Diagnostic Quandary: Premature Ovarian Failure and Galactosemia Variants in Adolescent Girls with Delayed Puberty

J Pediatr Adolesc Gynecol (2009) 22:330e335

Management Quandary Diagnostic Quandary: Premature Ovarian Failure and Galactosemia Variants in Adolescent Girls with Delayed Puberty Amanda C. Flint, MD, Nancy J. Hopwood, MD, and Josephine Z. Kasa-Vubu, MD, MS Pediatric Endocrinology, University of Michigan, Ann Arbor, MI 48109

Galactosemia is a metabolic disease wherein galactose, a sugar found in milk products, cannot be properly metabolized, causing an elevated blood galactose concentration.1 This disease has several variants, including a ‘‘classic’’ form. The ‘‘classic’’ form has long been associated with premature ovarian failure, although the mechanism by which this occurs is unclear. However, in our experience, variant forms of galactosemia can also be associated with premature ovarian failure, and the goal of this study is to present a series of cases wherein this association was found to occur, especially in circumstances where premature ovarian failure led to the diagnosis of a galactosemia variant. Galactose is present in a free form in some fruits and vegetables but is more typically found in milk products as part of the disaccharide lactose, which is hydrolyzed to glucose and galactose by the enzyme lactase. The galactose is then converted to glucose and used as an energy souce.1 End products of galactose metabolism typically include CO2, glycogen, glycolipid, and glycoproteins. This pathway includes several enzymes, and genetic disorders can lead to defectiveness in three of them, including galactose1-phosphate uridyl transferase (GALT), galactokinase (GALK), and uridine diphosphate galactose-4epimerase (GALE). Galactose therefore accumulates, and alternative pathways for metabolism lead to increased production of galactonic acid, which is metabolized through the pentose pathway, and galactitol, which accumulates in cells as an end product.2 GALT deficiency causes what is referred to as ‘‘classic’’ galactosemia and is an autosomal recessive disorder with several enzymatic variants caused by different missense mutations. One of the most common of these is the Q188R mutation, which is also responsible for one of the most severe forms of the disease. Severe mutations occur in about 1 in 35,000 newborns, but less severe mutations occur in

about 1 in 8,000. Infants with untreated galactosemia often have hepatocellular failure, growth failure, cataracts, and severe neurologic deficits such as mental retardation and seizures, and they are especially susceptible to E. coli sepsis.2 Early diagnosis, such as by newborn screening, and early initiation of treatment with dietary restriction of galactose usually prevents or resolves most of these signs and symptoms.1 However, developmental delays, including decreased IQ, speech, and motor function, were commonly seen. Also, premature ovarian failure is prevalent among these patients.3 Partial GALT activity occurs in several variants, most notably the Duarte variant. With this disorder, patients have one allele for classic galactosemia and one Duarte allele, which results in GALT activity that is approximately 25 percent of normal. Patients with two Duarte alleles or one Duarte allele and one normal allele will have altered GALT activity, as well, but this has not been thought to result in any neonatal or long-term morbidity, even without treatment.1 GALK deficiency is also autosomal recessive. The only described clinical manifestations are cataracts and rarely, pseudotumor cerebri. Treatment also consists of dietary restriction of galactose.4 A third form of the disease, also autosomal recessive, is caused by GALE deficiency. This deficiency manifests itself in two distinct ways. A benign form, wherein the enzyme deficiency is limited to leukocytes and erythrocytes, is without symptoms. More recently, a severe form of this defect has been discovered, and phenotype resembles that of GALT deficiency, with additional symptoms including hypotonia and nerve deafness. Because these patients cannot synthesize galactose, their diets cannot be completely galactose-free.4 As noted previously, premature ovarian failure is prevalent among galactosemia patients. Premature ovarian failure in this context is more specifically hypergonadotrophic hypogonadism, and is thought to be

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1083-3188/09/$36.00 doi:10.1016/j.jpag.2008.07.020

