Address correspondence to Daniel Golwyn, MD Dept. of Radiology, Vanderbilt University, 21^st and Garland, Nashville, TN 37232-5316. Ph: 615-343-0595; Fax: 615-343-4890;

Dept. of Pathology and Ob-Gyn.

Synonyms & related conditions: Acrocephalosyndactyly, acrocephalopolysyndactyly, craniosynostosis, and dyscraniodysphalangeal syndromes.

Definition: Craniosynostosis syndromes with associated syndactyly and/or polydactyly usually result in increased skull height with cutaneous and/or osseous fusion of phalanges.

Etymology: acro-cephalo-poly-syn-dactyly: akron: upper, kefalh: head, poluz: many, sun: together, daktuloz: fingers

Prevalence: Craniosynostosis with or without additional anomalies is 3.43:10,000 live births¹⁰.

Etiopathogenesis: Most cases are sporadic. Instances of both autosomal dominant and autosomal recessive inheritances exist. Pathogenetic theories also include genetic translocation². Faulty mesenchymal differentiation³ with abnormally close ossification centers is evident embryologically.

Associated anomalies: Choanal atresia, agenesis of the corpus callosum, hydrocephalus, congenital heart disease, and hypoplastic genitalia are frequently associated.

Differential diagnosis: These disorders may be divided into isolated craniosynostosis, craniosynostosis with syndactyly, craniosynostosis with polysyndactyly, and craniosynostosis with other features². Further classification is described below in the discussion section.

Prognosis: Most patients have intellectual impairment; however, some patients have normal intelligence^3,4.

MESH Acrocephalosyndactyly BDE MIM ICD9 756.0 CDC 756.055

Case report

The fetus was the product of a 19 week gestation to a 30-year-old woman, now G₂P₁₀₁₁, and a 30-year-old man. There was no family history of congenital anomalies. During a limited prenatal ultrasound evaluation performed to corroborate an outside examination, multiple anomalies were detected, including craniofacial malformations and skeletal malformations. The head shape was markedly abnormal with bulging of the frontal areas and narrowing of the skull at the level of the coronal suture (fig. 1-4).

Further, the profile of the fetus demonstrated frontal bossing, hypertelorism and micrognathia. Images of the hands and feet were obtained to document (poly)syndactyly, but the images were not convincing (fig. 5).

Both feet demonstrated a rockerbottom appearance (fig. 6). These findings were believed to represent a form of acrocephalo(poly) syndactyly, and the pregnancy was electively terminated. A CT performed with 3D reconstruction demonstrated the large frontal cranial defect (fig. 7), synostosis of the coronal sutures, depression of the nasal bridge, downward slanting orbits with hypertelorism and micrognathia.

Autopsy

The autopsy revealed a fetus with multiple craniofacial malformations (fig. 8-9).

Examination of the extremities demonstrated type B postaxial hexadactyly of the fingers (pedunculated postminimi) bilaterally (fig. 10). Both feet had a "rockerbottom" configuration (fig. 11). Postaxial polydactyly was evident on the right foot with a single lateral sixth digit. There was partial (proximal) syndactyly involving the fifth and supernumerary toes. There was also a lumbar meningocele. Mild ventriculomegaly of the lateral ventricles was noted. The presence of a corpus callosum could not be determined. The thoracic and abdominal viscera were normal in structure and position. The anus was imperforated. There was a two vessel umbilical cord with a normal placenta.

The digital anomalies and certain craniofacial defects (hypertelorism, downslanting palpebral fissures, broad nasal root, frontal bossing) closely resembled the Greig cephalopolysyndactyly syndrome⁷. The craniofacial defects and polysyndactyly were characteristic features. Additional anomalies in this fetus defy classification.

