Carey-Fineman-Ziter Syndrome

A number sign (#) is used with this entry because of evidence that Carey-Fineman-Ziter syndrome (CFZS) is caused by homozygous or compound heterozygous mutation in the MYMK gene (615345) on chromosome 9q34.

Description

Carey-Fineman-Ziter syndrome (CFZS) is a multisystem congenital disorder characterized by hypotonia, Moebius sequence (bilateral congenital facial palsy with impairment of ocular abduction), Pierre Robin complex (micrognathia, glossoptosis, and high-arched or cleft palate), delayed motor milestones, and failure to thrive. More variable features include dysmorphic facial features, brain abnormalities, and intellectual disability. It has been postulated that many clinical features in CFZS may be secondary effects of muscle weakness during development or brainstem anomalies (summary by Pasetti et al., 2016).

Di Gioia et al. (2017) determined that CFZS represents a slowly progressive congenital myopathy resulting from a defect in myoblast fusion.

Clinical Features

Carey et al. (1982) described a brother and sister with hypotonia, Moebius sequence (see 157900), Pierre Robin sequence, unusual face, and growth delay. The sibs required gavage feeding for a number of months. Weight and height remained persistently below normal but both sibs had normal intelligence. Carey et al. (1982) proposed that VIIth nerve palsy may give rise to altered mandibular movement with subsequent hypoplasia of the mandible and Robin sequence. In a follow-up, Carey (2004) reported that both sibs underwent rod placement for severe scoliosis during adolescence. The sister developed restrictive lung disease and died of pneumonia at age 37 years; the younger brother had a longstanding gastrointestinal disturbance with biopsy-proven villous atrophy.

Di Gioia et al. (2017) provided follow-up of the sibs with CFZS originally reported by Carey et al. (1982). Both had nocturnal hypoventilation and developed restrictive pulmonary disease and pulmonary hypertension after 35 years of age; 1 died at age 37. However, they had a family history of idiopathic pulmonary hypertension, so it was unclear if pulmonary involvement later in life is a feature of the disorder.

Schimke et al. (1993) reported an isolated case, which they suggested confirmed the validity of the Carey-Fineman-Ziter syndrome.

Ryan et al. (1999) described an affected brother and sister with CFZ syndrome. Features were craniofacial anomalies, micrognathia, Moebius sequence, generalized myopathy, relative macrocephaly, and developmental delay. Only 4 children, a sib pair and 2 sporadic cases, had previously been reported. Ryan et al. (1999) suggested that their report confirmed autosomal recessive inheritance and identified scoliosis, talipes equinovarus, and a nonspecific primary myopathy as important manifestations of the disorder.

Maheshwari et al. (2004) described a male infant with typical features of CFZ syndrome, except for a normal head circumference, who was born to nonconsanguineous parents. He had several features not previously reported in CFZ syndrome: unilateral hydronephrosis, glanular hypospadias, myopathy associated with type 1 fiber atrophy, and a small pons and brainstem with enlarged pre-pontine and pontocerebellar cisterns.

Dufke et al. (2004) described a patient with CFZ syndrome born to nonconsanguineous parents after a pregnancy complicated by polyhydramnios. In addition to typical features of CFZ syndrome, he had unilateral absence of the pectoralis major muscle with an ulnar deviation of the hand (Poland sequence), laryngostenosis, and unexplained intermittent arterial hypertension with facial flushing and sweating. Although relatively macrocephalic at birth, head circumference had decreased to less than the 25th percentile by 28 months of age. Cranial MRI at age 19 months detected enlarged ventricles with reduced white matter in the globus pallidus, hypothalamus, and right thalamus.

