PROCESO EVOLUTIVO DE LA CIUDAD DE JULIACA

The differential diagnosis includes Apert syndrome, Crouzon syndrome, Saethre-Chotzen syndrome, simple craniosynostosis and the Jackson-Weiss syndrome.

Close phenotypic similarity has been observed between Pfeiffer syndrome and Apert-type acrocephalosyndactyly, however, at present it seems likely that the two conditions are distinct entities as no transition from Pfeiffer syndrome to Apert syndrome or vice versa has been observed within

families despite variability in expression. However, Pfeiffer [1964] postulated that allelic mutations at the same locus could possibly account for the

differences between them.

Noack [1959], reported a 43 year old man and his daughter both of whom had acrocephaly and polysyndactyly with enlarged thumbs and great toes. The disorder was designated as acrocephalopolysyndactyly (ACPS) type I. Follow up of the kindred by Pfeiffer [1969] indicated that this was in fact the same as Pfeiffer syndrome.

Baraitser et al., [1980] reported a family considered to have Pfeiffer syndrome. The proband had craniosynostosis, broad great toes and syndactyly, whereas 8 individuals in 3 previous generations exhibited the digital anomalies but no cranial manifestations. The thumb abnormalities were subtle and Cohen [1986] suggested that this family represents an example of the Jackson-Weiss syndrome and not Pfeiffer syndrome.

There is considerable phenotypic overlap between Pfeiffer syndrome and the Jackson-Weiss syndrome and there has been much debate as to whether the two conditions are truly distinct entities. This is discussed in detail in the section below on the Jackson-Weiss syndrome.

6 .5 . Ap e r t S y n d r o m e

The cardinal features of Apert syndrome are the association of acrocephaly (due to mainly coronal craniosynostosis) and a specific

symmetrical form of complete syndactyly involving the 2nd to 5th digits of all four limbs with typical mid-digital masses - “mitten hands and sock feet". The facies is characterised by a steep, flat forehead, depressed nasal bridge, maxillary hypoplasia and relative mandibular prognathism [Apert, 1906; Park and Powers, 1920]. Congenital heart defects are found in

approximately 10% of Apert syndrome patients and genitourinary anomalies also occur with significant frequency (9.6%) [Cohen and Kreiborg, 1993].

In Apert syndrome there is dysplasia of the proximal phalanx of the thumb which acquires a triangular or trapezoid shape before being fused with the terminal phalanx giving rise to the varus deformity. Preaxial polydactyly has occasionally been reported [Lefort et al., 1992]. Similar abnormalities of the proximal phalanx of the thumb and great toe are seen in Pfeiffer syndrome. Acrocephalosyndactyly type I (Apert syndrome) differs primarily from ACS V (Pfeiffer syndrome) by the presence of complete

syndactyly of the hands and feet with radiological evidence of interdigital osseous bridges.

Most cases of Apert syndrome occur sporadically and as there appears to be an association with increased paternal age [Blank, 1960; Erikson, 1974] it has been suggested that the sporadic cases represent new dominant mutations. To date 10 familial instances have been recorded [Cohen and Kreiborg, 1991]. All pedigrees have had affected individuals in two generations except for the family reported by Allanson, [1986], with affected sisters born to normal parerits, which is considered to represent an , example of germinal mosaicism. Germinal mosaicism has been observed in other conditions including Crouzon disease. The finding of mostly sporadic cases with very few familial Instances suggests that a chromosome

microdeletion may be responsible for Apert syndrome.

6 . 6 . Ja c k s o n- We i s sSy n d r o m e

Jackson and Weiss, [1976] reported 88 individuals with

acrocephalosyndactyly in a large Amish kindred. Enlarged great toes and craniofacial abnormalities suggested Pfeiffer syndrome; however thumb abnormalities were not present. They observed considerable phenotypic variation and felt that the entire spectrum of dominantly inherited

craniofacial dysostoses and acrocephalosyndactylies, except for Apert syndrome, was represented. All of those affected had clinical or radiological abnormalities of the feet but enlargement of the thumb did not occur.

Minimal manifestations comprised broad first metatarsals and fused tarsal bones. Several affected members of the family had normal facies. Others had a Crouzon-like appearance but with radiographic changes in the feet similar to those described in Pfeiffer syndrome. However, none of those affected had Pfeiffer-like thumbs.

