Autor: jack_X 11 February 2010
Words: 3215 | Pages: 13
A Genetically Hairy Disposition
BURMA, 1826, a visitor named John Crawfurd accounted of a man named Shwe-Maong who had been serving as a court entertainer of the king of Ava, a province of Burma, since he was given to the king at age five. Shwe-Maongâ€™s face and body was covered in thick hair giving him a resemblance of a hairy animal. However he was only a man with an extremely rare genetic mutation and the first in a four generation line within his family that would inherit his mutation. His daughter, grandson, and great granddaughter would all inherit his disorder and would infamously become known as the â€œThe Hairy Family of Burma.â€ The family fascinated people from all over the world who would come to see them. (2)
â€œThe Hairy Family of Burma,â€ actually suffered from an extremely rare genetic mutation referred to generally as Congenital Hypertrichosis (CH). Hypertrichosis, as defined by the Encyclopedia Britannica Online, is â€œexcessive, abnormal hairiness that may be localized or cover the entire bodyâ€¦â€ Because of its extreme rarity and slightly varied possible sub classifications(7), scientists throughout the years have referred to Congenital Hypertrichosis by many names, all of which can mostly be used interchangeably and have similar meanings. For example, terminology has included: Hypertrichosis Universalis, Hypertrichosis Lanuginosa, Hypertrichosis Universalis Lanuginosa, Congenital Hypertrichosis Terminalis congenital generalized Hypertrichosis and Ambras Syndrome among others.
History of CH: Past and Present
The first recorded case of CH is believed to be that of Petrus Gonzales. Gonzales was born in the Canary Islands in 1556. Out of curiosity, Petrus was brought to France where he was presented as a gift to the nobles. Once it was realized Petrus was a bright young mind, he was educated and learned multiple classic and contemporary languages. He produced 2 daughters and a son all of whom were affected, even one grandchild was affected. (8) Eventually, they were known as the family of Ambras, from which the name Ambras Syndrome, the most studied subclass of CH, was taken. The Ambras name was given because the family portraits were discovered in Ambras castle amongst an art collection started by the archduke Ferdinand II (1529-1595). Although Gonzales was born in the Canary Islands and lived in France, the Ambras castle is in modern-day Austria. Today, the same paintings hang in the Kunsthistorisches museum in Vienna. (7) Over the past 300 years, more than 50 similar appearing cases have been described, and 34 patients with presumed Congenital Hypertrichosis have been adequately identified including the â€œThe Hairy Family of Burmaâ€. (8)
During the 19th and 20th centuries individuals with Congenital Hypertrichosis conditions have been documented to have worked in side shows and in circus acts for entertainment purposes becoming money making phenomena. These people would be called â€œwerewolves,â€ â€œape-men,â€ â€œdog-boy,â€ â€œhuman Skye terriers,â€ â€œHomo silvestris," or man from the woods, and most notably â€œthe bearded lady,â€ among others. (1, 4) People with Hypertrichosis have been stigmatized throughout history, and they are thought to be the source of the werewolf legend. (1) It has even been dubbed "Werewolf syndrome" by the media.
Most of the people recently featured in the media and on television with CH are from the Aceves clan of Loreto, Zacatecas, Mexico, some of whom have immigrated to the United States. Many of them have worked for circuses. The brothers Victor Ramon "Danny" Ramos and Gabriel "Larry" Ramos have worked as acrobats. Their cousins, Jesus "Chuy" Aceves, and his sister, Lili, have worked in sideshowsin Mexico (1). Some of the boys and men in the family work mightily to get rid of their excess hair, shaving every part of their face every day, sometimes repeatedly.
