Desorden Genetico

Human Reproduction Update, Vol.8, No.4 pp. 483±491, 2002

Genetic disorders in premature ovarian failure
È T.Laml1,3, O.Preyer1, W.Umek1, M.Hengstschlager2 and E.Hanzal1
University of Vienna Medical School, Department of Obstetrics and Gynaecology, 1Division of Gynaecology and 2Division of Prenatal Diagnosis and Therapy, Waehringer Guertel 18-20, A-1090 Vienna, Austria
3

To whomcorrespondence should be addressed. E-mail: thomas.laml@akh-wien.ac.at

This review presents the genetic disorders associated with premature ovarian failure (POF), obtained by Medline, the Cochrane Library and hand searches of pertinent references of English literature on POF and genetic determinants cited between the year 1966 and February 2002. X monosomy or X deletions and translocations are known tobe responsible for POF. Turner's syndrome, as a phenotype associated with complete or partial monosomy X, is linked to ovarian failure. Among heterozygous carriers of the fragile X mutation, POF was noted as an unexpected phenotype in the early 1990s. Autosomal disorders such as mutations of the phosphomannomutase 2 (PMM2) gene, the galactose-1-phosphate uridyltransferase (GALT) gene, the FSHreceptor (FSHR) gene, chromosome 3q containing the Blepharophimosis gene and the autoimmune regulator (AIRE) gene, responsible for polyendocrinopathy-candidiasis-ectodermal dystrophy, have been identi®ed in patients with POF. In conclusion, the relationship between genetic disorders and POF is clearly demonstrated in this review. Therefore, in the case of families affected by POF a thorough screening,including cytogenetic analysis, should be performed.
Key words: autosomal disorders/FSH receptor/inhibin/premature ovarian failure/X chromosome abnormalities

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TABLE OF CONTENTS
Introduction Literature search X chromosome abnormalities Autosomal disorders Inhibin FSH receptor Discussion References

IntroductionPremature ovarian failure (POF) is de®ned as cessation of ovarian function at the age of 4 months of amenorrhoea and two serum FSH levels of >40 mIU/ml obtained >1 month apart in a woman aged 150 documented mutations associated with galactosaemia, and raised the possibility of genotype± phenotype relationships. The many genes and their enzyme products involved in carbon dioxide production are considered`epigenetic' to the GALT gene (Guerrero et al., 2000). The development of POF in females with galactosaemia is more likely if the patient's genotype is Q188R/Q188R, if the mean erythrocyte galactose 1-phosphate level is >3.5 mg/dl during therapy, and if the recovery of 13CO2 from whole-body 13 C-galactose oxidation is reduced below 5% of administered 13 C-galactose. This study also con®rmed thathypergonadotrophic hypogonadism occurs in prepubertal girls with galactosaemia (46,XX) (Guerrero et al., 2000). Histological studies of ovarian tissue in galactosaemia complicated with POF described follicular depletion (Beauvais and Guilhaume, 1984; Robinson et al., 1984). In a report of two sisters with galactosaemia and POF (Fraser et al., 1986), ovarian biopsy in the younger showed an appearanceconsistent with resistant ovary syndrome, whilst the ovary of the elder showed follicular depletion. This indicated that follicular resistance may precede follicular loss, but the exact mechanism of ovarian failure has not yet been elucidated in patients with galactosaemia and POF.

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominantly inherited disorder,whereby the affected patients exhibit characteristic facial abnormalities, i.e. small palpebral ®ssures, ptosis and a skinfold running inward and upward from the lower lid. Two forms of BPES exist. In type I, infertility in the form of ovarian failure is an adjunct to the condition and is sex-limited, i.e. only females are affected. In type II, only facial abnormalities are present (Zlotogora et al.,...