MASS syndrome a medical disorder similar to Marfan syndrome.

MASS stands for: mitral valve prolapse, aortic root diameter at upper limits of normal for body size, stretch marks of the skin, and skeletal conditions similar to Marfan syndrome. MASS Phenotype is a connective tissue disorder that is similar to Marfan syndrome. It is caused by a similar mutation in the gene called fibrillin-1 that tells the body how to make an important protein found in connective tissue. This mutation is an autosomal dominant mutation in the FBN1 gene that codes for the extracellular matrix protein fibrillin-1; defects in the fibrillin-1 protein cause malfunctioning microfibrils that result in improper stretching of ligaments, blood vessels, and skin.

Someone with MASS phenotype has a 50 percent chance of passing the gene along to each child.

People with features of MASS Phenotype need to see a doctor who knows about connective tissue disorders for an accurate diagnosis; often this will be a medical geneticist. It is very important that people with MASS Phenotype get an early and correct diagnosis so they can get the right treatment. Treatment options for MASS phenotype are largely determined on a case-by-case basis and generally address the symptoms as opposed to the actual disorder; furthermore, due to the similarities between these two disorders, individuals with MASS phenotype follow the same treatment plans as those with Marfan syndrome.

MASS stands for the Mitral valve, myopia, Aorta, Skin and Skeletal features of the disorder. MASS Phenotype affects different people in different ways.

In MASS Phenotype:

Mitral valve prolapse may be present. This is when the flaps of one of the heart’s valves (the mitral valve, which regulates blood flow on the left side of the heart) are “floppy” and don’t close tightly. Aortic root diameter may be at the upper limits of normal for body size, but unlike Marfan syndrome there is not progression to aneurysm or predisposition to dissection. Skin may show stretch marks unrelated to weight gain or loss (striae). Skeletal features, including curvature of the spine (scoliosis), chest wall deformities, and joint hypermobility, may be present. People with MASS Phenotype do not have lens dislocation but have myopia, also known as nearsightedness.

MASS syndrome and Marfan syndrome are overlapping connective tissue disorders. Both can be caused by mutations in the gene encoding a protein called fibrillin. These conditions share many of the same signs and symptoms including long limbs and fingers, chest wall abnormalities (indented chest bone or protruding chest bone), flat feet, scoliosis, mitral valve prolapse, loose or hypextensible joints, highly arched roof of the mouth, and mild dilatation of the aortic root.

Individuals with MASS syndrome do not have progressive aortic enlargement or lens dislocation, while people with Marfan syndrome do. Skin involvement in MASS syndrome is typically limited to stretch marks (striae distensae). Also, the skeletal symptoms of MASS syndrome are generally mild.

It is characterized by developmental defects including cryptophthalmos (where the eyelids fail to separate in each eye), and malformations in the genitals (such as micropenis, cryptorchidism or clitoromegaly). Congenital malformations of the nose, ears, larynx and renal system, as well as mental retardation, manifest occasionally. Syndactyly (fused fingers or toes) has also been noted.

Fraser syndrome (also known as Meyer-Schwickerath's syndrome, Fraser-François syndrome, or Ullrich-Feichtiger syndrome) is an autosomal recessive congenital disorder. Fraser syndrome is named for the geneticist George R. Fraser, who first described the syndrome in 1962.

The classical triad of symptoms that defines 3C syndrome includes certain heart defects, hypoplasia (underdevelopment) of the cerebellum, and cranial dysmorphisms, which can take various forms. The heart defects and cranial dysmorphisms are heterogeneous in individuals who are all classed as having Ritscher-Schinzel syndrome.

Heart defects commonly seen with Ritscher-Schinzel syndrome are associated with the endocardial cushion and are the most important factor in determining a diagnosis. The mitral valve and tricuspid valve of the heart can be malformed, the atrioventricular canal can be complete instead of developing into the interatrial septum and interventricular septum, and conotruncal heart defects, which include tetralogy of Fallot, double outlet right ventricle, transposition of the great vessels, and hypoplastic left heart syndrome. Aortic stenosis and pulmonary stenosis have also been associated with 3C syndrome.

