Gonadal Mosaicism in Severe Pallister-Hall Syndrome

David Ng, Jennifer J. Johnston, Joyce T. Turner, Eilis Boudreau, Edythe A. Wiggs, William H. Theodore, Leslie G. Biesecker

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Pallister-Hall syndrome (PHS,MIM #146510) is characterized by central and postaxial polydactyly, hypothalamic hamartoma (HH), bifid epiglottis, imperforate anus, renal abnormalities, and pulmonary segmentation anomalies. It is inherited in an autosomal dominant pattern. Here, we describe a family with two affected children manifesting severe PHS with mental retardation, behavioral problems, and intractable seizures. Both parents are healthy, with normal intelligence, and have no malformations on physical, laryngoscopic, and cranial MRI exam. The atypical presentation of these children and the absence of parental manifestations suggested an autosomal recessive mode of inheritance or gonadal mosaicism. Sequencing of GLI3 revealed a two nucleotide deletion in exon 15 (c.3385_3386delTT) predicting a frameshift and premature stop at codon 1129 (p.F1129X) in the children while both parents have wild type alleles. Genotyping with GLI3 intragenic markers revealed that both children inherited the abnormal allele from their mother thus supporting gonadal mosaicism as the underlying mechanism of inheritance (paternity was confirmed). This is the first reported case of gonadal mosaicism in PHS. The severe CNS manifestations of these children are reminiscent of children with non-syndromic HH who often have progressive mental retardation with behavioral problems and intractable seizures. We conclude that the phenotypic spectrum of PHS can include severe CNS manifestations and that recurrence risks for PHS should include a proviso for gonadal mosaicism, though the frequency cannot be calculated from a single case report.

Original languageEnglish (US)
Pages (from-to)296-302
Number of pages7
JournalAmerican Journal of Medical Genetics
Volume124 A
Issue number3
StatePublished - Jan 30 2004
Externally publishedYes

Fingerprint

Pallister-Hall Syndrome
Mosaicism
Intellectual Disability
Seizures
Parents
Alleles
Imperforate Anus
Epiglottis
Paternity
Nonsense Codon
Intelligence
Exons
Nucleotides
Mothers
Kidney
Recurrence
Lung

Keywords

  • Hypothalamic hamartoma
  • Mental retardation

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Ng, D., Johnston, J. J., Turner, J. T., Boudreau, E., Wiggs, E. A., Theodore, W. H., & Biesecker, L. G. (2004). Gonadal Mosaicism in Severe Pallister-Hall Syndrome. American Journal of Medical Genetics, 124 A(3), 296-302.

Gonadal Mosaicism in Severe Pallister-Hall Syndrome. / Ng, David; Johnston, Jennifer J.; Turner, Joyce T.; Boudreau, Eilis; Wiggs, Edythe A.; Theodore, William H.; Biesecker, Leslie G.

In: American Journal of Medical Genetics, Vol. 124 A, No. 3, 30.01.2004, p. 296-302.

Research output: Contribution to journalArticle

Ng, D, Johnston, JJ, Turner, JT, Boudreau, E, Wiggs, EA, Theodore, WH & Biesecker, LG 2004, 'Gonadal Mosaicism in Severe Pallister-Hall Syndrome', American Journal of Medical Genetics, vol. 124 A, no. 3, pp. 296-302.
Ng D, Johnston JJ, Turner JT, Boudreau E, Wiggs EA, Theodore WH et al. Gonadal Mosaicism in Severe Pallister-Hall Syndrome. American Journal of Medical Genetics. 2004 Jan 30;124 A(3):296-302.
Ng, David ; Johnston, Jennifer J. ; Turner, Joyce T. ; Boudreau, Eilis ; Wiggs, Edythe A. ; Theodore, William H. ; Biesecker, Leslie G. / Gonadal Mosaicism in Severe Pallister-Hall Syndrome. In: American Journal of Medical Genetics. 2004 ; Vol. 124 A, No. 3. pp. 296-302.
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