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Flint et al: Premature Ovarian Failure and Galactosemia with Delayed Puberty

due to increased follicular atresia due to the toxic effects of galactose metabolites.5 In a study by Waggoner et al,6 regarding long-term prognosis in galactosemia, it was discovered that while 26 out of 34 patients had menarche before age 18, most developed oligomenorrhea and then secondary amenorrhea within a few years. In contrast to affected females, males typically have normal gonadotropin levels and normal testicular function,7 suggesting the testis appears to be resistant to the effects of abnormal galactose metabolism.8 This may be because GALT expression in the testis is lower than anywhere else in the body.9 While ovarian failure associated with galactosemia is thought to be associated with the metabolites that accumulate due to the disease, the exact etiology of the failure is still unclear. Pregnant rats fed a 50% galactose diet produced offspring with a striking reduction in oocyte numbers.10 This may be due to inhibition of follicular development, possibly through down-regulation of GDF-9 in the rat ovary,11 or may be related to impaired germ cell migration.12 Additionally, it has been shown that galactosemic patients have qualitatively abnormal FSH isoforms that have a higher binding affinity to its receptor without being able to function there normally, and seems to imply that GALT may be necessary for correct FSH structure.13 The actual toxic product may be galactose1-phosphate, as levels greater than 3.5 mg/dL during therapy correlated with an increased likelihood of ovarian failure.14 However, galactitol may also play a role, as administration of an aldolase reductase inhibitor, which metabolizes galactitol, to rats fed a 40% galactose diet prevented abnormal oocyte maturation and improved ovarian response to exogenous gonadotropins.9 It is also postulated that deficiency of uridine diphosphate-galactose may be the cause.15 Generally, premature ovarian failure has been described only in ‘‘classic’’ galactosemia. Two different studies screened series of patients presenting with primary or secondary hypergonadotrophic amenorrhea and found no significant difference in the prevalence of alleles associated with galactosemia.16,17 Another study focused at heterozygotes for the GALT mutation and found no association with premature ovarian failure.18 However, in a study of 104 normal postmenopausal women, 15 had decreased GALE activity and an abnormal GALE allele, and these women had a lower mean age at menopause (45 years versus 49 years).19 Additionally, a case series of patients published in 2006 suggests that GALE deficiency is not limited to the dichotomous ‘‘peripheral’’ and ‘‘generalized’’ forms but may in fact represent a continuum disorder possibly impacting a range of tissues in a variety of ways.20 The link between galactosemia variants and premature ovarian failure suggests possible mechanisms of

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ovarian failure that have not been elucidated and merit further investigation in both basic and clinical research. In the meantime, identification of affected patients expediently may allow for strategies to be employed to assist fertility, such as hormonal supplementation or egg preservation,14 as well as to prevent some of the other complications of galactosemia for which earlier recognition of the disease would be beneficial. In our clinical practice, several patients have presented with primary amenorrhea with phenotypic or laboratory features suggestive of a galactosemia variant. It is the purpose of this article to discuss these cases and encourage more investigation into galactosemia variants and their link to ovarian pathology. This case review and report was authorized by the University of Michigan Institutional Review Board. Case 1 Our interest in patients with galactosemia and ovarian failure began with a patient, PT1. She was referred for evaluation of short stature and delayed puberty at age 14 years, 2 months. Born after an uncomplicated pregnancy, PT1 had a complicated neonatal course consisting of jaundice, lethargy, and failure to thrive. Elevated tyrosine levels led to the diagnosis of transient tyrosinemia of the newborn, a condition caused by immaturity of 4-OH phenylpyruvate dioxygenase (HPD), which is involved in an early step of tyrosine degradation and which leads to lethargy, poor feeding, metabolic acidosis, and prolonged jaundice.21 After the initiation of a tyrosine-free diet, PT1 demonstrated remarkable improvement. She remained on this diet until 15 months of age. However, when a regular diet, including cow’s milk and other dairy products, was attempted, PT1 did poorly, with poor weight gain, vomiting, and diarrhea. Eventually, her health stabilized, although she maintained weight gain only along the 5th percentile, which was attributed to constitutional growth delay. She was also found to be developmentally delayed and required special education accommodations. It was only at presentation to endocrinology clinic for evaluation of pubertal delay at age 14 years that galactosemia came to be suspected. At the time of that evaluation, PT1’s height was 142.8 cm (less than 5th percentile) with a height age of 10 years, 6 months. Her weight was 41.1 kg (10th percentile) with a weight age of 12 years. She appeared non-dysmorphic and anicteric with minimal pubic hair and no other signs of sexual maturation. Bone age was compatible with the Greulich and Pyle female standard of 10 years. A urine metabolic screen, thyroid hormone levels, and Westergren erythrocyte sedimentation rate were all within normal limits. Follicle stimulating hormone (FSH) was elevated at 22.2 mIU/ml, which indicated ovarian failure

