Fragile X syndrome [fra (X)] is currently accepted as the second most frequent chromosomal disorder associated with developmental disability. Although next to Down syndrome in frequency, no postmortem studies of confirmed adult cases had been reported. The autopsy examination of a 62-year-old, moderately retarded man with the fra (X) syndrome confirmed the preferential involvement of cerebral and testicular structures in this disorder.Dendritic spine abnormalities of the type observed in trisomic chromosomal disorders were associated with synaptic immaturity. Severe testicular hypogonadism accompanied bilateralmacro-orchidism, normal penis, and unilateral hydrocele. Valvular, articular, and testicular interstitial compartments showed normal histochemical staining characteristics for glycoproteins and lipids.

Adult fragile X syndrome. Clinico-neuropathologic findings.

We have evaluated 62 fragile X syndrome [fra(X)] individuals (55 males and 7 females) with different degrees of developmental disabilities that were clinically non-progressive and non-focal in character. The mean age for the 55 males was 23.1 years ± 14.3 SD with a range of 2–70: for the 7 females, the mean age was 15.7 years ± 3.5 SD with a range of 10–20 years. Mental retardation (MR) was found in 53 males (8/53 [15.1%] mild, 26/53 [49.1%] moderate, 14/53 [26.4%] severe, and 5/53 [9.4%] profound). Learning disabilities were found in 2/55 (3.6%) of males. One of the 7 females had mild and one had moderate MR: the other 5 were learning disabled. Autistic stigmata were present in 10/62 (16%) of the patients. Only 14/62 (23%) had a history of seizures, all of which were controlled with anticonvulsants. In 36/62 cases, an electroencephalogram (EEG) was performed. We compared these data with that of others. Brain stem auditory evoked response (BAER) was performed in 12 cases. Abnormalities were found in only 5/12. Neuroimaging and computerized cranial transaxial tomography (CT scan) were performed on 21/62 (34%) of the patients. Only 8 of these 21 (38%) studies were abnormal. One patient died; neuropathological studies showed mild brain atrophy, with light microscopic and ultrastructural abnormalities. Rapid Golgi dendritic spine patterns showed that the proximal apical segments were abnormally developed. Very thin, long tortuous spines with prominent terminal heads and irregular dilatations were present. Marked reductions in the length of the synapses, as determined on EPTA-postfixed tissue where noted. The mean synaptic contact area was 35% shorter than the normal length observed in controls. In summary, the neurological abnormalities are mainly in the cognitive function, seizures appear similar to the benign age-related epilepsies, whereas the neuropathological abnormalities are in the wiring system, showing synaptic dysgenesis.

The fra(X) syndrome: Neurological, electrophysiological, and neuropathological abnormalities

The fragile X syndrome is characterised by mental retardation, behavioural features, and physical features, such as a long face with large protruding ears and macro-orchidism. In 1991, after identification of the fragile X mental retardation (FMR1) gene, the cytogenetic marker (a fragile site at Xq27.3) became replaced by molecular diagnosis. The fragile X syndrome was one of the first examples of a "novel" class of disorders caused by a trinucleotide repeat expansion. In the normal population, the CGG repeat varies from six to 54 units. Affected subjects have expanded CGG repeats (>200) in the first exon of the FMR1 gene (the full mutation). Phenotypically normal carriers of the fragile X syndrome have a repeat in the 43 to 200 range (the premutation). The cloning of the FMR1 gene led to the characterisation of its protein product FMRP, encouraged further clinical studies, and opened up the possibility of more accurate family studies and fragile X screening programmes.

https://jmg.bmj.com/content/jmedgenet/35/7/579.full.pdf

The fragile X syndrome.

