Apert Syndrome Workup

Updated: Aug 21, 2018
  • Author: Harold Chen, MD, MS, FAAP, FACMG; Chief Editor: Maria Descartes, MD  more...
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Workup

Laboratory Studies

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  • Molecular analysis of Apert syndrome

    • The molecular mechanism is exquisitely specific with a narrow mutational spectrum.

    • More than 98% of cases are caused by specific missense substitution mutations, involving adjacent amino acids (Ser252Trp, Ser252Phe, or Pro253Arg) in exon 7 of FGFR2.

    • The remaining cases are due to Alu-element insertion mutations in or near exon 9.

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Imaging Studies

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  • Skull radiography

    • Skull radiography can be performed to evaluate for craniostenosis, which usually involves coronal sutures and maxillary hypoplasia.

    • Abnormalities include sclerosis of suture line, bony bridging and beaking along the suture line, an indistinct suture line, turribrachycephaly, shallow orbits, and hypoplastic maxillae.

  • Spinal radiography

    • Spinal fusions, most commonly at the levels of C3-4 and C5-6, appear to be progressive and occur at the site of subtle congenital anomalies. They may not be apparent as congenital features.

    • Small-sized vertebral body and reduced intervertebral disc space are indicators of subsequent bony fusion.

  • Limb radiography: Radiographs of the limbs depict multiple epiphyseal dysplasia, short humeri, and glenoid dysplasia.

  • Hand radiography

    • Radiography of the hands can be performed to evaluate for cutaneous and osseous syndactyly.

    • The characteristic finding is complete syndactyly involving the second and fifth digits (mitten hands).

    • Multiple progressive synostosis involves distal phalanges, proximal fourth and fifth metacarpals, capitate, and hamate.

    • Symphalangism of interphalangeal joints is progressive.

    • Radiography of the distal phalanx reveals shortened and radial deviation.

    • Radiography of the proximal phalanx of the thumbs reveals delta-shaped deformity.

  • Foot radiography

    • Radiography of the feet can be performed to evaluate for cutaneous and osseous syndactyly. The characteristic finding is complete syndactyly involving the second and fifth digits (sock feet).

    • Fusion of tarsal bones, metatarsophalangeal and interphalangeal joints, and adjacent metatarsals

    • Delta-shaped proximal phalanx of the first toes

    • Occasional partial or complete duplication of the proximal phalanx of the great toes and first metatarsals

  • CT scanning

    • CT with comparative 3-dimensional reconstruction analysis of the calvaria and cranial bases has become the most useful radiological examination in identifying skull shape and presence or absence of involved sutures.

    • CT can precisely reveal the pathological anatomy and permit specific operative planning.

  • MRI

    • MRI reveals the anatomy of the soft-tissue structures and associated brain abnormalities (ie, nonprogressive ventriculomegaly; hydrocephalus; complete or partial absence of the septum pellucidum; absence of septal leaflets; and thinning, deficiency, or agenesis of the corpus callosum). [22, 23]

    • MRI can also reveal spatial arrangement of the bones.

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Other Tests

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  • Psychometric evaluation

  • Hearing assessment

Genetic counseling  [24]

A negligible risk for Apert syndrome is noted in siblings of affected individuals when parents are not affected, except in the case of germinal mosaicism; in this case, the risk in future siblings depends on the proportion of germ cells that bear the mutant allele. [25]

A 50% risk for Apert syndrome is present in the siblings of an affected individual if a parent is also affected.

A 50% risk for Apert syndrome is observed in offspring of an affected individual.

Advanced paternal age effect in new mutations has been shown clinically and demonstrated conclusively at the molecular level.

Prenatal diagnosis  [24]

Despite the striking physical features seen in newborns with Apert syndrome, de novo cases are often not diagnosed prenatally, or are only identified in the third-trimester. [22, 23]

Prenatal ultrasonographic diagnosis can be made based on findings of acrocephaly, mittenlike hands, and proximally placed and radially deviated thumbs. [26] CNS malformations such as mild ventriculomegaly and agenesis of corpus callosum may be visible in some fetuses with Apert syndrome before the pathognomonic skeletal changes are revealed. The abnormal cranial shape and orbital hypertelorism may be absent or very subtle in the second trimester of pregnancy, becoming obvious only in the third trimester. However, Apert syndrome can be accurately suspected in the second trimester by careful ultrasonographic examination of the fetus, including the extremities and skull shape using 3-dimensional ultrasonography.

Use of 3-dimensional ultrasonography to demonstrate the fetal abnormalities (eg, premature closure of the coronal suture; a wide metopic suture; abnormalities of the hands, feet, and face) is particularly useful in parental counseling. [27]

If the molecular defect has been identified in the affected parent, prenatal molecular diagnosis can be achieved by direct DNA testing on fetal DNA obtained from amniocentesis or chronic villus sampling (CVS). In general, linkage analysis can be considered if a mutation has not been detected in the affected parent (although >98% of patients with Apert syndrome tested so far have FGFR2 mutations) and at least 2 affected relatives are available.

The abnormal sonographic findings with a high suspicion of Apert syndrome should be confirmed by detection of a mutation in the FGFR2 gene. Two mutations, S252W C→G and P253R C→G are found in 98% of patients. [28]

Fetoscopy to visualize fetal anomalies comparable to Apert syndrome in a pregnancy at risk is an invasive procedure and is not currently used.

Noninvasive prenatal diagnosis of Apert syndrome using polymerase chain reaction (PCR) and restriction enzyme digestion of cffDNA in maternal plasma has been reported. [29] Au et al have developed a real-time qPCR assay using molecular beacon probes to detect the S252W mutation in the FGFR2 gene, in fetal DNA extracted from plasma of pregnant women at risk for Apert syndrome. [30]

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