Microcephaly, Short Stature, And Impaired Glucose Metabolism 2

A number sign (#) is used with this entry because of evidence that microcephaly, short stature, and impaired glucose metabolism-2 (MSSGM2) is caused by homozygous mutation in the PPP1R15B gene (613257) on chromosome 1q32.

Another syndrome involving microcephaly, short stature, and impaired glucose metabolism (MSSGM1; 616033) is caused by mutation in the TRMT10A gene (616013) on chromosome 4q23.

Clinical Features

Abdulkarim et al. (2015) studied a brother and sister from a consanguineous Algerian family who had microcephaly, short stature, and insulin-dependent diabetes mellitus. The 28-year-old brother had acute onset of polyuria and polydipsia at age 15 years and was diagnosed with diabetes. Type I diabetes-specific autoantibodies were negative, and there was evidence for residual beta-cell mass. Diabetes was initially well-controlled with relatively low doses of insulin, but evolved to significant glucose variability with severe hypoglycemic episodes and seizures. He also exhibited growth retardation, delayed puberty, and undescended right testis, but had normal growth hormone, testosterone, luteinizing hormone, and follicle-stimulating hormone levels. He eventually achieved full pubertal development, with adult genitalia and complete epiphyseal closure. He had microcephaly, severe intellectual disability, and neurogenic deafness. Brain MRI showed rarefaction of white matter. Other features included kyphoscoliosis, pectus excavatum, mild abnormalities of vertebral bodies, oligodontia and dental hypoplasia, sparse hair, and a high-pitched voice. Eye fundus was normal. Ultrasound showed small kidneys, with mild dilation of calyces. The proband's 31-year-old sister was similarly affected, with growth retardation, microcephaly, intellectual disability, and diabetes presenting with acute hyperglycemia and ketoacidosis at age 28 years. She also had dental hypoplasia and a high-pitched voice. She underwent menarche at 14 years of age. Both sibs were small for gestational age at birth. Their first-cousin parents had normal fasting glucose values, and the mother was not known to have had gestational diabetes.

Kernohan et al. (2015) reported a Canadian sister and brother, born to second-cousin parents, who had severe microcephaly, short stature, intellectual disability, and hypoplastic brainstem and cord with delayed myelination. The 5-year-old sister and 3.75-year-old brother shared similar dysmorphic features that included round face, full cheeks, hypotelorism, downslanting palpebral fissures, epicanthal folds, small mouth with downturned corners, micrognathia, large ears, fine sparse hair, and shoulders that were rounded and sloping. The sister had a small vocabulary and her speech was dysarthric; her brother could mimic sounds but had no clear words. Neurologic evaluation showed decreased axial tone with spasticity that was greater in the lower than upper extremities and weak distal strength. Plantar reflexes were downgoing with brisk reflexes in the sister, whereas the brother had upgoing plantar reflexes. Sensation appeared intact. Both sibs had a wide-based ataxic gait with truncal instability and everted feet. The sister also had a low amplitude/high frequency kinetic tremor in both hands and mild dysmetria. Brain MRI in both sibs showed delayed myelination, small brainstem, decreased cerebellar volume, thin corpus callosum, and diminished volume of the cervical cord. The brother also had pectus excavatum with strikingly visible veins.

Molecular Genetics

By whole-exome sequencing in an Algerian man from a consanguineous family with microcephaly, short stature, intellectual disability, and diabetes, Abdulkarim et al. (2015) identified homozygosity for a missense mutation in the PP1R15B gene (R658C; 613257.0001). His affected sister was also homozygous for the mutation, but parental DNA was unavailable for study. Analysis of PP1R15B in 50 additional patients with a similar clinical presentation did not reveal any mutations.

In a 5-year-old Canadian girl and her 3.75-year-old brother with severe microcephaly, short stature, hypoplastic brainstem and cord, delayed myelination, and intellectual disability, Kernohan et al. (2015) performed whole-exome sequencing and identified homozygosity for the R658C missense mutation in the PP1R15B gene.