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Nils Krone,
Nicole Reisch,
Jan Idkowiak,
Vivek Dhir,
Hannah E Ivison,
Beverly A Hughes,
Ian T Rose,
Donna M O'Neil,
Raymon Vijzelaar,
Matthew J Smith, [......],
Elizabeth Sweeney, Maria Szarras-Czapnik,
John R Waterson,
Lori Williamson,
Michaela F Hartmann,
Norman F Taylor,
Stefan A Wudy,
Ewa M Malunowicz,
Cedric H L Shackleton,
Wiebke Arlt
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ABSTRACT: P450 oxidoreductase deficiency (PORD) is a unique congenital adrenal hyperplasia variant that manifests with glucocorticoid deficiency, disordered sex development (DSD), and skeletal malformations. No comprehensive data on genotype-phenotype correlations in Caucasian patients are available.
The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort.
The design of the study was the clinical, biochemical, and genetic assessment including multiplex ligation-dependent probe amplification (MLPA) in 30 PORD patients from 11 countries.
We identified 23 P450 oxidoreductase (POR) mutations (14 novel) including an exonic deletion and a partial duplication detected by MLPA. Only 22% of unrelated patients carried homozygous POR mutations. p.A287P was the most common mutation (43% of unrelated alleles); no other hot spot was identified. Urinary steroid profiling showed characteristic PORD metabolomes with variable impairment of 17α-hydroxylase and 21-hydroxylase. Short cosyntropin testing revealed adrenal insufficiency in 89%. DSD was present in 15 of 18 46,XX and seven of 12 46,XY individuals. Homozygosity for p.A287P was invariably associated with 46,XX DSD but normal genitalia in 46,XY individuals. The majority of patients with mild to moderate skeletal malformations, assessed by a novel scoring system, were compound heterozygous for missense mutations, whereas nearly all patients with severe malformations carried a major loss-of-function defect on one of the affected alleles.
We report clinical, biochemical, and genetic findings in a large PORD cohort and show that MLPA is a useful addition to POR mutation analysis. Homozygosity for the most frequent mutation in Caucasians, p.A287P, allows for prediction of genital phenotype and moderate malformations. Adrenal insufficiency is frequent, easily overlooked, but readily detected by cosyntropin testing.
The Journal of clinical endocrinology and metabolism 12/2011; 97(2):E257-67. · 6.50 Impact Factor
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Jan Idkowiak,
Stephen O'Riordan,
Nicole Reisch,
Ewa M Malunowicz,
Felicity Collins,
Michiel N Kerstens,
Birgit Köhler,
Luitgard Margarete Graul-Neumann, Maria Szarras-Czapnik,
Mehul Dattani,
Martin Silink,
Cedric H L Shackleton,
Dominique Maiter,
Nils Krone,
Wiebke Arlt
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ABSTRACT: P450 oxidoreductase (POR) is a crucial electron donor to all microsomal P450 cytochrome (CYP) enzymes including 17α-hydroxylase (CYP17A1), 21-hydroxylase (CYP21A2) and P450 aromatase. Mutant POR causes congenital adrenal hyperplasia with combined glucocorticoid and sex steroid deficiency. P450 oxidoreductase deficiency (ORD) commonly presents neonatally, with disordered sex development in both sexes, skeletal malformations, and glucocorticoid deficiency.
The aim of the study was to describe the clinical and biochemical characteristics of ORD during puberty.
Clinical, biochemical, and genetic assessment of seven ORD patients (five females, two males) presenting during puberty was conducted.
Predominant findings in females were incomplete pubertal development (four of five) and large ovarian cysts (five of five) prone to spontaneous rupture, in some only resolving after combined treatment with estrogen/progestin, GnRH superagonists, and glucocorticoids. Pubertal development in the two boys was more mildly affected, with some spontaneous progression. Urinary steroid profiling revealed combined CYP17A1 and CYP21A2 deficiencies indicative of ORD in all patients; all but one failed to mount an appropriate cortisol response to ACTH stimulation indicative of adrenal insufficiency. Diagnosis of ORD was confirmed by direct sequencing, demonstrating disease-causing POR mutations.
