About Albright syndrome-like metacarpal and metatarsal shortening (2q37.3 deletion syndrome) [Doctor-supervised]

Overview

2q37 deletion syndrome can cause various symptoms depending on the gene responsible. A typical symptom is Albright syndrome-like shortening of the metacarpals and midcrus.

Albright-like metacarpal and midcruris shortening is a genetic disorder caused by the deletion of a portion of the terminal portion of the long arm of chromosome 2 (2q37.3). The first case was reported in 1989, and it is an extremely rare disease with at least 115 cases reported worldwide to date. Approximately half of affected individuals have physical characteristics such as short fingers and toes, especially the fourth finger. Other physical characteristics include a distinctive facial appearance and thinning hair. Neurological abnormalities include developmental delays in motor skills such as standing, sitting, and walking, and approximately 25% of these individuals have autism spectrum disorder, which means impaired social communication and social interaction. Other symptoms include inflammatory skin diseases, malformations of the brain, heart, digestive system, kidneys, and reproductive organs, and in very rare cases, a very rare form of liver cancer called Wilms tumor. Due to the above characteristics, this condition is sometimes called 2q37 entire autosomal region partial deletion disorder, Albright hereditary osteodystrophy-like syndrome, or brachial neurological mental retardation syndrome.

Reason

Albright syndrome-like metacarpal is a disease caused by the deletion of a part of a chromosome, but it is still unknown why such a deletion occurs. Since most (approximately 95%) of the parents of affected patients have normal karyotypes, it is known that inheritance from parents is rare, and the majority of cases are due to de novo mutations (*1). For this reason, it is thought that the deletion is caused by DNA replication errors during the formation of the parents’ sperm and eggs, or in the fertilized egg at the early stage of embryogenesis. Due to the small number of cases overall and the small number of patients with parents, brothers, and sisters with similar genotypes due to the de novo mutation, molecular biology and genetic research has not progressed much, and genotype-phenotype association has been rarely performed.

The area where the deletion occurs is often near the end of the long arm of chromosome 2, and the deletion has been identified as the 2q37 region. It is believed that a pure deletion in this region is the cause of the disease. The size of the deletion varies greatly from person to person, ranging from 2 Mbp to 9 Mbp. Approximately 100 genes are encoded in this region, and it is believed that the disease develops when the function of one or more of these genes is impaired. In particular, one of the main genes is the HDAC4 gene (*2), which shows deletion of one allele and the associated loss of heterozygosity. HDAC4 is a gene that codes for a histone deacetylase and is known to be involved in skeletal and muscular development, but its molecular relationship with Albright syndrome-like metacarpal and midfoot shortening has not yet been clarified.

What is Trisomy 18 (Edwards Syndrome)? Characteristics, Possible Symptoms, Treatment and Expectations (*Written with Supervision of a Doctor)

We will look at the causes, symptoms and testing for 18 Trisomy (Edwards Syndrome) in detail / and how to prepare and pr...

Symptoms

The typical presentation of individuals with Albright-like short metacarpals and mid-crus syndrome is primarily physical and neurological. Physical characteristics: Approximately half of affected individuals have brachydactyly or polydactyly, especially in the fourth digits of the hands and feet. Additionally, most cases have distinctive facial features, including prominent forehead, round face, thin and arched eyebrows, sunken nasal bridge, missing or prominent nasal passages, thin lips, thin eyelids, upper eyelid folds, upturned cleft palate, smooth palate, prominent lower cheekbones, and ear abnormalities. Short stature, obesity, thinning hair, and nipple abnormalities, including inverted nipples, are also common. Organ developmental deficiencies have been observed, with cardiac, gastrointestinal, and renal abnormalities seen in one-third of affected individuals. Wilms tumors, renal dysplasia, and bronchomalacia have been seen in a few affected children, but only in those with proximal 2q37.1 deletions. An Albright hereditary osteodystrophy-like phenotype (*3) is seen in patients with telomeric deletions at 2q37.3, who subsequently develop seizures and cystic kidney disease.

