ESPE2024 Poster Category 1 Sex Endocrinology and Gonads 3 (6 abstracts)
A Little Known But Very Common Phenotype in Patients with Congenital Neutropenia Due to HAX1 Deficiency: Premature Ovarian Failure
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 , Cansu Koç 5 , Ayşegül Ünüvar 6 , Zerrin Orbak 7 , Zafer Bıçakçı 8 , Leyla Akın 9 , Canan Albayrak 10 , Ahmet Anık 11 , Yusuf Ziya Aral 12 , Emine Ayça Cimbek 13 , Ayşenur Bahadır 14 , Cem Mete 15 & Samim Özen 1
1Ege University Faculty of Medicine, Division of Paediatric Endocrinology and Diabetes, İzmir, Turkey. 2Ege University Faculty of Medicine, Division of Paediatric Haematology, İzmir, Turkey. 3Gaziantep University Faculty of Medicine, Division of Paediatric Endocrinology and Diabetes, Gaziantep, Turkey. 4Gaziantep Liv Hospital, Division of Paediatric Haematology, Gaziantep, Turkey. 5İstanbul University Faculty of Medicine, Division of Paediatric Endocrinology and Diabetes, İstanbul, Turkey. 6İstanbul University Faculty of Medicine, Division of Paediatric Haematology, İstanbul, Turkey. 7Atatürk University Faculty of Medicine, Division of Paediatric Endocrinology and Diabetes, Erzurum, Turkey. 8Atatürk University Faculty of Medicine, Division of Paediatric Haematology, Erzurum, Turkey. 9Ondokuz Mayıs University Faculty of Medicine, Division of Paediatric Endocrinology and Diabetes, Samsun, Turkey. 10Ondokuz Mayıs University Faculty of Medicine, Division of Paediatric Haematology, Samsun, Turkey. 11Adnan Menderes University Faculty of Medicine, Division of Paediatric Endocrinology and Diabetes, Aydın, Turkey. 12Adnan Menderes University Faculty of Medicine, Division of Paediatric Haematology, Aydın, Turkey. 13Karadeniz Technical University Faculty of Medicine, Division of Paediatric Endocrinology and Diabetes, Trabzon, Turkey. 14Karadeniz Technical University Faculty of Medicine, Division of Paediatric Haematology, Trabzon, Turkey. 15Şırnak State Hospital, Division of Paediatric Endocrinology and Diabetes, Şırnak, Turkey
Aim: Homozygous mutations in the HAX1 gene have been described in autosomal recessive severe congenital neutropenia (CN). In this rare disease, ovarian failure has been reported only in 9 female patients in the literature. There is insufficient data on childhood patients with HAX1 deficiency and the age of onset of ovarian failure is unknown. The aim of this cross-sectional study was to evaluate the gonadal functions and pubertal development in paediatric patients with severe CN due to mutations in the HAX1 gene.
Methods: Forty-three patients including 23 females (median age 11.3 (1.5-31) years, 12 pubertal/11 prepubertal) and 20 males (median age 9.5 (3-18.8) years, 11 pubertal/9 prepubertal) who were followed in 7 centers were included in the study. Premature ovarian failure (POF) is defined as delayed puberty and/or amenorrhea with increased follicle stimulating hormone (FSH) and low antimullerian hormone (AMH).
Results: Premature ovarian failure was diagnosed in 11 (91.6%) pubertal girls. Seven patients had secondary amenorrhea, 3 had primary amenorrhea and 1 had oligomenorrhea. One patient with Tanner stage 2 puberty and 11 prepubertal girls had high FSH and low AMH levels according to age, therefore these patients are followed up for POF risk. Gonadal insufficiency was not detected in male patients. Among females, homozygous p.Trp44* variant in HAX1 gene was detected in 21 (91.4%) cases. The other variants associated with the disease were homozygous p.Arg86*(n = 1, 4.3%) and p.Glu60Aspfs*25 (n = 1, 4.3%) variants. Table 1 shows the evaluation of gonadal function in female patients.
| Female patients, n = 23 | Pubertal, n = 12 | Prepubertal, n = 11 | |
| n = 11, POF(+) | n = 1 Tanner stage 2 | ||
| Age (year) | 16.5 (14-31) | 11.7 | 9.5 (1.5-11.7) |
| FSH (U/L) | 78.5 (53.9-118) | 7.02 | 8.8 (3.4-42) |
| LH (U/L) | 39.3 (21-89) | 2.96 | 0.38 (0.09-16.8) |
| AMH (ng/mL) | 0.03 (0.01-0.74) | 0.85 | 0.01 (0.01-0.85) |
Conclusion: This study is the largest case series in the literature showing pubertal girls with variants in the HAX1 gene developing POF, prepubertal girls at increased risk, and unaffected male patients. Our results demonstrate that HAX1 has an important role in ovarian development and/or function. The genotype-phenotype relationship of these patients and the effect of clinical features of severe CN on gonadal function should be further investigated.
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