Wednesday, 27 October 2010

Klinefelter’s syndrome

Klinefelter’s syndrome was named after Harry Klinefelter, an endocrinologist at Massachusetts General Hospital, USA in 1942 who thought it was an endocrine disorder due to lack of a second testicular hormone that he postulated but was unable to identify. The postulated hormone, inhibin, was isolated later.

There are two inhibins (inhibin A and inhibin B), both of which inhibit FSH release by direct action on the pituitary though inhibin B appears to be the FSH regulating inhibin. Inhibin B is a marker of spermatogenesis and Sertoli cell function and is produced by the Sertoli cells and it is the major negative feedback regulator of FSH release. It is undetectable in patients with Klinefelter’s syndrome hence the elevated FSH.  Inhibin B correlates positively with sperm concentration and testicular volume and it correlates negatively with the degree of testicular damage.

The 47, XXY karyotype characteristic of Klinefelter syndrome was first described in Scotland, UK in 1959. XXY karyotype of maternal origin arises by an error at either meiosis I (MI) [commonest source of maternal nondisjunction - ? advanced maternal age] or meiosis II (MII). XXY karyotype of paternal origin arises by an MI error with the formation of XY sperm (? advanced paternal age) because, error at MII forms XX sperm or YY sperm rather than XY sperm.

Klinefelter’s syndrome is the commonest sex chromosome abnormality.

Klinefelter’s syndrome is a classic example of seminiferous tubular sclerosis (where germ cells and Sertoli cells are not identified lining  many sclerotic seminiferous tubules that reveal hyalinising fibrosis with absent spermatogenesis, seminiferous tubules can be completely obliterated). In isolated cases several tubules may show intact spermatogenesis with elongated spermatids and sperms. 

Germ cell presence and sperm production are variable in men with Klinefelter’s mosaicism. The term mosaic describes an art form in which pictures are produced by joining together tiny pieces of different coloured stone or glass. The term is used in genetics to describe individuals composed of cells of different genotypes, such as  Klinefelter’s mosaicism patients and patients with Turner syndrome who have both 45, XO and 46, XX cells. The pattern may vary according to cell type and timing of mosaicism. Mosaic forms of Klinefelter's syndrome represent mitotic nondisjunction within the developing zygote and are thought to occur in approximately 10% of individuals with this condition. The commonest form observed is 46, XY / 47, XXY mosaicism. Patients with mosaic Klinefelter's syndrome may have less severe signs and symptoms. 

A nonmosaic Klinefelter’s syndrome patient was able to impregnate his wife without assisted reproductive technology then showed severe oligoasthenozoospermia followed by azoospermia*. This and other studies suggest that early (before the age of 35 years) sperm (if detected) retrieval and cryopreservation for future management of infertility in Klinefelter's syndrome should be considered.

The mechanism by which an extra X chromosome renders patients infertile is not known. Usually azoospermia is established. In some patients few sperm or severe oligoasthenoteratospermia can be found. Spontaneous pregnancies are extremely rare.

The phenotype is normal (there might be disproportionately long legs, clinodactyly and learning difficulties) before puberty, which starts at the normal age but as a process fails to progress normally.

Adult men with Klinefelter’s syndrome have small firm testicles (testicular volume is rarely over 4 ml). The phenotype can vary from a normally virilised man to one with stigmata of androgen deficiency (Leydig cell function is commonly impaired but Leydig cells are present in normal or increased numbers), including female hair distribution, scanty body hair and long legs (usually tall patients) because of late epiphyseal closure. Patients may develop gynaecomastia (with risk of breast cancer). Ultrasound findings of testicular microlithiasis can be seen in men with Klinefelter’s syndrome. There are some Klinefelter's syndrome variants that were reported e.g. 49 , XXXXY variant with several additional features such as microcephaly, mental retardation, facial dysmorphism, radioulnar synostosis, micropenis, and muscular hypotonia. As the number of X chromosomes increases, the severity of mental retardation and of malformations also increases. Each extra X is associated with a 15- to 16-point reduction in IQ, with language most affected, particularly expressive language skills. Compared with their classmates, patients may notice differences and become socially alienated (social maladjustment). This may explain the fact that some patients become criminals on trying to prove one's manhood!