Background Infertility affects ∼7% of all men. Despite much progress, mainly in genetics, its etiology remains obscure in ∼50% of cases. To fill this gap, imaging of the male genital tract (MGT) has progressively expanded, providing useful information in the assessment of MGT abnormalities. Methods A critical, systematic review of the available literature was performed using Medline, with no restrictions regarding date of publication (i.e. from inception date until March 2014), along with analysis of previous reports in color Doppler ultrasound (CDUS) atlas textbooks. Normal anatomy and sonographic characteristics of the MGT have also been summarized. Results Testicular volume (TV) is tightly associated with both sperm and hormonal parameters. Ultrasound (US) offers a greater accuracy in TV measurement than Prader orchidometer (PO). However US- and PO-derived TV are closely related, making PO-derived TV informative enough in the work-up of the infertile man in everyday clinical practice. US-derived TV might play an independent role in specific clinical conditions (i.e. large hydrocele, inguinal testis, enlarged epididymis). Scrotal US may detect signs of testicular dysgenesis, often related to an impaired spermatogenesis and to a higher risk of malignancy, or testicular lesions suggestive of malignancy. A decreased testis vascularization is characteristic of testicular torsion, whereas hyperemia is often observed in epididymo-orchitis or in some malignant conditions (i.e. lymphoma, leukemia). The impact of varicocele detection and surgical correction on sperm parameters/fatherhood is debated. At present, the clinical management of varicocele is mainly based on physical examination. However, CDUS is useful in assessing venous reflux, when palpation is unreliable and/or in detecting recurrence/persistence after surgery. Epididymis head and/or tail dilation is suggestive of MGT obstruction or inflammation and both are related, along with echo-texture abnormalities, to impaired sperm parameters. Scrotal and transrectal US (TRUS) are useful in detecting congenital uni- or bilateral absence of vas deferens (CBAVD), which may be associated with epididymis, seminal vesicles (SV) or kidney abnormalities/agenesis. TRUS plays a key role in assessing obstructive azoospermia and detecting distal CBAVD or anomalies related to ejaculatory ducts obstruction, such as ejaculatory duct abnormalities, prostate median cysts or SV enlargement/emptying impairment. TRUS findings lead to operational decision-making, such as testicular sperm extraction in the case of CBAVD, cyst aspiration in the case of a large prostatic median cyst, and surgical treatment if ejaculatory duct abnormalities are observed. TRUS may reveal prostate volume reduction (suggestive of hypogonadism) or enlargement, which can be related to aging or even metabolic abnormalities. Finally, TRUS may reveal prostate and SV echo-texture abnormalities suggestive of inflammation or SV stasis. Conclusions MGT-CDUS is a useful tool in detecting abnormalities related to impaired male reproductive health. However, it suffers from a lack of standardization and often produces subjective/vague diagnoses. To fill this gap, the European Academy of Andrology has promoted an ongoing multicenter study aimed at defining the MGT-CDUS characteristics of healthy, fertile men.

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Ultrasound of the male genital tract in relation to male reproductive health

X-linked mental retardation, macro-orchidism, and the Xq27 fragile site

Four 46,XY siblings with congenital bilateral megalorchidia, macrogenitosomia, and severe mental deficiency were investigated. The testicular size was significantly larger than age-matched normal males. A normal hypothalamic-pituitary gonadotropin function was demonstrated by the finding of normal levels of luteinizing and follicle-stimulating hormones in blood samples drawn at frequent intervals and by normal responses to gonadotropin-releasing hormone and testosterone adminstration. A normal testicular function was shown by the finding of normal (a) plasma testosterone and estradiol levels, (b) gonadal response to human chorionic gonadotropin, (c) sperm analysis, and (d) morphology and cell architecture of the testes. Adrenal function was found to be within normal limits. These results demonstrated the existence of normofunctional testicular hyperplasia. The family studies suggested that this distinct congenital disorder is inherited as an X-linked recessive trait.

Inherited congenital normofunctional testicular hyperplasia and mental deficiency.

Three 46,XY unrelated individuals out of 84 postpubertal male inpatients with severe mental deficiency in a psychiatric hospital were found to have megalorchidia and macrogenitosomia. One of the cases had a similarly affected brother. Endocrine studies were performed in two of the cases with similar results. Normal plasma levels of pituitary gonadotropins were found. A normal testicular function was demonstrated by the finding of normal: (a) baseline plasma testosterone levels and a significant rise following human chorionic gonadotropin administration, (b) sperm analysis, and (c) morphology and cell architecture of the testes. These results were compatible with normofunctional testicular hyperplasia confirming previous observations and allowing the definite individualization of a syndrome with mental deficiency probably due to an X-linked recessive mutation.

T. Morato

Papers

Inherited congenital normofunctional testicular hyperplasia and mental deficiency.

Inherited congenital normofunctional testicular hyperplasia and mental deficiency. A corroborative study.