The Carey–Fineman–Ziter syndrome: Follow‐up of the original siblings and comments on pathogenesis

In 1981 at the Festschrift honoring the many contributions of David W. Smith, I presented a unique pair of siblings with a distinctive pattern of malformation. The paper from this presentation was published as part of a series in the Journal of Pediatrics [Carey et al., 1982], and this condition has come to be called the Carey–Fineman–Ziter syndrome (CFZ). The described disorder included the following components: facial diplegia with an opthalmoplegia comprising the Moebius sequence, the Pierre Robin sequence, short stature, postnatal-onset microcephaly, congenital and persistent hypotonia, brachydactyly with absent digital flexion creases, and a generalized muscular hypoplasia. The sibs, a male and female, showed normal intelligence, a characteristic face, and an apparent myopathy although no specific muscle disorder was recognized on biopsy. The family was described in the context of a review of the causes and pathogenesis of the Robin sequence [Carey et al., 1982]. In fact, the observation that these sibs had Pierre Robin sequence as a component of a generalized neuromuscular disorder lent support to the notion that the disruption of palatal closure could be due to altered jaw or tongue movement during early development (the so-called Robin complex as discussed by Cohen [1999]). The purpose of my Commentary here is to provide an update on the original patients in the context of the ensuing articles in this issue of theJournal [Dufke et al., 2004; Maheshwari et al., 2004; Verloes et al., 2004]. In addition, I will discuss the nosology of the Moebius sequence and its associated syndromes and propose two candidate genes as the potential basis of the CFZ syndrome. The overall significance of this disorder and its place in our understanding of the Moebius and Robin sequences will be addressed briefly. I have had the privilege of following the two original siblings with the CFZ syndrome since 1980. The original Patient 1 (Fig. 1) recently completed a 2 year mission for the Church of Jesus Christ of Latter Day Saints. Despite challenges in school related to hearing and verbal expression, the patient completed high school and is now enrolled in college. His medical problems since the original report have included longstanding GI disturbances related to biopsy-proven villous atrophy. Like his older sister, he has had significant scoliosis requiring surgery and placement of rods. At the time of this surgery at age 16 years, we performed a repeat muscle biopsy that again showed nonspecific findings and, in particular, there were no alterations of mitochondria. He continues to be in relatively good health and has not had the significant restrictive lung disease and pulmonary insufficiency that his older sister experienced. The original Patient 2, the older sib of Patient 1, is shown in updated photographs in Figures 2 and 3. She also had normal intelligence and finished junior college. She, however, did have significant restrictive lung disease and died of pneumonia at age 37. She also had rods placed for her scoliosis as a teenager. The physical examination of both patients was updated in 1996 when these most recent photographs were taken (Figs. 1 and 2). Note the consistent facial diplegia, but also the characteristic nasal configuration. Both had microcephaly and short stature (<2nd centile). Examination of hands showed absence of distal flexion creases on the 4th and 5th digits and brachydactyly. Both individuals had marked decrease in muscle mass and normal, but decreased, deep tendon reflexes.