FSH and LH levels increase to hypergonadotropic levels, inhibin B decreases to undetectable levels, testosterone levels are low or low-normal (thus libido can be normal) and oestradiol levels are normal or elevated. The diagnosis is confirmed by chromosome studies.


Reported associated features include e.g. osteoporosis, psychiatric disorders, leg ulcers especially in combination with hyperpigmentation or atrophie blanche (androgens may protect against their development), incontinentia pigmenti (as incontinentia pigmenti trait is usually lethal in males, it has been proposed that the second X chromosome protects against foetal death), and systemic lupus erythematosus [SLE](androgens may normalise SLE haematological and serological abnormalities with clinical remission).

Due to the significant increase of sex chromosomal and autosomal abnormalities in the embryos of Klinefelter patients generated through ICSI, pre-implantation genetic diagnosis (PGD) is strongly advised.

Testosterone replacement is needed as the patient ages and it should be noted that a threshold serum testosterone level is required to achieve full efficacy with PDE5i (phosphodiesterase-5 inhibitors) when required. There is controversy over the indication for testosterone treatment of children with Klinefelter's syndrome (? might improve learning ability). As stated before, compared with their classmates, patients may notice differences and become socially alienated (social maladjustment). This may explain the fact that some patients become criminals on trying to prove one's manhood! Thus testosterone replacement should not lead to exceeding the upper normal values.  

Yearly follow up of men with Klinefelter’s syndrome is required and androgen replacement therapy should be started when testosterone level is in the range of hypoandrogenism. All men with Klinefelter’s syndrome who undergo testicular biopsy procedures for sperm retrieval need long-term endocrine follow-up.

*Ichioka K, Utsunomiya N, Kohei N, Ueda N, Inoue K, Terai A. Adult onset of declining spermatogenesis in a man with nonmosaic Klinefelter’s syndrome. Fertil Steril 2006; 85(5): 1511.e1-2.

This page was last updated in April 2013

Tuesday, 26 October 2010


Gonococcal urethritis (Gonorrhoea). Gonorrhoea owes its name to the Greek physician Galen in the second century AD, as it was then thought that the discharge of urethral pus was seminal fluid-hence being misnamed “gonorrhoea” (Greek, flow of seed). Thus from the very earliest times it was characterised as being “a male disease” and little attention was given to its manifestations in females.

As the concept developed that gonorrhoea resulted from coitus (venery), steps were taken for its control and it is said that in the Middle Ages prostitutes of Paris were quartered in domiciles in the Les Clapiers (les clapiers meaning rabbit hutches, the slang name for brothels in Paris during the Middle Ages) district there, hence the term clap, which is still commonly used to refer to this disease.

Extragenital infections include rectal, pharyngeal and conjunctival infections. 

Gonorrhoea has a high infectivity and is easily transmitted before symptoms appear (during the incubation period - the incubation period ranges from 1 to 14 days or even longer in men). In males, the usual presentation is with acute anterior urethritis. There may be slight tender enlargement of the superficial inguinal lymph nodes. Urethritis in men may be divided into gonococcal (gonorrhoea) or non-gonococcal urethritis (NGU); there is considerable overlap and differentiation on clinical grounds alone is not advised. More than 50% of females are asymptomatic (seen as contacts on examination). Symptoms if present (e.g. lower abdominal pain, dysuria, and vaginal discharge) appear within 10 days of infection.

NGU occurring soon after curative therapy for urethral gonorrhoea is called postgonococcal urethritis. NGU can be further classified into Chlamydia trachomatis-positive and Chlamydia trachomatis -negative NGU. There is a proportion of cases of NGU that are not sexually transmitted.

