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.