Possibly the most famous of the hairy "human curiosities" was Julia Pastrana, a Mexican Indian born in the 1830's who had long, thick, glossy and straight black hair covering most of her body, as well as overdevelopment of the jaw and an unusually broad, flattened nose. Scientists have tentatively diagnosed Pastrana's condition as "generalized hypertrichosis terminalis with gingival hyperplasia," (1)
As mentioned, Congenital Hypertrichosis has been referred to by various terms some of which are dependent on the specific phenotype present. The terminology has not always been consistent due to the sheer lack of modern case studies. However, all forms of CH are characterized by abnormal amounts and types of hair covering the patientâ€™s body. In fact, patients can be even hairier than chimpanzees or gorillas, which lack fur around the cheeks, nose and eyes. (1) Generally, CH conditions can have varied degrees of hair thickness, color, amount, and affected areas. Nearly all the skin of the human body except palms of hands and soles of feet are covered with hair. The density of the hair, thickness of the hair, color of the hair, speed of hair growth, and qualities such as kinkiness, vary from one part of the body to another and from one person to another. (1)
The diagnosis of CH is made on the basis of hair pattern, analysis of hair type by histology, genetic analysis, and absence of endocrinologic abnormality. In addition, various levels of dysmorphisms may be present. Analysis of hair type histology is critical to determine if the type of Hypertrichosis represents either vellus or lanuginosa hair. (7)
A variety of dysmorphisms have been recorded throughout history, most involving the head. Some recorded examples are, a dysmorphic triangular coarse face, broad intercantha, broad palpebral fissures, long nose with round tip, broad interalar distance, anteverted nares, short integumental lower lip, and flat sulcus mentolabialis. Occasional patients have hexadactyly and supranumery nipples. Other facial anomalies and abnormalities including retarded first and second dentition, and absence of teeth. (7) Given the rarity of patients with CH variations, there may be other complications that have not been reported because of diagnostic and technical limitations.
In the family reported by Tadin-Strapps et al. (2003), dental anomalies of those affected became evident around the age of 4 years. These primarily affected the shape of the teeth, which appeared misshapen and mispositioned. Tooth eruption was not delayed and there were no missing teeth. Notably, gingival fibromatosis seen in other forms of Hypertrichosis was not present in the affected individuals. (5)
The exact incidence of individuals with CH syndromes is unknown; however, reported incidence ranges from 1 in a billion to 1 in 10 billion. Although, currently it is reported that 19 people alive today have a form of CH; out of approximately 6.5 billion people in the world, which makes for an average of 1 in 340 million. There is no geographic tendency for any forms Hypertrichosis, and there is no documented increased susceptibility of any race or sex. (8)
Congenital Hypertrichosis and its subclasses are not known to be associated with an increased mortality rate. No documented long-term medical or physical morbidities are associated either. Psychological tribulations may occur because of the presence of excessive hair growth, the maintenance involved with removing the unwanted hair, and the obvious social problems that would arise. (8)
Hair: A Closer Look
Human hair differentiates into three types of hair: lanugo, vellous, and terminal hair. (8) Lanugo hair is the very first hair to be made by an embryoâ€™s hair follicles when still inside the womb. This hair can grow quite long but it is usually very fine and unpigmented. This first wave of hair growth is normally shed by the embryo at around 8 months of gestation and is replaced by vellus hair. (9) Vellus hair is seen over the face and arms of children; it is shorter, softer, lightly pigmented, and may be medullated. Vellus hair is the hair on the rest of the body which has not been stimulated and transformed by the sex hormones. Terminal hair arises from vellus hair follicles under the influence of androgens like testosterone. (7, 9) Terminal or androgenic hair is longer, coarser, and medullated; it is found on the scalp, eyebrows, and eyelashes from birth, and is the hair that greatly increases in heaviness and rate of growth with puberty.
