Pfeiffer syndrome by A.Griguolo

Generality

Pfeiffer syndrome is a rare genetic disorder characterized by craniosynostosis and the presence of large thumbs and big toes abnormally deviated inwards.

Observable in one newborn per 100, 000, Pfeiffer syndrome is associated with the mutation of the FGFR1 and FGFR2 genes; both these genes have the task of regulating the fusion of the cranial sutures and the development of the fingers and toes.

For the diagnosis of Pfeiffer syndrome the physical examination, the anamnesis, a radiological evaluation of the skull and of the fingers and toes, and, finally, a genetic test are fundamental.

Currently, those who suffer from Pfeiffer syndrome can only rely on symptomatic treatments, ie those that alleviate symptoms.

Brief review of cranial sutures and their fusion

The cranial sutures are the fibrous joints, which serve to fuse together the bones of the cranial vault (ie the frontal, temporal, parietal and occipital bones).

In normal conditions, the process of fusion of the cranial sutures takes place in the post-natal period, beginning at 1-2 years of age, for some articular elements, and ending at the threshold of 20 years, for others. This long and rhythmic fusion process allows the brain to grow and develop properly.

What is Pfeiffer Syndrome?

Pfeiffer syndrome is a rare genetic disorder characterized by:

Premature fusion of one or more cranial sutures. In medicine, this anomalous phenomenon is called craniostenosis or craniosynostosis ;

The presence of thumbs and toes abnormally large and deviated in such a way that they seem to move away from the other fingers (medial deviation).

Pfeiffer syndrome, therefore, is a genetic condition that, in its bearer, determines, mainly, anomalies to the damage of the skull and of the hands.

As readers will learn more about in the chapter on symptoms, however, Pfeiffer syndrome can be associated with other problems and other physical malformations.

Epidemiology: how common is Pfeiffer syndrome?

According to statistics, one individual per 100, 000 would be born with Pfeiffer syndrome.

Did you know that ...

Genetic diseases that, like Pfeiffer syndrome, cause craniosynostoses are around 150.

Among these, in addition to Pfeiffer syndrome, stand out for importance: Crouzon syndrome, Apert syndrome and Saethre-Chotzen syndrome .

Causes

Pfeiffer syndrome can arise due to a specific mutation of the FGFR2 gene, located on chromosome 10, or due to a double specific mutation, one due to the aforementioned FGFR2 gene and one to the FGFR1 gene, the whose seat is on chromosome 8.

In the human being, the aforementioned mutations can be hereditary - that is, transmitted by parental means - or acquired in a completely spontaneous way from nothing, without precise reasons, during embryonic development - that is, after the sperm has fertilized the egg and embryogenesis began.

What causes the mutation of the gene associated with Pfeiffer 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.

When they are free of mutations (and therefore in a healthy person), the FGFR1 and FGFR2 genes produce the Fibroblast Growth Factor Receptor 1 and the Fibroblast Growth Factor Receptor 2 in the right quantities, respectively, which are two receptor proteins indispensable to mark the timing relative to the fusion of the cranial sutures and to regulate the development of the fingers and toes (in other words, they signal when it is the appropriate moment for the fusion of the cranial sutures and control the formation of the fingers of hands and feet).

When instead they undergo the mutations observed in the presence of Pfeiffer syndrome, the FGFR1 and FGFR2 genes are hyperactive and produce the aforementioned receptor proteins in such massive quantities, that the melting times of the cranial sutures are altered (they are faster) and the process of Finger and toe formation does not occur correctly.

Pfeiffer 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.

Pfeiffer 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.

Types of Pfeiffer syndrome

In 1993, after numerous studies on Pfeiffer syndrome, the American doctor Michael Cohen published a typological classification of the genetic disease in question, which foresaw the existence of three pathological variants, simply identified with the terms " Type I ", " Type II " and Type III "and all united by the presence of craniostenosis and abnormalities affecting the thumb and big toes. The medical-scientific community immediately accepted this classification and since then Pfeiffer syndrome experts have used it as a diagnostic tool and for assessing the severity of the present genetic condition, it should be pointed out that the classification of Dr. Cohen distinguishes Pfeiffer syndrome based on the severity of cranial and digital anomalies, and the presence of other symptoms and signs.

