Kallmann syndrome and schizencephaly: concurrent neuron migration defects. (#241)
The pathogenesis of Kallmann syndrome lies in faulty migration of olfactory sensory neurons and gonadotrophin-releasing neurons from the olfactory placode through the cribriform plate into the olfactory bulb and hypothalamus, respectively. Genetic mutations of anosmin-1, FGF8, FGFR1, PROK2, PROKR2, WDR11 and CHD7 genes cause neuron migration failure, hypogonadotrophic hypogonadism and variable anosmia. We describe a patient with dual neuron migration disorders.
A 20 year old woman presented to the endocrinology service with failure of coitus, primary amenorrhoea and arrested puberty. Medical history was significant for an eating disorder at age 15. She performed poorly at school and has received a disability pension since a cognitive assessment at age 17 confirming learning disability. Examination revealed height 166cm, weight 55kg, BMI 19.9, Tanner stage 2. Cardiovascular, respiratory, and abdominal examinations were unremarkable. There were no features of Turner syndrome, craniofacial abnormalities, acne, hirsutism, or excess pigmentation.
Initial investigations revealed hypogonadotrophic hypogonadism with FSH <1IU/L, LH <1IU/L, E2 <70pmol/L, progesterone <0.5nmol/L. All other pituitary axes were intact. Karyotype and DNA microarray were normal. Bone age on wrist X-ray was concordant with chronological age. Ultrasound demonstrated hypolastic uterus and atrophic ovaries.
Anosmia was confirmed clinically. MRI brain demonstrated a normal pituitary, lack of olfactory sulci, and olfactory bulb aplasia, consistent with Kallmann syndrome. However the MRI also demonstrated an abnormal corpus callosum and schizencephaly, a neuron migration abnormality. Literature review suggests this is the first reported case of dual neuron migration abnormalities in a patient with Kallmann syndrome. Given the common pathogenesis of these disorders, we propose to perform whole-brain MRI scanning in a series of new diagnoses of Kallmann syndrome, rather than limiting scans to pituitary and olfactory areas, in an attempt to characterise any concurrent neuron migration abnormalities that may represent an unknown associated feature of the disorder.