Verloes et al. (2004) summarized features of 9 previously unreported patients with possible CFZ syndrome. All 9 had Moebius sequence, hypotonia, and micrognathia, and 6 had Pierre Robin complex. Neuropathologic examination in 2 patients showed a combination of neuronal heterotopias and small foci of necrosis with microcalcifications. Verloes et al. (2004) also reviewed the findings of previously reported patients with CFZ syndrome, including the patients reported by Ryan et al. (1999). Verloes et al. (2004) suggested that their 9 patients and most patients reported as having CFZ syndrome have a distinct clinical variant of Moebius sequence, which they designated Robin-Moebius phenotype, with extensive brainstem involvement, Robin complex, hypotonia without a specific muscle disorder, clubfeet, and variable acral anomalies. The authors considered the Robin-Moebius phenotype to include a higher risk of mental disability and a higher recurrence risk than 'common' Moebius sequence, although not as high as 25%, and suggested that the original CFZ syndrome family could represent a private syndrome fitting within the Robin-Moebius spectrum.

Carey (2004) disagreed that the sibs described by Ryan et al. (1999) had CFZ syndrome, and although in agreement with Verloes et al. (2004) that there was a spectrum of Moebius and Robin sequence association, he considered that the original family had a discrete entity because facial features were distinct from other reported cases.

Pasetti et al. (2016) reported a 21-month-old Italian girl, born of unrelated parents, with a complex phenotype consistent with CFZS. She had severe respiratory distress apparent at birth and was in intensive care for the first 4 months of life. She had plagiocephaly, flat nasal root, epicanthus, ptosis, and Pierre Robin complex with retrognathia, cleft palate, and glossoptosis. She had severe hypotonia, facial palsy, oculomotor palsy, absent swallowing, absent speech, and laryngostenosis. Brain imaging showed enlarged ventricles, subependymal heterotopia, and thinning of the white matter. Other features included long tapered fingers, talipes equinovarus, and atrial septal defect. Inability to suck or swallow necessitated gastrostomy placement. The patient also had reduced mouth opening with no proper mandibular movements resulting from abnormal development of temporomandibular joint (TMJ) articular structures, with hypoplasia of joint capsule and ligaments. The condition was reminiscent of TMJ ankylosis, although radiographs excluded true TMJ ankylosis. Pasetti et al. (2016) concluded that the abnormal TMJ function was related to muscular weakness and neurologic dysfunction. Whole-exome sequencing failed to identify a molecular basis for the disorder.

Di Gioia et al. (2017) reported 8 individuals from 5 unrelated families with CFZS, including one of the original sibs reported by Carey et al. (1982). All patients had congenital bilateral facial weakness, upturned and/or broad nasal tip, micro- or retrognathia, muscle hypoplasia with mild axial and appendicular weakness, and delayed motor milestones. However, all patients achieved independent ambulation and did not show significant progression of appendicular muscle weakness. None had abducens nerve palsy, but there were mild eye movement limitations in extreme gaze positions. Cognition was normal. Other common but more variable findings included congenital sometimes distal contractures, poor growth and feeding problems sometimes requiring a feeding tube, ptosis, high-arched or cleft palate, thin neck, pectoralis hypoplasia, hypoglossia, and scoliosis. The only 2 male patients had cryptorchidism. Electrophysiologic studies were consistent with myopathic, not neurogenic, changes, and several patients had increased serum creatine kinase. Brain imaging was normal. Muscle biopsy of 1 patient at age 15 years showed congenital fiber-type disproportion (CFTD) with increased numbers of variably sized type I fibers, many of which were atrophic or hypotrophic, and hypertrophy of type II fibers. Dystrophic features were not present in the muscle biopsy, and mitochondria were normal. Muscle imaging showed atrophy and fatty replacement. The findings were consistent with a congenital myopathy.

Alrohaif et al. (2018) reported a 69-year-old British man with mild asymmetrical weakness, with greater proximal than distal involvement. He also had marked facial weakness, lagophthalmos, minimal limitation in horizontal gaze, dysphagia, and chronic gastrointestinal symptoms consisting of alternating diarrhea and constipation. He had mild dysmorphic features, including micrognathia, high-arched palate, and a prominent broad nasal tip. He also had spinal rigidity, scoliosis, bilateral pectoralis hypoplasia, and cryptorchidism. He developed epilepsy, sensorineural hearing loss, unilateral cataract, and glaucoma. He remained ambulatory. His creatinine kinase levels were mildly elevated, and EMG showed a chronic, mildly active necrotizing myopathy. The onset appeared to have been in the late teens and progression was not remarkable.