Going into the details of the individual pathological variants, at this point in the article it is important to emphasize that:

Type I is the less severe version of Pfeiffer syndrome, as craniostenosis and thumb and big toe abnormalities have contained consequences.
Other important information: it is due to the FGFR2 mutation, sometimes combined with the FGFR1 mutation; it can be an inherited or acquired condition.
Type II is the most severe version of Pfeiffer syndrome, as it is associated with severe craniostenosis, almost incompatible with life, and profound anomalies affecting the hands and feet.
Other important information: it is due exclusively to the FGFR2 mutation; it is always an acquired condition.
Type III is the version of Pfeiffer syndrome that is placed, under a gravity scale, just below Type II, but largely above Type I, since the craniostenosis present is almost as severe as that of the variant described in the previous point.
Other important information: it is due exclusively to the FGFR2 mutation; it is always an acquired condition.

Symptoms and Complications

As already mentioned, Pfeiffer syndrome could add to craniostenosis and abnormalities affecting thumbs and big toes other symptoms and signs, which are:

Brachydactyly . It is the congenital malformation characterized by an abnormal shortness of the fingers and toes;
Syndactyly . It is the congenital malformation characterized by the fusion of two or more fingers or toes;
Bony ankylosis ;
Abnormalities of the respiratory tract and other internal organs .

craniostenosis

In Pfeiffer syndrome carriers, craniosynostosis may, depending on the number of cranial sutures involved in the early fusion process, the following consequences:

Completely abnormal vertical development of the head, combined with the lack of lateral expansion of the skull. Thus, the patient with Pfeiffer syndrome has a narrow and long head;
Formation of a high and prominent forehead ;

Increase in intracranial pressure, on which symptoms depend such as: persistent headache, vision problems, vomiting, irritability, hearing problems, respiratory problems, altered mental status, papilledema;
Intellectual deficits that involve a reduced IQ. Intellectual deficiencies are the result of the reduced growth space enjoyed by the brain, after the coronal cranial sutures have fused prematurely;
Lack of development of the intermediate part of the face, which appears flat if not even concave ;
Presence of bulging eyes ( proptosis ), wide open and abnormally spaced ( ocular hypertelorism );
Presence of beaked nose ;
Lack of jaw development (maxillary hypoplasia ), which results in a condition of crowded teeth;
Clover-like appearance of the head (" clover skull "). The "clover skull" is the cause of hydrocephalus .

TYPE I

Type I Pfeiffer syndrome is associated with a mild clinical clinical craniostenosis, which very often limits itself to giving the skull an elongated shape and determining a visibly high forehead and a flat face.

If subjected to the right treatment, those who suffer from Pfeiffer syndrome type I usually lead a normal life and have a normal IQ.

TYPE II

Pfeiffer syndrome type II is the only pathological variant that determines the so-called "clover skull"; this cranial anomaly has serious repercussions on intellectual capacity and is often associated with premature death.

Those suffering from Pfeiffer Syndrome type II have the entire clinical picture exposed above, regarding the consequences of craniostenosis.

Image taken from Wikipedia.org

TYPE III

Pfeiffer syndrome type III has the same impact, on its carriers, as Type II Pfeiffer syndrome, except for the "clover skull".

Sufferers of Type III Pfeiffer Syndrome do not enjoy a long life expectancy.

Abnormalities affecting thumbs and toes

If particularly severe, the abnormalities of the thumbs and toes can profoundly affect the functional capacity of the hands and feet, causing problems in grasping objects and / or walking.

Did you know that ...

The medial deviation that affects the thumbs and toes of patients with Pfeiffer syndrome is an example of varus . More precisely, the doctors speak of a launching thumb, for the medial deviation of the thumbs, and of varus hallux, due to the medial deviation of the toes.

brachydactyly

In Pfeiffer syndrome, brachydactyly is a fairly common anomaly, which can affect only a few fingers or the entire digital complex of hands and / or feet.

The problem of brachydactyly is observable in all the typological variants, even if with different frequency.