The cranial dysmorphisms associated with 3C syndrome are heterogeneous and include a degree of macrocephaly, a large anterior fontanel, a particularly prominent occiput and forehead, ocular hypertelorism (wide-set eyes), slanted palpebral fissures, cleft palate, a depressed nasal bridge, cleft palate with associated bifid uvula, low-set ears, micrognathia (an abnormally small jaw), brachycephaly (flattened head), and ocular coloboma. Low-set ears are the most common cranial dysmorphism seen in 3C syndrome, and ocular coloboma is the least common of the non-concurrent symptoms (cleft lip co-occurring with cleft palate is the least common).

Cranial dysplasias associated with 3C syndrome are also reflected in the brain. Besides the cerebellar hypoplasia, cysts are commonly found in the posterior cranial fossa, the ventricles and the cisterna magna are dilated/enlarged, and Dandy-Walker malformation is present. These are reflected in the developmental delays typical of the disease. 75% of children with 3C syndrome have Dandy-Walker malformation and hydrocephalus.

Signs and symptoms in other body systems are also associated with 3C syndrome. In the skeletal system, ribs may be absent, and hemivertebrae, syndactyly (fusion of fingers together), and clinodactyly (curvature of the fifth finger) may be present. In the GI and genitourinary systems, anal atresia, hypospadia (misplaced urethra), and hydronephrosis may exist. Adrenal hypoplasia and growth hormone deficiency are associated endocrine consequences of Ritscher-Schinzel syndrome. Some immunodeficiency has also been reported in connection with 3C syndrome.

Many children with the disorder die as infants due to severe congenital heart disease. The proband of Ritscher and Schinzel's original study was still alive at the age of 21.

A fetus with 3C syndrome may have an umbilical cord with one umbilical artery instead of two.

8p23.1 duplication syndrome is a rare genetic disorder caused by a duplication of a region from human chromosome 8. This duplication syndrome has an estimated prevalence of 1 in 64,000 births and is the reciprocal of the 8p23.1 deletion syndrome. The 8p23.1 duplication is associated with a variable phenotype including one or more of speech delay, developmental delay, mild dysmorphism, with prominent forehead and arched eyebrows, and congenital heart disease (CHD).

The symptoms of Rabson–Mendenhall syndrome vary from case to case. Major symptoms of Rabson–Mendenhall syndrome include abnormalities of the teeth and nails, such as dental dysplasia, and deformities of the head and face, which include a coarse prematurely-aged facial appearance with a prominent jaw. A skin abnormality known as acanthosis nigricans, which involves a discoloration (hyperpigmentation) and “velvety” thickening (hyperkeratosis) of the skin around skin fold regions of the neck, groin and under arms is also a common symptom. Symptoms will negatively impact the daily life of the patient, and will persist until treated.

Minor symptoms may include an enlargement of the genitalia and precocious puberty and a deficiency or absence of fat tissue. Because individuals with Rabson–Mendenhall syndrome fail to use insulin properly, they may experience abnormally high blood sugar levels (hyperglycemia) after eating a meal, and abnormally low blood sugar levels (hypoglycemia) when not eating.

The phenotypic data on 11 patients indicated that cases are not always ascertained for CHD but that CHD was the most common single feature found in 6 out of 11 individuals. Developmental delay and/or learning difficulties were found in 5 out of 11 cases, but one prenatal case was developing normally at 15 months of age (Case 1,). Three other prenatal cases could not yet be reliably assessed. A variable degree of facial dysmorphism was present in 5 out of 11 individuals. Partial toe syndactyly has been found in one mother and son diad and adrenal anomalies in two probands but not in the duplicated mother of one of them. The phenotype is compatible with independent adult life with varying degrees of support.

Duplication of the GATA4 transcription factor () is believed to underlie the congenital heart disease and other genes, common to the duplication and deletion syndromes, can be regarded as candidates for the 8p23.1 duplication syndrome. These include the SOX7 transcription factor () for both CHD and developmental delay and the TNKS gene () for behavioural difficulties. The diaphragmatic hernia found in the 8p23.1 deletion syndrome has not been found in the 8p23.1 duplication syndrome to date.

The duplication may be associated with copy number changes of the adjacent olfactory receptor/defensin repeats (ORDRs) that predispose to the 8p23.1 deletion and duplication syndromes. High total copy numbers of these repeats have been associated with predisposition to psoriasis and low copy number with predisposition to Crohn's disease.

