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A novel PTF1A mutation in a patient with severe pancreatic and cerebellar involvement

To the Editor : In 1999, Hoveyda and colleagues described the autosomal recessive syndrome of neonatal diabetes and cerebellar hypoplasia (1). Mutations in PTF1A were later identified as the cause of this syndrome (2). In this communication, we describe another case with this syndrome and a novel truncating mutation. Index is a 2-month-old male infant, the first child of healthy first cousin Saudi parents. Antenatal ultrasound showed intrauterine growth retardation and atrophic cerebellum. He was born at 36 weeks of gestation by emergency cesarean section due to fetal distress. The liquor was noted to be gelatinous. Growth parameters were well below the third percentile. Dysmorphism was noted in the form of triangular face, small chin, generalized joint stiffness and bilateral talipes equinovarus (photos declined). Breathing was irregular and mechanical ventilation was required shortly after birth. He passed a remarkably thick meconium plug (Fig. 1a) and was diagnosed to have neonatal diabetes mellitus. MRI brain showed cerebellar agenesis (Fig. 1b). Ophthalmological examination showed bilateral optic atrophy. Pancreas could not be visualized on abdominal ultrasound. Thyroid function test was normal and he had normal male karyotype. He remained dependent on mechanical ventilation, failed to gain weight, and suffered from TPN-related hepatopathy and anemia that required multiple blood transfusions. He died at 4 months of age. After obtaining written informed consent, DNA was extracted from whole blood followed by polymerase chain reaction (PCR) amplification and sequencing of PTF1A (PCR primers and conditions are available upon request). A novel homozygous deletion was identified (c.437-460del) that predicts frameshift and premature truncation of the protein (p.Ala146_Arg154 delfsX115) (Fig. 1c). Among the earliest regulators of pancreatic development is PTF1A, a transcription factor that binds specific motifs found in the vicinity of downstream genes that are in turn important for proper pancreatic development (3). Evidence for PTF1A being necessary for pancreatic development came first from Ptf1a knockout mouse which displays early lethality due to lack of pancreatic tissue (4). Interestingly, these mice have ectopic β-cells that generate trivial amounts of insulin (4–5). PTF1A is also required for normal cerebellar development through the induction of GABAergic-specific genes and suppression of glutamatergic-specific genes, a dual role that is critical for the generation of the major populations of GABAergic neurons in the cerebellum (6–8). The role of PTF1A in the cerebellar and pancreatic agenesis syndrome was demonstrated in two previous studies (2, 9). Our patient increases to four, the number of pathogenic variants identified in PTF1A, all of which are truncating. In fact, our mutation, almost certainly renders the protein inactive because not only will the protein be devoid of the C-terminal domain that was experimentally shown to be necessary for the transcriptional co-activation, but it also eliminates the helix-loop-helix motif, the defining motif of this protein (2, 10). The clinical phenotype being similar to the previous cases suggests that they all had a similar degree of loss of function, most probably complete null. This raises the intriguing possibility that mutations with less dramatic effect on the protein function may result in a different phenotype. Indeed, that PTF1A acts in a dosage-sensitive manner to regulate pancreatic development suggests that milder loss of function mutations may lead to milder pancreatic phenotype (11–12). This was partially addressed by screening patients with isolated neonatal diabetes for mutations in PTF1A although none were identified (2). It is noteworthy that our patient’s meconium ileus, a common phenotype of in utero abnormal exocrine pancreas, was not documented in previous reports so it could be that ectopic pancreatic cells may have ameliorated the phenotype in those patients. Unfortunately, available data on mouse and human exocrine pancreatic deficiency