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and a karyotype demonstrated normal 46,XX chromosomes. Immunological evaluation for ovarian, pancreatic, adrenal, and thyroid antibodies was entirely negative, and a pelvic ultrasound revealed a normal prepubertal uterus and ovaries. Thus, alternative causes for PT1’s growth and ovarian failure were considered. Review of her medical records from the neonatal and early childhood periods, especially given the diagnosis of transient neonatal tyrosinemia of the newborn and the known toxic effects of galactosemia on the ovaries, suggested galactosemia as the diagnosis. This was confirmed by undetectable GALT activity and elevated galactose-1-phosphate levels, which are diagnostic of classic galactosemia. Retrospectively, it was established that the tyrosine-free formula used to treat her altered tyrosine metabolism in infancy was also galactose-free. Further review of the elevated tyrosine levels during PT1’s neonatal period revealed that the elevated levels coincided with an event of multi-organ failure that was strongly suggestive of neonatal sepsis from which she eventually recovered with aggressive treatment. In addition, it was speculated that, after the discontinuation of tyrosine-free formula, PT1, who was then a toddler, had preferentially avoided dairy products, notably ice cream, which may have helped account for her maintenance of growth along the 5th percentile and lack of more significant consequences from untreated galactosemia. Given the unusual presentation of classic galactosemia in PT1, our awareness of galactosemia as a cause or contributing cause of ovarian failure was heightened, as was our awareness that galactosemia could present in somewhat unusual or unexpected ways. It seemed reasonable to expand our differential to include galactosemia in cases of premature ovarian failure, particularly in cases where no other cause for ovarian failure was evident. Case 2 PT2’s contact with a pediatric endocrinology clinic began with the diagnosis of thyroid disease at age 11 years, 9 months. She had a previous history of attention deficit hyperactivity disorder (ADHD), and she had been followed in a pediatric cardiology practice for congenital cardiomyopathy since infancy. During an evaluation for tachycardia, her total triiodothyronine (T3) was 363 mg/dl (normal 60e170 mg/dl), total thyroxine (T4) was 16.5 mg/dl (normal 4.7e12.4 mg/dl), and thyroid stimulating hormone (TSH) was 7.0 mIU/ml (0.3e6.5 mIU/ml), free T4 was 8.98 ng/ dl (0.73e1.79 ng/dl). Thyroid antibody studies were negative, including thyroglobulin, microsomal, and thyroid stimulating immunoglobulins. Magnetic resonance imaging (MRI) of the pituitary revealed mild diffuse enlargement of the gland but no discrete

