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Diagnostic and Interventional Imaging
Volume 93, n° 10
pages 785-789 (octobre 2012)
Doi : 10.1016/j.diii.2012.06.002
Pfeiffer syndrome type II discovered perinatally: Report of an observation and review of the literature
 

H. Ben Hamouda a, , Y. Tlili a, S. Ghanmi a, H. Soua a, S. Jerbi b, M.M. Souissi c, H. Hamza b, M.T. Sfar a
a Unité de néonatologie, service de pédiatrie, CHU Tahar Sfar, 5111 Mahdia, Tunisia 
b Service de radiologie, CHU Tahar Sfar, 5111 Mahdia, Tunisia 
c Service de gynéco-obstétrique, CHU Tahar Sfar, 5111 Mahdia, Tunisia 

Corresponding author.

Keywords : Pfeiffer syndrome, Cloverleaf skull, Craniosynostosis, Syndactyly, Prenatal diagnosis


Pfeiffer syndrome, described for the first time by Pfeiffer in 1964, is a rare hereditary condition combining osteochondrodysplasia with craniosynostosis [1]. This syndrome is also called acrocephalosyndactyly type 5, which is divided into three sub-types. Type I is the classic Pfeiffer syndrome, with autosomal dominant transmission, often associated with normal intelligence. Types II and III occur as sporadic cases in individuals who have craniosynostosis with broad thumbs, broad big toes, ankylosis of the elbows and visceral abnormalities [2]. We report a case of Pfeiffer syndrome type II, discovered perinatally, which is distinguished from type III by the skull appearing like a cloverleaf, and we shall discuss the clinical, radiological and evolutive features and the advantage of prenatal diagnosis of this syndrome with a review of the literature.

Observation

The case involved a male premature baby born at 36weeks of amenorrhoea with multiple deformities at birth. The parents were not blood-related and in good health who had two other boys and a girl with normal morphology. The mother was 35years old, it was her 4th pregnancy and 4th child. The pregnancy was poorly monitored and passed without any particular feature. Antenatal ultrasound examinations at 18 and 20weeks of amenorrhoea found no morphological abnormalities. At 36weeks of amenorrhoea the mother went into premature labour. Ultrasound at the beginning of labour found polyhydramnios with hydrocephalus and the appearance of a cloverleaf skull (Figure 1). Presentation was cephalic and delivery was vaginal without incident with an Apgar of 3 then 6 at the 5th and 10th minute respectively.



Figure 1


Figure 1. 

Foetal ultrasound at 36weeks of amenorrhoea: cloverleaf skull with hydrocephalus.

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Clinical examination of the baby on admission found hypotrophy with a birth weight of 2400g, length of 50cm, macrocephaly with a cranial circumference of 37cm, respiratory distress, facial dysmorphia with a cloverleaf skull, centro-facial hypoplasia, severe exophthalmia, low set ears, broad and divergent thumbs and big toes, ankylosis of the elbows and partial bilateral syndactyly between the second and third toes (Figure 2, Figure 3). Radiological exploration of the skeleton showed bilateral coronal craniosynostosis, radio-humeral synostosis and duplication of the first phalange of the thumbs (Figure 4, Figure 5, Figure 6). A cerebral and cranio-facial CT scan showed hydrocephalus, intraventricular haemorrhage, malformation of the bones of the skull with no coronal sutures (Figure 7, Figure 8). Evolution was marked by aggravation of the respiratory distress and the patient died on the third day of life.



Figure 2


Figure 2. 

Cloverleaf skull with bilateral exophthalmia.

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Figure 3


Figure 3. 

Partial syndactyly between the second and third toes with broad, divergent big toes.

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Figure 4


Figure 4. 

X-ray of the skull: craniosynostosis of the coronal sutures.

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Figure 5


Figure 5. 

X-ray of the elbow: radio-humeral synostosis.

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Figure 6


Figure 6. 

X-ray of the hand: duplication of the 1st phalange of the thumb.

