Atrichia

Overview

Hereditary baldness can take on a variety of forms and is caused by a single gene issue that recurs in a typical autosomal recessive Mendelian pattern. Baldness can occur on its own or in conjunction with other conditions such as microcephaly, cataract, retinitis pigmentosa, epilepsy, mental retardation, pyorrhea, whole or partial anodontia, abnormalities of the teeth and nails, and epilepsy. One such instance of autosomal recessive-inherited whole-body hair loss is congenital atrichia. Congenital atrichia with papules may be a more accurate description of the phenotype to avoid misunderstanding the more prevalent form of alopecia universalis. Cases similar to this illness from Pakistan have recently been reported, with hair loss affecting the entire body.

The molecular mechanism has only been described thus far for one type of inherited alopecia, congenital atrichia. Following the loss of natural hair shortly after birth, those who suffer from this type of hair loss often have no hair on their scalp and almost no eyebrow, eyelash, axillary, or pubic hair. A scalp skin sample from affected patients showed that sebaceous glands were sparsely distributed and there were no hair follicles.

The additional distinctive clinical finding of clustered cystic and milia-like skin lesions is present in the affected people. Affected people displayed no developmental or growth delays, healthy hearing, teeth, and nails, and no excessive sweating.

Heterozygous people have typical hair and are clinically indistinguishable from people with genetically healthy people. Congenital atrichia has an autosomal recessive mode of inheritance. Atrichia with papular lesions, a rare human condition first described in the 1950s, is characterized by normal hair growth at birth followed by hair loss accompanied by the development of comedones and follicular cysts. The idea that the human papular atrichia is a homolog of the hairless mouse mutation was originally put forth in the late 1980s.

What is Atrichia?

Congenital atrichia is a form of total baldness inherited in an autosomal recessive fashion. Following the natural hair loss soon after birth, those who suffer from this type of hair loss often have no hair on their scalp and almost no eyebrow, eyelash, axillary, or pubic hair. The human hairless gene, which is located within this interval, was newly cloned. Researchers have recently connected this condition to the chromosomal region 8p12. They have found several hairless gene mutations in atrichia populations from different parts of the world. The hair matrix cells in hairless people appear to undergo early and large apoptosis, which is accompanied by a drop in Bcl-2 expression, a loss of NCAM positivity, and a break with the overlaying epithelial sheath necessary for the movement of the dermal papilla. As a result, vital signals between the dermal papilla and the bulge's stem cells cannot be sent, leaving the hair bulb and dermal papilla trapped in the dermis and preventing future hair growth. According to these findings, the hairless gene product may be essential for preserving the delicate equilibrium between cell proliferation, differentiation, and death in the hair follicle and the inter-follicular epidermis.

Different Terms Equivalent to Atrichia

In the literature, the terms alopecia, hypotrichosis, and atrichia are frequently used interchangeably. Their exact meanings, nevertheless, are quite different. The noncongenital process of hair loss known as alopecia can lead to partial or total baldness. Contrary to hypotrichosis, which is the name for diffuse (congenital or acquired) forms of significant hair loss resulting in a paucity of hair, some forms of pattern alopecia may be lifelong or reversible.

The most extreme and dramatic types of hair loss, particularly those that are characterized by a lack of hair follicles, are referred to as atrichia. Congenital or early-onset hair loss that quickly results in a completely smooth bald scalp is the hallmark of atrichia. Only a very small number of disorders characterized by a lack of hair (and hair follicles) have been identified, making these conditions incredibly rare. Congenital atrichia, also known as atrichia with papular lesions (APL), and atrichia associated with vitamin D-dependent rickets, often known as a rickets-alopecia syndrome, are two examples of these disorders. Hypocalcemia, hyperparathyroidism, rickets, and osteomalacia are phenotypic traits that patients with recessively inherited mutations in the VDR gene (vitamin D-dependent rickets type II, VDDR II) manifest. Patients with dietary vitamin D deficiency or those with vitamin D-dependent rickets type I (VDDR I), who lack the enzyme 25-hydroxyvitamin D-1 hydroxylase, also manifest each of these characteristics. Only a small minority of patients with VDDR II (referred to as VDDR IIA) present with complete early-onset atrichia.

