Sotos syndrome by A.Griguolo

Generality

Sotos syndrome is a rare genetic disorder characterized by excessive skeletal growth, craniofacial anomalies, mental retardation, motor problems and behavioral problems.

Due to the mutation of the NSD1 gene, Sotos syndrome is a condition acquired during embryonic development, in more than 90% of cases, and a hereditary condition, in the percentage of remaining cases; therefore, it is almost always the result of a new mutational event.

The symptoms and signs of Sotos syndrome are found, in part, already at birth, which makes early diagnosis possible.

Currently, unfortunately, those suffering from Sotos syndrome can only rely on symptomatic treatments - that is, aimed at alleviating the symptoms - as there is no cure capable of canceling the consequences of the mutation on the NSD1 gene.

What is Sotos Syndrome?

Sotos syndrome is a genetic disease that leads to: excessive pre- and post-natal skeletal growth, distinctive cranial and facial anomalies, mental retardation with consequent learning difficulties, delay in the development of motor skills and, finally, particular behavioral problems.

Other names of Sotos syndrome

Sotos syndrome is also known as cerebral gigantism (referring to) or Sotos-Dodge syndrome .

Epidemiology

According to statistics, an individual every 10, 000-14, 000 would be born with Sotos syndrome.

Causes

Sotos syndrome is due to a specific mutation in the NSD1 gene, located on chromosome 5 .

In the human being, the aforementioned mutation is, in 90-95% of clinical cases, acquired spontaneously, from nothing and without precise reasons, during embryonic development (ie after the spermatozoon fertilized the egg and had start embryogenesis) and, only in the remaining 5-10% of clinical cases, hereditary (ie transmitted by parental means).

Thus, Sotos syndrome is, in 90-95 cases out of 100, a condition resulting from a "new" mutation and, in only 5-10 cases out of 100, a condition inherited from the parents.

What causes the mutation of the gene associated with Sotos syndrome?

Premise: the genes present on human chromosomes are DNA sequences that have the task of producing fundamental proteins in biologic processes indispensable to life, including cell growth and replication.

In the absence of mutations against him, the NSD1 gene produces a protein from the group of histone methyltransferases, whose function is to regulate the activity of genes involved in growth and development processes, avoiding cellular hyperproliferation phenomena.

More simply…

In healthy people, NSD1 produces a protein that finely controls the activity of a series of genes involved in the growth and development of the human body.

In the presence instead of the mutation responsible for Sotos syndrome, the NSD1 gene loses part of its regulatory capacity against the aforementioned genes (NB: the loss is due to a quantitative decrease of NSD1) and this leads to an anomalous expression of the latter with repercussions on body and mental development.

More simply…

If mutated, NSD1 is little and this leads to an anomalous activity on the part of the genes under its control, followed by an alteration of physical and mental development.

Sotos syndrome is an autosomal dominant disease

To understand...

Each human gene is present in two copies, called alleles, one of maternal origin and one of paternal origin.

Sotos syndrome has all the characteristics of an autosomal dominant disease .

A genetic disease is autosomal dominant when the mutation of only one copy of the gene that causes it is sufficient to manifest itself.

Symptoms and Complications

With some of its symptoms and characteristic signs, Sotos syndrome is evident at birth and in the first years of life .

As mentioned at the beginning, this rare genetic disease involves excessive skeletal growth, the presence of facial and cranial anomalies and a delay in the development of intellectual and motor skills.

Excessive skeletal growth

In Sotos syndrome, excessive skeletal growth is the first clinical manifestation that can be seen first and from the earliest moments of life . After all, patients are already subject to it in the pre-natal phase.

The physical consequences of this excessive skeletal growth are:

At birth, large head and weight above average ;
In the first years of life, high statural development (ie in height), large hands, large feet and large head.

To this, it is important to add that the impact of Sotos syndrome on skeletal growth also affects bone aging : compared to their healthy peers, children with Sotos syndrome demonstrate a bone age that is 2-4 years older.

IS EXCESSIVE GROWTH HAS AN END?

The most important effects on skeletal growth, by the Sotos syndrome, end around 3-4 years of life . From this age on, in fact, the high rate of skeletal growth gradually tends to fade, up to normality.

CONSEQUENCES IN ADULT AGE

Due to excessive skeletal growth at a very young age, individuals with Sotos syndrome reach a height of not less than 193 cm in adulthood.

It is interesting to point out to readers that the weight of these subjects is in line with the weight of healthy individuals of equal height; this means that the Sotos syndrome only affects height and not body weight.

Craniofacial anomalies

The craniofacial abnormalities related to Sotos syndrome are:

Prominent front;
Elusive hairline;

Dolicocefalia (ie long and narrow head);
Eyes abnormally spaced (ocular hypertelorism);
Sharp chin;
Eyelid fissures facing downwards;
Narrow palate;
Long and narrow face.