Inheritance

The transmission pattern of CFZS in the families reported by Di Gioia et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 8 patients from 5 unrelated families with CFZS, Di Gioia et al. (2017) identified homozygous or compound heterozygous mutations in the MYMK gene (615345.0001-615345.0005). Seven patients shared a missense mutation on 1 allele (P91T; 615345.0001), and haplotype analysis suggested a founder effect for that mutation. The mutations in the first 3 families were found by whole-exome sequencing and confirmed by Sanger sequencing; mutations in the 2 other families were found by sequencing the MYMK gene in over 300 additional probands with similar phenotypes. All mutations segregated with the disorder in the families. Western blot analysis of HeLa cells transfected with each of the mutations showed absence of the mutant proteins, suggesting protein instability and degradation and consistent with a loss of function. However, immunostaining, cellular expression studies, and rescue experiments in mutant zebrafish showed that 2 of the mutations (P91T, 615345.0001 and I154T, 615345.0005) were hypomorphic, showing some expression at the cell membrane and some residual ability to induce myoblast fusion. In contrast, the other 3 mutations (C185R, 615345.0002; G100S, 615345.0003; and c.2T-A, 615345.0004) formed cytoplasmic aggregates and had no fusogenic activity, consistent with being null alleles. Di Gioia et al. (2017) concluded that recessive mutations in MYMK cause CFZS through a combination of 1 hypomorphic and 1 null allele, or 2 hypomorphic alleles that reduce MYMK function and myoblast fusion below a threshold, but not to zero. The craniofacial abnormalities in CFZS patients likely reflect selective vulnerability of specific muscle groups to reduced levels of MYMK, as craniofacial muscles have specific developmental pathways and influence bone development. Mymk expression was not found in mouse sciatic nerve, thus excluding a neurogenic basis for the disorder. The findings enabled classification of CFZS as a congenital myopathy.

By whole-exome sequencing in a 69-year-old British man with CFZS, Alrohaif et al. (2018) identified compound heterozygosity for previously identified mutations in the MYMK gene (P91T, 615345.0001 and C185R, 613545.0002).

Animal Model

Millay et al. (2013) found that deletion of myomaker in mice was perinatal lethal. Hearts of full-term myomaker -/- embryos were beating, but the animals were paralyzed and kyphotic with flaccid limbs. In myomaker -/- muscle, expression of muscle-specific transcription factors and differentiation markers was normal, and muscle cell precursors were organized appropriately; however, myomaker -/- muscle failed to form multinucleated myofibers. In culture, myomaker -/- myoblasts lacked the ability to fuse, but they were able to fuse with wildtype mouse myoblasts and C2C12 cells, and with myomaker-expressing mouse fibroblasts.

Di Gioia et al. (2017) found that zebrafish mymk is exclusively expressed in multinucleated type II fast-twitch muscle fibers, where it plays a role in differentiation and fusion. This expression pattern is in contrast to human and mouse muscle, where Mymk localizes to both slow type I and fast type II fibers. Di Gioia et al. (2017) used CRISPR-Cas9 technology to create zebrafish mutants with a truncating mutation and showed that they lacked fast-twitch myoblast fusion and had variably-sized hypotrophic fibers with fatty infiltration in the muscle, as well as misplaced myonuclei. Mutant zebrafish were viable, likely due to preservation of slow-twitch fibers.

History

Carey (2004) noted that targeted disruption of the Hoxb1 gene (142968) in the mouse causes failure of formation of the motor nucleus of the VIIth cranial nerve in homozygous mice, and that mutation in the mouse Cacna1s gene (114208) causes a form of muscular dysgenesis characterized by cleft palate, myopathy, and congenital contracture. He suggested that the human homologs of both genes are candidate genes for CFZ syndrome.