Delayed and disordered puberty can be the first sign leading to a diagnosis of ORD. Appropriate testosterone production during puberty in affected boys but manifest primary hypogonadism in girls with ORD may indicate that testicular steroidogenesis is less dependent on POR than adrenal and ovarian steroidogenesis. Ovarian cysts in pubertal girls may be driven not only by high gonadotropins but possibly also by impaired CYP51A1-mediated production of meiosis-activating sterols due to mutant POR.
The Journal of clinical endocrinology and metabolism 12/2010; 96(3):E453-62. · 6.50 Impact Factor
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Jan Idkowiak,
Ewa M Malunowicz,
Vivek Dhir,
Nicole Reisch, Maria Szarras-Czapnik,
Donna M Holmes,
Cedric H L Shackleton,
John D Davies,
Ieuan A Hughes,
Nils Krone,
Wiebke Arlt
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ABSTRACT: Undervirilization in males, i.e. 46,XY disordered sex development (46,XY DSD), is commonly caused by either lack of androgen action due to mutant androgen receptor (AR) or deficient androgen synthesis, e.g. due to mutations in 17alpha-hydroxylase (CYP17A1). Like all other microsomal cytochrome P450 (CYP) enzymes, CYP17A1 requires electron transfer from P450 oxidoreductase (POR).
The objective of the study was to analyze the clinical and biochemical phenotype in a 46,XY individual carrying concomitant POR and AR mutations and to dissect their impact on phenotypic expression.
We characterized the clinical and biochemical phenotype, genetic identification, and functional analysis of POR missense mutation by yeast micrososomal coexpression assays for CYP17A1, CYP21A2 and CYP19A1 activities.
The patient presented neonatally with 46,XY DSD and was diagnosed as partial androgen insensitivity syndrome carrying a disease causing AR mutation (p.Q798E). She was raised as a girl and gonadectomized at the age of 4 yr. At 9 yr progressive clitoral enlargement prompted reassessment. Urinary steroid analysis was indicative of POR deficiency, but surprisingly androgen production was normal. Genetic analysis identified compound heterozygous POR mutations (p.601fsX12/p.Y607C). In vitro analysis confirmed p.Y607C as a pathogenic mutation with differential inhibition of steroidogenic CYP enzymes.
Both mutant AR and POR are likely to contribute to the neonatal presentation with 46,XY DSD. Virilization at the time of adrenarche appears to suggest an age-dependent, diminishing disruptive effect of both mutant proteins. This case further highlights the importance to assess both gonadal and adrenal function in patients with 46,XY DSD.
The Journal of clinical endocrinology and metabolism 07/2010; 95(7):3418-27. · 6.50 Impact Factor
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Krystyna H Chrzanowska, Maria Szarras-Czapnik,
Maria Gajdulewicz,
Maria A Kalina,
Malgorzata Gajtko-Metera,
Malgorzata Walewska-Wolf,
Jolanta Szufladowicz-Wozniak,
Henryk Rysiewski,
Hanna Gregorek,
Bozena Cukrowska,
Malgorzata Syczewska,
Dorota Piekutowska-Abramczuk,
Roman Janas,
Malgorzata Krajewska-Walasek
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ABSTRACT: Nijmegen breakage syndrome (NBS) is a severe chromosomal instability disorder characterized by microcephaly, growth retardation, immune deficiency, and predisposition for malignancy. It is caused by hypomorphic mutations in the NBN gene, which product belongs to the protein complex critical for processing DNA double-strand breaks during mitotic and meiotic recombination. Data on gonadal function in patients with NBS are limited.
Growth and sexual development, along with hormonal assays, were evaluated in girls and young women with NBS homozygous for c.657_661del5 mutation.
The group comprised 37 girls and young women with NBS (ages, 0.17-24.25 yr), followed between 1993 and 2008. Patients were divided into three age groups: 1) 1-3 yr; 2) 4-9 yr; and 3) 10 yr and older. Growth, puberty, concentrations of gonadotropins and 17-beta-estradiol, bone age, and pelvic ultrasound were assessed.
