A working knowledge of genetic transmission in cutaneous disease can be valuable to a practicing clinician, both for patient care and for a more complete understanding of new dermatological literature. Due to advances in science, genetic testing of certain diseases is now available. Genodermatoses, inherited skin disorders, encompass 560 skin ailments associated with 501 distinct protein-encoding genes.1 Genodermatoses are inherited either via monogenetic or polygenetic transmission. A monogenetic disorder occurs due to a mutation in a single gene. In contrast, polygenetic inheritance may involve the additive effect of two or more gene loci on a single phenotypic character. Dermatologists see many patients with inherited disorders. We will briefly review the types of inheritance seen in these conditions.
Autosomal Dominant Inheritance
Autosomal dominance is a pattern of inheritance in which an affected individual has one copy of a mutant dominant gene and one normal, recessive gene on a pair of autosomal chromosomes. The mutant gene dominates the normal gene and the illness is expressed. A classic example of a genodermatosis due to autosomal dominance is dermatopathia pigmentosa reticularis (DPR). DPR is a rare, monogenetic, autosomal dominant disorder that is caused by a missense mutation at the KRT14 gene resulting in an amino acid alteration in the KRT14 protein.2 DPR is characterized by reticulate hyperpigmented macules on the trunk, neck and proximal limbs, palmoplantar keratoderma, nail dystrophy, reduced sweating, mild alopecia, acral skin fragility and onychodsytrophy.2,3,4 Additional examples of autosomal dominant dermatological conditions include neurofibromatosis type 1 and 2,5 LEOPARD syndrome, .6 tuberous sclerosis,7 ichthyosis vulgaris,8 and epidermolysis bullosa simplex.9
Autosomal Recessive Inheritance
Autosomal recessive disorders require the presence of two mutant recessive genes. Both genes must be present in their recessive forms in order to be expressed. If a mutant recessive gene is coupled with a normal dominant gene, then the expression of the illness would be suppressed. Xeroderma pigmentosum (XP) is a rare, autosomal recessive disease that is characterized by hypersensitivity to sunlight, abnormal pigmentation, excessive freckling, poikiloderma, skin atrophy, skin aging, and neurological and ocular anomalies.10,11 Additionally, individuals afflicted with XP are at a significantly higher risk (2000 times) of acquiring skin cancer relative to the general population.12 This discrepancy can be attributed to gene mutations resulting in defective nucleotide excision repair (NER) enzymes. 11 Seven types (A-G) of XP have been described, based on the particular gene affected.13. Although types C and D are the most common, type A is the most severe — ending in early fatality for most. XPA is the defective gene in XP type A; it is located on chromosome 9q22.314 XPA encodes a 273 amino acid protein required for the early stages of NER, with a role in damage verification and stabilizing of other NER proteins.15 Other autosomal recessive cutaneous illnesses include lamellar ichthyosis, .8 dystrophic epidermolysis bullosa,16 and Bloom syndrome.17
X-linked Inheritance
X-linked, commonly referred to as “sex-linked,” genes refer to the recessive genes that reside on the X-chromosome. Females, who possess the chromosomal type XX, have the opportunity to suppress expression of a defective recessive gene with a normal dominant gene. Males possess an XY chromosomal type and are thus unable to counter the expression of a defective X-linked gene. Therefore, X-linked illnesses are more prevalent in males. X-linked ichthyosis is a common keratinization disorder caused by the deletion or inactivation of the steroid sulfatase (STS) gene and the consequent steroid sulfatase deficiency. 18,19 Decreased keratin degradation, hyperkeratosis, scaly skin, elevated cholesterol sulphate levels and increased stability of intercellular cohesion in the stratum corneum characterize this deficiency.20, 21 It generally appears early in life and is manifested by large scales of brownish pigment on various body parts (especially the extremities). STS gene deletions may extend to adjacent genes, causing a contiguous gene syndrome, combining X-linked ichthyosis with Kallman syndrome, short stature, mental retardation or ocular albinism.22