Sometimes a child can be born with most or all of the lanugo hairs still growing. This gives the appearance of the child being covered in a light colored fur. This excessively long hair all over the body can persist throughout life as with a CH condition. (9)
However, there is much that remains unknown about hair development. Several key molecules involved in hair growth have yet to be identified. Also unknown are the mechanisms for distribution of hair. Humans are unique in that they can grow all three different kinds of hair from the same follicles at different times. Congenital Hypertrichosis can involve any of these. (4)
Hirsutism: Not Hypertrichosis
It is of importance to note the difference between Hirsutism and Hypertrichosis. Hair growth is controlled by a complex interaction of genetic and endocrine factors. Hirsutism is the form of excess hairiness associated with hormone imbalances involving sites under androgen control. Hypertrichosis, in contrast, is hair growth that is abnormal in quantity or location and can involve any area of the body and is not related to androgens (7, 8) It can have an acquired or, in the case of CH, a genetic cause. (4) Hirsutism is most often attributed to females with abnormal androgen secretion who exhibit male-pattern hair growth of the terminal type. (8) Congenital hypertrichosis is not associated with abnormal androgen secretion. (7)
Ambras Syndrome, a subclass of CH, for example, as studied by Scientist F.A. Baumesiter, suggests the lifelong presence of Hypertrichosis in Ambras Syndrome occurs due to a disturbance of the development of vellus hair. Baumesiter postulates that AS is associated with a relative decrease of the telogen phase (resting phase) of the hair growth cycle, and an increased percentage of follicles in the anagen phase (active phase) or more hair follicles per unit area of skin. (7)
The slight variations or subclasses of Congenital Hypertrichosis can have minor differences in manifestation. The generalized condition Congenital Hypertrichosis (CH), sometimes named Congenital generalized hypertrichosis (CGH), describes the extremely rare disorder characterized by excessive hair growth on the face and upper body. (4) Disorders of Hypertrichosis are distinguished by the distribution of hair, as well as by the temporal pattern of growth, the possible associated congenital anomalies, such as facial and skeletal abnormalities and mental retardation, (1) and also the possible inheritance pattern. (8)
The most severe appearing subclass is termed Congenital Hypertrichosis Terminalis. It involves the presence of dark pigmented terminal hair, and often has associated gingival hyperplasia (teeth defects). (9) In congenital hypertrichosis terminalis, there is terminal hair growth over the body but the facial hair distribution follows more of a male pattern. This type of Hypertrichosis has been associated with gingival hypertrophy and "simian facial characteristics". Hypertrichosis Terminalis is presumably secondary to general defects in hair growth expression. It has been associated with other congenital abnormalities such as osteochondrodysplasia, ophthalmological anomalies, cone-rod amaurosis, ectropion, glaucoma and cataracts. (6)
F.A. Baumesiter documented a case of a 3 year old Greek girl who presented hair most excessive on the face, ears and shoulders. Her fine silky hair is of the vellus, not the lanugo type. This type of CH is most commonly referred to as Ambras Syndrome (AS) after the 16th Century family that was first documented with the disease. (3) AS is the most documented subclass and is distinguished by the patient's whole body covered with silky lightly colored hair, most prominently at the shoulders, face, and ears. Hair uniformly covers the eyelids, nose, cheeks, periauricular regions and shoulder. The length of hair can reach several centimeters. Hair is absent in regions that do not normally grow hair. (7) Genetic analysis of Ambras syndrome in 2 patients has revealed an association with a paracentric inversion of chromosome 8q22. (8) Individuals with Ambras syndrome are classically described as having hypertrichosis at birth; however, the quantity of the excessive hair may be limited at that time. Unlike other forms of CH, Ambras syndrome may show increased hair growth in both distribution and density as the patient ages, and the hair does not spontaneously involute. (8)
Patients with Congenital Hypertrichosis Lanugosa (CHL), another subclass of CH, have growth of the lanugo hair, which increases in length and extent of involvement from birth to approximately age 2 years. As a result, the density, length, and extent of involvement may decrease; the rate of hair growth also slows. Many individuals with CHL lose most, if not all, of their lanugo hair over time, and eventually, only limited areas of Hypertrichosis may be present. Occasionally, the lanugo hair may be totally lost by the time the patient becomes an adult. A variant in which patients do not lose their lanugo hair over time is called congenital Hypertrichosis Universalis or persistent Hypertrichosis Universalis. (8) In Congenital Hypertrichosis Lanuginosa the individual's skin surface, including the face, is covered by long, wavy, silky lanugo hair. The palms, soles, and mucous membranes are spared. The pubic, axillary and beard areas retain lanugo hair at puberty and terminal hair does not appear. It is suspected that this condition is due to a developmental arrest resulting in persistence of embryonic hair. (6)