Syndactyly

In Pfeiffer syndrome, syndactyly is a fairly frequent anomaly (less common than brachydactyly), which may have different connotations (it may be incomplete, complete, complex, etc.).

The problem of brachydactyly is observable in all the typological versions of Pfeiffer syndrome, even if with different recurrence.

Bone ankylosis

Pfeiffer syndrome is associated, above all, with bone ankylosis of the elbow, although, in reality, it could cause the same problem to any great articulation of the human body.

Bone ankylosis is a problem that can only be found in the most serious types of Pfeiffer syndrome (especially in Type II).

Respiratory anomalies

The possible abnormalities affecting the respiratory tract induced by Pfeiffer syndrome are such as to cause respiratory problems with serious repercussions on the patient's general health (the brain is the most affected).

Like the bony ankylosis, the aforementioned anomalies can be observed only in the more severe typological variants (Type II in particular).

When is it possible to notice Pfeiffer syndrome?

In general, cranial and digital abnormalities due to Pfeiffer syndrome are evident at birth, therefore diagnosis and treatment planning are immediate.

Diagnosis

In general, the process of investigations leading to the diagnosis of Pfeiffer syndrome begins with the physical examination and the medical history ; therefore, it continues with a series of radiological tests at the head (X-rays at the head, CT at the head and / or magnetic resonance at the head) and at the hands and feet; finally, it ends with a genetic examination .

Physical examination and medical history

Physical examination and anamnesis consist essentially in an accurate evaluation of the symptomatology exhibited by the patient.

In a context of Pfeiffer syndrome, it is in these phases of the diagnostic procedure that the doctor ascertains the craniostenosis and the anomalies of the thumbs and toes, and, based on the other symptoms present, hypothesizes the typological variant in place.

Radiological examinations of the head and fingers of hands and feet

In a context of Pfeiffer syndrome,

Radiological examinations on the head are necessary for the doctor to confirm the presence of an early fusion of the cranial sutures and to estimate the severity of the cranio-encephalic anomalies.
Radiological examinations, on the other hand, are essential to investigate the extent of varus and any brachydactyly and / or possible syndactyly.

Genetic test

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

In a context of Pfeiffer syndrome, it represents a diagnostic confirmation, as it allows to highlight the mutation of FGFR2 and / or FGFR1.

The genetic test is also the exam that allows to establish the type of Pfeiffer syndrome present.

Therapy

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

Symptomatic therapy: what does it consist of?

At the base of every symptomatic therapy adopted in the presence of Pfeiffer syndrome is the surgical treatment of craniostenosis and its possible consequences (morphological alteration of the ear canal, flat or concave face, dental problems, etc.).

Therefore, depending on the typological variant present, the attending physician could add to the aforementioned surgical treatment:

A therapeutic plan aimed at combating respiratory problems;
A therapeutic plan against abnormalities affecting thumbs and toes;
A surgical-based treatment plan against brachydactyly and syndactyly;
A surgical-based treatment plan against bone ankylosis.

THE CRANIOSINOSTOSI SURGICAL CARE

For the carrier of Pfeiffer syndrome, surgical treatment of craniosynostosis includes:

A first intervention at a young age (within the year of life), whose objective is to separate the fusesi sutures earlier than expected and allow the brain to grow according to normality.
This intervention has a high probability of success in the presence of Pfeiffer syndrome type I, while it has decidedly limited benefits in the presence of the most serious typological variants.
A second operation between 4 and 12 years, aimed at giving a normal appearance to the face, which is flat if not even concave.
The operation in question involves the incision of some bones of the face and their repositioning according to a structure that reflects at least in part the normality.
Its execution is rare in patients with Pfeiffer syndrome type II and type III, as the life expectancy of these patients is reduced.
A third eventual intervention in the years of childhood, with the aim of eliminating or at least reducing the ocular Belarusianism .

Prognosis

If the treatments are timely and appropriate, the prognosis in the case of Pfeiffer syndrome depends only on the typological variant present: for Type I, it is benevolent (patients develop a normal IQ and live as a healthy person), while for the Type III and even more for the Type II is inauspicious (patients die prematurely or, if this does not happen, they develop very serious neurological and respiratory problems).