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Expanding the Clinical Spectrum Associated With GLIS3 Mutations.

Dimitri P, Habeb AM, Garbuz F, Millward A, Wallis S, Moussa K, Akcay T, Taha D, Hogue J, Slavotinek A, Wales JK, Shetty A, Hawkes D, Hattersley AT, Ellard S, De Franco E - J. Clin. Endocrinol. Metab. (2015)

Bottom Line: Thyroid disease varied among patients.Hepatic and renal disease was common with liver dysfunction ranging from hepatitis to cirrhosis; cystic dysplasia was the most common renal manifestation.All but 2 of the patients within our cohort are still alive, and we describe the first patient to live to adulthood with a GLIS3 mutation, suggesting that even patients with a severe GLIS3 phenotype may have a longer life expectancy than originally described.

View Article: PubMed Central - PubMed

Affiliation: Department of Paediatric Endocrinology (P.D.), Sheffield Children's NHS Foundation Trust, Sheffield S10 2TH, United Kingdom; Paediatric Department (A.M.H.), Prince Mohamed Bin Abdulaziz Hospital, National Guard Health Authority, Al-Madinah, Riyadh 14214, Kingdom of Saudi Arabia; Ankara Pediatric Hematology Oncology Education and Training Hospital (F.G.), Ankara, Turkey; Diabetes Clinical Research Centre (A.M.), Plymouth Hospitals NHS Trust, Derriford PL6 8DH, United Kingdom; Department of Paediatrics (S.W.), Bradford Teaching Hospitals NHS Foundation Trust, Bradford, West Yorkshire BD9 6RJ, United Kingdom; Paediatric Department (K.M.), Maternity and Children Hospital, Jeddah 23342, Kingdom of Saudi Arabia; Kanuni Sultan Süleyman Education and Research Hospital (T.A.), 34303 Küçükçekmece, Istanbul, Turkey; Division of Pediatric Endocrinology (D.T.), Children's Hospital of Michigan, Wayne State University, Detroit, Michigan 48201; Department of Paediatrics (J.J.), Madigan Army Medical Center, Tacoma, Washington 98431; Institute for Human Genetics (A.S.), University of California, San Francisco, California 94143; Department of Paediatric Endocrinology and Diabetes (J.K.H.W.), Lady Cilento Children's Hospital, South Brisbane, Queensland 4101, Australia; Department of Paediatrics (A.S.), Nevill Hall Hospital, Abergavenny NP7 7EG, Wales, United Kingdom; Department of Paediatrics (D.H.), Royal Gwent Hospital, Newport NP20 2UB Wales, United Kingdom; and Institute of Biomedical and Clinical Science (A.T.H., S.E., E.D.F.), University of Exeter Medical School, EX2 5DW, United Kingdom.

ABSTRACT

Context: GLIS3 (GLI-similar 3) is a member of the GLI-similar zinc finger protein family encoding for a nuclear protein with 5 C2H2-type zinc finger domains. The protein is expressed early in embryogenesis and plays a critical role as both a repressor and activator of transcription. Human GLIS3 mutations are extremely rare.

Objective: The purpose of this article was determine the phenotypic presentation of 12 patients with a variety of GLIS3 mutations.

Methods: GLIS3 gene mutations were sought by PCR amplification and sequence analysis of exons 1 to 11. Clinical information was provided by the referring clinicians and subsequently using a questionnaire circulated to gain further information.

Results: We report the first case of a patient with a compound heterozygous mutation in GLIS3 who did not present with congenital hypothyroidism. All patients presented with neonatal diabetes with a range of insulin sensitivities. Thyroid disease varied among patients. Hepatic and renal disease was common with liver dysfunction ranging from hepatitis to cirrhosis; cystic dysplasia was the most common renal manifestation. We describe new presenting features in patients with GLIS3 mutations, including craniosynostosis, hiatus hernia, atrial septal defect, splenic cyst, and choanal atresia and confirm further cases with sensorineural deafness and exocrine pancreatic insufficiency.

Conclusion: We report new findings within the GLIS3 phenotype, further extending the spectrum of abnormalities associated with GLIS3 mutations and providing novel insights into the role of GLIS3 in human physiological development. All but 2 of the patients within our cohort are still alive, and we describe the first patient to live to adulthood with a GLIS3 mutation, suggesting that even patients with a severe GLIS3 phenotype may have a longer life expectancy than originally described.

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Related in: MedlinePlus

Extensive renal cystic dysplasia in patient 2 with a mutation in GLIS3 at 5 months of age.
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Figure 2: Extensive renal cystic dysplasia in patient 2 with a mutation in GLIS3 at 5 months of age.

Mentions: Liver disease was documented in 7 of our 12 patients. The hepatic dysfunction presented concomitantly with renal abnormalities and ranged from hepatitis (patients 3b and 4) to hepatic fibrosis and cirrhosis (patients 2, 3a, 6, 7, 9, and 10). Nine patients have anatomical kidney changes. Of these, 7 children showed variable renal cystic dysplasia ranging from an isolated cyst observed in patient 10 and bilateral calyceal calcification in patient 11 to extensive cystic renal dysplasia (patients 2, 3a, 3b, 4, and 9) (Figure 2). Patient 7 lacks renal corticomedullary differentiation, and renal ultrasonography in patient 6 demonstrated bilateral renal enlargement with no cystic changes.