None of the patients presented a typical growth spurt; the adult height ranged between the 3rd and 25th centiles. Median bone age was delayed by 4.05 yr. Pubarche reached stadium P2 in eight patients and P3 in two patients. In all but one girl, thelarche did not exceed Th2, with low 17beta-estradiol levels. Gonadotropin levels showed a biphasic pattern, with median FSH values of 55.0, 10.9, and 81.9 IU/liter, and LH of 3.2, 0.8, and 21.0 IU/liter in consecutive age groups. Ultrasound visualized small ovaries or solid streaks and the hypoplastic uterus.
Primary ovarian insufficiency and the associated hypergonadotropic hypogonadism are hallmark manifestations in girls and young women with NBS. Our findings emphasize the need for long-term endocrinological and interdisciplinary supervision of these patients.
The Journal of clinical endocrinology and metabolism 05/2010; 95(7):3133-40. · 6.50 Impact Factor
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Clinical dysmorphology 06/2009; 18(3):168-71. · 0.47 Impact Factor
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ABSTRACT: To provide late adolescent and young adult psychosexual follow-up information on a consecutive series of patients with either mixed or partial gonadal dysgenesis.
Children's Memorial Health Institute (Warsaw, Poland).
19 patients (age range, 17-26 years), 9 raised as females and 10 raised as males.
Clinical interview and psychologic tests were used to evaluate gender identity, gender role, and sexual behavior.
All patients raised as male had a normal male gender identity, displayed masculine gender role behavior in childhood, and had a heterosexual sexual orientation. Seven of the 10 male patients had experienced heterosexual intercourse. Two out of nine women did not identify with the female gender. The majority had masculine gender role interests in childhood. The female patients were significantly less likely to have experienced sexual activity with a partner than the male patients.
Although gender identity differentiated largely in accordance with sex assignment or sex of rearing in our sample, the patients reared as female appeared to have poorer sexual adjustment than the males. Cultural factors may have impacted on this latter outcome.
Journal of Pediatric and Adolescent Gynecology 01/2008; 20(6):333-8. · 1.54 Impact Factor
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ABSTRACT: In males AMH is produced by the testes from fetal life to puberty. The main role of AMH in the male fetus is to cause Müllerian duct regression, in prepubertal boys AMH is involved in testicular development and function. THE AIM OF THIS STUDY was to assess the use of a sensitive assay kit of AMH measurements in the diagnosis and management of children with abnormal sexual differentiation and cryptorchidism. We also compared the serum AMH levels with testosterone levels after hCG stimulation.
We assessed serum AMH levels in 79 prepubertal patients: gonadal dysgenesis (n=23), partial androgen insensitivity (n=4), scrotal hypospadiasis (n=16), bilateral cryptorchidism (n=20), anorchia (n=10) and unilateral cryptorchidism (n=6). Earlier hCG test was performed (one dose of 2000 IU/m2 i.m.) and testosterone levels were determined.
AMH level was not impaired in patients with unilateral cryptorchidism and partial androgen insensitivity (median 350 pmol/l). AMH was normal in most of boys with scrotal hypospadiasis (median 317 pmol/l). Significant differences were observed between AMH levels in boys with hypospadias and patients with gonadal dysgenesis (median 174 pmol/l; p<0,001). In the cryptorchid group AMH level was normal in 50% of boys. There was a significant difference between AMH levels in cryptorchid boys (median 249.5 pmol/l) and patients with anorchia; (p<0,001). AMH levels were almost undetectable in boys with vanishing testes (median 1.0 pmol/l). The basal AMH levels were correlated with testosterone response to hCG.
When testes are non-palpable a single measurement of serum AMH level can distinguish between cryptorchidism and anorchia. AMH determination can help in the diagnosis of intersex conditions. Our data demonstrated that basal AMH measurements correlate with testosterone response to hCG. Serum AMH concentration in prepubertal children is a marker of testicular function. Preoperative measurement of AMH can be useful in the management of children with cryptorchidism and intersex disorders.
