Clinical summary
The index case was the third child of non-consangineous parents. He was delivered prematurely with C-section at age 34+4 due to reduced umbilical blood flow. It was noted that the umbilical cord was thick and had a jelly-like appearance. His weight was 1627 g (-3SD), his head circumference 28,5 cm (-3SD) and his length 39 cm (-4SD) (Fig1A). His APGAR was 9,10,10, and apart from an early hypoglycemic event, and one suspected seizure, he was stable during the neonatal period. Magnetic Resonance Imaging (MR) performed at age 2 months showed large ventricles with thin periventricular substance, underdeveloped corpus callosum, and a delayed myelination. Metabolic investigation did not reveal any cause. CGH-array did not show any alterations of significance. He initially had repeated episodes of hypoglycaemia, and was diagnosed with hyperinsulinemia, for which he received diazoxide. Unfortunally, this induced a lung edema, and was discontinued. He subsequently shifted to an insulin dependent diabetes instead. At age three months he developed epilepsy with multiple seizure types: generalized tonic-clonic, migrating focal, myoclonias and absenses. Virtually no response to anti-epileptic treatment was noted despite trying Levetiracetam, Lamictal, Lakosamide, Clonazepam, Fenobarbital and Zonisamid. He also had numerous central endocrinologic symptoms, including hypothyreosis, obesity and micropenis. In addition, he was often hypothermic, even at ambient room temperature, down to 32° C rectal temperature. He had a poor exocrine pancreatic function, with low pancreatic amylase, despite normal ultrasound of the abdomen, and required substitution of fat-soluble vitamins. He did however, never develop pancreatitis. He had until his death, in multiorgan failure, virtually no development. He had a progressive microcephaly, and obesity, despite adequate nutrition (Fig 1A, 1B).
He had an older brother (Fig 1C), born in Germany 2001, with an almost identical clinical presentation, with the exception of the hypothyreosis. He also died at age 4 years.