Stac3 Disorder

Clinical characteristics.

STAC3 disorder is characterized by congenital myopathy, musculoskeletal involvement of the trunk and extremities, feeding difficulties, and delayed motor milestones. Most affected individuals have weakness with myopathic facies, scoliosis, kyphosis or kyphoscoliosis, and contractures. Other common findings are ptosis, abnormalities of the palate (including cleft palate), and short stature. Risk for malignant hyperthermia susceptibility and restrictive lung disease are increased. Intellect is typically normal. Originally described in individuals from the Lumbee Native American tribe (an admixture of Cheraw Indian, English, and African American ancestry) in the state of North Carolina and reported as Native American myopathy, STAC3 disorder has now been identified in numerous other populations worldwide.

Diagnosis/testing.

The diagnosis of STAC3 disorder is established in a proband with suggestive clinical findings and biallelic pathogenic variants in STAC3 identified by molecular genetic testing.

Management.

Treatment of manifestations: At present, no treatment halts or reverses the manifestations of STAC3 disorder. Treatment of musculoskeletal involvement is symptomatic and ideally provided by a multidisciplinary neuromuscular team to address the following:

• Occupational and physical therapy needs regarding range of motion and mobility
• Use of adaptive devices for mobility and activities of daily living
• Feeding difficulties
• Speech delays
• Scoliosis
• Respiratory insufficiency

Due to the medical comorbidities in STAC3 disorder, decisions regarding type and timing of cleft palate surgery should be determined by a multidisciplinary craniofacial team. Depending on the structure of the managing craniofacial team, interventions for ptosis may be undertaken by an ophthalmologist as part of team care, or as an insertion intervention.

Surveillance: Routine monitoring of growth, musculoskeletal complications (e.g., scoliosis and/or joint contractures), speech development, swallowing function, respiratory function, and educational needs.

Agents/circumstances to avoid: Anesthetic agents with a high risk of triggering malignant hyperthermia.

Genetic counseling.

STAC3 disorder is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Unless an individual with STAC3 disorder has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in STAC3. Once the STAC3 pathogenic variants have been identified in an affected family member, carrier testing of at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

STAC3 disorder (also known as Native American myopathy) should be suspected in individuals with the following clinical and laboratory findings.

Clinical findings

• Congenital myopathy
  • Congenital weakness
  • Myopathic facies, characterized by ptosis, inability to raise corners of mouth, and (in some individuals) hollowed-out cheeks from loss of facial musculature, which may cause an open-mouthed expressionless appearance with downturned corners of the mouth. Over time, the face often becomes long and narrow.
• Musculoskeletal anomalies
  • Congenital contractures ranging from talipes equinovarus (bilateral or unilateral) with or without other joint contractures to arthrogryposis (i.e., multiple contractures of the joints in more than one area of the body present at birth) [Hall 2010]
  • Scoliosis, kyphosis, or kyphoscoliosis
• Palatal anomalies including cleft palate
• Micrognathia
• Characteristic facial features. Myopathic facies, micrognathia, and palatal anomalies can be seen in a number of neuromuscular disorders of varying etiologies; the characteristics that best distinguish STAC3 disorder from other conditions include low-set and/or posteriorly rotated ears, short and/or downslanting palpebral fissures, and telecanthus [Stamm et al 2008a] (see Figure 2: A-I).
• Short stature
• Susceptibility to malignant hyperthermia

Laboratory findings. Creatine kinase baseline levels are most often normal [Stewart et al 1988].

Establishing the Diagnosis

The diagnosis of STAC3 disorder is established in a proband with clinical findings consistent with Suggestive Findings and biallelic pathogenic variants in STAC3 identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of STAC3 disorder is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of STAC3 disorder has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

STAC3 disorder is characterized by congenital myopathy and musculoskeletal involvement of the trunk and extremities. Most children have weakness with myopathic facies, progressive kyphoscoliosis, and contractures. Other common findings are palatal anomalies (including cleft palate) and short stature. Risks for malignant hyperthermia susceptibility and restrictive lung disease are increased. Intellect is typically normal.

Prior to knowledge of its genetic cause, STAC3 disorder was initially reported as Native American myopathy in an infant from the Lumbee tribe whose findings at birth included arthrogryposis with talipes equinovarus, cleft palate, and micrognathia; at age three months she developed malignant hyperthermia during halothane anesthesia for gastrostomy tube placement due to poor feeding [Bailey & Bloch 1987]. Subsequently 20 additional individuals of Lumbee descent with a clinical diagnosis of Native American myopathy were reported, six by Stewart et al [1988] and 14 by Stamm et al [2008a]. Additional variable findings included ptosis, congenital joint contractures, and scoliosis.

