Fig. 2.

Brainstem pathology in CCHS probands. a Cartoon of human hindbrain at levels of pons (pink) and medulla (blue) is shown. b Dramatic losses were observed in NPARM PHOX2BΔ8 proband locus coeruleus (LC), dorsal median raphe (MnR), mesencephalic trigeminal nucleus (MesV) and dorsal motor nucleus of vagus (DMNV). Note lack of dopamine β-hydroxylase (DBH) expression in LC and tryptophan hydroxylase (TrypH) in dorsal MnR indicating defects in synthesis of noradrenaline and serotonin production. DMNV showed diminished cholinergic neurons, indicated by choline acetyltransferase (CHAT) expression. Asterisk indicates diminished MesV fibers originating from the nucleus in the proband. H&E hematoxylin and eosin. c Dramatic loss was observed in PARM PHOX2B 20/27 proband LC. Note a significant reduction of DBH expression