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Absence of Male-Pattern Baldness in Men with X-Linked Recessive Ichthyosis?
Abstract
X-linked recessive ichthyosis (XRI) is caused by a deficiency of steroid sulfatase. Because this enzyme plays an important role in androgen metabolism, we advance the hypothesis that men with XRI do not show androgenetic alopecia or develop only mild forms of this common type of hair loss. Clinical studies should show whether this hypothesis can be supported.
Androgenic alopecia (AGA) is characterized by the local and gradual transformation of terminal scalp hair into vellus hair, which has a shorter and thinner shaft. It is the most common form of hair loss in people with a genetic predisposition for baldness. Objective: The aim of this study was to evaluate the prevalence, AGA type, family history, co-morbidity diseases stress factors and endocrine factors of AGA patients. Methods: We examined a total of 432 male and female AGA patients who visited for two years at the Department of Dermatology, School of Medicine, Chung-Ang University. Results: There were 2.06 times more men (291 patients) than women (141 patients) among the study subjects. Most of the men were in their twenties (108, 37.1%), however, most of the women were in their forties (42, 29.7%). In the 291 male patients, Norwood class IIIv was dominant (120 patients, 41.2%). In the 141 female patients, Ludwig class I was dominant (87 patients, 61.7%). 219 (75.2%) of the 291 male patients and 81 (73.6%) of the 141 female patients had a family history of AGA. 224 (76.9%) of the 291 male patients and 101 (53.4%) of the 141 female patients had a co-morbidity disorder. The most common among these disorders in both the male and female patients was seborrheic dermatitis. Stress factors were observed in 162 (55.6%) of the 291 male patients and in 78 (55.3%) of the 141 female patients. The most common stress factor in both the male and female patients was work tasks. The serum testosterone levels was increased in 51 (17.5%) of the 291 male patients and in 20 (14.1%) of the 141 female patients. Conclusion: Most of the study results are compatible with those of our previous study. Yet the following results were different: (1) the number of female AGA patients in their forties is increasing; and (2) stress was found to be associated with AGA in both the male and female patients.
Background: Androgenetic alopecia is the most common form of hair loss in people with a genetic predisposition. It is characterized by the miniaturization of terminal hair follicles and the formation of velhis-iike follicles. Objective: The aim of this study was to evaluate the prevalence, clinical manifestation, genetic and endocrine factor, and associated diseases of Korean patients with androgenetic alopecia. Methods: We studied 789 Korean men and women with androgenetic alopecia. A detailed history was taken and their hormonal values were measured. A pelvic ultrasound scan was performed to check for abnormalities the ovaries and uterus of 56 women with androgeneric alopecia. Results: The number of men was 1.9 times more (520) than that of women (269). Most of them were in their twenties (male 223; 42.8%, female 85; 31.5%). In the 520 male patients, Norwood class IHv was dominant (161 patients; 30.9%). In the 269 female patients, Ludwig class 1 was superior (218 patients; 81%). 395 (75.9%) of male patients and 198 (73.6%) of female patients had a family history of androgenetic alopecia. The most common associated disorder was seborrheic dermatitis (male 407; 78.2%, female 155; 57.6%). And others included atopic dermatitis, hypertension, thyroid disease, etc. Serum testosterone levels were increased in 92 (17.6%) of the male patients and in 36 (13.3%) of the female patients. Abnormal pelvic ultrasound findings were observed in 10 (18%) of 56 female patients, and the conditions were ovarian cysts (8.9%), Uterine myoma (5.4%). uterine mass (2%), endometrial mass (2%). Conclusion: Androgenetic alopecia is a disease that has genetic and familial tendency and is associated with the androgen level. The number of androgenetic alopecia patients was increasing and type IHv was most common in the male patients. The pelvic ultrasound showed an increased rate of abnormal findings in the female patients with androgenetic alopecia, but ultrasound is not an appropriate routine test to evaluate.
Background: X-linked recessive ichthyosis (XRI) is a genetic disorder of keratinization with extracutaneous manifestations due to deficiency of steroid sulfatase (STS). Because STS plays an important role in androgen metabolism, and elevated levels of dehydroepiandrosterone sulfate have been reported in young men with andogenetic alopecia (AGA), the hypothesis was advanced that men with XRI do not show AGA or develop only mild forms of common baldness. Methods: Patients with a diagnosis of XRI confirmed by analysis of the microsomal sulfatases in our clinic between 1984 and 1998, and in whom study of the case histories depicted the typical clinical presentation of XRI, were sent a questionnaire with the Hamilton-Norwood scale of patterns of hair loss in men, inquiring them to designate the condition of their scalp hair. Results and Conclusions: Of 15 questionnaires returned, 7 indicated Hamilton-Norwood I, 3 Hamilton-Norwood II, 3 Hamilton-Norwood III-vertex, 1 Hamilton-Norwood IV and 1 Hamilton-Norwood VII. The results of this survey do not support the hypothesis that XRI and AGA are mutually exclusive, in as much as advanced AGA was found among these men.