adenoma, leaving thyroid hormone resistance the most likely etiology of her thyroid disease, despite a negative family history. PT2 was treated with propranolol and propylthiouracil (PTU) and had good control of her symptoms; the propranolol was therefore gradually discontinued. Subsequent thyroid function testing revealed consistently elevated TSH levels but free T4 levels only slightly above normal. In the meantime, PT2 was diagnosed with dyslexia and continued to be treated for ADHD. Concerns about PT2’s pubertal development began at age 13 years, 7 months. On physical exam at that time, she had pubertal staging at Tanner stage 3 for pubic hair but no obvious breast development with the exception of some fullness of the areola and subareolar tissue. At age 14 years, her physical exam remained essentially unchanged with regard to pubertal development and her height was at the 25th percentile with a weight between the 25th and 50th percentile. A bone age was obtained at this time, which was 12 years according to the standards of Greulich and Pyle. Pelvic ultrasound did not show the presence of ovaries or a uterus, and pelvic MRI confirmed the lack of ovaries but did distinguish a hypoplastic uterus. Laboratory studies revealed thyroid studies at the patient’s baseline, normal 46,XX karyotype, FSH of 75 mIU/ml (markedly elevated for a premenopausal adult female), estradiol less than 10 pg/ml (consistent with prepubertal levels), prolactin 11.3 ng/ml (normal 1.0e17.0 ng/ ml), testosterone 0.32 ng/ml (normal 0.10e0.90 ng/ ml), and negative anti-ovarian antibodies. Given the appearance of primary ovarian failure, galactosemia was considered. The GALT level was 27.1 mmol/hr/ g hemoglobin (normal 17e37 mmol/hr/g hemoglobin), ruling out classic galactosemia, but the GALE level was notably low at 3.8 mmol/hr/g hemoglobin (normal 14.3e26.2 mmol/hr/g hemoglobin). As PT2’s thyroid studies were not felt to be sufficiently abnormal to explain her pubertal delay and associated laboratory abnormalities, the cause of her pubertal delay remained unclear, and no specific cause was ever elucidated. PT2’s stature and pubertal development improved with the initiation of hormonal therapy, but PT2 expressed distress at several junctures regarding her height and delay of breast development. Also unclear was the significance of the low GALE level and whether it could have contributed to her ovarian failure. Case 3 The next case to present to us was PT3, who was evaluated in a pediatric endocrinology clinic at age 15 years, 9 months, for delayed onset of puberty. Prior to her referral to the pediatric endocrinology clinic, she had undergone an extensive evaluation by her primary care physician for this complaint. Studies

Flint et al: Premature Ovarian Failure and Galactosemia with Delayed Puberty

included a free T4 of 1.08 ng/dl (normal 0.89e1.8 ng/ dl) with an elevated TSH at 8.84 mIU/L (normal 0.5e6.4 mIU/L) and a positive antithyroglobulin antibody at 4 (normal less than 2) but normal thyroid antimicrosomal antibody at less than 2. She had an estradiol of 13 pg/ml, an FSH of 106 mIU/ml, and an LH of 21 mIU/ml, indicating primary hypogonadism. Her karyotype was normal (46,XX). A pelvic ultrasound showed a hypoplastic uterus, and no ovaries could be visualized. Her bone age was significantly delayed at 11 years with a chronologic age of 15 years. Because of these preliminary results, a gonadotropin-releasing hormone (GnRH) stimulation test and a thyrotropin-releasing hormone (TRH) test were done simultaneously. The TRH test revealed a baseline thyroid-stimulating hormone (TSH) of 31.5 mIU/L and prolactin of 26.7 ng/ml at zero minutes. At 15 minutes TSH was 112.1 mIU/L and prolactin 94.4 ng/ml, and at 30 minutes TSH was 119.9 mIU/L and prolactin 94.9 ng/ml indicating hyperresponsiveness of both hormones and suggesting primary hypothyroidism. Likewise, primary ovarian failure was inferred by supranormal baseline and stimulated values of FSH (normal 101 mIU/ml to 163 mIU/ml) and LH (normal 54 mIU/ml to 109 mIU/ml). Thyroid hormone therapy was initiated as well as estrogen replacement to induce secondary sexual characteristics. At the time of her presentation to pediatric endocrinology, her physical exam did reveal stage II early breast development and scant pubic hair. Her elevated TSH was suspected to be related to thyroid hormone resistance, although this was difficult to conclude definitively. However, the etiology of her primary ovarian failure remained unclear. To further evaluate this, ovarian antibodies were sent, which were negative at !1:5. Additionally, given our findings in other patients, a GALT level was obtained. This was 14.2 mmol/hr/g hemoglobin (normal 17.0e37.0 mmol/hr/g hemoglobin), suggestive of a Duarte-normal heterozygote genotype. PT3 had no other symptoms suggestive of galactosemia, and she noted specifically that she consumed a variety of foods containing galactose on a regular basis without difficulty. Since no other etiology for her ovarian failure was found, we speculated that her ovarian failure might be linked to her galactosemia variant status. She was found to have significant osteopenia on DEXA scan, which is an important consequence of primary ovarian failure and reinforces the need for prompt diagnosis. Case 4 PT4 was 17 years, 5 months old when she presented to the pediatric endocrinology clinic due to concern for poor growth. Review of her records at that time revealed birth weight to be small for gestational age. By age 5, she had short stature consistent with being at