Molecular Basis of Atrichia

Congenital Atrichia in Pakistan

Researchers analyzed a large Pakistani family with atrichia segregating as a solitary aberration without concomitant disorders to comprehend the genetic basis of hereditary congenital atrichia. Earlier research identified the disease gene and provided a thorough description of the phenotypic of the family members who were affected. Employing 400 microsatellite markers, a genome-wide search using homozygosity mapping allowed them to locate the illness locus on human chromosome 8p12.

Due to the striking parallels between the human and mouse phenotypes, researchers became interested in cloning and mapping the human homolog of the mouse hairless gene. Using the GeneBridge 4 panel of 93 radiation-induced human-hamster cell hybrids, they performed radiation hybrid mapping to pinpoint the exact chromosomal location of the human homolog of the mouse hairless gene, which was shown to be on chromosome 8p. The human hairless gene was advanced to a leading candidate gene for congenital atrichia as a result of its genomic colocalization. All affected people had a homozygous mutation in exon 15 of the hairless gene, which was only seen in the heterozygous state in the family's obligatory carriers and was not present in unaffected relatives. These discoveries established the molecular basis of atrichia and, for the first time, allowed the identification of more families from around the globe.

Congenital Atrichia in Ireland

Researchers gathered several other families from throughout the globe, whose affected members had a phenotypic with the affected family members from Pakistan. They discovered a second missense mutation in exon 6 of the gene in an Irish immigrant family with five male and four female affected members with autosomal recessive congenital atrichia. Using chromosome 8 microsatellite markers connected to the locus, the haplotype results show a perfect correlation between the presence of the mutation and those results. This family has members in both England and Northern Ireland. Since olden history, there have been different indigenous Irish travelers living in Ireland. Within Ireland, distinctive cultures and traditions based on a nomadic lifestyle, as well as resistance to assimilationist policies, have preserved their cultural uniqueness. About 22000 travelers in 4083 families make up 0.5% of the population of the Republic of Ireland. Irish traveler families frequently have consanguineous marriages and have a high reproduction rate, and earlier research has shown that uncommon gene abnormalities are rather common in this population. The zinc-finger domain of the hairless gene contains the missense mutation discovered in this family. The fact that the mutant arginine residue has not changed during 90 million years of evolution in humans, mice, and rats indicates that the domain's function depends heavily on it.

Atrichia Clinical Manifestations

In a town in upper Galilee, Sprecher et al. described a large consanguineous kindred of Arab lineage with 7 affected people over 5 generations. Except for thin eyelashes and brows, all patients showed full hair loss. On the entire skin surface, there were little follicular skin-colored or white papules, more apparent over the cheeks, thighs, and buttocks. Nails and teeth were both normal. A histologic study revealed well-developed infundibula but neither the other components of a hair follicle nor the establishment of a hair shaft. Instead, the mid and lower dermis contained tiny keratinous cysts encircled by healthy sebaceous glands and smooth muscles. Epithelial cells that resembled those found in the middle and lower regions of the hair follicle surrounded these cysts. They frequently produced little epithelial buds.

Speaking of a large consanguineous kindred, Sprecher et al. evaluated the pattern of androgenetic alopecia in 31 fit young second-degree relatives of APL patients. Healthy homozygotes and heterozygous carriers of the mutation did not differ in age at onset or the severity of androgenetic alopecia. Sprecher et al. concluded that the pattern of androgenetic hair loss is unaffected by the presence of a harmful mutation in one allele of the hairless gene.

Ahmad et al. reported the discovery of a missense mutation in the zinc finger region of the hairless gene in a large inbred family of Irish Travelers, referring to this disease as congenital atrichia. Since ancient times, the gypsies known as Irish Travelers have been a separate indigenous ethnic minority in Ireland. Patients often had no hair on their scalps, with natal hair beginning to fall out soon after delivery. They also had no eyebrows, eyelashes, axillary hair, or pubic hair. A biopsy of one of the affected patient’s scalps skin revealed poorly dispersed sebaceous glands and no hair follicles. Histological proof of an inflammatory process was absent. On the knees and elbows, all affected people showed clustered cystic and papular lesions that looked like milia both clinically and histopathologically. Affected people displayed no developmental or growth delays, healthy hearing, teeth, and nails, and no excessive sweating. Clinically, heterozygous people could not be distinguished from genotypically normal people since they had normal hair.