The most common characteristics include a distinct craniofacial phenotype (microcephaly, micrognathia, short philtrum, prominent glabella, ocular hypertelorism, dysplastic ears and periauricular tags), growth restriction, intellectual disability, muscle hypotonia, seizures, and congenital heart defects. Less common characteristics include hypospadias, colobomata of the iris, renal anomalies, and deafness. Antibody deficiencies are also common, including common variable immunodeficiency and IgA deficiency. T-cell immunity is normal.

People who are affected by Liebenberg Syndrome suffer from three main symptoms:

1. Dysplasia (improper formation) of the bony components of the elbow

2. Abnormal shape of carpal bones

3. Brachydactyly, a symptom where the fingers and toes are shorter than normal.

There are two types of SGBS, each found on a different gene:

SGBS is also considered to be an overgrowth syndrome (OGS). OGS is characterized by a 2-3 standard deviation increase in weight, height, or head circumference above the average for sex and age. One of the most noted features of OGS is the increased risk of neoplasms in certain OGSs. SGBS in particular has been found to have a 10% tumor predisposition frequency with 94% of cases occurring in the abdominal region, most being malignant. It is common for tumors to be embryonal in type and appear before the age of 10.

There are five different types of tumors that patients with SGBS might develop, all intra-abdominal: Wilms tumor, Hepatoblastoma, Hepatocarcinoma, Gonadoblastoma, and Neuroblastoma.

The most common types of tumors developed in patients are the Wilms tumor and hepatoblastoma.

There is an overlap in symptoms between 3C syndrome and Joubert syndrome. Joubert syndrome often manifests with similar cerebellar hypoplasia and its sequelae, including hyperpnea, ataxia, changes in eye movement, and cleft lip and palate. Occasionally, Joubert syndrome will include heart malformations. Brachmann-de Lange syndrome must also be differentiated from 3C syndrome. It presents with similar craniofacial and heart abnormalities and can include Dandy-Walker phenotype, making it difficult to distinguish. Dandy-Walker malformation is also occasionally seen in Ellis-van Creveld syndrome, which is characterized by heart defects and malformed alveolar ridge. Many disorders include the Dandy-Walker phenotype and thus it is not pathognomonic for 3C syndrome.

CHARGE syndrome can also be misdiagnosed. This is because both CHARGE syndrome and 3C syndrome share symptoms of ocular colobomas, cardiac defects, growth retardation, and minor facial abnormalities.

Coffin-Siris syndrome presents with fifth-finger deformities and congenital heart defects. It is distinguished from 3C syndrome by differences in facial dysmorphisms.

Affected individuals present with a broad array of medical and behavioral manifestations (tables 1 and 2). Patients are consistently characterized by global developmental delay, intellectual disability, speech abnormalities, ASD-like behaviors, hypotonia and mild dysmorphic features. Table 1 summarizes the dysmorphic and medical conditions that have been reported in individuals with PMS. Table 2 summarize the psychiatric and neurological associated with PMS. Most of the studies include small samples or relied on parental report or medical record review to collect information, which can account in part for the variability in the presentation of some of the presenting features. Larger prospective studies are needed to further characterize the phenotype.

Table 1: Dysmorphic features and medical comorbid conditions that have been reported in individuals with Phelan McDermid Syndrome.

Table 2: Psychiatric and Neurologic Manifestations associated with Phelan McDermid Syndrome

LIG4 syndrome (also known as Ligase IV syndrome) is an extremely rare condition caused by mutations in the DNA Ligase IV (LIG4) gene. Some mutations in this gene are associated with a resistance against multiple myeloma and Severe Combined Immunodeficiency. Severity of symptoms depends on the degree of reduced enzymatic activity of Ligase IV or gene expression.

As DNA ligase IV is essential in V(D)J recombination, the mechanism by which immunoglobulins, B cell and T cell receptors are formed, patients with LIG4 syndrome may suffer from less effective or defective V(D)J recombination. Some patients have a severe immunodeficiency characterized by pancytopenia, causing chronic respiratory infections and sinusitis. Clinical features also include Seckel syndrome-like facial abnormalities and microcephaly. Patients also suffer from growth retardation and skin conditions, including photosensitivity, psoriasis and telangiectasia. Although not present in all, patients may also present with hypothyroidism and type II diabetes and possibly malignancies such as acute T-cell leukemia. The clinical phenotype of LIG4 syndrome closely resembles that of Nijmegen breakage syndrome (NBS).

