Background: Klinefelter syndrome (KS) is the most prevalent sex chromosome disorder in man; it affects approximately one in 660 men and is a common cause of hypogonadism and infertility. Our current knowledge of morbidity in KS is based on observational studies and case reports and therefore is limited. Design: We used Danish registers to obtain dates of hospital admissions and discharge diagnoses in a cohort of all males diagnosed with KS in Denmark and a randomly selected, age-matched control group. Our cohort consisted of 832 KS subjects and 4033 control subjects, contributing with a total of approximately 100,000 person years. We used stratified Cox regression analysis on main groups of diagnoses. Where significant results were found, subsequent analyses were performed on subgroups of diagnoses. Results: We found a significantly increased risk of being hospitalized among the KS subjects [hazard ratio (HR), 1.69; 95% confidence interval,1.54–1.86].Theincreasedadmissionriskwaspresentinallbut one of the main diagnosis groups, with the highest HRs for congenital malformations (HR, 10.7), psychiatric disorders (HR, 3.7), and endocrine and metabolic disorders (HR, 3.2). We compared hospitalization ratesbeforeandafterthediagnosisofKSandfoundthattheincreased rate was present even before the diagnosis of KS. Conclusions: Males suffering from KS experienced an increased hospitalization rate from a variety of disorders. Some are likely to be causedbyhypogonadism,andsomemaybelinkedtothesyndromeper se, whereas others are not readily explained. However, other factors, e.g. socioeconomic, may be involved. (J Clin Endocrinol Metab 91: 1254–1260, 2006)

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Morbidity in Klinefelter Syndrome: A Danish Register Study Based on Hospital Discharge Diagnoses

Data for 331 cri du chat cases, including 34 Danish probands, are reviewed. The incidence and the prevalence among the mentally retarded population amounted to 1/45,000 and 1.5/1000, respectively. No striking association with prenatal events, parental ages, or birth order could be demonstrated. There was a significant excess of females.

The cri-du-chat syndrome : Epidemiology, cytogenetics, and clinical features

The term Klinefelter syndrome (KS) describes a group of chromosomal disorder in which there is at least one extra X chromosome to a normal male karyotype, 46,XY. XXY aneuploidy is the most common disorder of sex chromosomes in humans, with prevalence of one in 500 males. Other sex chromosomal aneuploidies have also been described, although they are much less frequent, with 48,XXYY and 48,XXXY being present in 1 per 17,000 to 1 per 50,000 male births. The incidence of 49,XXXXY is 1 per 85,000 to 100,000 male births. In addition, 46,XX males also exist and it is caused by translocation of Y material including sex determining region (SRY) to the X chromosome during paternal meiosis. Formal cytogenetic analysis is necessary to make a definite diagnosis, and more obvious differences in physical features tend to be associated with increasing numbers of sex chromosomes. If the diagnosis is not made prenatally, 47,XXY males may present with a variety of subtle clinical signs that are age-related. In infancy, males with 47,XXY may have chromosomal evaluations done for hypospadias, small phallus or cryptorchidism, developmental delay. The school-aged child may present with language delay, learning disabilities, or behavioral problems. The older child or adolescent may be discovered during an endocrine evaluation for delayed or incomplete pubertal development with eunuchoid body habitus, gynecomastia, and small testes. Adults are often evaluated for infertility or breast malignancy. Androgen replacement therapy should begin at puberty, around age 12 years, in increasing dosage sufficient to maintain age appropriate serum concentrations of testosterone, estradiol, follicle stimulating hormone (FSH), and luteinizing hormone (LH). The effects on physical and cognitive development increase with the number of extra Xs, and each extra X is associated with an intelligence quotient (IQ) decrease of approximately 15–16 points, with language most affected, particularly expressive language skills.

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Klinefelter syndrome and other sex chromosomal aneuploidies

There are no guidelines available for diagnostic studies in patients with mental retardation (MR) established in an evidence-based manner. Here we report such study, based on information from original studies on the results with respect to detected significant anomalies (yield) of six major diagnostic investigations, and evaluate whether the yield differs depending on setting, MR severity, and gender. Results for cytogenetic studies showed the mean yield of chromosome aberrations in classical cytogenetics to be 9.5% (variation: 5.4% in school populations to 13.3% in institute populations; 4.1% in borderline-mild MR to 13.3% in moderate-profound MR; more frequent structural anomalies in females). The median yield of subtelomeric studies was 4.4% (also showing female predominance). For fragile X screening, yields were 5.4% (cytogenetic studies) and 2.0% (molecular studies) (higher yield in moderate-profound MR; checklist use useful). In metabolic investigations, the mean yield of all studies was 1.0% (results depending on neonatal screening programmes; in individual populations higher yield for specific metabolic disorders). Studies on neurological examination all showed a high yield (mean 42.9%; irrespective of setting, degree of MR, and gender). The yield of neuroimaging studies for abnormalities was 30.0% (higher yield if performed on an indicated basis) and the yield for finding a diagnosis based on neuroradiological studies only was 1.3% (no data available on value of negative findings). A very high yield was found for dysmorphologic examination (variation 39-81%). The data from this review allow conclusions for most types of diagnostic investigations in MR patients. Recommendations for further studies are provided.

