Hyperosmia, ectrodactyly, mild intellectual disability, and other defects in a male patient with an X-linked partial microduplication and overexpression of the KAL1 gene.

[kallmann syndrome]

Loss -of-function mutations of the KAL 1 gene are a known cause of Kallmann syndrome , a disorder characterized by the coexistence of hypogonadotropic hypogonadism and anosmia /hiposmia . On the other hand , neither complete nor partial duplications of KAL 1 have been reported in the literature ; thus , clinical symptoms associated with such alterations remain unknown . Ectrodactyly is a clinically and genetically heterogeneous abnormality presenting with hypoplasia of the central rays of the extremity , which , in around 68 Â % of cases , has unknown underlying molecular defect . In this paper , we report on a sporadic male patient manifesting hyperosmia and ectrodactyly accompanied by additional symptoms involving mild intellectual disability , unilateral hearing loss , genital anomalies , stocky build , and facial dysmorphism . Using a combination of high -resolution array comparative genomic hybridization (array CGH ) and breakpoint analysis , we detected a hemizygous tandem duplication of 110 ,967 Â bp on Xp 22 .31 , encompassing the promoter region and the first two exons of KAL 1 . In order to confirm pathogenicity of the duplication , we tested the level of KAL 1 transcript in blood lymphocytes , showing 79 times higher expression in the proband compared to controls . We , therefore , hypothesize that olfactory hypersensitivity in our proband directly results from KAL 1 overproduction . Additionally , a literature review allowed us to conclude that KAL 1 protein at high levels may interfere with FGFR 1 signaling activity , most probably indirectly giving rise to ectrodactyly , intellectual disability , and genital anomalies . Noteworthy , those symptoms overlap with Hartsfield syndrome caused by FGFR 1 loss -of-function mutations . To conclude , our paper highlights the role of KAL 1 in embryogenesis and provides data on the contribution of KAL 1 overexpression to human pathology .

Diseases
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Diseases presenting "mild intellectual disability" symptom

hirschsprung disease

kallmann syndrome

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