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Figure 7


Figure 7. 

Axial cerebral CT scan: hydrocephalus with malformation of the skull (a, b).

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Figure 8


Figure 8. 

Cranio-facial CT scan with three-dimensional reconstruction: wide open metopic suture with absence of coronal sutures (a, b).

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Discussion

The exact incidence of Pfeiffer syndrome is unknown. It is estimated to be 1/100,000 births [3]. In 1993, Cohen [4] classified Pfeiffer syndrome into three sub-types. This classification is useful both clinically and for prognosis. Type I is the classic Pfeiffer syndrome with autosomal dominant transmission. It includes patients who have moderate dysmorphia with broad thumbs and big toes, centro-facial hypoplasia and craniosynostosis of the coronal sutures. The intellectual development of these patients is generally normal and their prognosis is good [3].

Type II, our patient’s case, presents as sporadic cases. It combines a cloverleaf skull, severe exophthalmia, ankylosis or synostosis of the elbow, broad thumbs and big toes and neurological complications. Hydrocephalus, as seen in our patient, is the most common neurological complication [2]. On the other hand, the ventricular haemorrhage found in our patient was very probably related to severe neonatal stress and has never been described as a complication of Pfeiffer syndrome. Other abnormalities can be associated with this syndrome and are shown in Table 1 [2, 5, 6]. Type III resembles type II, but the patient does not have a cloverleaf skull. Absence of this sign can make diagnosis more difficult. The prognosis for Pfeiffer syndrome types II and III is very poor, with a high risk of early death of the child through neurological and respiratory complications [3]. The intellectual development of patients with a cloverleaf skull seems to be poor even if there are no other neurological abnormalities [2]. This is explained by the craniosynostosis resulting in insufficient brain development [3].

The diagnosis of Pfeiffer syndrome is essentially clinical. However, radiological exploration can confirm the skeletal abnormalities of the syndrome and look for associated malformations. X-rays of the skull show the major malformation of the cranium and the coronal craniosynostosis. In Pfeiffer syndrome type II they show the cloverleaf appearance of the skull with bulging in the temporal regions and on the convexity, a widely open sagittal suture and synostosic coronal sutures [2]. Indeed, these abnormalities are shown better by a cranio-facial CT scan with three-dimensional reconstruction which must be performed as soon after birth as possible, as was the case for our patient. This imaging technique is very useful, because it provides direct visualisation of the sutures of the cranial vault and shows the cranio-facial bony anatomy [7].

Moreover, X-rays of the feet show broad, short big toes with incorrectly formed phalanges. X-rays of the hands show broad, short thumbs. X-rays of the upper limbs may show ankylosis of the elbows involving the radius, ulna and humerus.

Transfontanellar ultrasonography is the primary imaging technique in the newborn for detecting congenital hydrocephalus, which is the most common abnormality in Pfeiffer syndrome type II. However, cerebral MRI is the examination of choice for a complete assessment of the cerebral lesions allowing evaluation of any hydrocephalus and the status of the cerebral parenchyma [8].

Molecular genetics has recently provided better understanding of the molecular basis of Pfeiffer syndrome, which is due to mutations of exon IIIa or IIIc of fibroblast growth factor receptor 1 (FGFR1) located on chromosome 8p11.2-p11 or of FGFR2 located on chromosome 10q26 [3, 9]. Indeed, the less serious forms, seen as Pfeiffer syndrome type I, are related to mutation of the FGFR1 gene while the more severe forms, seen as types II and III, are linked to mutation of the FGFR2 gene. The FGFR1 and FGFR2 genes are involved in the response of the cell to its environment probably by way of a signal inducing maturation or division of the cell. Mutation of this gene prolongs this signal which may be the cause of early maturation of bone cells and consequently of fusion of the bones of the skull, arms and feet [3]. The same mutation of the FGFR gene has been identified in the Jackson-Weiss and Crouzon syndromes. This phenomenon may be explained by the expression of the same mutation possibly being variable and producing different phenotypes [9]. Sporadic cases have been reported in patients with elderly fathers. Such fathers are susceptible to this type of mutation. These sporadic cases are due to a “de novo” mutation or mosaicism in the parents [10].