The gonococcus (Neisseria gonorrhoeae)  has a predilection for columnar epithelium which is readily available after the organism has gained entrance to the urethra, rectum, pharynx and conjunctiva in both sexes and endocervix and Bartholin’s ducts in females. The infection can spread to other structures lined with susceptible epithelium such as Littré’s glands, Cowper’s glands, prostate gland, seminal vesicles and epididymes in the male and Skene’s glands and Fallopian tubes in the female. The gonococci, with the help of pili and other surface proteins, attach themselves to the epithelial cells. This attachment protects them from being dislodged by the normal flow of urine or mucous secretions. They may also become embedded within the epithelial cells. However, once phagocytosed by neutrophils (microphages), the gonococci may undergo lysis, especially after appropriate antibiotic treatment.

In contrast to female adults, in prepubertal girls the nonoestrogenized alkaline thin immature vaginal mucosa may be infected and colonised with N. gonorrhoeae. A clinician who is examining a prepubertal female for a gonococcal infection should be aware that contrary to female adults, it is not necessary to obtain a specimen from the cervical canal; a specimen from the vaginal canal suffices.

Gonococcal urethritis in boys, vulvo-vaginitis in girls and pharyngeal and rectal infection in both sexes are almost always the result of sexual abuse.

Complications in males include infection of the median raphe, Tysonitis, meatal paraurethral gland abscess, inflammation of Littré’s glands and periurethral cellulitis and abscess, urethral strictures and fistulae, Cowperitis and abscess formation, prostatitis and seminal vesiculitis and epididymitis.

Complications in females include inflammation of the paraurethral (Skene’s) glands, Bartholinitis with abscess formation, and pelvic inflammatory disease (PID). In pregnancy, genital infection is less likely to be complicated by PID (because of thickening of cervical mucus) but other adverse outcomes include e.g. premature rupture of membranes, and postpartum/intrapartum or postabortal endometritis.

Systemic complications include perihepatitis and disseminated gonococcal infection (DGI) (In DGI factors include e.g. serogroup IA-1 & 2/ auxotype AHU [arginine, hypoxanthine, and uracil] dependent). In DGI, the preceding genital infection tends to be asymptomatic and the patient usually presents with mild fever, gonococcal dermatitis especially at extremities, and arthralgia +/- arthritis.  AHU/IA-1 & 2 strains accumulate in the population because of their ability to cause asymptomatic infection in men. AHU/IA-1 & 2 strains are particularly susceptible to the penicillins but this varies over time and penicillin resistant strains now play a significant role.

Neonatal gonococcal infection occurs because of exposure in birth canal during labour and includes gonococcal ophthalmia neonatorum, gonococcal arthritis, anogenital infection, pharyngeal infection and other infections such as scalp abscess following trauma to scalp e.g. with intrauterine foetal monitoring.

Five or more polymorphonuclear leucocytes per high power field (in at least five x 1000 oil immersion microscopic fields) in the Gram-stained urethral smear will confirm urethritis and the presence of Gram-negative intracellular diplococci (red kidney bean-shaped organisms) within polymorphonuclear leucocytes (microphages) would enable the physician to make a presumptive diagnosis of gonococcal urethritis. Confirmation is by culture of the organism (also allows sensitivity testing) and differentiation from other Neisseria species by antigenic (monoclonal antibody test) or biochemical testing (gonococcus utilises glucose only). The culture medium is examined at 24 and 48 hours for growth. Growth is optimal at 35–37 °C in a 5% CO2 atmosphere, at a pH of about 6.5–7.5. For urethral specimens from symptomatic men, cultures on selective “antibiotic-containing” (e.g. modified Thayer-Martin medium) and nonselective media are equally sensitive, because the concentration of gonococci in the urethra usually exceeds that of other flora. In contrast, selective media are preferred for culturing the endocervix, rectum, and pharynx, where other, less fastidious bacteria often outnumber N. gonorrhoeae. Test of cure by culture should be delayed for at least 72 after treatment.