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less than the 5th percentile for both height and weight. This growth pattern persisted for the following four years. By age 9 years her growth pattern worsened and reached the 1st percentile in both height and weight. At the time of her evaluation, her height was 145.6 cm and her weight was 45.0 kg. Pubertal development at that time was delayed as well, with breast development at Tanner Stage II and pubic hair at Tanner Stage III and no history of menses. Her medical history was significant for coarctation of the aorta that was corrected in infancy without complication. She maintained a normal diet and had no gastrointestinal complaints. Preliminary studies to the pediatric endocrinology evaluation included a normal 46,XX karyotype. Following her visit, further testing was performed, revealing a normal complete blood count (CBC), normal electrolytes, kidney, and liver functions, normal sedimentation rate, and normal thyroid function, including a TSH and free T4 that were within normal limits. Bone age was 13.5 years by the standards of Greulich and Pyle. FSH was 78.4 mIU/ ml, which is elevated, suggesting ovarian failure. Prolactin level was normal. Growth hormone deficiency was ruled out by standard laboratory studies. Because of the severity of the short stature in a girl with a normal karyotype, a SHOX gene analysis was performed and failed to detect a mutation. Given these results, additional testing was ordered including anti-ovarian antibodies, which were negative, and GALT and GALE levels, of which the GALT level was normal and the GALE was 13.7 mmol/hr/g hemoglobin (normal 14.3e26.3 mmol/hr/g hemoglobin). Again, this was an example of the discovery of a slight abnormality in the GALE level without other findings, either by history, physical, or laboratory evaluation, to suggest an alternative cause for ovarian failure. After the initiation of estrogen supplementation PT4 experienced a modest growth spurt and was able to further advance her pubertal development. Case 5 PT5 was the next patient to present to endocrinology clinic with findings suspicious for a galactosemia variant. She presented at age 16 years, 1 month for primary amenorrhea. At the time, she was otherwise healthy, developmentally normal, and quite physically active. Her height was 162.4 cm, which was at the 48th percentile for age at that time. Her breasts were immature and her pubic and axillary hair was advanced consistent with Tanner stage IV. Preliminary evaluation included an FSH of 98.6 mIU/ml and an LH of 31.4 mIU/ml, both of which are consistent with ovarian failure. Estradiol level was undetectable. Her thyroid function tests were normal with a TSH of 0.64mIU/L (normal 0.37 to 6.00 mIU/L) and a free T4 1.02 ng/dL (normal 0.70 to 1.48 ng/dL). A

