A number sign (#) is used with this entry because of evidence that microcephaly, short stature, and impaired glucose metabolism-1 (MSSGM1) is caused by homozygous mutation in the TRMT10A gene (616013) on chromosome 4q23.

Microcephaly, short stature, and impaired glucose metabolism-1 (MSSGM1) is an autosomal recessive syndrome characterized by microcephaly associated with impaired intellectual development, short stature, and early-onset diabetes or abnormalities of glucose homeostasis (Igoillo-Esteve et al., 2013; Gillis et al., 2014).

Genetic Heterogeneity of Microcephaly, Short Stature, and Impaired Glucose Metabolism

MSSGM2 (616817) is caused by mutation in the PPP1R15B gene (613257) on chromosome 1q32.

Also see Wolcott-Rallison syndrome (226980), which is characterized by multiple epiphyseal dysplasia, microcephaly, short stature, and early-onset diabetes mellitus and is caused by mutation in the EIF2AK3 gene (604032) on chromosome 2p11.

Igoillo-Esteve et al. (2013) reported 3 sibs from a consanguineous family of Moroccan descent who had microcephaly with mental retardation, short stature, and early-onset diabetes. The female proband had a history of petit mal seizures in adolescence; brain MRI showed a small brain with no other abnormalities. She developed diabetes at age 22 years, and also had osteoporosis with no other bony abnormalities. Dysmorphic features included short neck, wide nose, low hairline, dorsocervical fat pad, retraction of the right fifth toe, scoliosis, and joint laxity. Her sister and brother, who both had short stature, microcephaly, and mental retardation, also developed diabetes at 19 and 14 years of age, respectively. None of the sibs had ketoacidosis and all were treated with insulin at diagnosis. They were negative for diabetes-associated autoantibodies and had an HLA genotype that did not confer risk for type I diabetes. Endogenous insulin secretion persisted for up to 20 years of follow-up. Their parents developed diabetes in the sixth decade of life and were treated with oral agents; family history included a paternal grandfather and 2 paternal aunts who had adult-onset diabetes, and a sister who developed gestational diabetes at 22 years of age but had a normal fasting plasma glucose at age 30.

Gillis et al. (2014) described a sister and 2 brothers from a consanguineous Jewish Uzbek family who had microcephaly, short stature, and abnormalities of glucose homeostasis. All 3 had delayed psychomotor development, and all experienced recurrent seizures from 5 to 6 years of age, with normal EEG recordings and CT scans. Oral glucose tolerance testing (OGTT) was consistent with insulin resistance (high fasting insulin with low to normal fasting glucose levels) as well as inappropriately low insulin secretion in response to glucose. The 19-year-old female proband was treated with diet alone, including nocturnal feedings to prevent hypoglycemia, and reported occasional seizures following high-carbohydrate meals. She also exhibited delayed pubertal development at 16 years of age, with Tanner stage 2 breast and pubic hair development, and had primary amenorrhea at age 19. OGTT in her 2 affected brothers demonstrated inappropriate insulin secretion, with elevated insulin levels during hypoglycemia; the 14-year-old brother was treated with oral diazoxide, whereas the 13-year-old brother was withdrawn from further study by the parents and treated only by frequent feedings.

In 3 sibs from a consanguineous family of Moroccan descent who had microcephaly, short stature, mental retardation, and early-onset diabetes, Igoillo-Esteve et al. (2013) performed SNP array analysis and identified a 12.4-Mb region of homozygosity, between SNPs rs4128340 and rs10516462 on chromosome 4q22-q23, that was common to all 3 affected sibs. Microsatellite analysis confirmed homozygosity and biparental inheritance of a haplotype shared by both parents, and a multipoint lod score of 3.0 was obtained. Recombination events narrowed the critical region to a 3.1-Mb segment at 4q23.

In a consanguineous family of Moroccan descent in which 3 sibs had microcephaly with mental retardation, short stature, and early-onset diabetes mapping to chromosome 4q23, Igoillo-Esteve et al. (2013) sequenced 5 positional candidate genes but found no mutations. Exome sequencing in the proband revealed homozygosity for a nonsense mutation in the TRMT10A gene (R127X; 616013.0001) that was confirmed by Sanger sequencing. The mutation segregated with disease in the family and was not found in 51 in-house control exomes or in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases. Igoillo-Esteve et al. (2013) screened the TRMT10A gene in 20 patients with a similar phenotype of microcephaly, intellectual disability, seizures, developmental delay, and/or short stature, as well as in 26 probands with early-onset nonautoimmune diabetes who were negative for mutations in MODY (see 125850)-associated genes, but did not detect any mutations.

In the proband from a consanguineous Jewish Uzbek family with microcephaly, short stature, mental retardation, and hyperinsulinemic hypoglycemia, Gillis et al. (2014) identified homozygosity for a missense mutation (G206R; 616013.0002) in the TRMT10A gene. The mutation, which was found by whole-exome sequencing, segregated with disease in the family. The variant was not found in the dbSNP (build 138) database or in 6,503 exomes in the NHLBI Exome Sequencing Project Exome Variant Server database. The proband's 10-month-old brother, who had microcephaly and developmental delay and was born late in the study, was also found to be homozygous for the mutation; fasting blood glucose tested on several occasions was normal, indicating that hypoglycemia was not present in infancy. Gillis et al. (2014) noted that their patients shared the neuronal and growth failures described in association with a nonsense mutation in TRMT10A (Igoillo-Esteve et al., 2013); however, the glucose metabolism disturbances in the Uzbek family, which included ketotic and nonketotic hyperinsulinemic hypoglycemia and postprandial hyperglycemia, differed from those of the Moroccan patients, who had only nonautoimmune insulinopenic diabetes without ketoacidosis.