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Diagnostic investigations in individuals with mental retardation: a systematic literature review of their usefulness

Although clinical features in Turner syndrome have been well defined, underlying genetic factors have not been clarified. To deduce the factors leading to the development of clinical features, we took the following four steps: (1) assessment of clinical features in classic 45,X Turner syndrome; (2) review of clinical features in various female sex chromosome aberrations (karyotype-phenotype correlations); (3) assessment of factors that could lead to Turner features; and (4) correlation of the clinical features with the effects of specific factors. The results indicate that the clinical features in 45,X and in other female sex chromosome aberrations may primarily be determined by: (1) degree of global non-specific developmental defects caused by quantitative alteration of a euchromatic or noninactivated region; (2) dosage effect of a pseudoautosomal growth gene(s), a Y-specific growth gene(s), and an Xp-Yp homologous lymphogenic gene(s); and (3) degree of chromosome pairing failure in meiocytes that are destined to develop as oocytes in the absence of SRY.

Turner syndrome and female sex chromosome aberrations: deduction of the principal factors involved in the development of clinical features.

In a series of 412 patients with Klinefelter's syndrome observed over periods ranging from 1 to 20 years, the frequency of hypostatic ulceration, deep vein thrombosis and pulmonary embolism was found to be raised. The prevalence of past or present hypostatic ulceration was 6%, which is 20-50 times higher than in the general population. The incidence of deep vein thrombosis in subjects aged between 30 and 70 years was 22.8 cases per 10,000 patient-years at risk. In community studies the incidence of this condition is around 4 new cases per 10,000 men per year. The frequency of pulmonary embolism was 16 cases per 10,000 patient-years at risk, compared with an expected figure of 0.9 to 3 cases per 10,000 men per year.

Venous thromboembolic disease in Klinefelter's syndrome.

Details of a cytogenetic survey of 1,255 patients over 15 years of age in a hospital for the mentally subnormal are reported in this and a previous communication. In this hospital only 17 % of the male patients and 11 % of the female patients had I.Q levels above 50 %.



A total of 128 patients were found to have an abnormal chromosome complement. Of these, 10 had abnormalities of the sex chromosome complement, 104 had the clinical and cytogenetic features of Down's Syndrome and 14 had other abnormalities of the autosomes. Of the 104 patients with Down's Syndrome, 95 were trisomic for chromosome 21 (1 patient also had a Robertsonian translocation between two D group choromosomes), 4 had a mosaic constitution with one cell line trisomic for chromosome 21 and 5 patients had translocations of the D/G or G/G type.



The 14 patients with autosomal abnormalities not associated with Down's Syndrome included 4 with an apparently balanced translocation, 3 with deletions of chromosome material, and 7 with additional chromosome material either translocated onto another chromosome or in the form of a supernumerary chromosome.



Clinical and cytogenetic details and family studies are reported.

Chromosome survey of a hospital for the mentally subnormal Part 2: Autosome abnormalities

In a chromosome survey of 694 men and 561 women in a hospital for the mentally subnormal, 3 men (0.4%) and 7 women (1.2%) were found to have an abnormal chromosome constitution. No males with a 47,XYY sex chromosome complement were found.

A chromosome survey of a hospital for the mentally subnormal Part 1: Sex chromosome abnormalities

A further study of the electrocardiogram in patients with sex chromosome abnormalities who have no evidence of heart disease is described. It is confirmed that in 47, XYY males the atrioventricular conduction is delayed and that in 45, X females it is accelerated. In 47, XYY males there is also a higher than normal frequency of minor defects of intraventricular conduction. No significant deviation from normal was found in the electrocardiogram of men with a 47, XXY karyotype or in 47, XXX women. The significance of the finding is discussed.

The electrocardiogram and sex chromosome aneuploidy.

Anthropometric data have been collected from 47, XXY men, 47, XYY men and 47, XXX women and compared with those of 46,XY men and 46,XX women in the population and in mental subnormality hospitals. Although the 47, XYY men were taller and heavier than the 46,XY men, the other measurements of body size were similar when allowance was made for the greater height. On the other hand, 47, XXY men when compared with 46, XY men had a greater mean subischid height but showed significantly smaller mean values for sitting height, span-height ratio, biacromial diameter and androgyny score. Women with an extra X chromosome were taller than mentally subnormal 46, XX women but their height was the same as that of women in the population. Biacromial diameter and androgyny score were, however, smaller in 47, XXX women compared with 46, XX women from the population, but no difference was found comparing these variables in 47, XXX women and mentally subnormal 46,XX women.

W. H. Price

Papers

Venous thromboembolic disease in Klinefelter's syndrome.

Chromosome survey of a hospital for the mentally subnormal Part 2: Autosome abnormalities

A chromosome survey of a hospital for the mentally subnormal Part 1: Sex chromosome abnormalities

The electrocardiogram and sex chromosome aneuploidy.

Anthropometry in sex chromosome abnormality