Neurological abnormalities: Developmental delays and mental disorders are observed, ranging from mild to severe, with individual differences, but the most typical is hypotonia-induced muscle tone . Approximately half of patients have these symptoms, which have been reported to improve over time. Patients are also at high risk for seizures, including epilepsy. In addition, motor development has been delayed, leading to abnormalities in behaviors such as standing, sitting, and walking. Patients with terminal deletions at 2q37.3 have been reported to have disorders of repetitive behaviors, communication, and social interaction, and to show typical symptoms of the autism spectrum. Specifically, intermittent aggression , hyperactivity, attention deficit, obsessive-compulsive disorder, and sleep disorders have been noted. It has been pointed out that the severity and number of these neurodevelopmental abnormalities depend on the size of the gene deletion, but the number of cases is still too small to prove this, so the significance of this relationship has not yet been clarified. As the symptoms of Albright syndrome-like shortened metacarpals and midcrus are diverse, treatment is basically limited to symptomatic treatment for the above symptoms. In addition, health management for secondary diseases such as obesity is also performed.

Diagnosis

By carefully recording the characteristic abnormalities described above, clinical diagnosis of Albright-like shortened metacarpals and mid-crus can be made in some newborns and infants. However, in most cases, the diagnosis is definitively made in children of a later age. In such cases, the initial physical findings are detected by ultrasound or X-rays. Since Albright-like shortened metacarpals and mid-crus is a de novo mutation, genetic testing of parents is of little use except in a few cases. Pathological diagnosis is made by examining genomic defects, which are broadly divided into cytogenetic testing and molecular genetic testing as follows.

Cytogenetic testing: 80% of cases of Albright syndrome-like shortened metacarpals and midcrus can be diagnosed by simple karyotyping (*4) or other chromosome testing. However, this method is limited to cases with a relatively large deletion region. Cases with a small deletion region will have a normal karyotype in regular chromosome testing, so in order to diagnose this disease with a high degree of individual variability in the deletion region with high accuracy and sensitivity, it is necessary to use molecular genetic testing, which will be described later.

Molecular genetic testing: Genetic diagnosis is performed using molecular biology techniques, mainly FISH (Fluorescent in situ hybridization) and DNA microarray methods.

FISH method

In this method, single-stranded DNA complementary to the target gene region is fluorescently labeled and observed using a fluorescent microscope. The fluorescently labeled single-stranded DNA is called a FISH probe, and can be designed to match the sequence of the target gene region. Since Albright syndrome-like shortened metacarpals and midfoot are often found in the terminal regions of chromosomes, FISH probes are often designed to target telomere and subtelomere regions, and some are commercially available as kits. In regions that contain many repeat sequences, the FISH probe binds multivalently, increasing the effective concentration of the fluorescent dye and enhancing the signal. On the other hand, if a deletion occurs, the FISH probe cannot bind to the target region and is washed away by the subsequent washing procedure, so no fluorescent signal is detected. Therefore, by staining the chromosomes with dyes that specifically bind to DNA, such as DAPI or Hoechst, and hybridizing the FISH probe, it is possible to map which region on the chromosome the target region is located in. The FISH method is a technology that can detect even very small deletions in small regions, and can diagnose Albright syndrome-like shortened metacarpals and midfoot with high accuracy. However, the deletion region must contain the target sequence of the FISH probe. In some cases, there is a mid-deletion in the subtelomeric region, and in such cases, if a FISH probe is designed for the telomeric region, it will be a false negative and will not be detected, so the selection and design of the FISH probe is extremely important.

DNA microarrays

This method uses a chip on which known DNA fragments (in this case, fragments of the entire human genome) are densely packed on a substrate , and the DNA extracted from the tissue to be tested is hybridized with a control DNA with a normal sequence for comparison. If the sample contains a complementary DNA fragment on the substrate, it will bind to the complementary sequence on the substrate and emit fluorescence. By comparing the spatial distribution of the fluorescent signal on the control and the chip, it is possible to comprehensively analyze which part of the genome has a deletion. This type of method is specifically called CGH (Comparative genomic hybridization) microarray. This method analyzes changes in the copy number of gene loci on chromosomes, but while it can detect an increase in copy number with high sensitivity, it is difficult to detect partial deletions unless they are 5 to 10 Mbp in size.