The clinical phenotype of 3q29 microdeletion syndrome is variable. Clinical features can include mild/moderate mental retardation with mildly dysmorphic facial features (long and narrow face, short philtrum and a high nasal bridge). Of the 6 reported patients, additional features including autism, ataxia, chest-wall deformity and long, tapering fingers were found in at least two patients. A review of 14 children with insterstitial deletions of 3q29, found 11 who had the common recurrent 1.6Mb deletion and displayed mental retardation and microcephaly.

The variability of phenotype is underscored by the report on a 6 and 9/12 year-old male patient with a de novo chromosome 3q29 microdeletion identified by BAC array comparative genomic hybridization assay (aCGH), with accompanying normal 46,XY high-resolution chromosome analysis. The patient has language-based learning disabilities and behavioral features consistent with diagnoses of autism and attention deficit hyperactivity disorder (ADHD) of the inattentive type. He also displays some other features previously associated with chromosome 3q29 microdeletion such as an elongated face, long fingers, and joint laxity. Most notably the patient, per formal IQ testing, was not found to have frank mental retardation as has been previously reported among patients with chromosome 3q29 terminal deletion, but rather the patient has demonstrated an average full-scale IQ result. This report further expands the phenotypic spectrum to include the possibility of normal intelligence as corroborated by formal, longitudinal psycho-educational testing.

The presence of two homologous low copy repeats either side of the deletion break-point suggests that non-allelic homologous recombination is the likely mechanism underlying this syndrome.

Heart abnormalities are present in 25–35% of people with distal 18q-. The majority of these defects are septal. Congenital orthopedic anomalies are also relatively common, particularly rocker-bottom feet or clubfoot. Cleft lip and palate are relatively common in people with distal 18q-. Kidney abnormalities have also been reported and include horseshoe kidney, hydronephrosis, polycystic kidney, and absent kidney. Boys with distal 18q- may have genital anomalies, the most frequent being cryptorchidism and hypospadias.

A contiguous gene syndrome (CGS), also known as a contiguous gene deletion syndrome is a clinical phenotype caused by a chromosomal abnormality, such as a deletion or duplication that removes several genes lying in close proximity to one another on the chromosome. The combined phenotype of the patient is a combination of what is seen when any individual has disease-causing mutations in any of the individual genes involved in the deletion. While it can be caused by deleted material on a chromosome, it is not, strictly speaking, the same entity as a segmental aneuploidy syndrome. A segmental aneuploidy syndrome is a subtype of CGS that regularly recur, usually due to non-allelic homologous recombination between low copy repeats in the region. Most CGS involve the X chromosome and affect male individuals.

One of the earliest and most famous examples of a CGS involves a male patient with Duchenne muscular dystrophy (DMD), chronic granulomatous disease (CGD), retinitis pigmentosa and intellectual disability. When it was discovered that an X chromosome deletion (specifically Xp21) was the underlying cause of all of these features, researchers were able to use this information to clone the genes responsible for DMD and CGD.

One of those more common CGS involves a deletion on the X chromosome (near Xp21) that encompasses "DMD" (causing Duchenne muscular dystrophy), "NROB1" (causing X-linked adrenal hypoplasia congenita) and "GK" (causing glycerol kinase deficiency). These patients will have all the common features of each individual disease, resulting in a very complex phenotype. Deletions near the distal tip of the p arm of the X chromosome are also a frequent cause of CGS. In addition to the previously described CGS that occur on the X chromosome, two other common syndromes are Langer-Giedion syndrome (caused by deletions of "TRPS1" and "EXT1" on 8q24 and WAGR syndrome (caused by deletions on 11q13 encompassing "PAX6" and "WT1".)

Ring 18 causes a wide range of medical and developmental concerns. As discussed above, people with ring 18 can have features of both distal 18q- and 18p-. The features of distal 18q- and 18p- vary greatly because of the variability of the deletion size and breakpoint locations between people. Because ring 18 can involve unique deletions of both the p and q arms of the chromosome there is twice as much reason for the variability between individuals. This variation is also partly attributable to the incidence of mosaicism, which is relatively common in people with ring 18.

- Holoprosencephaly has been reported in some people with ring 18. This is due to the deletion of the TGIF gene on the short arm of chromosome 18 in some people with ring 18.Approximately 30-40% of people with ring 18 have a congenital heart anomaly. Septal defects are the most common type of defect reported in this population.

- Hypotonia is frequently seen in the ring 18 population. Seizures, though uncommon, have been reported in people with ring 18.