Polygenetic Inheritance
Polygenetic disorders, in contrast to monogenetic disorders, may involve multiple genes at various loci, and are often dependent on the population studied (as well as other confounding factors). Two well-known polygenetic disorders are psoriasis and vitiligo. Psoriasis is an immune-meditated, inflammatory disease that affects 2% of the population.23 Psoriasis vulgaris, the most common form, can be diagnosed by the presence of distinctive red plaques with silver-white flaky scales. 24 Additionally, 30% of those afflicted also have psoriatic arthritis, inflammatory arthritis associated with psoriasis. 25 The precise etiology of psoriasis is unknown and many factors likely play a role in its pathogenesis. From a genetics standpoint, several candidate genes have been identified, including PSORS1 on 6p21.3, PSORS2 on 17q, PSORS3 on 4q, PSORS4 on 1q21.3, PSORS5 on 3q21, PSORS6 on 19p, PSORS7 on 1p, PSORS8 on 16q, PSORS9 on 4q28-q32 and PSORS10 on 18p11.26, 27 Furthermore, environmental factors, (ie, human immunodeficiency virus), trauma, smoking, stress and obesity, also affect the presence of psoriasis. Like psoriasis, multiple susceptibility loci and candidate genes have been implicated in vitiligo, a chronic depigmenting disorder seen in all races and both sexes. Candidate genes for vitiligo have been described on chromosomes 1, 2, 3, 6, 7, 8, 10, 11, 12, 14, 17, 21 and 22.28
Conclusion
Given the integral role genetics play in dermatology, it is critical to obtain a detailed family history in all patient encounters. Moreover, the field of gene therapy is rapidly advancing, and may be a solution to some of the most difficult dermatological conditions. Porphyrias, a group of genetically and clinically heterogenous metabolic disorders, are a result of heredity dysfunctions of specific enzymes involved in heme biosynthesis.29 Due to the rapid progress in molecular technology, most of the genes of the heme biosynthesis pathway have been identified. Thus, creating animal models and transferring normal genes or cDNAs to target cells is becoming a viable treatment option for porphyrias. Animal models for several types of porphyrias are currently being employed in gene therapy research.30 Currently, replacement enzyme therapy has been successful in treating patients with acute intermittent porphyria.29 Preemptive treatment strategies, such as pathway interference, enzyme replacement, and gene therapy, represent future possibilities for preventing and treating dermatological disorders. Fatima Sasha Alikhan is a graduate student at Columbia University, Mailman School of Public Health, New York, NY. Dr. Ali Alikhan is with the Mayo Clinic, Department of Dermatology, Rochester, MN. Disclosures: Neither of the authors has any conflicts of interest to declare.
A working knowledge of genetic transmission in cutaneous disease can be valuable to a practicing clinician, both for patient care and for a more complete understanding of new dermatological literature. Due to advances in science, genetic testing of certain diseases is now available. Genodermatoses, inherited skin disorders, encompass 560 skin ailments associated with 501 distinct protein-encoding genes.1 Genodermatoses are inherited either via monogenetic or polygenetic transmission. A monogenetic disorder occurs due to a mutation in a single gene. In contrast, polygenetic inheritance may involve the additive effect of two or more gene loci on a single phenotypic character. Dermatologists see many patients with inherited disorders. We will briefly review the types of inheritance seen in these conditions.
