CORRESPONDENCE
GLI2 Mutations Typically Result in Pituitary Anomalies With or Without Postaxial Polydactyly Kelly A. Bear1 and Benjamin D. Solomon2,3,4* 1
Department of Pediatrics, Tripler Army Medical Center, Honolulu, Hawaii
2
Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia
3
Inova Translational Medicine Institute and Inova Children’s Hospital, Inova Health System, Falls Church, Virginia Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, Virginia
4
Manuscript Received: 8 April 2015; Manuscript Accepted: 28 April 2015
TO THE EDITOR: Mutations in GLI2 were first identified by analyzing a large cohort of patients with holoprosencephaly (HPE) and/or with manifestations suggestive of midline neurodevelopmental anomalies [Roessler et al., 2003; Roessler et al., 2005]. More recently, it has become clear that mutations in GLI2 do not tend to result in frank HPE, but instead cause a distinct phenotype that includes pituitary insufficiency and/or polydactyly, as well as subtle facial variants [Franca et al., 2010, 2013; Bear et al., 2014]. In a recent review of all reported cases, only 1 of 43 (2%) of patients with loss-of-function mutations (these included whole-gene or near whole-gene deletions) had true HPE. In fact, the proportion of patients with GLI2 mutations and HPE may be even lower than this 2% value, as there remains an ascertainment bias based on the originally studied cohorts. The studies included in the review consisted mainly of individuals from cohorts tested secondary to HPE, cleft lip/palate, pituitary hormone deficiencies, and craniofacial anomalies. Many other patients have been described with GLI2 variants and similar phenotypes, but the pathogenicity of these variants remains unclear and the observed phenotypes may well be unrelated to the GLI2 variants [Bear et al., 2014]. In OMIM (http://www.ncbi.nlm.nih.gov/omim, last accessed April 6, 2015), mutations in GLI2 are now described as causing Culler–Jones syndrome (as well as Holoprosencephaly 9). “Culler–Jones syndrome” is based on a report of a family – described over 30 years ago – with hypopituitarism and postaxial polydactyly [Culler and Jones, 1984]. This family was later found to segregate a truncating GLI2 mutation [Roessler et al., 2005]. Interestingly, and reflecting challenges with naming syndromes, “Culler–Jones syndrome” replaces a short-lived OMIM designation of “Pallister–Hall syndrome 2.” The recent article by Kordaß et al. [2015] is a valuable addition to the literature in terms of describing an interesting family in which the proband was ascertained due to growth retardation, and was noted to have other clinical findings, including cardiac defects, a multicystic kidney, scoliosis, and dysmorphic facial features. The patient’s phenotype may well result from loss of multiple genes and other genetic factors in the deleted region on chromosome 2q14. As with many conditions resulting from contiguous gene deletions, a
© 2015 Wiley Periodicals, Inc.
How to Cite this Article:
Bear KA, Solomon BD. 2015. GLI2 mutations typically result in pituitary anomalies with or without postaxial polydactyly. Am J Med Genet Part A 167A:2491–2492.
satisfying biologic explanation of how this deletion resulted in this exact phenotype is currently lacking. However, the growth retardation described in the patient can likely be ascribed to the deletion of GLI2 within the identified interval. It is important to emphasize that the phenotype due to GLI2 mutations is distinct from that caused by mutations in genes such as SHH, ZIC2, and SIX3. These latter might be considered the “classic” (and certainly most frequently involved) HPE genes, though the phenotype of affected patients can differ both among and between patients with mutations in these genes [Solomon et al., 2010]. In other words, it is unsurprising that the patient reported by Kordaß et al. [2015] did not have HPE (or a family history thereof). Based on the literature mentioned above, the reverse would be more surprising, and might today prompt further studies for another genetic explanation, such as a mutation affecting a “true HPE” gene. Awareness of the GLI2-related phenotype (whether called Culler–Jones syndrome or something else) is important in terms of genetic counseling and management of patients with identified mutations. Recognition of this phenotype is also important to Neither author has any conflicts of interest or disclosures. Correspondence to: Benjamin D. Solomon, M.D., Inova Translational Medicine Institute, 3300 Gallows Road/Claude Moore Building, 2nd Floor, Falls Church, VA 22042. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 14 May 2015 DOI 10.1002/ajmg.a.37160
2491
2492 help with the molecular differential diagnosis for affected patients. As GLI2 is a highly polymorphic gene with many rare/ family-specific variants [Bear et al., 2014], sequencing will very frequently reveal variants of unknown significance that may be challenging to interpret and explain to families. Until whole-genome sequencing becomes ubiquitous, we would suggest that most patients with GLI2 mutations may first come to the attention of endocrinologists rather than neurologists, neonatologists, or even geneticists, and that this gene be primarily considered on the differential diagnosis of any patient with pituitary insufficiency with or without polydactyly.
ACKNOWLEDGMENTS Pertaining to KAB, the views expressed in this abstract/manuscript are those of the author and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the US Government.