Nucleic acid amplification tests (NAATs) are extremely sensitive and will detect very small amounts of DNA or rRNA. Detection does not necessarily indicate that the organism is viable [the test of cure should be delayed for at least 2 weeks after treatment to avoid false positive results]. Using NAATs that exhibit little cross-reactivity reduces false positive results. NAATs are more sensitive than culture and can also be used as diagnostic/screening tests on non-invasively collected specimens (urine in men and self-taken vulvovaginal swabs). NAATs allow dual detection of N. gonorrhoeae and Chlamydia trachomatis too. Urine is a suitable sample in NAAT screening for Chlamydia trachomatis and so may be tested additionally for N. gonorrhoeae in both men and women, but NAATs sensitivity to detect N. gonorrhoeae in women is higher if a self-taken vulvovaginal swab is used. Confirmation of NAAT reactivity by culture is necessary (urine is not considered a suitable sample for culturing of N. gonorrhoeae or Chlamydia trachomatis) and allows antimicrobial sensitivity testing and thus resistant strains can be identified. Resistance may be due to plasmids (circular DNA fragments independent of chromosome) or chromosome mutations.

Gonorrhoea is known to facilitate the transmission of HIV (increase in detectable HIV in urethral/cervical secretions when infection is present). The impact of untreatable gonorrhoea (given the lack of new anti-gonococcal drugs on the horizon, gonorrhoea may eventually become untreatable) on HIV transmission could be enormous in countries with a high HIV prevalence*.

Uncomplicated gonorrhoea responds to a single dose of suitable antimicrobial (in view of the global increase in multidrug-resistant gonorrhoea, the wisdom of continued single-dose treatment may be challenged and extended treatment may be required), the choice of dose and drug depending on antimicrobial sensitivity

Ceftriaxone 1g intramuscular monotherapy is generally the current treatment approach for uncomplicated gonorrhoea when antimicrobial susceptibility is not known prior to treatment.  A high level of vigilance through use of culture, follow up of patients and test of cure coupled with maintenance of strong surveillance is vital in order to monitor the impact of this approach. Ciprofloxacin 500 mg can be used when infection is known to be susceptible. Test of cure is recommended for all gonorrhoea patients and should be by culture at least 72 hours after completion of therapy if symptomatic and by DNA NAAT 14 days after completion of therapy or by RNA NAAT 7 days after completion of therapy if asymptomatic. This is followed by culture if NAAT-positive. 

A 1g dose of azithromycin may be insufficient to clear infection and a 2g dose of azithromycin could potentially be more effective than 1g and alternative therapies if indeed to replace monotherapy include dual therapy with azithromycin 2g where possible trying to avoid treatment failure e.g. cefixime 400 mg orally as a single dose plus azithromycin 2g orally but note that the incidence of gastrointestinal side-effects is higher with 2g azithromycin. 

Dual treatment with ceftriaxone plus azithromycin was advised for the treatment of uncomplicated gonorrhoea in the past (irrespective of the results of chlamydia testing) in order to mitigate against the selection of gonococci with reduced susceptibility to cephalosporins. The rationale was that it was difficult for an organism to develop simultaneous resistance to two different antimicrobial classes, meaning that dual treatment created a pharmacological barrier to the emergence of isolates exhibiting resistance to one component of the recommended therapy. There is no good evidence for any antimicrobial synergy between ceftriaxone and azithromycin and this was NOT the reason for recommending dual therapy but for now the best strategy to delay the emergence of resistance remains to be seen thus ceftriaxone monotherapy is the current treatment approach. 

Management of sexually transmitted urethritis includes, screening for other STIs, contact tracing and sexual partner(s) notification, education/counselling, examination, investigation and treatment

*Lewis DAThe Gonococcus fights back: is this time a knock out? Sex Transm Infect 20108641521.

This page was last updated in May 2019

Lymphomatoid papulosis

Lymphomatoid (resembling lymphoma) papulosis represents part of a spectrum of primary cutaneous CD30+ lymphoproliferative disorders. Primary cutaneous CD30+ lymphoproliferative disorders consist of a spectrum of conditions; lymphomatoid papulosis and CD30+ large cell lymphomas which are defined on the basis of clinical and pathologic features. Where a distinction cannot be made, patients are designated as ‘borderline cases’.