Autosomal Dominant Inheritance
Autosomal dominance is a pattern of inheritance in which an affected individual has one copy of a mutant dominant gene and one normal, recessive gene on a pair of autosomal chromosomes. The mutant gene dominates the normal gene and the illness is expressed. A classic example of a genodermatosis due to autosomal dominance is dermatopathia pigmentosa reticularis (DPR). DPR is a rare, monogenetic, autosomal dominant disorder that is caused by a missense mutation at the KRT14 gene resulting in an amino acid alteration in the KRT14 protein.2 DPR is characterized by reticulate hyperpigmented macules on the trunk, neck and proximal limbs, palmoplantar keratoderma, nail dystrophy, reduced sweating, mild alopecia, acral skin fragility and onychodsytrophy.2,3,4 Additional examples of autosomal dominant dermatological conditions include neurofibromatosis type 1 and 2,5 LEOPARD syndrome, .6 tuberous sclerosis,7 ichthyosis vulgaris,8 and epidermolysis bullosa simplex.9
Autosomal Recessive Inheritance
Autosomal recessive disorders require the presence of two mutant recessive genes. Both genes must be present in their recessive forms in order to be expressed. If a mutant recessive gene is coupled with a normal dominant gene, then the expression of the illness would be suppressed. Xeroderma pigmentosum (XP) is a rare, autosomal recessive disease that is characterized by hypersensitivity to sunlight, abnormal pigmentation, excessive freckling, poikiloderma, skin atrophy, skin aging, and neurological and ocular anomalies.10,11 Additionally, individuals afflicted with XP are at a significantly higher risk (2000 times) of acquiring skin cancer relative to the general population.12 This discrepancy can be attributed to gene mutations resulting in defective nucleotide excision repair (NER) enzymes. 11 Seven types (A-G) of XP have been described, based on the particular gene affected.13. Although types C and D are the most common, type A is the most severe — ending in early fatality for most. XPA is the defective gene in XP type A; it is located on chromosome 9q22.314 XPA encodes a 273 amino acid protein required for the early stages of NER, with a role in damage verification and stabilizing of other NER proteins.15 Other autosomal recessive cutaneous illnesses include lamellar ichthyosis, .8 dystrophic epidermolysis bullosa,16 and Bloom syndrome.17
X-linked Inheritance
X-linked, commonly referred to as “sex-linked,” genes refer to the recessive genes that reside on the X-chromosome. Females, who possess the chromosomal type XX, have the opportunity to suppress expression of a defective recessive gene with a normal dominant gene. Males possess an XY chromosomal type and are thus unable to counter the expression of a defective X-linked gene. Therefore, X-linked illnesses are more prevalent in males. X-linked ichthyosis is a common keratinization disorder caused by the deletion or inactivation of the steroid sulfatase (STS) gene and the consequent steroid sulfatase deficiency. 18,19 Decreased keratin degradation, hyperkeratosis, scaly skin, elevated cholesterol sulphate levels and increased stability of intercellular cohesion in the stratum corneum characterize this deficiency.20, 21 It generally appears early in life and is manifested by large scales of brownish pigment on various body parts (especially the extremities). STS gene deletions may extend to adjacent genes, causing a contiguous gene syndrome, combining X-linked ichthyosis with Kallman syndrome, short stature, mental retardation or ocular albinism.22
Polygenetic Inheritance
Polygenetic disorders, in contrast to monogenetic disorders, may involve multiple genes at various loci, and are often dependent on the population studied (as well as other confounding factors). Two well-known polygenetic disorders are psoriasis and vitiligo. Psoriasis is an immune-meditated, inflammatory disease that affects 2% of the population.23 Psoriasis vulgaris, the most common form, can be diagnosed by the presence of distinctive red plaques with silver-white flaky scales. 24 Additionally, 30% of those afflicted also have psoriatic arthritis, inflammatory arthritis associated with psoriasis. 25 The precise etiology of psoriasis is unknown and many factors likely play a role in its pathogenesis. From a genetics standpoint, several candidate genes have been identified, including PSORS1 on 6p21.3, PSORS2 on 17q, PSORS3 on 4q, PSORS4 on 1q21.3, PSORS5 on 3q21, PSORS6 on 19p, PSORS7 on 1p, PSORS8 on 16q, PSORS9 on 4q28-q32 and PSORS10 on 18p11.26, 27 Furthermore, environmental factors, (ie, human immunodeficiency virus), trauma, smoking, stress and obesity, also affect the presence of psoriasis. Like psoriasis, multiple susceptibility loci and candidate genes have been implicated in vitiligo, a chronic depigmenting disorder seen in all races and both sexes. Candidate genes for vitiligo have been described on chromosomes 1, 2, 3, 6, 7, 8, 10, 11, 12, 14, 17, 21 and 22.28