REFERENCES Bear KA, Solomon BD, Antonini S, Arnhold IJ, Franca MM, Gerkes EH, Grange DK, Hadley DW, Jaaskelainen J, Paulo SS, Rump P, Stratakis CA, Thompson EM, Willis M, Winder TL, Jorge AA, Roessler E, Muenke M. 2014. Pathogenic mutations in GLI2 cause a specific
AMERICAN JOURNAL OF MEDICAL GENETICS PART A phenotype that is distinct from holoprosencephaly. J Med Genet 51:413–418. Culler FL, Jones KL. 1984. Hypopituitarism in association with postaxial polydactyly. J Pediatr 104:881–884. Franca MM, Jorge AA, Carvalho LR, Costalonga EF, Otto AP, Correa FA, Mendonca BB, Arnhold IJ. 2013. Relatively high frequency of nonsynonymous GLI2 variants in patients with congenital hypopituitarism without holoprosencephaly. Clin Endocrinol (Oxf) 78:551–557. Franca MM, Jorge AA, Carvalho LR, Costalonga EF, Vasques GA, Leite CC, Mendonca BB, Arnhold IJ. 2010. Novel heterozygous nonsense GLI2 mutations in patients with hypopituitarism and ectopic posterior pituitary lobe without holoprosencephaly. J Clin Endocrinol Metab 95:E384–E391. Kordaß U, Schr€ oder C, Elbracht M, Soellner L. Eggermann T. 2015. A familial GLI2 deletion (2q14.2) not associated with the holoprosencephaly syndrome phenotype. Am J Med Genet 167:1121–1124. Roessler E, Du YZ, Mullor JL, Casas E, Allen WP, Gillessen-Kaesbach G, Roeder ER, Ming JE, Ruiz i Altaba A, Muenke M. 2003. Loss-of-function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly-like features. Proc Natl Acad Sci USA 100:13424–13429. Roessler E, Ermilov AN, Grange DK, Wang A, Grachtchouk M, Dlugosz AA, Muenke M. 2005. A previously unidentified amino-terminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2. Hum Mol Genet 14:2181–2188. Solomon BD, Mercier S, Velez JI, Pineda-Alvarez DE, Wyllie A, Zhou N, Dubourg C, David V, Odent S, Roessler E, Muenke M. 2010. Analysis of genotype-phenotype correlations in human holoprosencephaly. Am J Med Genet C Semin Med Genet 154C:133–141.
GLI2 Mutations Typically Result in Pituitary Anomalies With or Without Postaxial Polydactyly Kelly A. Bear1 and Benjamin D. Solomon2,3,4* 1
Department of Pediatrics, Tripler Army Medical Center, Honolulu, Hawaii
2
Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia
3
Inova Translational Medicine Institute and Inova Children’s Hospital, Inova Health System, Falls Church, Virginia Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, Virginia
4
Manuscript Received: 8 April 2015; Manuscript Accepted: 28 April 2015
TO THE EDITOR: Mutations in GLI2 were first identified by analyzing a large cohort of patients with holoprosencephaly (HPE) and/or with manifestations suggestive of midline neurodevelopmental anomalies [Roessler et al., 2003; Roessler et al., 2005]. More recently, it has become clear that mutations in GLI2 do not tend to result in frank HPE, but instead cause a distinct phenotype that includes pituitary insufficiency and/or polydactyly, as well as subtle facial variants [Franca et al., 2010, 2013; Bear et al., 2014]. In a recent review of all reported cases, only 1 of 43 (2%) of patients with loss-of-function mutations (these included whole-gene or near whole-gene deletions) had true HPE. In fact, the proportion of patients with GLI2 mutations and HPE may be even lower than this 2% value, as there remains an ascertainment bias based on the originally studied cohorts. The studies included in the review consisted mainly of individuals from cohorts tested secondary to HPE, cleft lip/palate, pituitary hormone deficiencies, and craniofacial anomalies. Many other patients have been described with GLI2 variants and similar phenotypes, but the pathogenicity of these variants remains unclear and the observed phenotypes may well be unrelated to the GLI2 variants [Bear et al., 2014]. In OMIM (http://www.ncbi.nlm.nih.gov/omim, last accessed April 6, 2015), mutations in GLI2 are now described as causing Culler–Jones syndrome (as well as Holoprosencephaly 9). “Culler–Jones syndrome” is based on a report of a family – described over 30 years ago – with hypopituitarism and postaxial polydactyly [Culler and Jones, 1984]. This family was later found to segregate a truncating GLI2 mutation [Roessler et al., 2005]. Interestingly, and reflecting challenges with naming syndromes, “Culler–Jones syndrome” replaces a short-lived OMIM designation of “Pallister–Hall syndrome 2.” The recent article by Kordaß et al. [2015] is a valuable addition to the literature in terms of describing an interesting family in which the proband was ascertained due to growth retardation, and was noted to have other clinical findings, including cardiac defects, a multicystic kidney, scoliosis, and dysmorphic facial features. The patient’s phenotype may well result from loss of multiple genes and other genetic factors in the deleted region on chromosome 2q14. As with many conditions resulting from contiguous gene deletions, a
© 2015 Wiley Periodicals, Inc.