Differential diagnosis of Pfeiffer syndrome is particularly with syndromes characterised by craniosynostosis, such as Apert syndrome, Carpenter syndrome, Crouzon syndrome, an isolated cloverleaf skull and thanatophoric dysplasia [3]. For a diagnosis of Pfeiffer syndrome, the ratio of the maximum circumference of the big toe to that of the second toe must be between 1.7 and 2.2. A ratio less than 1.7 is an argument against this syndrome [2]. Pfeiffer syndrome type II may be confused with Antley-Bixler syndrome. This is an autosomal recessive syndrome which is characterised by craniosynostosis without a cloverleaf skull, radio-humeral synostosis, various visceral abnormalities such as clitoral hypertrophy, coalescence or hypoplasia of the lips and the absence of syndactyly [2]. Pfeiffer syndrome is sometimes confused with Saethre-Chotzen or Jackson-Weiss syndrome which may both have broad toes [3].

As far as therapy is concerned, there is no specific treatment for Pfeiffer syndrome. However, multidisciplinary management by neonatologists, paediatricians, specialists in orthopaedics and plastic surgery, ophthalmologists and neurosurgeons is essential [6]. The aim of surgery is to correct the various abnormalities. It consists of decompressing the brain by modifying the shape of the skull with expansion of the eyeballs and freeing the upper airways by bringing the nasotracheal complex forward [5]. Experience in this area is very limited. Improvement in intellectual development following cranioplasty has been reported in one case alone [11]. Orbit morphology is often compromised in patients with Pfeiffer syndrome. The exophthalmia may cause exposure keratitis requiring the use of artificial tears during the day and a lubricant at night [6].

Given the very poor prognosis for Pfeiffer syndrome type II, prenatal diagnosis is fundamental for genetic counselling. In the majority of cases reported in the literature, prenatal diagnosis of Pfeiffer syndrome type II was based on two-dimensional ultrasound examinations. The warning signs were cloverleaf skull type cranio-facial abnormalities, exophthalmia or ventriculomegaly and abnormalities of the extremities in the form of broad thumbs and big toes [7]. However, these abnormalities are better shown by three-dimensional foetal ultrasonography which can in addition show the bilateral coronal craniosynostosis, the hypertelorism, the small nose and the syndactyly of the hands and feet [12]. In the same way, foetal CT scans with three-dimensional reconstruction can show the same cranio-facial abnormalities as the three-dimensional foetal ultrasound, but performing a CT scan is not current practice. In all cases, foetal magnetic resonance imaging has a great advantage because it allows better detection of cerebral abnormalities which may be associated with craniosynostosis and provides a better prognostic evaluation [7, 8].

Finally, a molecular biology analysis can provide a precise diagnosis of a suspected Pfeiffer syndrome in utero , give the prognosis of the different sub-types and provide the indication for medical termination of the pregnancy after informing the couple of the poor prognosis, particularly in the case of a mutation in the FGFR2 gene [9]. Prevention of possible recurrence of Pfeiffer syndrome type II is based on screening the parents for mosaicism.

Conclusion

Pfeiffer syndrome type II is a rare genetic disorder with a very poor prognosis because of the many complications, particularly ocular and neurological. Prenatal diagnosis of this syndrome remains difficult and is based on methodical foetal ultrasonography exploring the head, face and extremities, with, in addition, if there are abnormalities, a three-dimensional ultrasound examination and foetal MRI with a molecular biology analysis.

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

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Schell U., Hehr A., Feldman G.J., Robin N.H., Zackai E.H., De Die-Smulders C., and al. Mutations in FGFR1 and FGFR2 cause familial and sporadic Pfeiffer syndrome Hum Mol Genet 1995 ;  4 : 323-328
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