Pancreatic And Cerebellar Agenesis

A number sign (#) is used with this entry because of evidence that pancreatic and cerebellar agenesis (PACA) is caused by homozygous mutation in the PTF1A gene (607194) on chromosome 10p12.

A form of isolated pancreatic agenesis (PAGEN2; 615935) is caused by mutation in a distal enhancer of the PTF1A gene.

Clinical Features

Hoveyda et al. (1999) described neonatal diabetes mellitus with cerebellar hypoplasia/agenesis, and dysmorphism. The patients they observed were referred to as Asian (specifically Pakistani). There was a strong family history of noninsulin-dependent diabetes mellitus (see 125853) in the absence of obesity. Three cases were described, 2 sisters and a female first cousin. All 3 had dysmorphic facial features consisting of beaked nose and low set, dysplastic ears. A wizened triangular face and presence of very little subcutaneous fat were noted. Prenatal diagnosis of the condition was possible in this family by demonstration of the absence of the cerebellum on imaging studies and severe intrauterine growth retardation (IUGR).

Sellick et al. (2004) studied an individual from a consanguineous northern European family with a phenotype identical to that of the patients of Hoveyda et al. (1999). Severe IUGR, flexion contractures of arms and legs, very little subcutaneous fat, and optic nerve hypoplasia were seen. A computed tomography scan of the brain demonstrated agenesis of cerebellum and vermis. No pancreas was present at autopsy, and detailed macroscopic and microscopic examination failed to detect any pancreatic tissue in the abdominal cavity.

Al-Shammari et al. (2011) described a male infant, the first child of healthy first-cousin Saudi parents, with this syndrome. Antenatal ultrasound showed intrauterine growth retardation and atrophic cerebellum. At birth, his growth parameters were below the third percentile. Dysmorphic features included triangular face, small chin, generalized joint stiffness, and bilateral talipes equinovarus. He had meconium ileus and was found to have diabetes mellitus. Brain MRI showed cerebellar agenesis. Ophthalmologic examination showed bilateral optic atrophy. The pancreas could not be visualized on abdominal ultrasound. The infant died at 4 months of age.

Molecular Genetics

In the consanguineous Pakistani family which Hoveyda et al. (1999) first described the syndrome of pancreatic and cerebellar agenesis, Sellick et al. (2004) found by positional candidate gene approach a mutation in the PTF1A gene (607194.0001). They found a different PTF1A mutation in a consanguineous family of northern European descent (607194.0002).

Tutak et al. (2009) reported a male infant, born of consanguineous Turkish parents, who had cerebellar agenesis and neonatal diabetes mellitus and died at 1.5 months of age. The parents declined permission for necropsy, but the authors identified heterozygosity for a frameshift mutation in the PTF1A gene (Gly240fsTer276) in both parents. Tutak et al. (2009) stated that this was the fifth patient with cerebellar agenesis and diabetes mellitus reported to date.

In a male infant with PACA, whose parents were healthy first cousins, Al-Shammari et al. (2011) identified a homozygous truncating mutation in the PTF1A gene (607194.0003).