Following the identification of biallelic pathogenic variants in STAC3 in five individuals with Native American myopathy from five families of Lumbee descent by Horstick et al [2013], STAC3 disorder has been confirmed molecularly in another 23 individuals from 15 families of various ancestry: African (5 families), Middle Eastern (4), Puerto Rican (1), Turkish (1), Afro-Caribbean (1), Comoro Islands (1), South American (1), and mixed African and Afro-Caribbean (1) [Grzybowski et al 2017, Telegrafi et al 2017, Zaharieva et al 2018].

The findings of all individuals reported to date with molecularly confirmed STAC3 disorder and clinically diagnosed Native American myopathy are summarized in Table 2 and discussed in more detail in the text that follows the table.

Congenital myopathy. The congenital myopathy is slowly progressive with myopathic facies. Deep tendon reflexes in the upper and lower extremities are often decreased or absent. Strength is often decreased in facial, axial, and proximal limb muscles, and may be decreased in distal limb muscles. Examination of older affected individuals may reveal muscle wasting.

Motor delays are most often present by infancy or very early childhood. The maximum motor ability in 15 individuals old enough for evaluation was walking (11), short walk (2), running (1), and sitting independently (1) [Zaharieva et al 2018]. Some affected individuals may be wheelchair bound by adolescence.

Feeding problems. Poor feeding may be due to a combination of structural differences (e.g., cleft palate or high-arched palate, micrognathia) and functional differences (e.g., weak suck, impaired coordination of feeding, abnormal tongue movements, respiratory insufficiency). Descending aspiration may also contribute to feeding and respiratory difficulties. Children with micrognathia and cleft palate may be at increased risk for respiratory issues during feeding (see Management).

Ptosis refers to downward placement (i.e., drooping) of the upper eyelids. In children, ptosis that obstructs the pupil may result in vision impairment or amblyopia. Ptosis may also cause loss of peripheral vision and blurred vision. To maximize vision individuals with ptosis may assume a posture with head tilted backwards and chin pointed upwards.

Musculoskeletal. Congenital contractures can involve the fingers (camptodactyly), hands, wrists, elbows, hips, knees, or feet/ankles (talipes equinovarus). The severity and functional disability range from mild to severe and depend on the joint involved.

Joint laxity has been seen in individuals with or without contractures.

Spinal involvement, including scoliosis, kyphosis, or kyphoscoliosis, is often present by early childhood and is often progressive.

Short stature. Adult height is commonly below the third percentile. Birth length is most often normal.

Speech impairments. Speech development is typically abnormal and dysarthria is common. Factors that can contribute to speech issues in children with STAC3 disorder include the following (see also Management):

• Abnormal palatal formation, including cleft palate
• Abnormal tongue movement
• Compensatory misarticulation
• Velopharyngeal insufficiency
• Neurologic factors
• Atypical resonance
• Respiratory insufficiency
• Apraxia

Malignant hyperthermia (MH). All individuals with a reported history of MH survived. Of the cases in which details were provided, most individuals were treated by discontinuing the anesthetic and surgery, and administering dantrolene [Bailey & Bloch 1987, Stamm et al 2008a].

Although MH has been reported in a significant number of individuals, the true frequency of MH susceptibility is likely higher as not all reported individuals had prior surgery or had been exposed to an MH-provoking anesthetic.

Respiratory impairment. Respiratory insufficiency may present in early childhood, late childhood, or adulthood [Stamm et al 2008a, Telegrafi et al 2017, Zaharieva et al 2018].

Other. The majority of affected individuals have normal intelligence; mild intellectual disability is rare [Stewart et al 1988, Stamm et al 2008a].

Conductive hearing loss is common.

Facial hemangiomas may also be present.

Life expectancy. Thirty-six percent of individuals affected with STAC3 disorder died by age 18 years [Horstick et al 2013]. In a study of 14 affected individuals, three died during the first year of life, one from severe pulmonary hypoplasia and one from apnea secondary to enterococcal pneumonia [Stamm et al 2008a].

Muscle findings. Muscle biopsy reveals variable findings:

• Light microscopy. Small type I and II fibers in some individuals and fiber-type disproportion in others. Increased numbers of central nuclei may be seen.
• Electron microscopy. An increase in lipid droplets and/or subsarcolemmal mitochondrial accumulations

Electromyogram revealed normal results in some individuals and evidence of myopathy in others [Stewart et al 1988, Stamm et al 2008a].

Genotype-Phenotype Correlations

To date no genotype-phenotype correlations are known.

Prevalence

STAC3 disorder was originally identified in individuals of the Lumbee Native American tribe, which is recognized by the state of North Carolina and has approximately 60,000 enrolled members. The ancestry of Lumbee Native Americans is a mixture of Cheraw Indian, English, and African American [Stamm et al 2008b]. A founder pathogenic variant has been identified in this population (see Molecular Genetics). It is estimated that one in 5,000 Lumbee Native Americans has STAC3 disorder.

See Clinical Description for other populations in which STAC3 disorder has been observed.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with STAC3 disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

At present, no treatment halts or reverses the manifestations of STAC3 disorder; treatment involves reducing symptoms and preventing secondary complications (see Table 5).