Atrichia Differential Diagnosis

Hereditary vitamin D-dependent type IIA rickets. a condition caused by mutations in the vitamin D receptor gene. Patients have papular lesions and irreversible hair loss, which are histopathologically and clinically similar to APL. Hypocalcemia, hypophosphatemia, normal or elevated levels of calcidiol (25-hydroxyvitamin D) and calcitriol (1,25-dihydroxyvitamin D), raised alkaline phosphatase, hyperparathyroidism, osteomalacia, and rickets are characteristics of these patients. Patients respond well to calcium and calcitriol supplements.
Alopecia universalis. Alopecia may be reversed and has a variable onset. Trichoscopy may reveal black dots, yellow dots (hyperkeratotic plugs), and micro-exclamation mark hairs (destroyed hairs in follicle opening). No papular lesions are present. Systemic therapies may affect patients.

Other genodermatoses characterized by atrichia:

Oral-facial-digital syndrome. an ectodermal dysplastic condition with hypotrichosis and congenital papular lesions that is X-linked dominant. The patients also have intellectual disability, brachydactyly, hypoplastic ala nasi, cleft lip and palate, and are at risk for polycystic kidney disease (PCKD).
Schopf-Schulz-Passarge syndrome. an ectodermal abnormality with congenital papular lesions and hypotrichosis that has an unknown genetic cause. Numerous eyelid apocrine hidrocystoma, hypodontia, grooved nails, and palmoplantar keratoderma have all been observed in patients.
Generalized basaloid follicular hamartoma syndrome. An autosomal dominant disorder with congenital or early-onset colored papular lesions, hypotrichosis. Along with palmoplantar pits, follicular hamartomas, comedones, and acrochordons, the patients also have palmoplantar pits and are at risk for basal cell carcinoma, systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome (APS), cystic fibrosis, and/or myasthenia gravis.
Bazex-Dupre-Christol syndrome. a condition with early-onset papular lesions and congenital atrichia that is X-linked dominant. Patients also have basal cell carcinoma, trichoepithelioma of the hair shaft, comedones, hidradenitis suppurativa, and follicular atrophoderma.
Rombo syndrome. Papular lesions and baldness with a late onset first appear between the ages of 7 and 10. It is an autosomal dominant disorder. Additionally, patients have basal cell carcinoma, trichoepithelioma, peripheral vasodilatation, telangiectasia, and vermiculate atrophoderma.

Atrichia Diagnosis

There are established revised criteria to diagnose patients with universal alopecia that starts at an early age (atrichia).

Major Criteria

Hair on the scalp is absent entirely and permanently by the first few
weeks of life.
From childhood or early adulthood, a few to many smooth, whitish, or milia-like papules have appeared on the face, scalp, arms, elbows, thighs, or knees.
In scalp histology, mature hair follicle structures are replaced by follicular cysts loaded with cornified material.
Genetic testing revealed human hairless gene mutations.
Vitamin D-dependent rickets must be excluded clinically and/or genetically.

Minor Criteria

History of consanguinity in the family.
Lack of pubic, body, or secondary axillary hair growth as well as thin brows and eyelashes.
Healthy growth and development include healthy bones, teeth, and sweat glands.
Streaks of white hypopigmentation on the scalp
Failure to respond to any form of therapy.

Atrichia Treatment

Sadly, there are no cures for atrichia at this time. You may have considered hair transplants when thinking about how to reverse general hair loss. But many medical professionals claim that this course of treatment is ineffective for atrichia. First off, since hair transplants use the recipient's hair, you must already have hair. But more importantly, with atrichia, the loss of all hair follicles results in hair loss, which affects any transplanted hair and makes it fall out as well.

Conclusion

Atrichia is a rare autosomal recessive form of total alopecia that has been linked to mutations in the hairless gene. Unfortunately, no treatment is available for this disease and the researchers try to find novel treatments after finding three distinct genes implicated in its origin.