The CD30 marker was originally identified as a marker on Reed–Sternberg (RS) cells in Hodgkin’s disease. The classical RS cells are multinucleate, nucleoli are large and prominent. If two nuclei are present, one appears to be the mirror image of the other, and this gives an “owl’s-eye” appearance. In the skin, primary CD30+ lymphoproliferative disorders are invariably of T-cell origin (some biopsies may not show a T-cell receptor clonal pattern though). The nodal CD30+ lymphomas can be derived from B, T or null cells.

Identical T‐ cell clones can be detected in skin biopsies from patients with both mycosis fungoides (MF) and lymphomatoid papulosis. Studies using laser captured CD30+ cells and sequencing of T-cell receptor genes have shown contradictory findings. The pathophysiology of the disease remains to be clarified.

The term lymphomatoid papulosis was first used in 1968 by
Macaulay to describe a ‘self-healing rhythmical paradoxical papular eruption, histopathologically malignant but clinically benign’. Since then, there has been continued discussion as to whether lymphomatoid papulosis is a malignant, a premalignant or a benign condition. Long-term follow-up is necessary in all cases because of the risk of progression to a bona fide lymphoma such as a primary cutaneous CD30+ large cell lymphoma, MF (patients more commonly have coexistent MF) or Hodgkin’s disease in less than 5% of cases. Similarly, some patients develop lymphomatoid papulosis‐ like lesions with a preceding history of Hodgkin disease and patients with pre‐existing MF may subseqently develop lesions indistinguishable from those of lymphomatoid papulosis. There appear to be no currently available clinical or pathological prognostic markers to indicate whether such progression is likely. There is debate whether these patients actually have lymphoma from the start, which is low grade and may regress, or whether benign disease actually transforms into lymphoma. The prognosis in patients with both MF and lymphomatoid papulosis appears to be excellent.

Affected patients have recurrent crops of asymptomatic papular or papulonecrotic or nodular lesions
predominantly affecting the trunk, although any body site can be involved. The red–brown papules and nodules develop central haemorrhage, necrosis and crusting, and subsequently spontaneously disappear. Healing may leave atrophic (varioliform) scars. Characteristically, skin lesions in different stages of evolution coexist. The disease is chronic and recurrent (waxes and wanes or comes and goes). The cycle recurs every few months, with no obvious initiating factor. The lesions generally occur first in adult life and may recur in crops for up to 40 years or more. Over time, every individual skin lesion will resolve and there may eventually be a persistent remission. Angioinvasive and follicular variants of lymphomatoid papulosis have been described

It has been suggested that
interactions between CD30 and its ligand (CD30L) may contribute to apoptosis of the neoplastic T cells and the subsequent regression of the skin lesions.

It should be noted that
in general cutaneous lymphomas that are CD30+ ab initio are associated with a good prognosis.

Because of the clinical similarities between
lymphomatoid papulosis and pityriasis lichenoides et varioliformis acuta, a relationship between the two conditions was initially suggested. Clonal T-cell populations have been demonstrated in skin biopsies of both conditions. Pityriasis lichenoides et varioliformis acuta occurs more often in younger patients, is generally short-lived, does not develop nodular lesions, is more vesicular and less necrotic, and progression to a malignant lymphoma is exceedingly rare, if it occurs at all. CD30 is generally negative and if CD30+ atypical lymphocytes are found they are few and invariably CD8+ while the presence of CD30+ atypical lymphocytes (usually CD4+ but occasionally CD8+) is the hallmark of lymphomatoid papulosis as will be discussed below. It should also be noted that small recurrent lymphomatoid papulosis lesions can be misdiagnosed as folliculitis or arthropod bites for years. 

