Kallmann syndrome

Abstract

The Kallmann syndrome (KS) combines hypogonadotropic hypogonadism (HH) with anosmia. This is a clinically and genetically heterogeneous disease. KAL1, encoding the extracellular glycoprotein anosmin-1, is responsible for the X chromosome-linked recessive form of the disease. Mutations in FGFR1 or FGF8, encoding fibroblast growth factor receptor-1 and fibroblast growth factor-8, respectively, underlie an autosomal dominant form with incomplete penetrance. Finally, mutations in PROKR2 and PROK2, encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous, and compound heterozygous states. These two genes are likely to be involved both in monogenic recessive and digenic/oligogenic KS transmission modes. Notably, mutations in any of the above-mentioned KS genes have been found in less than 30% of the KS patients, which indicates that other genes involved in the disease remain to be discovered.

Figure 1

Genetic testing strategy for Kallmann syndrome. The strategy is based on patient's gender, familial history (if any) and putative mode of disease inheritance, and the presence of additional clinical anomalies that may direct the geneticist towards a particular disease gene or, occasionally, a contiguous gene syndrome at Xp22.3 or 8p11.2 p12. The search for KAL1 mutations is restricted to affected males, either isolated cases or patients with a familial history compatible with X-linked recessive mode of inheritance. Mutation screening of the known KS genes (KAL1, FGFR1, FGF8, PROKR2, PROK2) leads to the identification of a mutation in less than one-third of the patients. Notably, as many as 30% of the mutations found in FGFR1 might be de novo mutations, certainly a possibility to be considered before assessing recurrence risk of this genetic form in a family. The main differential diagnoses of KS are normosmic idiopathic hypogonadotropic hypogonadism and CHARGE syndrome.

Figure 2

Cranial magnetic resonance imaging (MRI) of the olfactory bulb region in a control man (a and b) and a man affected by Kallmann syndrome (c and d). (a and b) MRI T2-weighted sequence in coronal plane shows normal olfactory bulbs in the control individual (a, white arrows), and posterior to the olfactory bulbs, good differentiation of the rhinal sulci (b, white arrows) and olfactory tracts (b, white arrowheads). (c) MRI T2-weighted sequence in coronal plane shows very small olfactory bulbs in the KS patient (white arrows). On the right side, the rhinal sulcus (white arrowhead) is visible, with good differentiation between the right gyrus and orbital gyrus. On the left side, there is no rhinal sulcus (black arrowhead), and no differentiation between the right and orbital gyri. (d) MRI T1-weighted sequence in coronal plane, posterior to olfactory bulbs, confirms the presence of the rhinal sulcus on the right side (white arrow), with a relatively good differentiation between the right (white arrowhead) and orbital (black arrowhead) gyri, and the absence of the rhinal sulcus on the left side (black arrow).