What is Trisomy 13 (Patau Syndrome)? (*Written with Supervision of a Doctor)

13 trisomy, also known as Patou syndrome, is a congenital chromosomal abnormality that can occur in 1 in 5,000 to 12,000...

Future outlook

In recent years, genome sequence analysis using next-generation sequencers has been developing, and it is expected that it will play a major role in genotype-phenotype association. However, due to the cost of the equipment itself and the running costs, it is not yet realistic to use it for actual diagnostic purposes. The two methods mentioned above are based on fluorescence detection, so they are relatively inexpensive and are actually used for pathological diagnosis. Currently, it is becoming possible to outsource relatively inexpensively, and the price of the next-generation sequencer equipment itself is gradually decreasing. As for reagents, etc., efforts are being made to reduce running costs by reducing the number of runs by simultaneously analyzing multiple samples in a piggyback manner.

As genotype-phenotype associations progress, it is expected that it will be possible to predict what symptoms will occur depending on the deletion location and its size. This is expected to contribute not only to elucidating the cause of Albright syndrome-like metacarpal and mid-crus shortening and developing treatment methods, but also to elucidating other important genetic diseases. In particular, the 2q37.3 region is thought to contain candidate genes related to the onset of autism spectrum disorder, and can be said to be an important genomic region. The minimum deletion interval of 240.1-242.2 Mb is known to cause autism spectrum disorder, hyperkinetic behavior, and epilepsy, and contains at least 29 genes, including axonal transporters of synaptic vesicles. Interestingly, this 2.1 Mb deletion interval overlaps with the minimum deletion interval for eczema (1.5 Mb). In recent years, although it has not yet been proven, it has been suggested that autism spectrum disorders and atopic dermatitis are related, and if this hypothesis is true, the overlap of the deletion interval seems reasonable from the perspective of genotype-phenotype. As such, since deletions in the 2q37 region have been observed to cause a variety of symptoms, more detailed analysis may elucidate the relationship between unexpected diseases. If this happens, we can expect further development of approaches such as the development of completely new treatments as well as repurposing of existing drugs and treatments.

Summary

This article explains Albright syndrome-like metacarpal and midfoot shortening, a genetic disease caused by a deletion in the genomic region, with a deletion in 2q37. Because it is a very rare disease, many aspects remain unknown, and it is expected that in the future, the latest genetic techniques will be actively adopted to analyze the molecular biological mechanism of the disease and correlate genotype-phenotype. It is expected that such information will also lead to developments in the mechanisms, diagnosis, and treatment of other genetic diseases.

At Hiro Clinic NIPT , we also perform tests for partial deletions and duplications of all autosomal regions, which are conditions that involve deletions or duplications in parts of chromosomes. Please consider doing this in conjunction with whole chromosome testing.

Sotos syndrome: causes, symptoms, and clinical diagnosis [supervised by a doctor]

Sotos syndrome is one of the most common overgrowth disorders and is generally associated with a predisposition to devel...

Footnote

• (*1) De novo mutation: This is a type of mutation that is not genetically inherited from a parent, but rather occurs de novo in an individual. It is also called a new mutation.
• (*2) HDAC4 gene: A gene that codes for histone demethylase (HDAC4). It is thought to play an important role in inducing differentiation of fibroblasts into myoblasts by transforming growth factor β1 (TGF-β1).
• (*3) Albright hereditary osteodystrophy-like syndrome: This is specifically called when physical and intellectual developmental disorders, brachydactyly, short stature, and obesity are observed simultaneously.
• (*4) Karyotyping: Karyotype analysis using band patterns characteristic of chromosomes. There are Q-band analysis using Hoechst dye and G-band analysis using Giemsa staining, and these can be used to easily identify chromosomes and determine ploidy, translocations, etc. from the chromosome structure.