The histopathology of lymphomatoid papulosis in part correlates with the age of the sampled skin lesion. The features are a relative lack of epidermotropism and Pautrier microabscesses, but the presence in the dermis of a mixed infiltrate composed of atypical lymphocytes with large nuclei and frequent abnormal mitoses, eosinophils, neutrophils, extravasated red cells and large histiocytic cells. Some of these cells may show marked cytological atypia. The epidermis may be ulcerated and the infiltrate may extend deeply into the reticular dermis. True vasculitis is rarely seen.

Lymphomatoid papulosis can be divided on histopathological grounds
into A, B, C and D subgroups.

In the
A subgroup, lesions show non-epidermotropic infiltrate with large "Reed-Sternberg like cells" (CD30+), interspersed in an extensive inflammatory infiltrate of lymphocytes, eosinophils, neutrophils, and extravasated red blood corpuscles.

In the
B subgroup, lesions show lymphocytic infiltrates showing early infiltration of the basal and parabasal layers of the epidermis. These smaller atypical T lymphocytes are with convoluted (cerebriform) nuclei similar to those seen in mycosis fungoides and are CD30-. This subgroup might present with clinical lesions resembling pityriasis lichenoides et varioliformis acuta causing confusion.

In the
C subgroup, lesions show a monotonous population of large CD30+ lymphocytes with an overall pattern suggestive of primary cutaneous CD30+ large cell lymphoma.

In the
D subgroup, atypical CD30+ lymphoid cells express CD8 with a cytotoxic phenotype.

Many cases, however, have all types of lesions coexisting simultaneously.

There is
no evidence that intensive combination chemotherapy alters beneficially the course of lymphomatoid papulosis, and indeed there are individual case reports suggesting that high-dose intensive chemotherapy may cause transition to a more aggressive disorder!

Skin‐directed therapy options include narrow‐band UVB therapy and topical or intralesional steroids. Radiotherapy may be tried.

In the case
of cosmetically disturbing lesions (e.g. scarring or many papulonodules), low-dose oral methotrexate (5-20 mg/week) appears to be the most effective systemic therapy
for reducing the number of skin lesions. There are reports of a beneficial effect with oral dapsone too. 

This page was last updated in July 2018.  

Main Works of Reference List (The first eight are my top favourites)

  • British National Formulary
  • British National Formulary for Children
  • Guidelines (BAD - BASHH - BHIVA - Uroweb)
  • Oxford Handbook of Genitourinary Medicine, HIV, and Sexual Health
  • Oxford Handbook of Medical Dermatology
  • Rook's Textbook of Dermatology
  • Simple Skin Surgery
  • Weedon's Skin Pathology
  • A Concise Atlas of Dermatopathology (P Mckee)
  • Andrews' Diseases of the Skin
  • Andrology (Nieschlag E FRCP, Behre M and Nieschlag S)
  • Bailey and Love's Short Practice of Surgery
  • Davidson's Essentials of Medicine
  • Davidson's Principles and Practice of Medicine
  • Fitzpatrick's Colour Atlas and Synopsis of Clinical Dermatology (Klaus Wolff FRCP and Richard Allen Johnson)
  • Fitzpatrick’s Dermatology in General Medicine
  • Ganong's Review of Medical Physiology
  • Gray's Anatomy
  • Hamilton Bailey's Demonstrations of Physical Signs in Clinical Surgery
  • Hutchison's Clinical Methods
  • Lever's Histopathology of the Skin
  • Lever's Histopathology of the Skin (Atlas and Synopsis)
  • Macleod's Clinical Examination
  • Martindale: The Complete Drug Reference
  • Oxford Handbook of Clinical Examination and Practical Skills
  • Oxford Textbook of Medicine
  • Practical Dermatopathology (R Rapini)
  • Sexually Transmitted Diseases (Holmes K et al)
  • Statistics in Clinical Practice (D Coggon FRCP)
  • Stockley's Drug Interactions
  • Treatment of Skin Disease: Comprehensive Therapeutic Strategies
  • Yen & Jaffe's Reproductive Endocrinology