X-linked recessive ichthyosis (XRI) is a relatively common genetic disorder of keratinization caused by deficiency in steroid sulfatase (STS) activity. STS appears to play an important role in testosterone metabolism. Therefore it has been discussed that the presence of normally functioning STS may be a presupposition for the development of androgenetic alopecia (AGA).
Patients with the diagnosis of XRI were sent questionnaires.
We reviewed 26 cases with XRI and noticed 11 patients with AGA in an advanced stage. The existence of two pathways for the steroid biosynthesis may be the explanation for a compensatory mechanism in XRI males. The Delta5 pathway depends on steroid sulfate activity, whereas the working Delta4 pathway produces AGA in XRI males.
Zusammenfassung: Die androgenetische Alopezie (AGA) ist die häufigste Form des Haarausfalls bei Männern. Die relativ ausgeprägte Konkordanz der Glatzenausprägung bei Vätern und ihren Söhnen unterliegt keinem gewöhnlichen Mendelschen Erbgang, sondern beruht wahrscheinlich auf einer polygenen Vererbung. Die prädisponierenden Gene für eine AGA sind bis heute unbekannt und die molekularen Grundlagen des Androgen-abhängigen Bartwuchses versus Androgen-abhängigen Haarausfalls sind ungeklärt, die AGA kann jedoch als Dihydrotestosteron (DHT)-abhängiger Prozess mit kontinuierlicher Miniaturisierung der empfindlichen Haarfollikel beschrieben werden. Die 2, 5-α-Reduktase spielt eine zentrale Rolle bei der intrafollikulären Konversion von Testosteron (T) zu Dihydrotestosteron. Da das Wissen auf diesem Gebiet ständig zunimmt, soll diese Arbeit aktuelle Erkenntnisse kritisch beleuchten.
Summary: Androgenetic alopecia (AGA) is the most common type of hair loss in men. The relative strong concordance of the degree of baldness in fathers and sons is not consistent with a simple Mendelian trait and a polygenic basis is considered to be most likely. So far the predisposing genes for AGA are unknown and we do not understand the molecular steps involved in androgen-dependent beard growth versus androgen-dependent hair loss, but AGA can be defined as a DHT-dependent process with continuous miniaturization of sensitive hair follicles. The type 2 ,5-α-R plays a central role by the intrafollicular conversion of T to DHT. Due to the increasing knowledge in this field, this article shall provide an critical overview of recent discoveries.
Die androgenetische Alopezie ist bei Frauen und Mnnern die hufigste Form von Haarverlust. Wenngleich sich der Haarausfall bei Frau und Mann klinisch unterschiedlich manifestiert, so sind dennoch die zugrunde liegenden, zur Alopezie fhrenden Pathomechanismen dieselben. Es kann davon ausgegangen werden, dass aufgrund genetischer Prgung bestimmte Haarfollikel am Kapillitium eine verstrkte Sensitivitt gegenber Androgenen aufweisen. Die Forschungsergebnisse der letzten Jahre haben eine Vielzahl pathophysiologisch, diagnostisch und therapeutisch bedeutsamer Erkenntnisse hervorgebracht, deren klinisch relevante Aspekte und Neuerungen in dieser bersicht dargestellt werden.Androgenetic alopecia is the most common form of hair loss in men and women. Although the clinical manifestations are different in men and women, the pathogenetic pathways leading to this type of hair loss are similar in both sexes. In short genetically predestined hair follicles show an increased sensitivity to androgens. In recent years, much new data concerning the pathophysiology, management and therapy of androgenetic alopecia has been gathered. This article gives a critical overview of these new findings and assesses their practical relevance.
X-linked recessive ichthyosis (XRI) is a genetic disorder of keratinization with extracutaneous manifestations due to deficiency of steroid sulfatase (STS). Because STS plays an important role in androgen metabolism, and elevated levels of dehydroepiandrosterone sulfate have been reported in young men with andogenetic alopecia (AGA), the hypothesis was advanced that men with XRI do not show AGA or develop only mild forms of common baldness.
Patients with a diagnosis of XRI confirmed by analysis of the microsomal sulfatases in our clinic between 1984 and 1998, and in whom study of the case histories depicted the typical clinical presentation of XRI, were sent a questionnaire with the Hamilton-Norwood scale of patterns of hair loss in men, inquiring them to designate the condition of their scalp hair.
Of 15 questionnaires returned, 7 indicated Hamilton-Norwood I, 3 Hamilton-Norwood II, 3 Hamilton-Norwood III-vertex, 1 Hamilton-Norwood IV and 1 Hamilton-Norwood VII. The results of this survey do not support the hypothesis that XRI and AGA are mutually exclusive, in as much as advanced AGA was found among these men.
