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 % 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 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
Validation

Diseases presenting "high levels" symptom

22q11.2 deletion syndrome

adrenal incidentaloma

allergic bronchopulmonary aspergillosis

alpha-thalassemia

aromatase deficiency

cadasil

canavan disease

classical phenylketonuria

congenital adrenal hyperplasia

congenital toxoplasmosis

cutaneous mastocytosis

cystinuria

dentin dysplasia

dentinogenesis imperfecta

dracunculiasis

dystrophic epidermolysis bullosa

erythropoietic protoporphyria

gm1 gangliosidosis

hereditary cerebral hemorrhage with amyloidosis

holt-oram syndrome

homocystinuria without methylmalonic aciduria

kabuki syndrome

kallmann syndrome

liposarcoma

papillon-lefèvre syndrome

phenylketonuria

primary effusion lymphoma

primary hyperoxaluria type 1

scrub typhus

severe combined immunodeficiency

systemic capillary leak syndrome

triple a syndrome

von hippel-lindau disease

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

You can validate or delete this automatically detected symptom