Escobar and Bixler [1977b] reported a family which showed great similarity to the Jackson-Weiss kindred with phenotypic features varying from Saethre-Chotzen-like, Pfeiffer-like to Crouzon-like, but in addition encompassing the Apert phenotype. Individuals had no evidence of foot abnormalities on radiography. At present these families are listed in the same entry in McKusick’s Catalogue but it is possible that the 2 conditions are not identical. Cohen, [1986] suggested that the family reported by

Baraitser et al.,[1980] as an example of Pfeiffer syndrome represents the Jackson-Weiss syndrome as none of the affected individuals over 4 generations had true Pfeiffer-like thumbs. (This dilemma is resolved in chapter 9).

6 .7 . C r o u z o n Cr a n i o f a c i a l Dy s o s t o s i s ( C F D )

CFD is characterised by craniosynostosis with frontal bossing, shallow orbits and ocular proptosis, parrot-beaked nose, maxillary hypoplasia and mandibular prognathism. Inheritance is autosomal

dominant with virtually complete penetrance and variable expressivity. The hands and feet are generally normal in CFD and it is the absence of digital anomalies that distinguishes this condition from the acrocephalosyndactyly syndromes. However, a number of authors including Jackson and Weiss [1976] and Escobar and Bixler [1977b] have reported individuals with Crouzon-like facies within acrocephalosyndactyly pedigrees.

6 .8 . Di s t i n g u i s h i n g f e a t u r e s

Table 6.2 shows the salient features of 4 of the dominant craniosynostosis syndromes (Saethre-Chotzen syndrome, Pfeiffer

syndrome, Jackson-Weiss syndrome and Crouzon syndrome), on the basis of which these conditions are currently distinguished. The findings in

Robinow-Sorauf syndrome have been incorporated with those of the Saethre-Chotzen syndrome, further evidence to support the proposal that Robinow-Sorauf and Saethre-Chotzen syndromes in fact represent expressions of one and the same disorder is presented in chapter 7. From the table it can be seen that the degree of overlap remains considerable between these different syndromes and precise clinical identification is not clear-cut with diagnostic confusion continuing to occur.

6 .9 . Su m m a r y.

Most authors recognise Apert syndrome, Pfeiffer syndrome and Saethre-Chotzen syndrome as distinct entities but there is still uncertainty about the place of the Jackson Weiss syndrome (which shows considerable overlap with both Crouzon craniofacial dysostosis and Pfeiffer syndrome) and the Robinow-Sorauf syndrome (which closely resembles Saethre- Chotzen syndrome). Some have documented the presence of Apert, Pfeiffer

and transitional syndromes in multiple generations of the same family and suggest that the subdivisions within this group of disorders are spurious. However, without doubt there are several large families with Saethre- Chotzen, Pfeiffer and Crouzon syndromes which breed true.

Table 6.2. Features distiguishing 4 (dominant craniosynostosis syndromes Syndrome Features Craniofacial Forehead Parietal foramina Frontal Hairline Ptosis Proptosis A bn. nasolacrimal duct Hypertelorism

E is

Deviation nasal septum Facial asymmetry M axillary hypoplasia Teeth

Limbs

Soft tissue syndactyly (H)

(F) Thumbs Great toes Other CROUZON broad N + + 4-4- N beaked 4- 4- 4-/- aplasia, abn.incisors N N subluxation head radius/ankylosis SAETHRE-tCHOTZEN high, flat/oblique 4- low 4- 4-

small, prominent crus fla t FN A, beaked 4- 4-4- 4" abn. incisors 2-3 3-4 N/spatulate N/broad, valgus hypoplastic toes 2/3/4 clinodactyly PFEIFFER broad, prominent N 4- N/low-set

depressed bridge, beaked + / -

4- N

2-3 3-4

Broad, short, radial deyn. broad, short, varus, radiohumeral synostosis

ankylosis D IP joints absence middle phalanges

toes JACKSON-WEISS broad, prominent N - k / - ? 4- ? ? 4-/- 4- N 3-4(1) 2-3 N, not broad broad, varus preaxial polydactyly (1) symphalangism M T /navicular/cuneiform fusion broad, short M T

Chapter 7.

A CLINICAL STUDY OF THE NON-APERT