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Multicenter Study
. 2025 May;72(5):e31591.
doi: 10.1002/pbc.31591. Epub 2025 Feb 21.

A Little Known but Very Common Phenotype in Patients With Severe Congenital Neutropenia Due to HAX1 Deficiency: Premature Ovarian Insufficiency

Deniz Özalp Kızılay  1 , Deniz Yılmaz Karapınar  2 , Nihal Karadaş  2 , Murat Karaoğlan  3 , Sinan Akbayram  4 , Damla Gökşen  1 , Ayşe Gadashova  2 , Serpil Albayrak  3 , Esra Pekpak Şahinoğlu  4 , Zerrin Orbak  5 , Zafer Bıçakçı  6 , Leyla Akın  7 , Canan Albayrak  8 , Cansu Koç  9 , Ayşegül Ünüvar  10 , Ahmet Anık  11 , Yusuf Ziya Aral  12 , Emine Ayça Cimbek  13 , Ayşenur Bahadır  14 , Cem Mete  15 , Samim Özen  1
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Multicenter Study

A Little Known but Very Common Phenotype in Patients With Severe Congenital Neutropenia Due to HAX1 Deficiency: Premature Ovarian Insufficiency

Deniz Özalp Kızılay et al. Pediatr Blood Cancer. 2025 May.

Abstract

Background: Autosomal recessive severe congenital neutropenia (SCN) has been associated with homozygous variants in the HAX1 gene. The aim of this cross-sectional study was to evaluate the gonadal function and pubertal development in pediatric patients with SCN due to HAX1 gene variant (HAX1-SCN).

Methods: Forty-five patients, including 24 females (median age 11.3 [1.5-31] years, 13 pubertal, 11 prepubertal), and 21 males (median age 9.5 (3-18.8) years, 7 pubertal, 14 prepubertal), followed in seven centers, were included. POI is defined as a menstrual disturbance with increased follicle-stimulating hormone (FSH) and low anti-Mullerian hormone (AMH). We classified prepubertal female patients as impending POI when they had low AMH and high FSH values, indicating impaired ovarian function.

Results: A homozygous single nucleotide insertion (position 130-131insA) leading to a premature stop codon; p.Trp44*(c.132G>A) variant in HAX1 gene was detected in 42 (93.3%) affected individuals. Other homozygous variants were p.Arg86*(c.256C>T) and p.Glu60Aspfs*25(c.180delA). We detected elevated serum FSH levels in 10/11 (90.9%) of prepubertal female patients, supporting the diagnosis of impending POI, and in 12/13 (92.3%) of pubertal female patients, classifying them as POI. All female patients had low AMH levels. Male patients did not exhibit gonadal insufficiency.

Conclusions: This is the first and largest case series covering early childhood to evaluate patients with HAX1-SCN for gonadal function. It has been observed that pubertal females develop POI, prepubertal females are at increased risk for gonadal failure, and male patients are not affected. Our results suggest that HAX1 has an important role in ovarian maturation and/or function.

Keywords: HAX1 deficiency; amenorrhoea; hypergonadotropic hypogonadism; premature ovarian insufficiency; severe congenital neutropenia.

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References

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