Expanding the Clinical Spectrum Associated With GLIS3 Mutations.

Dimitri P, Habeb AM, Garbuz F, Millward A, Wallis S, Moussa K, Akcay T, Taha D, Hogue J, Slavotinek A, Wales JK, Shetty A, Hawkes D, Hattersley AT, Ellard S, De Franco E - J. Clin. Endocrinol. Metab. (2015)

Extensive renal cystic dysplasia in patient 2 with a mutation in GLIS3 at 5 months of age.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4596041&req=5

Figure 2: Extensive renal cystic dysplasia in patient 2 with a mutation in GLIS3 at 5 months of age.
Mentions: Liver disease was documented in 7 of our 12 patients. The hepatic dysfunction presented concomitantly with renal abnormalities and ranged from hepatitis (patients 3b and 4) to hepatic fibrosis and cirrhosis (patients 2, 3a, 6, 7, 9, and 10). Nine patients have anatomical kidney changes. Of these, 7 children showed variable renal cystic dysplasia ranging from an isolated cyst observed in patient 10 and bilateral calyceal calcification in patient 11 to extensive cystic renal dysplasia (patients 2, 3a, 3b, 4, and 9) (Figure 2). Patient 7 lacks renal corticomedullary differentiation, and renal ultrasonography in patient 6 demonstrated bilateral renal enlargement with no cystic changes.

Bottom Line: Thyroid disease varied among patients.Hepatic and renal disease was common with liver dysfunction ranging from hepatitis to cirrhosis; cystic dysplasia was the most common renal manifestation.All but 2 of the patients within our cohort are still alive, and we describe the first patient to live to adulthood with a GLIS3 mutation, suggesting that even patients with a severe GLIS3 phenotype may have a longer life expectancy than originally described.

View Article: PubMed Central - PubMed

Affiliation: Department of Paediatric Endocrinology (P.D.), Sheffield Children's NHS Foundation Trust, Sheffield S10 2TH, United Kingdom; Paediatric Department (A.M.H.), Prince Mohamed Bin Abdulaziz Hospital, National Guard Health Authority, Al-Madinah, Riyadh 14214, Kingdom of Saudi Arabia; Ankara Pediatric Hematology Oncology Education and Training Hospital (F.G.), Ankara, Turkey; Diabetes Clinical Research Centre (A.M.), Plymouth Hospitals NHS Trust, Derriford PL6 8DH, United Kingdom; Department of Paediatrics (S.W.), Bradford Teaching Hospitals NHS Foundation Trust, Bradford, West Yorkshire BD9 6RJ, United Kingdom; Paediatric Department (K.M.), Maternity and Children Hospital, Jeddah 23342, Kingdom of Saudi Arabia; Kanuni Sultan Süleyman Education and Research Hospital (T.A.), 34303 Küçükçekmece, Istanbul, Turkey; Division of Pediatric Endocrinology (D.T.), Children's Hospital of Michigan, Wayne State University, Detroit, Michigan 48201; Department of Paediatrics (J.J.), Madigan Army Medical Center, Tacoma, Washington 98431; Institute for Human Genetics (A.S.), University of California, San Francisco, California 94143; Department of Paediatric Endocrinology and Diabetes (J.K.H.W.), Lady Cilento Children's Hospital, South Brisbane, Queensland 4101, Australia; Department of Paediatrics (A.S.), Nevill Hall Hospital, Abergavenny NP7 7EG, Wales, United Kingdom; Department of Paediatrics (D.H.), Royal Gwent Hospital, Newport NP20 2UB Wales, United Kingdom; and Institute of Biomedical and Clinical Science (A.T.H., S.E., E.D.F.), University of Exeter Medical School, EX2 5DW, United Kingdom.

ABSTRACT

Context: GLIS3 (GLI-similar 3) is a member of the GLI-similar zinc finger protein family encoding for a nuclear protein with 5 C2H2-type zinc finger domains. The protein is expressed early in embryogenesis and plays a critical role as both a repressor and activator of transcription. Human GLIS3 mutations are extremely rare.

Objective: The purpose of this article was determine the phenotypic presentation of 12 patients with a variety of GLIS3 mutations.

Methods: GLIS3 gene mutations were sought by PCR amplification and sequence analysis of exons 1 to 11. Clinical information was provided by the referring clinicians and subsequently using a questionnaire circulated to gain further information.

Results: We report the first case of a patient with a compound heterozygous mutation in GLIS3 who did not present with congenital hypothyroidism. All patients presented with neonatal diabetes with a range of insulin sensitivities. Thyroid disease varied among patients. Hepatic and renal disease was common with liver dysfunction ranging from hepatitis to cirrhosis; cystic dysplasia was the most common renal manifestation. We describe new presenting features in patients with GLIS3 mutations, including craniosynostosis, hiatus hernia, atrial septal defect, splenic cyst, and choanal atresia and confirm further cases with sensorineural deafness and exocrine pancreatic insufficiency.

Conclusion: We report new findings within the GLIS3 phenotype, further extending the spectrum of abnormalities associated with GLIS3 mutations and providing novel insights into the role of GLIS3 in human physiological development. All but 2 of the patients within our cohort are still alive, and we describe the first patient to live to adulthood with a GLIS3 mutation, suggesting that even patients with a severe GLIS3 phenotype may have a longer life expectancy than originally described.

Show MeSH
Related in: MedlinePlus