Androgenetic alopecia (AGA) is the most common type of hair loss in men. The relative strong concordance of the degree of baldness in fathers and sons is not consistent with a smiple Mendelian trait and a polygenic basis is considered to be most likely. So far the predisposing genes for AGA are unknown and we do not understand the molecular steps involved in androgen-dependent beard growth versus androgen-dependent hair loss, but AGA can be defined as a DHT-dependent process with continuous miniaturization of sensitive hair follicles. The type 2 5aR plays a central role by the intrafollicular conversion of T to DHT. Due to the inceasing knowledge in this field, this article shall privide an critical overwiew of recent discoveries.
The skin, especially the pilosebaceous unit composed of sebaceous glands and hair follicles, can synthesize androgens de novo from cholesterol or by locally converting circulating weaker androgens to more potent ones. As in other classical steroidogenic organs, the same six major enzyme systems are involved in cutaneous androgen metabolism, namely steroid sulfatase, 3beta-hydroxy-steroid dehydrogenase, 17beta-hydroxysteroid dehydrogenase, steroid 5alpha-reductase, 3alpha-hydroxysteroid dehydrogenase, and aromatase. Steroid sulfatase, together with P450 side chain cleavage enzyme and P450 17-hydroxylase, was found to reside in the cytoplasm of sebocytes and keratinocytes. Strong steroid sulfatase immunoreactivity was observed in the lesional skin but not in unaffected skin of acne patients. 3beta-hydroxysteroid dehydrogenase has been mainly immunolocalized to sebaceous glands, with the type 1 being the key cutaneous isoenzyme. The type 2 17beta-hydroxysteroid dehydrogenase isoenzyme predominates in sebaceous glands and exhibits greater reductive activity in glands from facial areas compared with acne nonprone areas. In hair follicles, 17beta-hydroxysteroid dehydrogenase was identified mainly in outer root sheath cells. The type 1 5alpha-reductase mainly occurs in the sebaceous glands, whereby the type II isoenzyme seems to be localized in the hair follicles. 3alpha-hydroxysteroid dehydrogenase converts dihydrotestosterone to 3alpha-androstanediol, and the use of 3alpha-androstanediol glucuronide serum level to reflect the hyperandrogenic state in hirsute women may be a reliable parameter, especially for idiopathic hirsutism. In acne patients it is still controversial if 3alpha-androstanediol glucuronide or androsterone glucuronide could serve as suitable serum markers for measuring androgenicity. Aromatase, localized to sebaceous glands and to both outer as well as inner root sheath cells of anagen terminal hair follicles, may play a "detoxifying" role by removing excess androgens. Pharmacologic development of more potent specific isoenzyme antagonists may lead to better clinical treatment or even prevention of androgen-dependent dermatoses.
Androgenetic alopecia (AGA), or male pattern hair loss, affects approximately 50% of the male population. AGA is an androgen-related condition in genetically predisposed individuals. There is no treatment to completely reverse AGA in advanced stages, but with medical treatment (eg, finasteride, minoxidil, or a combination of both), the progression can be arrested and partly reversed in the majority of patients who have mild to moderate AGA. Combination with hair restoration surgery leads to best results in suitable candidates. Physicians who specialize in male health issues should be familiar with this common condition and all the available approved treatment options.
SummaryX-linked recessive ichthyosis (XLI) is caused by a deletion, or mutation, of the steroid sulphatase gene on the distal short arm of the X chromosome (Xp22.3). This region of the X chromosome is particularly susceptible to deletions. Such deletions can occasionally extended to involve neighbouring genes, causing a contiguous gene defect. Therefore, XLI may be associated with Kallmann's syndrome (KS), mental retardation, X-linked recessive chondrodysplasia punctata and short stature. We have reviewed 33 patients with XLI. Nine showed evidence of contiguous gene defects. A further four had neurological deficit sustained at the time of birth. This study highlights the importance of screening patients with X-linked recessive ichthyosis for neighbouring genetic disorders and, in particular, the early identification of KS, as delay in diagnosis may lead to infertility and osteoporosis. Parents should be warned about possible obstetric complications due to prolonged labour in future pregnancies.
Cloned fibroblasts from women heterozygous for X-linked ichthyosis (steroid sulfatase deficiency) were examined to see whether
or not this locus is subject to X-inactivation. Of 103 clones examined, all had normal levels of steroid sulfatase activity.
Two of the women studied were also heterozygous for glucose-6-phosphate dehydrogenase deficiency. This allowed the demonstration
that both X chromosomes were represented as the active X in various clones and that selection did not account for these findings.
