchange is the most frequent mechanism for inverted duplication with terminal deletion rearrangements. J Med Genet 46(10):694–702. https://doi.org/10.1136/jmg.2008.065052

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Fund of Shanghai Municipal Science and Technology Commission (Grant Number 16411963100); Hospital development center (Grant Number SHDC 12016117); Shanghai municipal commission of health and family planning (Grant Number 201540195); Shanghai municipal medical and health discipline construction projects (Grant Number 2017ZZ02015). JLH receives funding from the Robbins Foundation.

Author information

Authors and Affiliations

  1. Department of Fetal Medicine and Prenatal Diagnosis center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, 2699 West Gaoke Rd, Pudong New District, Shanghai, 201204, China

    Ya Xing, Yong Liu, Meizhen Yuan, Qi Sun, Xiaoxing Qu, Linbei Deng, Jia Zhou, Yingjun Yang, Ming Guo & Luming Sun

  2. Division of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    Jimmy Lloyd Holder Jr

  3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Sau-Wai Cheung

Authors
  1. Ya Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jimmy Lloyd Holder Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Meizhen Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qi Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaoxing Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Linbei Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jia Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yingjun Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ming Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sau-Wai Cheung
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Luming Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LMS: study/protocol planning and oversight; manuscript editing. YX: study/protocol planning and manuscript writing. YL, MZY and QS: ultrasound data collection. YJY: clinical data collection. JLH and SWC: manuscript editing. XXQ, LBD and JZ: SNP array data analysis. MG: karyotyping analysis.

Corresponding author

Correspondence to Luming Sun.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 1413 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xing, Y., Holder, J.L., Liu, Y. et al. Prenatal diagnosis of Wolf–Hirschhorn syndrome: from ultrasound findings, diagnostic technology to genetic counseling. Arch Gynecol Obstet 298, 289–295 (2018). https://doi.org/10.1007/s00404-018-4798-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00404-018-4798-1

Keywords

Search

Navigation