How to Cite this Article:
Bear KA, Solomon BD. 2015. GLI2 mutations typically result in pituitary anomalies with or without postaxial polydactyly. Am J Med Genet Part A 167A:2491–2492.
satisfying biologic explanation of how this deletion resulted in this exact phenotype is currently lacking. However, the growth retardation described in the patient can likely be ascribed to the deletion of GLI2 within the identified interval. It is important to emphasize that the phenotype due to GLI2 mutations is distinct from that caused by mutations in genes such as SHH, ZIC2, and SIX3. These latter might be considered the “classic” (and certainly most frequently involved) HPE genes, though the phenotype of affected patients can differ both among and between patients with mutations in these genes [Solomon et al., 2010]. In other words, it is unsurprising that the patient reported by Kordaß et al. [2015] did not have HPE (or a family history thereof). Based on the literature mentioned above, the reverse would be more surprising, and might today prompt further studies for another genetic explanation, such as a mutation affecting a “true HPE” gene. Awareness of the GLI2-related phenotype (whether called Culler–Jones syndrome or something else) is important in terms of genetic counseling and management of patients with identified mutations. Recognition of this phenotype is also important to Neither author has any conflicts of interest or disclosures. Correspondence to: Benjamin D. Solomon, M.D., Inova Translational Medicine Institute, 3300 Gallows Road/Claude Moore Building, 2nd Floor, Falls Church, VA 22042. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 14 May 2015 DOI 10.1002/ajmg.a.37160
2491
2492 help with the molecular differential diagnosis for affected patients. As GLI2 is a highly polymorphic gene with many rare/ family-specific variants [Bear et al., 2014], sequencing will very frequently reveal variants of unknown significance that may be challenging to interpret and explain to families. Until whole-genome sequencing becomes ubiquitous, we would suggest that most patients with GLI2 mutations may first come to the attention of endocrinologists rather than neurologists, neonatologists, or even geneticists, and that this gene be primarily considered on the differential diagnosis of any patient with pituitary insufficiency with or without polydactyly.
ACKNOWLEDGMENTS Pertaining to KAB, the views expressed in this abstract/manuscript are those of the author and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the US Government.
REFERENCES Bear KA, Solomon BD, Antonini S, Arnhold IJ, Franca MM, Gerkes EH, Grange DK, Hadley DW, Jaaskelainen J, Paulo SS, Rump P, Stratakis CA, Thompson EM, Willis M, Winder TL, Jorge AA, Roessler E, Muenke M. 2014. Pathogenic mutations in GLI2 cause a specific
AMERICAN JOURNAL OF MEDICAL GENETICS PART A phenotype that is distinct from holoprosencephaly. J Med Genet 51:413–418. Culler FL, Jones KL. 1984. Hypopituitarism in association with postaxial polydactyly. J Pediatr 104:881–884. Franca MM, Jorge AA, Carvalho LR, Costalonga EF, Otto AP, Correa FA, Mendonca BB, Arnhold IJ. 2013. Relatively high frequency of nonsynonymous GLI2 variants in patients with congenital hypopituitarism without holoprosencephaly. Clin Endocrinol (Oxf) 78:551–557. Franca MM, Jorge AA, Carvalho LR, Costalonga EF, Vasques GA, Leite CC, Mendonca BB, Arnhold IJ. 2010. Novel heterozygous nonsense GLI2 mutations in patients with hypopituitarism and ectopic posterior pituitary lobe without holoprosencephaly. J Clin Endocrinol Metab 95:E384–E391. Kordaß U, Schr€ oder C, Elbracht M, Soellner L. Eggermann T. 2015. A familial GLI2 deletion (2q14.2) not associated with the holoprosencephaly syndrome phenotype. Am J Med Genet 167:1121–1124. Roessler E, Du YZ, Mullor JL, Casas E, Allen WP, Gillessen-Kaesbach G, Roeder ER, Ming JE, Ruiz i Altaba A, Muenke M. 2003. Loss-of-function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly-like features. Proc Natl Acad Sci USA 100:13424–13429. Roessler E, Ermilov AN, Grange DK, Wang A, Grachtchouk M, Dlugosz AA, Muenke M. 2005. A previously unidentified amino-terminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2. Hum Mol Genet 14:2181–2188. Solomon BD, Mercier S, Velez JI, Pineda-Alvarez DE, Wyllie A, Zhou N, Dubourg C, David V, Odent S, Roessler E, Muenke M. 2010. Analysis of genotype-phenotype correlations in human holoprosencephaly. Am J Med Genet C Semin Med Genet 154C:133–141.