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prolactin level was obtained which was 5.2 ng/mL (normal 2.8 to 29.2 ng/mL). She also had a 46,XX normal female karyotype. Pelvic ultrasound revealed a prepubertal uterus and only one ovary was visualized. Given the lack of obvious etiology for PT5’s primary ovarian failure and the growing suspicion that a galactosemia variant might be playing a role, further laboratory studies were sent following that visit. These included anti-ovarian antibodies, a galactose1-phosphate level, and a GALE level. The anti-ovarian antibodies were negative, and the galactose-1phosphate level was within normal limits, but the GALE level was 11.0 mmol/hr/g hemoglobin (normal 14.3e26.3). Again, this suggested a possible variant form of galactosemia that may have been contributing to PT5’s ovarian failure. PT5 further laboratory testing included anti-thyroid antibodies, which were negative, and IGF-1 levels, which were normal. A bone density scan showed a z-score of negative 2 in the lumbar spine. She was prescribed estrogen replacement to induce pubertal changes and protect her bone density with the plan to transition to oral contraceptives once linear and breast growth was complete. PT5 was initially noncompliant with this recommendation, as she expressed frustration that this therapy seemed futile if she was going to be unable to bear children that were genetically hers in the future. She continued to have difficulty with compliance as well as frustration and confusion regarding her diagnosis and was eventually lost to follow-up. Discussion In conclusion, this series of patients is intriguing given their abnormalities in GALT or GALE enzymes and otherwise unexplained premature or primary ovarian failure. The first patient described in this series had other features consistent with classic galactosemia, namely developmental delay, and her history was the result of extraordinary circumstances. Some of these patients had complex medical histories, complicating attempts to pinpoint their ovarian failure to a particular cause. In addition, blood levels related to galactose variants are not routinely performed in laboratories, thus complicating handling conditions and making repeat confirmatory testing cumbersome and expensive in clinical practice. However, given that classic galactosemia is a known cause for premature ovarian failure and that these young women demonstrated abnormalities in the enzymatic pathway for galactose metabolism, it is possible that these galactosemia variants could be playing a role in ovarian failure. This case series highlights the need for further investigation into galactosemia variants and their link to ovarian failure. First, detection of such a link could allow for consideration of galactosemia more

routinely in the evaluation of pubertal delay or ovarian failure. Detection of galactosemia or galactosemia variants would then lead to the initiation of treatment and dietary adjustments, if appropriate, which may provide health benefits and dampen complications of untreated galactosemia, although as noted above, some of these variants are of somewhat unclear clinical significance. Second, and perhaps more importantly, more expedient discovery of the etiology of ovarian failure enables clinicians to initiate appropriate treatment and counseling to these patients. Hormonal therapy can be considered to improve growth and sexual maturity, which may improve self-esteem and overall wellbeing, as was demonstrated in a different population with ovarian failure.22 Patients can also be appropriately counseled regarding options for fertility, which as noted by one patient in our series, was of significant concern. Finally, appropriate therapy can be directed toward bone health, as osteopenia is a complication of ovarian failure23 and was detected in several of the patients in this series. As classic galactosemia is now featured on the standard newborn screening panel in all 50 states,24 it is less likely to go undiagnosed today than it was at the time of PT1’s birth. However, an older patient with premature ovarian failure and a birth history antedating the onset of newborn screening for galactosemia in her home state might share some similarities with PT1. On the other hand, the variants of galactosemia, namely GALE and GALK deficiencies, are not included in all states’ screening tests,25 likely because they are of unclear clinical significance. It is our supposition that these variants, especially GALE deficiency, may in fact be associated with premature ovarian failure. Since there is a lack of overt clinical symptoms prior to the onset of pubertal delay, these variants are undetected for years. Galactosemia variants have not been unequivocally associated with premature ovarian failure. Our series of patients with otherwise unexplained primary ovarian failure illustrates the gap in knowledge in identifiable causes of premature ovarian failure in a subset of patients. More research needs to be done to better define the role, if any, of mildly altered galactose metabolism on premature ovarian failure and to better classify premature ovarian failure in general. Acknowledgments: We are thankful to Dr. Joseph Muenzer for his expertise on altered galactose metabolism and transient thyrosinemia of the newborn.

