Klippel-Feil Syndrome 4, Autosomal Recessive, With Nemaline Myopathy And Facial Dysmorphism

A number sign (#) is used with this entry because of evidence that a form of Klippel-Feil syndrome associated with nemaline myopathy and facial dysmorphism (KFS4) is caused by homozygous mutation in the MYO18B gene (607295) on chromosome 22q12.

Description

Klippel-Feil syndrome-4 with nemaline myopathy and facial dysmorphism is an autosomal recessive disorder characterized mainly by severe hypotonia apparent from infancy. Klippel-Feil anomaly is primarily defined by fusion of the cervical spine, with associated low posterior hairline and limited neck mobility being observed in about half of patients (summary by Alazami et al., 2015).

For a general description and a discussion of genetic heterogeneity of Klippel-Feil syndrome, see KFS1 (118100).

Clinical Features

Alazami et al. (2015) studied an unrelated Saudi boy and girl with Klippel-Feil syndrome who also exhibited myopathy, mild short stature, microcephaly, and distinctive facies. The 14-year-old boy, born of consanguineous parents, presented at 16 months of age with motor delay and short stature, at which time microcephaly was also noted. He was floppy in infancy, sat at age 1 year, and walked at 2 years. Examination at 12.5 years of age revealed central and peripheral hypotonia and +4 muscle power (reduced resistance). Since childhood, his gait had been clumsy with frequent falls. Brain MRI was normal, but electromyography was suggestive of myopathy. Muscle biopsy showed mild to focally moderate variation in myofiber size, with atrophic and hypertrophic fibers. Ultrastructural examination showed diffuse myofibrillar disarray with prominent loss or disruption of myosin filaments. Focally, some fibers showed subsarcolemmal accumulation of globular deposits of electron-dense material, reminiscent of nemaline rods, and there was loss of normal banding due to loss of thick myosin filaments. The 12-year-old Saudi girl, born of first-cousin parents, had poor motor function in infancy but attained standing and walking at appropriate ages. Mild muscle weakness was present on examination, but no muscle biopsy was done. Both patients exhibited dysmorphic features including short webbed neck, low posterior hairline, bilateral ptosis, and bulbous nose with hypoplastic alae nasi. X-ray revealed fusion of the cervical spine in both, and the girl also had dextroconvex thoracolumbar scoliosis and bilateral acetabular dysplasia.

Clinical Variability

Malfatti et al. (2015) reported a female infant, born of consanguineous Portuguese parents, with severe nemaline myopathy and fatal cardiomyopathy. Prenatal ultrasound at 22 weeks' gestation showed reduced left ventricle and aortic valve growth. After birth, the infant showed hypotonia with reduced spontaneous movements, tendon contractures, and poor feeding. She also had dysmorphic features, including transversal enlargement of the skull, small and horizontal palpebral fissures, high-arched palate, low-set ears, pectus excavatum, large and low implanted thumbs, and clinodactyly. Cardiac abnormalities included hypertrophic left cavities, interatrial communication, and pulmonary hypertension. She had hemodynamic instability and poor respiratory status, resulting in death at age 4.5 months. Muscle biopsy showed marked fiber size variability and atrophic fibers with rare centralized nuclei. Small nemaline bodies were found in about 40% of fibers. Postmortem examination was not performed. Malfatti et al. (2015) noted that Klippel-Feil syndrome was diagnosed during childhood in the patients reported by Alazami et al. (2015), whereas their Portuguese patient died at 4.5 months of age; radiographs were not performed on the patient reported by Malfatti et al. (2015). Malfatti et al. (2015) suggested that the cardiomyopathy observed in this patient may be variant-specific, since a truncated MYO18B protein was detected in muscle samples from the infant; this may have caused a toxic effect as opposed to complete loss of MYO18B that was found in the patients reported by Alazami et al. (2015). Mutations in major nemaline myopathy genes had been excluded in the patient reported by Malfatti et al. (2015); she was 1 of 34 patients with mild nemaline myopathy and 17 with severe nemaline myopathy who underwent exome sequencing.

Inheritance

The transmission pattern of KFS4 in the families reported by Alazami et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a boy and a girl from unrelated consanguineous Saudi families with Klippel-Feil syndrome and myopathy, who were negative for mutation in Noonan syndrome (see 163950)-associated genes, Alazami et al. (2015) performed homozygosity mapping and found a single locus of identical haplotype spanning chr22:25641025-26665674 (GRCh37). Whole-exome sequencing identified homozygosity for a nonsense mutation in the MYO18B gene (S2302X; 607295.0001) that segregated with disease in both families. Analysis of the exome data for variants in 10 genes linked to nemaline myopathy did not reveal any other variants of interest.

Malfatti et al. (2015) reported a female infant, born of consanguineous Portuguese parents, with nemaline myopathy, dysmorphic facial features, and fatal cardiomyopathy associated with a homozygous truncating variant in the MYO18B gene (E2166X; 607295.0002). The infant died at age 4.5 months; Klippel-Feil anomaly was not observed, but radiographs were not performed. The variant was found by exome sequencing and segregated with the disorder in the family.