In-depth Investigations of Adolescents and Adults with Holoprosencephaly Identify Unique Characteristics

Overview

Journal Genet Med

Publisher Elsevier

Specialty Genetics

Date 2017 Jun 23

PMID 28640243

Citations 5

Authors

Karin Weiss

Paul Kruszka

Maria J Guillen Sacoto

Yonit A Addissie

Donald W Hadley

Casey K Hadsall

Bethany Stokes

Ping Hu

Erich Roessler

Beth Solomon

Edythe Wiggs

Audrey Thurm

Robert B Hufnagel

Wadih M Zein

Jin S Hahn

Elaine Stashinko

Eric Levey

Debbie Baldwin

Nancy J Clegg

Mauricio R Delgado

Maximilian Muenke

Affiliations

Soon will be listed here.

Abstract

PurposeWith improved medical care, some individuals with holoprosencephaly (HPE) are surviving into adulthood. We investigated the clinical manifestations of adolescents and adults with HPE and explored the underlying molecular causes.MethodsParticipants included 20 subjects 15 years of age and older. Clinical assessments included dysmorphology exams, cognitive testing, swallowing studies, ophthalmic examination, and brain magnetic resonance imaging. Genetic testing included chromosomal microarray, Sanger sequencing for SHH, ZIC2, SIX3, and TGIF, and whole-exome sequencing (WES) of 10 trios.ResultsSemilobar HPE was the most common subtype of HPE, seen in 50% of the participants. Neurodevelopmental disabilities were found to correlate with HPE subtype. Factors associated with long-term survival included HPE subtype not alobar, female gender, and nontypical facial features. Four participants had de novo pathogenic variants in ZIC2. WES analysis of 11 participants did not reveal plausible candidate genes, suggesting complex inheritance in these cases. Indeed, in two probands there was a history of uncontrolled maternal type 1 diabetes.ConclusionIndividuals with various HPE subtypes can survive into adulthood and the neurodevelopmental outcomes are variable. Based on the facial characteristics and molecular evaluations, we suggest that classic genetic causes of HPE may play a smaller role in this cohort.

Citing Articles

Holoprosencephaly: Review of Embryology, Clinical Phenotypes, Etiology and Management.

Malta M, AlMutiri R, Martin C, Srour M Children (Basel). 2023; 10(4).

PMID: 37189898 PMC: 10137117. DOI: 10.3390/children10040647.

Endocrinological Features of Hartsfield Syndrome in an Adult Patient With a Novel Mutation of .

Kobayashi S, Tanigawa J, Kondo H, Nabatame S, Maruoka A, Sho H J Endocr Soc. 2020; 4(5):bvaa041.

PMID: 32373773 PMC: 7192098. DOI: 10.1210/jendso/bvaa041.

Heterozygous mutation of sonic hedgehog receptor (Ptch1) drives cerebellar overgrowth and sex-specifically alters hippocampal and cortical layer structure, activity, and social behavior in female mice.

Jackson T, Bendfeldt G, Beam K, Rock K, Belcher S Neurotoxicol Teratol. 2020; 78:106866.

PMID: 32113901 PMC: 8018584. DOI: 10.1016/j.ntt.2020.106866.

Molecular testing in holoprosencephaly.

Kruszka P, Martinez A, Muenke M Am J Med Genet C Semin Med Genet. 2018; 178(2):187-193.

PMID: 29771000 PMC: 6125165. DOI: 10.1002/ajmg.c.31617.

Extracephalic manifestations of nonchromosomal, nonsyndromic holoprosencephaly.

Martinez A, Kruszka P, Muenke M Am J Med Genet C Semin Med Genet. 2018; 178(2):246-257.

PMID: 29761634 PMC: 6125181. DOI: 10.1002/ajmg.c.31616.

References

Lacbawan F, Solomon B, Roessler E, El-Jaick K, Domene S, Velez J . Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function. J Med Genet. 2009; 46(6):389-98. PMC: 3510661. DOI: 10.1136/jmg.2008.063818. View

BARR Jr M, Cohen Jr M . Holoprosencephaly survival and performance. Am J Med Genet. 1999; 89(2):116-20. View

Bullen P, Rankin J, Robson S . Investigation of the epidemiology and prenatal diagnosis of holoprosencephaly in the North of England. Am J Obstet Gynecol. 2001; 184(6):1256-62. DOI: 10.1067/mob.2001.111071. View

Hahn J, Barnes P . Neuroimaging advances in holoprosencephaly: Refining the spectrum of the midline malformation. Am J Med Genet C Semin Med Genet. 2010; 154C(1):120-32. DOI: 10.1002/ajmg.c.30238. View

Dickson P, Pariser A, Groft S, Ishihara R, McNeil D, Tagle D . Research challenges in central nervous system manifestations of inborn errors of metabolism. Mol Genet Metab. 2010; 102(3):326-38. PMC: 3040279. DOI: 10.1016/j.ymgme.2010.11.164. View