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Flint et al: Premature Ovarian Failure and Galactosemia with Delayed Puberty 2. Elsas LJ II: Galactosemia. In: Goldman L, Ausiello D, editors. Cecil Textbook of Medicine, (22nd ed.). Philadelphia, W.B. Saunders, 2004, pp 1268e1270 3. Sutton VR: Management and outcome of galactosemia. In: Rose BD, editor. UpToDate. Waltham, MA, UpToDate, 2007 4. Chen Y-T: Defects in galactose metabolism. In: Nelson Textbook of Pediatrics, (17th ed.). Edited by RE Behrman, RM Kliegman, HB Jenson. Philadelphia, W.B. Saunders Company, pp 475e476 5. Welt CK: Pathogenesis and causes of spontaneous premature ovarian failure. In: Rose BD, editor. UpToDate. Waltham, MA, UpToDate, 2007 6. Waggoner DD, Buist NR, Donnell GN: Long-term prognosis in galactosaemia: results of a survey of 350 cases. J Inherit Metab Dis 1990; 13:802 7. Grumbach MM, Styne DM: Miscellaneous causes of ovarian failure. In: Larsen PR, Kronenberg HM, Melmed S, editors. Williams Textbook of Endocrinology, (10th ed). Philadelphia, W.B., Saunders Company, 2003, pp 1195 8. Kaufman FR, Donnell GN, Roe TF, Kogut MD: Gonadal function in patients with galactosaemia. J Inherit Metab Dis 1986; 9:140 9. Forges T, Monnier-Barbarino P, Leheup B, et al: Pathophysiology of impaired ovarian function in galactosaemia. Hum Reprod Update 2006; 12:573 10. Chen Y-T, Mattison DR, Feigenbaum L: Reduction in oocyte number following prenatal exposure to a diet high in galactose. Science 1981; 214:1145 11. Liu G, Shi F, Blas-Machado U, et al: Dietary galactose inhibits GDF-9 mediated follicular development in the rat ovary. Reprod Toxicol 2006; 21:26 12. Bandyopadhyay S, Chakrabarti J, Banerjee S, et al: Prenatal exposure to high galactose adversely affects initial gonadal pool of germ cells in rats. Hum Reprod 2003; 18:276 13. Prestoz LL, Couto AS, Shin YS, et al: Altered follicle stimulating hormone isoforms in female galactosaemia patients. Eur J Pediatr 1997; 156:116

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14. Guerrero NV, Singh RH, Manatunga A, et al: Risk factors for premature ovarian failure in females with galactosemia. J Pediatr 2000; 137:833 15. Rapaport R: Hypergonadotropic hypogonadism in the female. In: Nelson Textbook of Pediatrics, (17th ed.). Edited by RE Behrman, RM Kliegman, HB Jenson HB. Philadelphia, W.B. Saunders Company, pp 1931e1935 16. Fraser IS, Shearman RP, Wilcken B, et al: Failure to identify heterozygotes for galactosaemia in women with premature ovarian failure. Lancet 1987 Sep 5; 2:566 17. Mlinar B, Gersak K, Karas N, et al: Galactose-1-phosphate uridyl transferase gene mutations in women with premature ovarian failure. Fertil Steril 2005; 84:253 18. Kaufman FR, Devgan S, Donnell GN: Results of a survey of carrier women for the galactosemia gene. Fertil Steril 1993; 60:727 19. Cramer DW, et al: Society for Gynecologic Investigation, 1989; Annual Meeting Abstract Number 400. 20. Openo KK, Schulz JM, Vargas CA, et al: Epimerasedeficiency galactosemia is not a binary condition. Am J Hum Genet 2006; 78:89 21. Grompe M: Disorders of tyrosine metabolism. In: Rose BD, editor. UpToDate. Waltham, MA, UpToDate, 2007 22. Ross JL, McCauley E, Roeltgen D, et al: Self-concept and behavior in adolescent girls with Turner syndrome: potential estrogen effects. J Clin Endocrinol Metab 1996; 81: 2191 23. Anasti JM, Kalantaridou SN, Kimzey LM, et al: Bone loss in young women with karyotypically normal spontaneous premature ovarian failure. Obstet Gynecol 1998; 91:12 24. Berry GT, Anadiotis GA: Galactose-1-Phosphate Uridyltransferase Deficiency (Galactosemia). eMedicine Sep 22, 2006, www.emedicine.com/ped/topic818.htm 25. National Newborn Screening and Genetics Resource Center: National Newborn Screening Report e 1997. Austin, TX, NNSGRC, May 2001