John B Mulliken

Publications (3)13.81 Total impact

• Article: Genotype-phenotype analysis of the branchio-oculo-facial syndrome.

  Jeff M Milunsky, Tom M Maher, Geping Zhao, Zhenyuan Wang, John B Mulliken, David Chitayat, Michele Clemens, Heather J Stalker, Mislen Bauer, Michele Burch, [......], Amy Roberts, Willie Reardon, Rhonda E Schnur, Rosemarie Smith, Miranda Splitt, Kamer Tezcan, Margo L Whiteford, Derek A Wong, Roberto Zori, Angela E Lin
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  ABSTRACT: Branchio-oculo-facial syndrome (BOFS; OMIM#113620) is a rare autosomal dominant craniofacial disorder with variable expression. Major features include cutaneous and ocular abnormalities, characteristic facies, renal, ectodermal, and temporal bone anomalies. Having determined that mutations involving TFAP2A result in BOFS, we studied a total of 30 families (41 affected individuals); 26/30 (87%) fulfilled our cardinal diagnostic criteria. The original family with the 3.2 Mb deletion including the TFAP2A gene remains the only BOFS family without the typical CL/P and the only family with a deletion. We have identified a hotspot region in the highly conserved exons 4 and 5 of TFAP2A that harbors missense mutations in 27/30 (90%) families. Several of these mutations are recurrent. Mosaicism was detected in one family. To date, genetic heterogeneity has not been observed. Although the cardinal criteria for BOFS have been based on the presence of each of the core defects, an affected family member or thymic remnant, we documented TFAP2A mutations in three (10%) probands in our series without a classic cervical cutaneous defect or ectopic thymus. Temporal bone anomalies were identified in 3/5 patients investigated. The occurrence of CL/P, premature graying, coloboma, heterochromia irides, and ectopic thymus, are evidence for BOFS as a neurocristopathy. Intrafamilial clinical variability can be marked. Although there does not appear to be mutation-specific genotype-phenotype correlations at this time, more patients need to be studied. Clinical testing for TFAP2A mutations is now available and will assist geneticists in confirming the typical cases or excluding the diagnosis in atypical cases.
  American Journal of Medical Genetics Part A 01/2011; 155A(1):22-32. · 2.39 Impact Factor
• Article: Lesser forms of cleft lip associated with the branchio-oculo-facial syndrome.

  Angela E Lin, Shunsuke Yuzuriha, Scott McLean, John B Mulliken
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  ABSTRACT: Lesser forms of incomplete cleft lip (CL) have been called microform, occult, forme fruste, and congenitally healed. The association of a minimal bilateral CL in branchio-oculo-facial syndrome (BOFS) is well described and commonly referred to as a "pseudocleft." We conducted a systematic analysis of CL types in BOFS, including a retrospective cross-sectional chart and photographic review with variable longitudinal follow-up of our patients and those described in the literature. We compared data on the type of CL and palate (CL/P) and craniofacial and extracranial anomalies in patients with BOFS and classified the lesser forms CL as either minor-form, microform, or mini-microform as defined by the extent of disruption at the vermilion-cutaneous junction. The study comprised 62 patients with BOFS (1 new and 61 in literature, 4 treated by J.B.M). Forty-four patients (71%) had CL only; 16 (26%) had CL/P; and 2 patients had neither CL nor isolated CP. Thirty-five patients with CL had adequate information for analysis (defined as either seen by J.B.M., having a published photograph, or having a detailed description). The most common type was bilateral symmetrical, lesser form CL (n = 20): minor-form (n = 2), microform (n = 6), or mini-microform (n = 12). Among 17 asymmetrical forms, the left side was more severely affected side than the right (12 vs 5). Of 9 patients with CL/P and adequate clinical description, 4 were bilaterally symmetrically complete. Other anomalies, in addition to the familiar cardinal features of BOFS, included facial nerve weakness (n = 6), chin dimple or cleft of the lower lip (n = 4), upper labial pits (n = 6), minor digital anomalies (n = 12), renal anomalies (n = 14), and ectopic thymus (n = 18). This analysis reaffirms the high frequency of CL or CL/P in BOFS and the rarity of isolated cleft palate and underscores that the term "pseudocleft" lip is incorrect. The more precise lesser form designations used in this study may prove useful for future clinical studies because the causative gene, TFAP2A, is known. Lesser forms of CL may be the most subtle expression of BOFS and assist in identifying patients. Unlike major forms of CL/P, either, syndromic or non syndromic, lesser forms suggest that the developmental insult occurs later in labial formation when fusion of the medial nasal process and maxillary process is nearly complete. The deficient vermilion-mucosa and hypoplastic orbicularis oris may be the result of incomplete or deficient mesodermal penetration of the ectodermal envelope. Another possible pathogenic explanation is that failure of labial closure occurs earlier than in a major cleft when the primitive cells of ectoderm and mesoderm retain the capacity to "heal" the defect.
  The Journal of craniofacial surgery 03/2009; 20 Suppl 1:608-11. · 0.81 Impact Factor
• Article: TFAP2A mutations result in branchio-oculo-facial syndrome.

  Jeff M Milunsky, Tom A Maher, Geping Zhao, Amy E Roberts, Heather J Stalker, Roberto T Zori, Michelle N Burch, Michele Clemens, John B Mulliken, Rosemarie Smith, Angela E Lin
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  ABSTRACT: Branchio-oculo-facial syndrome (BOFS) is a rare autosomal-dominant cleft palate-craniofacial disorder with variable expressivity. The major features include cutaneous anomalies (cervical, infra- and/or supra-auricular defects, often with dermal thymus), ocular anomalies, characteristic facial appearance (malformed pinnae, oral clefts), and, less commonly, renal and ectodermal (dental and hair) anomalies. The molecular basis for this disorder is heretofore unknown. We detected a 3.2 Mb deletion by 500K SNP microarray in an affected mother and son with BOFS at chromosome 6p24.3. Candidate genes in this region were selected for sequencing on the basis of their expression patterns and involvement in developmental pathways associated with the clinical findings of BOFS. Four additional BOFS patients were found to have de novo missense mutations in the highly conserved exons 4 and 5 (basic region of the DNA binding domain) of the TFAP2A gene in the candidate deleted region. We conclude BOFS is caused by mutations involving TFAP2A. More patients need to be studied to determine possible genetic heterogeneity and to establish whether there are genotype-phenotype correlations.
  The American Journal of Human Genetics 06/2008; 82(5):1171-7. · 10.60 Impact Factor