Thus, the steroid sulfatase locus, like the Xga locus to which it is linked, appears to escape X-inactivation in man.
It is considered axiomatic in human genetics that the study of relatively rare disorders may yield far more in dividends than might be anticipated based on the incidence of the condition in question. This has clearly been demonstrated in studies of human steroid sulfatase deficiency and the steroid sulfatase system during the past few years. Investigations of this infrequent human variation have led to expanded studies of sulfated steroid metabolism, the physiological control of epidermal keratinization, estrogen biosynthesis in pregnancy, testosterone biosynthesis, and the molecular mechanism of X-chromosome inactivation and the escape of inactivation of certain portions of the human X. In addition, the availability of a readily scoreable marker for the distal human short arm provides the potential basis for a number of observations regarding X/Y interchange involving this portion of the X and has raised a number of evolutionary issues as well. Further studies may help clarify several of these questions and substantially add to our understanding of a variety of human X-chromosome disorders, such as X aneuploid states, XX males, and true hermaphrodites.
Seventy-six ichthyotic male patients with a biochemically confirmed diagnosis of steroid sulphatase deficiency are reported. Ascertainment was based on either a previous diagnosis of placental steroid sulphatase deficiency (21 probands and 15 secondary cases), or ichthyosis with steroid sulphatase deficiency (29 probands and 11 secondary cases). The ichthyotic phenotype of the first group was indistinguishable from that of the other group, and completely fitting the classic description of recessive X-linked ichthyosis. A prominent skin peeling in early infancy was found to be a characteristic feature of this syndrome. Maldescent of the testis was registered in 9 patients; and testis cancer had been diagnosed in 2 males with normally descended gonads. This high proportion of patients with gonadal abnormalities strongly indicates a relation with the steroid sulphatase deficiency. Corneal opacities, not affecting visual acuity, were seen in 14 out of 28 males by slit-lamp examination.
Eighteen men aged 18 to 32 with rapidly progressive male pattern baldness had serum dehydroepiandrosterone sulfate and testosterone measured. Dehydroepiandrosterone sulfate levels were elevated in all patients, ranging from 340 to 730 micrograms/dl. The patients were otherwise healthy and serum testosterone levels were within normal limits. A control group of men of similar age without hair loss had lower dehydroepiandrosterone sulfate levels ranging from 124 to 300 micrograms/dl (p less than 0.005). The biochemistry of androgens, particularly dehydroepiandrosterone sulfate, suggests that adrenal hyperactivity may initiate alopecia in young men who are genetically susceptible.
In the past there have been several reports of testicular abnormalities (hypogonadism, cryptorchidism and so-called atypical germ cells) in patients with recessive X-linked ichthyosis. Anamnestic interviews, clinical as well as chemical investigations in ten patients (aged 25-52 years) with recessive X-linked ichthyosis have been undertaken in order to examine their endocrine and exocrine testicular function. Normal serum levels of gonadotropins were observed in nine of ten patients, while four of ten men had decreased levels of dehydroepiandrosterone. In addition, in eight of these ten patients spermatological alterations were found: two patients suffered from oligozoospermia, while asthenozzospermia occurred in seven patients and teratozoospermia was registered in three men. Although andrological abnormalities were found in five out of ten patients (cryptorchidism, varicocele), the high incidence of spermatological alterations is remarkable. Further investigations will be necessary to clarify whether steroid sulphatase is responsible for some of these alterations, especially for the pronounced asthenozoospermia.
When boys affected with steroid sulfatase deficiency are delivered, the lack of the enzyme in the placenta may cause birth complications. In postnatal life this gene defect gives rise to X-linked recessive ichthyosis. In a series of 25 patients birth complications were reported in 9 cases. Of these boys, 4 displayed bilateral inguinal cryptorchidism and one was affected unilaterally. In a further boy we observed unilateral inguinal cryptorchidism without a history of birth complications. In one patient who had been delivered by forceps, abdominal bilateral cryptorchidism resulted in severe hypogenitalism. A review of the literature revealed 30 cases with X-linked recessive ichthyosis displaying hypogenitalism or cryptorchidism or both. In conclusion, cryptorchidism should be considered as a further clinical manifestation of steroid sulfatase deficiency.
Androgens, in combination with a genetic susceptibility, have been demonstrated to be required for the development of androgenetic alopecia. Disturbances in androgen metabolism or target organ sensitivity are thought to underlie the pathophysiology of the condition. Observations of patients with disorders of androgen metabolism or function have determined the basic physiology involved in regulation of hair growth by androgens at selective body sites. More recently, in vitro studies of scalp skin and hair follicles have begun to define specific alterations in androgen metabolism at the local level that may play a key role in pathogenesis. The prominent role of 5-reductase in these studies suggests that inhibitors of this enzyme may provide new therapeutic opportunities for patients with androgenetic alopecia.