- In some children without “classic” holoprosencephaly, microforms of holoprosencephaly may be noted on MRI, including missing olfactory tracts and bulbs and absent or hypoplastic corpus callosum.

- Strabismus as well as nystagmus have both been reported in infants and children with ring 18.

- Hearing loss has been reported and may be related to ear canal atresia or stenosis.

- Umbilical and inguinal hernias have been reported in a small number of people with ring 18.

- Unilateral renal hypoplasia and aplasia have both been reported in individuals with ring 18. Hydronephrosis as well as pyelonephritis have also been reported in a few individuals. Cryptorchidism, hypospadias, and micropenis have been seen in males with ring 18, while females have been reported with hypoplastic labia.

- Foot abnormalities are common within the ring 18 population. Scoliosis as well as pectus excavatum have also been frequently reported.

- Several people with ring 18 have growth hormone deficiency. Hypothyroidism has also been reported in a minority of people.

- Cognitive ability varies; according to a literature review, the degree of impairment may fall anywhere between the mild and severe ends of the spectrum.

- Facial features of ring 18 include low-set, dysplastic ears, epicanthic folds, and hypertelorism. Micrognathia has also been reported.

Simpson–Golabi–Behmel syndrome (SGBS), also called Bulldog syndrome, Sara Agers syndrome, Golabi–Rosen syndrome, Simpson dysmorphia syndrome (SDYS) or X-linked dysplasia gigantism syndrome (DGSX), is a rare inherited congenital disorder that can cause craniofacial, skeletal, cardiac, and renal abnormalities.

The syndrome is inherited in an X-linked recessive fashion, where males express the phenotype and females usually do not. Females that possess one copy of the mutation are considered to be carriers of the syndrome and may express varying degrees of the phenotype.

Patients usually begin to notice symptoms in their 50s and the course is usually slowly progressive. Common features include peripheral neuropathy, cardiomyopathy, and hemolytic anemia. Other features include limb chorea, facial tics, other oral movements (lip and tongue biting), seizures, a late-onset dementia, and behavioral changes.

Common facial features include midfacial hypoplasia, short and downward- or upward-slanting palpebral fissures, epicanthic folds, and low-set ears with a prominent antihelix.

3q29 microdeletion syndrome is a rare genetic disorder resulting from the deletion of a segment of chromosome 3. This syndrome was first described in 2005.

Ring 18 is a genetic condition caused by a deletion of the two tips of chromosome 18 followed by the formation of a ring-shaped chromosome. It was first reported in 1964.

Hennekam syndrome also known as intestinal lymphagiectasia–lymphedema–mental retardation syndrome, is an autosomal recessive disorder consisting of intestinal lymphangiectasia, facial anomalies, peripheral lymphedema, and mild to moderate levels of growth and intellectual disability.

It is also known as "lymphedema-lymphangiectasia-mental retardation syndrome".

In a subset of patients it is associated with CCBE1 according research published by its namesake, Raoul Hennekam. Other causal mutations were found in the FAT4 gene. Previously, mutations in the FAT4 gene had been only associated with van Maldergem syndrome. The molecular mechanism of the lymphedema phenotype in CCBE1-associated cases was identified as a diminished ability of the mutated CCBE1 to accelerate and focus the activation of the primary lymphangiogenic growth factor VEGF-C.

Rabson and Mendenhall described 3 sibling (2 girls, 1 boy) who initially presented with dental and skin abnormalities, abdominal distention, and phallic enlargement. The children demonstrated early dentition, a coarse, senile-appearing , and striking hirsutism. An "adult growth of hair of head" at 5 years of age was pictured in the case of one of the girls. In the older girl the genitalia were large enough at the age of 6 months to permit vaginal examination for diagnosis of a left ovarian tumor which was removed soon afterward. The children were mentally precocious. Prognathism and very thick fingernails as well as acanthosis nigricans were also described. Insulin-resistant diabetes developed, and the patients died during childhood of ketoacidosis and intercurrent infections. At autopsy pineal hyperplasia was found in all three.

Biologically, infants display fasting hypoglycemia, postprandial hyperglycemia and hyperinsulinemia, which progress to permanent hyperglycemia and recurrent diabetic ketoacidosis.

Eiken syndrome is a rare autosomal bone dysplasia with a skeletal phenotype which has been described in a unique consanguineous family, where it segregates as a recessive trait.