Discussion

Classification

Craniosynostosis syndromes have been variously described with acronyms and a definitive classification remains controversial. Apert syndrome (Acrocephalosyndactyly, Type I), Apert-Crouzon syndrome (Acrocephalosyndactyly, Type II), Saethre-Chotzen syndrome (Acrocephalosyndactyly, Type III), and Pfeiffer syndrome (Acrocephalosyndactyly, Type V) categories have been reported. Craniosynostosis syndromes with polysyndactyly have also been reported. Noack syndrome (Acrocephalopolysyndactyly, Type I) which is now generally accepted as a variant of Acrocephalosyndactyly, Type V, Carpenter syndrome (Acrocephalopolysyndactyly, Type II), Sakati-Nyhan syndrome (Acrocephalopolysyndactyly, Type III) and Goodman syndrome (Acrocephalopolysynda- ctyly, Type IV) variants have been described, and Grieg cephalopolysyndactyly syndrome is another related entity that may actually represent a spectrum of phenotypic expression. There is a wide variability in phenotypic expression which has led to the inherent difficulties in nosology that is apparent in the literature.

Etiopathogenesis

Inheritance patterns for acrocephalosyndactyly and acrocephalopolysyndactyly are both autosomal dominant and autosomal recessive. However, the majority of cases occur sporadically, with most representing spontaneous mutations in families having no history of congenital aberrations. There appears to be an increased risk related to advanced parental age¹. Variability in phenotypic expression is well documented in the literature^4,8,9. The prevalence of craniosynostosis with or without additional anomalies has been estimated at approximately 3.43:10,000 by Lammer et al.¹⁰.

The etiology for these disorders is unknown; however, an abnormality in mesenchymal differentiation has been proposed¹². Furthermore, craniosynostosis may be better understood as an abnormality with various causes rather than an etiologic entity¹¹. Chromosome analyses are usually normal in these patients; however, a translocation¹³ has been reported. Spontaneous mutations account for the vast majority of cases¹.

The primary skeletal malformations exhibited by this fetus suggest a diagnosis that falls within the broad spectrum of craniosynostosis syndromes. Frequent overlap in clinical features and extreme variability among individuals in manifestations complicates definitive categorization. Classification schemes are constantly being revised as continued descriptions allow specific syndromes to be recognized as variants or subgroups of others.

The collective dysmorphic features identified in this fetus most likely represent a variant of one of the dyscraniophalangeal syndromes described above. However, syndactyly was not a prominent feature, and the limb malformations appeared more consistent with the acrocephalopolysyndactyly syndromes. The postaxial hexadactyly (pedunculated postminimi) present in the hands as well as agenesis of the corpus callosum has been described in association with Greig cephalopolysyndactyly¹⁴. Lumbar meningocele, imperforate anus, and "rockerbottom" feet were features present in this fetus that defy the current classification system and may represent fortuitous associations.

References

1 Risch N, Reich EW, et al.: Spontaneous mutation and parental age in humans. Am J Hum Genet 41:218-248, 1987.

2. Taravath S and Tonsgard JH: Cerebral malformations in Carpenter syndrome. Pediatr Neurol 9:230-4, 1993.

3. Patton MA, Goodship J, Hayward R, et al.: Intellectual development in Aperts syndrome: A long- term follow up of 29 patients. Medical Genetics 25:164-167, 1988.

4. Gershoni-Baruch R: Carpenter syndrome: Marked variability of expression to include the Summitt and Goodman syndromes. Am J Med Genet 35:236-240, 1990.

5. Kaplan, LC: Clinical assessment and multispecialty management of Apert syndrome. Clin Plast Surg 18 No 2, 1991.

6. Lefebvre A, Travis F, et al.: A psychiatric profile before and after reconstructive surgery in children with Aperts syndrome. Br J Plast Surg 39:510-513, 1986.

7. Gollop TR, Fontes LR: The Greig cephalopolysyndactyly syndrome: Report of a family and review of the literature. Am J Med Genet 22:59-68, 1985.

8. Niemann-Seyde SC, Eber SW, Zoll B. Saethre-Chotzen syndrome (ACS III) in four generations. Clin Genet 40:271-276, 1991.

9. Cohen, MM, Kreiborg S: Genetic and family study of the Apert syndrome. J Craniofac Genet Dev Biol 11:7-17, 1991.

10. Lammer EJ, Cordero JF, Wilson MJ, et al.: Investigation of a supspected increased prevalence of craniosynostosis -Colorado, 1978-1982 Proc Greenwood Genet. Ctr. 6, 126-127; Document EPI-83-56-2, Public Health Service-CDC-Atlanta 4/8/87;p.7.