Conclusion
Given the integral role genetics play in dermatology, it is critical to obtain a detailed family history in all patient encounters. Moreover, the field of gene therapy is rapidly advancing, and may be a solution to some of the most difficult dermatological conditions. Porphyrias, a group of genetically and clinically heterogenous metabolic disorders, are a result of heredity dysfunctions of specific enzymes involved in heme biosynthesis.29 Due to the rapid progress in molecular technology, most of the genes of the heme biosynthesis pathway have been identified. Thus, creating animal models and transferring normal genes or cDNAs to target cells is becoming a viable treatment option for porphyrias. Animal models for several types of porphyrias are currently being employed in gene therapy research.30 Currently, replacement enzyme therapy has been successful in treating patients with acute intermittent porphyria.29 Preemptive treatment strategies, such as pathway interference, enzyme replacement, and gene therapy, represent future possibilities for preventing and treating dermatological disorders. Fatima Sasha Alikhan is a graduate student at Columbia University, Mailman School of Public Health, New York, NY. Dr. Ali Alikhan is with the Mayo Clinic, Department of Dermatology, Rochester, MN. Disclosures: Neither of the authors has any conflicts of interest to declare.
A working knowledge of genetic transmission in cutaneous disease can be valuable to a practicing clinician, both for patient care and for a more complete understanding of new dermatological literature. Due to advances in science, genetic testing of certain diseases is now available. Genodermatoses, inherited skin disorders, encompass 560 skin ailments associated with 501 distinct protein-encoding genes.1 Genodermatoses are inherited either via monogenetic or polygenetic transmission. A monogenetic disorder occurs due to a mutation in a single gene. In contrast, polygenetic inheritance may involve the additive effect of two or more gene loci on a single phenotypic character. Dermatologists see many patients with inherited disorders. We will briefly review the types of inheritance seen in these conditions.
Autosomal Dominant Inheritance
Autosomal dominance is a pattern of inheritance in which an affected individual has one copy of a mutant dominant gene and one normal, recessive gene on a pair of autosomal chromosomes. The mutant gene dominates the normal gene and the illness is expressed. A classic example of a genodermatosis due to autosomal dominance is dermatopathia pigmentosa reticularis (DPR). DPR is a rare, monogenetic, autosomal dominant disorder that is caused by a missense mutation at the KRT14 gene resulting in an amino acid alteration in the KRT14 protein.2 DPR is characterized by reticulate hyperpigmented macules on the trunk, neck and proximal limbs, palmoplantar keratoderma, nail dystrophy, reduced sweating, mild alopecia, acral skin fragility and onychodsytrophy.2,3,4 Additional examples of autosomal dominant dermatological conditions include neurofibromatosis type 1 and 2,5 LEOPARD syndrome, .6 tuberous sclerosis,7 ichthyosis vulgaris,8 and epidermolysis bullosa simplex.9
Autosomal Recessive Inheritance
Autosomal recessive disorders require the presence of two mutant recessive genes. Both genes must be present in their recessive forms in order to be expressed. If a mutant recessive gene is coupled with a normal dominant gene, then the expression of the illness would be suppressed. Xeroderma pigmentosum (XP) is a rare, autosomal recessive disease that is characterized by hypersensitivity to sunlight, abnormal pigmentation, excessive freckling, poikiloderma, skin atrophy, skin aging, and neurological and ocular anomalies.10,11 Additionally, individuals afflicted with XP are at a significantly higher risk (2000 times) of acquiring skin cancer relative to the general population.12 This discrepancy can be attributed to gene mutations resulting in defective nucleotide excision repair (NER) enzymes. 11 Seven types (A-G) of XP have been described, based on the particular gene affected.13. Although types C and D are the most common, type A is the most severe — ending in early fatality for most. XPA is the defective gene in XP type A; it is located on chromosome 9q22.314 XPA encodes a 273 amino acid protein required for the early stages of NER, with a role in damage verification and stabilizing of other NER proteins.15 Other autosomal recessive cutaneous illnesses include lamellar ichthyosis, .8 dystrophic epidermolysis bullosa,16 and Bloom syndrome.17
