Ovarian failure in HAX1-deficient patients: is there a gender-specific difference in pubertal development in severe congenital neutropenia or Kostmann disease?

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Severe congenital neutropenia (SCN) is a rare disorder of myelopoiesis characterized by neutropenia, recurrent bacterial infections and a maturation arrest of the myelopoiesis in the bone marrow. Homozygous mutations in the HAX1 gene were described in patients with autosomal recessive SCN or Kostmann disease. Some of these patients display neurological disease. We noted, during the course of clinical management of patients with Kostmann disease, insufficient pubertal development in female patients, but not in our male patients. The study objective was to provide a detailed account of this phenotype and its possible relation to HAX1 mutations.


Detailed clinical histories and laboratory investigations of three patients with Kostmann disease belonging to the original kindred in northern Sweden described by Rolf Kostmann are reported.


We report one male patient with normal puberty and two female patients with insufficient pubertal development. Elevated levels of LH and FSH were recorded in both patients. All three patients harbour the same p.Glu190X mutation in the HAX1 gene.


We show for the first time that female patients with Kostmann disease display primary gonadal insufficiency. This suggests a possible role for HAX1 in the development and/or function of the human ovary.

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