Olsen C, Hughes J, Youngblood L . Epidemiology of holoprosencephaly and phenotypic characteristics of affected children: New York State, 1984-1989. Am J Med Genet. 1997; 73(2):217-26. DOI: 10.1002/(sici)1096-8628(19971212)73:2<217::aid-ajmg20>3.0.co;2-s. View

Dubourg C, Carre W, Hamdi-Roze H, Mouden C, Roume J, Abdelmajid B . Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway. Hum Mutat. 2016; 37(12):1329-1339. DOI: 10.1002/humu.23038. View

Mercier S, Dubourg C, Garcelon N, Campillo-Gimenez B, Gicquel I, Belleguic M . New findings for phenotype-genotype correlations in a large European series of holoprosencephaly cases. J Med Genet. 2011; 48(11):752-60. PMC: 3386902. DOI: 10.1136/jmedgenet-2011-100339. View

Mouden C, Dubourg C, Carre W, Rose S, Quelin C, Akloul L . Complex mode of inheritance in holoprosencephaly revealed by whole exome sequencing. Clin Genet. 2016; 89(6):659-68. DOI: 10.1111/cge.12722. View

10.

Virta M, Launes J, Valanne L, Hokkanen L . Adult with Middle Interhemispheric Variant of Holoprosencephaly: Neuropsychological, Clinical, and Radiological Findings. Arch Clin Neuropsychol. 2016; 31(5):472-9. DOI: 10.1093/arclin/acw026. View

11.

Roessler E, Ma Y, Ouspenskaia M, Lacbawan F, Bendavid C, Dubourg C . Truncating loss-of-function mutations of DISP1 contribute to holoprosencephaly-like microform features in humans. Hum Genet. 2009; 125(4):393-400. PMC: 2774849. DOI: 10.1007/s00439-009-0628-7. View

12.

Hahn J, Hahn S, Kammann H, Barkovich A, Clegg N, Delgado M . Endocrine disorders associated with holoprosencephaly. J Pediatr Endocrinol Metab. 2005; 18(10):935-41. DOI: 10.1515/jpem.2005.18.10.935. View

13.

Roessler E, Velez J, Zhou N, Muenke M . Utilizing prospective sequence analysis of SHH, ZIC2, SIX3 and TGIF in holoprosencephaly probands to describe the parameters limiting the observed frequency of mutant gene×gene interactions. Mol Genet Metab. 2012; 105(4):658-64. PMC: 3309119. DOI: 10.1016/j.ymgme.2012.01.005. View

14.

Traggiai C, Stanhope R . Endocrinopathies associated with midline cerebral and cranial malformations. J Pediatr. 2002; 140(2):252-5. DOI: 10.1067/mpd.2002.121822. View

15.

Croen L, Shaw G, Lammer E . Holoprosencephaly: epidemiologic and clinical characteristics of a California population. Am J Med Genet. 1996; 64(3):465-72. DOI: 10.1002/(SICI)1096-8628(19960823)64:3<465::AID-AJMG4>3.0.CO;2-O. View

16.

Lewis A, Simon E, Barkovich A, Clegg N, Delgado M, Levey E . Middle interhemispheric variant of holoprosencephaly: a distinct cliniconeuroradiologic subtype. Neurology. 2002; 59(12):1860-5. DOI: 10.1212/01.wnl.0000037483.31989.b9. View

17.

DEMYER W, Zeman W, Palmer C . THE FACE PREDICTS THE BRAIN: DIAGNOSTIC SIGNIFICANCE OF MEDIAN FACIAL ANOMALIES FOR HOLOPROSENCEPHALY (ARHINENCEPHALY). Pediatrics. 1964; 34:256-63. View

18.

Bakrania P, Ugur Iseri S, Wyatt A, Bunyan D, Lam W, Salt A . Sonic hedgehog mutations are an uncommon cause of developmental eye anomalies. Am J Med Genet A. 2010; 152A(5):1310-3. DOI: 10.1002/ajmg.a.33239. View

19.

Pineda-Alvarez D, Solomon B, Roessler E, Balog J, Hadley D, Zein W . A broad range of ophthalmologic anomalies is part of the holoprosencephaly spectrum. Am J Med Genet A. 2011; 155A(11):2713-20. PMC: 3200498. DOI: 10.1002/ajmg.a.34261. View

20.

Leoncini E, Baranello G, Orioli I, Anneren G, Bakker M, Bianchi F . Frequency of holoprosencephaly in the International Clearinghouse Birth Defects Surveillance Systems: searching for population variations. Birth Defects Res A Clin Mol Teratol. 2008; 82(8):585-91. DOI: 10.1002/bdra.20479. View