Rothmund–Thomson syndrome (RTS) is a rare

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosomes ...

recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...

skin condition. There have been several reported cases associated with

osteosarcoma An osteosarcoma (OS) or osteogenic sarcoma (OGS) (or simply bone cancer) is a cancerous tumor in a bone. Specifically, it is an aggressive malignant neoplasm that arises from primitive transformed cells of mesenchymal origin (and thus a sarcoma) ...

. A

hereditary Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic infor ...

basis,

mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...

in the DNA

helicase Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separat ...

'' RECQL4'' gene, causing problems during initiation of

DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inherita ...

has been implicated in the syndrome.

Signs and symptoms

* Sun-sensitive rash with prominent poikiloderma and telangiectasias * Juvenile

cataracts A cataract is a cloudy area in the lens of the eye that leads to a decrease in vision. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colors, blurry or double vision, halos around light, trouble w ...

Saddle nose Saddle nose is a condition associated with nasal trauma, congenital syphilis, relapsing polychondritis, granulomatosis with polyangiitis, cocaine abuse, and leprosy, among other conditions. The most common cause is nasal trauma. It is characteri ...

* Congenital bone defects, including short stature and radial ray anomalies such as absent thumbs * Hair growth problems (absent eyelashes, eyebrows and/or hair) *

Hypogonadism Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low est ...

has not been well documented *

Hypodontia Hypodontia is defined as the developmental absence of one or more teeth excluding the third molars. It is one of the most common dental anomalies, and can have a negative impact on function, and also appearance. It rarely occurs in primary teet ...

* Calcium problems (not documented in journals) * Ear problems (not documented in journals but identified by patients in support groups) * Produces osteosarcoma The skin is normal at birth. Between 3 and 6 months of age, the affected carrier develops poikiloderma on the cheeks. This characteristic "rash" that all RTS carriers have can develop on the arms, legs and buttocks. "Poikiloderma consists of areas of increased and decreased pigmentation, prominent blood vessels, and thinning of the skin."

Accelerated aging

In humans, individuals with RTS, and carrying the '' RECQL4'' germline

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...

, can have several clinical features of accelerated

aging Ageing ( BE) or aging ( AE) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. In ...

. These features include atrophic skin and pigment changes,

alopecia Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarr ...

osteopenia Osteopenia, known as "low bone mass" or "low bone density", is a condition in which bone mineral density Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (r ...

cataract A cataract is a cloudy area in the lens of the eye that leads to a decrease in vision. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colors, blurry or double vision, halos around light, trouble w ...

s and an increased incidence of

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...

. Also in mice, ''RECQL4'' mutants show features of accelerated aging.

Causes

RTS is caused by a mutation of the RECQL4 gene, located at

chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins ar ...

8q24.3. The disorder is inherited in an autosomal recessive manner. This means the defective gene responsible for the disorder is located on an autosome (chromosome 8 is an autosome), and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.

DNA repair

RECQL4 has a crucial role in DNA end resection that is the initial step required for

homologous recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may be ...

(HR)-dependent double-strand break repair. When RECQL4 is depleted, HR-mediated repair and 5’ end resection are severely reduced ''in vivo''. RECQL4 also appears to be necessary for other forms of

DNA repair DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...

including

non-homologous end joining Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology direct ...

nucleotide excision repair Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly because of chemicals (e.g. intercalating agents), radiation and other mutagens. Three excision repair pathways exist to repair single stranded DNA damage: Nucle ...

and

base excision repair Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from t ...

. The association of deficient RECQL4-mediated DNA repair with accelerated aging is consistent with the

DNA damage theory of aging The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear DN ...

Diagnosis

Management

History

The condition was originally described by August von Rothmund (1830–1906) in 1868. Matthew Sydney Thomson (1894–1969) published further descriptions in 1936.

References

External links

GeneReviews/NCBI/NIH/UW entry on Rothmund-Thomson Syndrome
* {{DEFAULTSORT:Rothmund-Thomson syndrome Autosomal recessive disorders DNA replication and repair-deficiency disorders Genodermatoses Rare diseases Syndromes affecting the skin Progeroid syndromes Syndromes affecting stature Syndromes affecting the eye