Alternative titles; symbols
ORPHA: 79118; DO: 0060638;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9p24.2 | Diabetes mellitus, neonatal, with congenital hypothyroidism | 610199 | Autosomal recessive | 3 | GLIS3 | 610192 |
A number sign (#) is used with this entry because of evidence that a syndrome of neonatal diabetes mellitus and congenital hypothyroidism can be caused by homozygous or compound heterozygous mutations in the GLIS3 gene (610192) on chromosome 9p24.
Neonatal diabetes mellitus with congenital hypothyroidism (NDH) syndrome is characterized by intrauterine growth retardation and onset of nonimmune diabetes mellitus within the first few weeks of life. Other features include renal parenchymal disease, primarily renal cystic dysplasia, and hepatic disease, with hepatitis in some patients and hepatic fibrosis and cirrhosis in others. Facial dysmorphism, when present, consistently involves low-set ears, epicanthal folds, flat nasal bridge, long philtrum, and thin upper lip. Most patients exhibit developmental delay (Dimitri et al., 2015).
Taha et al. (2003) described a consanguineous Saudi Arabian family in which 2 of 4 sibs had a syndrome involving neonatal nonimmune diabetes mellitus and severe congenital hypothyroidism, as well as proportionate intrauterine growth retardation, minor facial anomalies, congenital glaucoma, cholestasis, and polycystic kidneys. The liver disease progressed to hepatic fibrosis. The renal disease was characterized by large kidneys and multiple small cysts with deficient corticomedullary junction differentiation and normal kidney function. The phenotype observed in the 2 sibs was identical, and both died in early childhood: the girl at 16 months of age from pneumonia and respiratory failure, and her younger brother at 6 months of age with E. coli sepsis. Although a combination of liver, kidney, and pancreatic involvement had been described in renal-hepatic-pancreatic syndrome (see 263200), the coexistence of neonatal diabetes mellitus, congenital hypothyroidism, and glaucoma in the sibs suggested the possibility that this combination describes a distinct autosomal recessive syndrome.
Senee et al. (2006) studied the original NDH family described by Taha et al. (2003) as well as a second Saudi Arabian family and a consanguineous French family. They reported that a third affected child was born in the original Saudi family, bearing the same clinical features with the exception of cystic kidney disease; he died at 10 days of life from sepsis. In the 2-year-old proband from the second Saudi Arabian family, liver and kidneys were normal. The affected brother and sister from the French Gypsy family had normal liver, kidneys, and eyes, and they were alive at 22 years and 14 years of age.
Dimitri et al. (2011) reported a Bangladeshi girl and a Welsh boy with neonatal diabetes, hypothyroidism, neonatal hepatitis, and renal cysts, who both also developed pancreatic exocrine insufficiency. In addition, the Bangladeshi girl had portal hypertension and developed portal and esophageal varices. She also exhibited osteopenia with thoracolumbar lordosis and multiple left-sided rib fractures; at 1 year of age, the callus around earlier rib fractures remained, and her ribs appeared gracile with thin long bone cortices on x-ray. Additional features in the Welsh boy included hepatic cholestasis, patent ductus arteriousus, and bilateral sensorineural deafness requiring hearing aids.
Dimitri et al. (2015) studied 12 patients with NDH from 11 unrelated families, including the Bangladeshi girl and Welsh boy previously reported by Dimitri et al. (2011). Neonatal diabetes was diagnosed within the first few weeks of life in all 12 patients, 4 of whom also exhibited exocrine pancreatic dysfunction. All but 1 patient also had congenital hypothyroidism, in association with structural thyroid abnormalities ranging from athyreosis or glandular hypoplasia to apparently normal anatomy. Postmortem examination in 1 patient showed a paucity of colloid as well as extensive perifollicular and interstitial fibrosis despite initially normal thyroid ultrasonography. Renal parenchymal disease, primarily renal cystic dysplasia, was present in 10 patients. Liver disease was documented in 8 patients, including hepatitis in 2 and hepatic fibrosis and cirrhosis in 6. In the 9 patients who exhibited facial dysmorphism, consistent features included low-set ears, epicanthal folds, flat nasal bridge, long philtrum, and thin upper lip. Developmental delay was also present in 9 patients. Other features included skeletal abnormalities in 4 patients, congenital glaucoma in 4, and sensorineural deafness in 3; in addition, sagittal craniosynostosis, choanal atresia, hiatal hernia, atrial septal defect, and splenic cyst were also seen in 1 patient each.
In 2 Saudi Arabian families and 1 French Gypsy family with NDH syndrome, Senee et al. (2006) performed a genomewide linkage scan and obtained evidence of linkage, under a fully penetrant recessive model, to a single region on chromosome 9. Fine mapping with additional markers defined a 7.3-cM region, for which a lod score of 4.67 was obtained.
In affected members of the Saudi Arabian family with NDH syndrome, originally described by Taha et al. (2003), Senee et al. (2006) identified homozygosity for a 1-bp insertion in the GLIS3 gene (2067insC; 610192.0001). In affected individuals from another Saudi Arabian family and a French Gypsy family with NDH syndrome, they identified homozygosity for 2 different deletions, both involving part of the 5-prime UTR of the GLIS3 gene. In the proband from the second Saudi family, the deletion encompassed the SLC1A1 gene, but the patient did not exhibit any clinical features beyond those present in the affected sibs from the first Saudi family, who carried an intact SLC1A1 gene.
Dimitri, P., Habeb, A. M., Gurbuz, F., Millward, A., Wallis, S., Moussa, K., Akcay, T., Taha, D., Hogue, J., Slavotinek, A., Wales, J. K. H., Shetty, A., Hawkes, D., Hattersley, A. T., Ellard, S., De Franco, E. Expanding the clinical spectrum associated with GLIS3 mutations. J. Clin. Endocr. Metab. 100: E1362-E1369, 2015. Note: Electronic Article. Erratum: J. Clin. Endocr. Metab. 100: 4685 only, 2015. [PubMed: 26259131] [Full Text: https://doi.org/10.1210/jc.2015-1827]
Dimitri, P., Warner, J. T., Minton, J. A. L., Patch, A. M., Ellard, S., Hattersley, A. T., Barr, S., Hawkes, D., Wales, J. K., Gregory, J. W. Novel GLIS3 mutations demonstrate an extended multisystem phenotype. Europ. J. Endocr. 164: 437-443, 2011. [PubMed: 21139041] [Full Text: https://doi.org/10.1530/EJE-10-0893]
Senee, V., Chelala, C., Duchatelet, S., Feng, D., Blanc, H., Cossec, J.-C., Charon, C., Nicolino, M., Boileau, P., Cavener, D. R., Bougneres, P., Taha, D., Julier, C. Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nature Genet. 38: 682-687, 2006. [PubMed: 16715098] [Full Text: https://doi.org/10.1038/ng1802]
Taha, D., Barbar, M., Kanaan, H., Williamson Balfe, J. Neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, polycystic kidneys, and congenital glaucoma: a new autosomal recessive syndrome? Am. J. Med. Genet. 122A: 269-273, 2003. [PubMed: 12966531] [Full Text: https://doi.org/10.1002/ajmg.a.20267]