X-linked Inheritance
X-linked, commonly referred to as “sex-linked,” genes refer to the recessive genes that reside on the X-chromosome. Females, who possess the chromosomal type XX, have the opportunity to suppress expression of a defective recessive gene with a normal dominant gene. Males possess an XY chromosomal type and are thus unable to counter the expression of a defective X-linked gene. Therefore, X-linked illnesses are more prevalent in males. X-linked ichthyosis is a common keratinization disorder caused by the deletion or inactivation of the steroid sulfatase (STS) gene and the consequent steroid sulfatase deficiency. 18,19 Decreased keratin degradation, hyperkeratosis, scaly skin, elevated cholesterol sulphate levels and increased stability of intercellular cohesion in the stratum corneum characterize this deficiency.20, 21 It generally appears early in life and is manifested by large scales of brownish pigment on various body parts (especially the extremities). STS gene deletions may extend to adjacent genes, causing a contiguous gene syndrome, combining X-linked ichthyosis with Kallman syndrome, short stature, mental retardation or ocular albinism.22
Polygenetic Inheritance
Polygenetic disorders, in contrast to monogenetic disorders, may involve multiple genes at various loci, and are often dependent on the population studied (as well as other confounding factors). Two well-known polygenetic disorders are psoriasis and vitiligo. Psoriasis is an immune-meditated, inflammatory disease that affects 2% of the population.23 Psoriasis vulgaris, the most common form, can be diagnosed by the presence of distinctive red plaques with silver-white flaky scales. 24 Additionally, 30% of those afflicted also have psoriatic arthritis, inflammatory arthritis associated with psoriasis. 25 The precise etiology of psoriasis is unknown and many factors likely play a role in its pathogenesis. From a genetics standpoint, several candidate genes have been identified, including PSORS1 on 6p21.3, PSORS2 on 17q, PSORS3 on 4q, PSORS4 on 1q21.3, PSORS5 on 3q21, PSORS6 on 19p, PSORS7 on 1p, PSORS8 on 16q, PSORS9 on 4q28-q32 and PSORS10 on 18p11.26, 27 Furthermore, environmental factors, (ie, human immunodeficiency virus), trauma, smoking, stress and obesity, also affect the presence of psoriasis. Like psoriasis, multiple susceptibility loci and candidate genes have been implicated in vitiligo, a chronic depigmenting disorder seen in all races and both sexes. Candidate genes for vitiligo have been described on chromosomes 1, 2, 3, 6, 7, 8, 10, 11, 12, 14, 17, 21 and 22.28
Conclusion
Given the integral role genetics play in dermatology, it is critical to obtain a detailed family history in all patient encounters. Moreover, the field of gene therapy is rapidly advancing, and may be a solution to some of the most difficult dermatological conditions. Porphyrias, a group of genetically and clinically heterogenous metabolic disorders, are a result of heredity dysfunctions of specific enzymes involved in heme biosynthesis.29 Due to the rapid progress in molecular technology, most of the genes of the heme biosynthesis pathway have been identified. Thus, creating animal models and transferring normal genes or cDNAs to target cells is becoming a viable treatment option for porphyrias. Animal models for several types of porphyrias are currently being employed in gene therapy research.30 Currently, replacement enzyme therapy has been successful in treating patients with acute intermittent porphyria.29 Preemptive treatment strategies, such as pathway interference, enzyme replacement, and gene therapy, represent future possibilities for preventing and treating dermatological disorders. Fatima Sasha Alikhan is a graduate student at Columbia University, Mailman School of Public Health, New York, NY. Dr. Ali Alikhan is with the Mayo Clinic, Department of Dermatology, Rochester, MN. Disclosures: Neither of the authors has any conflicts of interest to declare.