The aforementioned anomalies are particularly evident at birth; then, with growth, they tend to "fade", to be less visible. The only stable craniofacial signs even in adulthood are: the prominent chin, the dolichocephaly, the prominent forehead and the receding hairline.

Delay in intellectual development

In Sotos syndrome, delay in intellectual development is the consequence of a problem in the central nervous system.

To reveal this intellectual delay are: a certain slowness in learning to speak, language problems (eg, stuttering, problems with sound reproduction, monotonous voice, etc.) and a reduced IQ (stable throughout life).

Did you know that ...

For 80-85% of patients with Sotos syndrome, the IQ is just over 70 (hence 30-40 points below normal); for the remaining percentage, however, it is normal.

Delay in motor development

In Sotos syndrome, delay in motor development occurs with:

Difficulty walking on all fours (it is clearly a problem of very young age);
Muscular hypotonia;
Clumsiness and coordination difficulties (for example, it is difficult to learn to ride a bicycle);
Motor problems due to poor control of striated muscles.

Except for the first one, all the other events mentioned above tend to last for life.

Behavioral problems

The typical behavioral problems that can be seen in patients with Sotos syndrome are: attention deficit hyperactivity disorder ( ADHD ), phobias of various types, aggressiveness, impulsiveness, irritability and obsessive-compulsive disorders .

Other symptoms

Sometimes, to the symptomatology reported above - which represents a classical symptomatology - Sotos syndrome can add another series of important clinical consequences, which are:

Jaundice (especially at birth);
Inability to feed (especially at birth);
Epilepsy;
Hearing loss;
Scoliosis (in about 40% of patients);
Malformations of kidneys and / or urinary tract (in about 20% of patients);
Heart defects (in no more than 35% of patients);
Vision problems, such as strabismus;
Predisposition to the development of respiratory infections;
Predisposition to the development of malignant tumors.

Diagnosis

To formulate the diagnosis of Sotos syndrome, information from:

The anamnesis ;
The objective examination ;
Radiological examinations, such as CT, X-rays or magnetic resonance, referred to the head or other clinically relevant anatomical compartments;
A genetic test .

Anamnesis and physical examination

Anamnesis and physical examination consist essentially in an accurate evaluation of the symptomatology exhibited by the patient.

In a context of Sotos syndrome, it is in these phases of the diagnostic procedure that the doctor ascertains the presence of cranial and facial anomalies, anomalous skeletal growth, intellectual deficit, delayed motor development and any other less common manifestations .

Radiological examinations

Radiological examinations are used to detect and analyze any abnormalities that may affect the urinary tract, the heart or the spine (scoliosis).

Genetic test

It is the DNA analysis aimed at detecting mutations of critical genes.

In a context of Sotos syndrome, it represents the confirmation diagnostic test, as it allows us to highlight the NSD1 mutation.

When is the diagnosis made?

Sotos syndrome can be diagnosed at birth.

It is good, however, to point out that none of the routine exams, performed in the prenatal phase, makes it possible to identify the disease in question; for prenatal diagnosis of Sotos syndrome, in fact, a prenatal genetic test (after an amniocentesis or a villocentesis ) is needed.

Therapy

The treatment of Sotos syndrome is purely symptomatic - that is aimed at controlling the symptomatology and avoiding / postponing complications - as there is still no cure capable of canceling, before birth, the mutation responsible for the disease in question.

Symptomatic therapy: what does it consist of?

The list of possible symptomatic treatments for Sotos syndrome includes:

The so-called occupational therapy to make everyday life less disturbed, the present genetic condition and its consequences;
The so - called cognitive-behavioral therapy to improve behavioral disorders (through cognitive-behavioral therapy, the patient learns a series of techniques to control certain wrong behaviors);

Logotherapy (or language therapy) to stem language disorders;
Physiotherapy to alleviate motor problems;
An ad hoc drug therapy, aimed at managing ADHD (if present) and / or any other behavioral problems;
The use of corrective glasses (if vision problems are present);
A pharmacological or surgical therapy focused on the control of any cardiac and / or urinary tract problems;
The implementation of an oncological screening program, aimed at the early detection of possible malignant tumors (remember that Sotos syndrome promotes neoplastic processes).

What medical figures does symptomatic therapy of Sotos syndrome involve?

The symptomatic treatment of Sotos syndrome requires the coordinated intervention of several medical specialists, including: pediatricians, geneticists, endocrinologists, neurologists, speech therapists, orthopedic surgeons, ophthalmologists, psychiatrists and physiotherapists.

Prognosis

Sotos syndrome does not affect the life expectancy of people it affects; however, it strongly conditions the quality of existence (think only of the consequences at an intellectual and motor level).