Congenital Hypertrichosis and its subclasses are linked on a genetic basis, mostly agreed to be autosomal dominant, but autosomal recessive, X-linked, and sporadic cases have been reported. (3, 6) It has also been noted that cases have involved patients with no family history of Hypertrichosis. Regardless of the inheritance pattern, a genetic alteration is believed to play a central, but still unresolved role. In Ambras Syndrome, confirmed genetic alterations have displayed a paracentric inversion at 8q23-24. (7)
Recently, the discovery of the multigenerational affected Mexican family, the Aceves clan of Loreto, Zacatecas, Mexico, has provided researchers a rare opportunity to try and track the gene associated with CH. Previous studies had shown an autosomal dominant pattern of inheritance. Segregation analysis revealed that affected women transmitted the trait to both male and female offspring. Males were more severely affected than females. Affected females showed asymmetric, somewhat patchy Hirsutism consistent with lyonization--the inactivation of an X chromosome. Affected persons were observed in 5 generations. The only affected father in this pedigree passed the mutant gene to all 4 daughters but none of his 9 sons. (5) These observations led researchers to postulate an X-linked dominant pattern of inheritance. (4)
Medical geneticists obtained DNA from the blood all family members available. The congenital nature of the disease, the complete penetrance and easily identifiable phenotype facilitated the classification of individuals for linkage analysis. They performed two-point and multi-point linkage analysis using 45 polymorphic markers along the X-chromosome. (4) After isolating the genomic DNA the researchers genotyped it using PCR based hypervariable microsatellites. Using these techniques the investigators localized the gene to an interval in Xq24-q27.1 region of the X-chromosome. These findings indicate that CH is a fully X-linked dominant trait. (4)
Although the CH phenotype is very rare, the underlying gene, when identified, may have significant applications in the treatment of inherited baldness and in the identification of other genes associated with hypertrichosis, notes Dr. Pragna Patel, Baylor College of Medicine, Houston, TX. (4) Presumably, the same or similar molecular signals involved in generalized Hypertrichosis also control the more cosmetically accepted form of hair growth, on the scalp. Once the gene is isolated, and the protein it makes is understood, the work could, in theory, lead to a better treatment for baldness. (1)
The presence of additional abnormalities in people with related kinds of Hypertrichosis indicates that the underlying genes may not only be involved in the control of hair growth but may also affect additional organs and tissues. Dr. Patel also believes that genes involved may encode growth factors and their receptors, adhesion molecules or important enzymes involved in the metabolism of connective tissue. (4)
Because CH is an X-linked trait, it finds its fullest expression in males. Females with the condition inherit only one copy of the mutant X chromosome, and so their other, normal copy of the X chromosome gives them partial protection against the disorder. As a result, they display only patchy spots of excess hair growth. (1) By contrast, if a boy inherits from his mother the X chromosome with the CH mutation, he has no second X to give him some buffer against its effect. With the mutation active in every cell of his body, he ends up with a more uniform coat of hair. (1)
The genetic anomaly for the most studied subclass of CH, Ambras Syndrome, is found on chromosome 8, but, the CH present in the Mexican family is X-linked genetic mutation. Even though AS is a subclass of CH, its genetic mutation occurs on a different chromosome. These discoveries will only lead to further study on this astounding rare condition.
The hairy appearance of those afflicted with CH is an example of an atavistic mutation--the reappearance of ancestral characteristics in individual members of a species that serve to remind us that the genetic and developmental information originally used in the production of such characteristics has not been lost during evolution but lies dormant within the genome and in the processes of embryonic development. (5) CH is a flash of the genetic information that lies deep within our DNA. (4) This particular genetic mutation has evoked a characteristic long forgotten. The loss of legs on snakes or tails in humans, does not mean the ability to make these structures has been lost. In contrast, the appearance of three toed horses and whales with hind limbs represents the reappearance of lost structures. (4) This CH atavism represents an ancestral pattern of a structure still present in the species
For people affect by forms of Congenital Hypertrichosis there is no known treatment available other than depilation. (9) Shaving the hair or removing the hair by other means is the only course of action available. The first patient described previously, Petrus Gonzales, lived a long life and was able to procreate. F.A. Baumeisterâ€™s case of a girl age 3, lived a relatively normal lifestyle with hair shaving every few weeks. (7) Today the world can see and learn more about the few people affected with this genetic disease by watching them on television, and come to realize that they are the same as normal humans