Endokrynologia, diabetologia i choroby przemiany materii wieku rozwojowego: organ Polskiego Towarzystwa Endokrynologow Dzieciecych 01/2006; 12(3):195-9.
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ABSTRACT: Insulin resistance--a key element of the metabolic syndrome--is observed in children with simple obesity. Adipose tissue is producing bioactive substances called adipocytokines. Some of them may play a role in the development of insulin resistance.
Estimation of the frequency of insulin resistance and its correlation with leptin, adiponectin and resistin levels in children with simple obesity.
The 53 children (BMI>97 centile), mean age 13.57 years. Mean BMI was +4.04 SDS. Oral glucose tolerance test (OGTT) was performed. Insulin levels at 0' < or = 15 microIU/mL and/or insulin peak during OGTT < or = 150 microIU/mL and/or peak at 120' < or =75 microIU/mL were established as normal values. Homa ratio was calculated. Patients were divided into groups depending on the presence or absence of hyperinsulinemia / insulin resistance. Concentrations of adiponectin, leptin, resistin were measured.
In 13.23 % children various types of hyperglycemia were diagnosed and hyperinsulinemia in OGTT was noted in 83.02 %. Severe insulin resistance (HOMA>3) was diagnosed in 71.82 %. In the hyperinsulinemia group higher glucose levels in OGTT were stated comparing to the non hyperinsulinemia group. In children with insulin resistance, higher BMI and SD BMI were observed. In this paper results of correlations of adipocytokines levels and anthropometric parameters or carbohydrates metabolism in children with / without insulin resistance are presented.
In children with severe insulin resistance adiponectin concentrations correlate negatively with glucose levels, there is a positive correlation of adiponectin and glucose and insulin in a group without severe insulin resistance. In patients with insulin resistance leptin concentrations correlate positively with the degree of obesity and insulin levels in OGTT.
Endokrynologia, diabetologia i choroby przemiany materii wieku rozwojowego: organ Polskiego Towarzystwa Endokrynologow Dzieciecych 01/2006; 12(3):211-5.
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Cedric Shackleton,
Josep Marcos,
Ewa M Malunowicz, Maria Szarras-Czapnik,
Petr Jira,
Norman F Taylor,
Nuala Murphy,
Ellen Crushell,
Michael Gottschalk,
Berthold Hauffa,
Deborah L Cragun,
Robert J Hopkin,
Masanori Adachi,
Wiebke Arlt
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ABSTRACT: Antley-Bixler syndrome (ABS, MIM 207410) is a skeletal abnormality syndrome primarily affecting head and limbs. Little is known of the origin of the condition but inactivating mutations in the fibroblast growth factor receptor (FGFR2) has been found in some patients. Genital ambiguity is seen occasionally in this condition, suggesting possible disordered steroidogenesis in early pregnancy. We report the steroid excretion of eight patients diagnosed with the syndrome and one with a related condition, a mild phenotype of the disorder since skeletal and genital abnormalities were not evident. The steroid excretion pattern was consistent and very distinctive in all nine patients. Metabolites of the two primary precursors of steroid hormones, pregnenolone and progesterone, were elevated as were the classical diagnostic metabolites for 17- and 21-hydroxylase deficiencies. Cortisol production was typically within the normal range but generally had blunted response to ACTH. Androgen metabolite excretion tends to be low in patients over 2 months of age, but may be elevated in the newborn period. The metabolome suggested attenuated steroid hydroxylation (including 17,20-lyase activity) although underlying cause is yet to be established. Mutations in CYP17 and CYP21 have not been found and currently the prime suspect is an abnormality in an essential redox partner (P450 oxidoreductase). This paper proposes use of the distinctive steroid metabolome as the primary biochemical parameter for diagnosis of ABS, at least the form not associated with FGFR2 mutations.
American Journal of Medical Genetics Part A 08/2004; 128A(3):223-31. · 2.39 Impact Factor
