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 the reproductive partner of an affected individual also has STAC3 disorder or is a carrier, 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 (or likely pathogenic) variants in STAC3 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic STAC3 variants of uncertain significance (or of one known STAC3 pathogenic variant and one STAC3 variant of uncertain significance) does not establish or rule out the diagnosis.

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).

Option 2

When the diagnosis of STAC3 disorder is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. Note: To date no large STAC3 deletions or duplications have been identified in individuals reported with molecularly confirmed STAC3 disorder.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in STAC3 Disorder

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.

Table 2.

Clinical Findings in Individuals with STAC3 Disorder

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.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with STAC3 Disorder

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).

Table 5.

Treatment of Manifestations in Individuals with STAC3 Disorder

Surveillance

Table 6.

Recommended Surveillance for Individuals with STAC3 Disorder

Agents/Circumstances to Avoid

Persons with STAC3 disorder are at increased risk for malignant hyperthermia (MH) crises when exposed to certain agents used with general anesthesia – most commonly volatile anesthetic gases (including halothane, isoflurane, and sevoflurane) and depolarizing muscle relaxants (e.g., succinylcholine and decamethonium). It is imperative that persons with STAC3 disorder discuss their diagnosis with anesthesiologists and treating physicians prior to surgical procedures to ensure that appropriate anesthetics are chosen to reduce the risk of MH.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

STAC3 disorder is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one STAC3 pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• 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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless the reproductive partner of an affected individual also has STAC3 disorder or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in STAC3.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a STAC3 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the STAC3 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the STAC3 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Author Notes

Bryn Webb is a clinical geneticist, clinical molecular geneticist, and pediatrician specializing in genetic studies of rare congenital anomalies. She is co-director of the Cleft and Craniofacial Program at the Icahn School of Medicine at Mount Sinai. Webb Laboratory

Irini Manoli is a clinical and biochemical geneticist and pediatrician with a focus on clinical and translational research in rare genetic syndromes and inborn errors of metabolism. She works at the National Human Genome Research Institute of the National Institutes of Health.

Ethylin Wang Jabs is a medical geneticist with a clinical focus in dysmorphology and a clinical, translational, and basic research interest in developmental genetics, in particular craniofacial disorders. Ethylin Wang Jabs Laboratory

Revision History

• 20 June 2019 (bp) Review posted live
• 13 August 2018 (bw) Original submission

Literature Cited

• Alrohaif H, Töpf A, Evangelista T, Lek M, McArthur D, Lochmüller H. Whole-exome sequencing identifies mutations in MYMK in a mild form of Carey-Fineman-Ziter syndrome. Neurol Genet. 2018;4:e226. [PMC free article: PMC5858950] [PubMed: 29560417]

• Bailey AG, Bloch EC. Malignant hyperthermia in a three-month-old American Indian infant. Anesth Analg. 1987;66:1043–5. [PubMed: 3631569]

• Carey JC, Fineman RM, Ziter FA. The Robin sequence as a consequence of malformation, dysplasia, and neuromuscular syndromes. J Pediatr. 1982;101:858–64. [PubMed: 7131178]

• D'Arcy CE, Bjorksten A, Yiu EM, Bankier A, Gillies R, McLean CA, Shield LK, Ryan MM. King-Denborough syndrome caused by a novel mutation in the ryanodine receptor gene. Neurology. 2008;71:776–7. [PubMed: 18765655]

• Di Gioia SA, Connors S, Matsunami N, Cannavino J, Rose MF, Gilette NM, Artoni P, de Macena Sobreira NL, Chan WM, Webb BD, Robson CD, Cheng L, Van Ryzin C, Ramirez-Martinez A, Mohassel P, Leppert M, Scholand MB, Grunseich C, Ferreira CR, Hartman T, Hayes IM, Morgan T, Markie DM, Fagiolini M, Swift A, Chines PS, Speck-Martins CE, Collins FS, Jabs EW, Bönnemann CG, Olson EN, Carey JC, Robertson SP, Manoli I, Engle EC, et al. A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome. Nat Commun. 2017;8:16077. [PMC free article: PMC5504296] [PubMed: 28681861]

• Dowling JJ, Lillis S, Amburgey K, Zhou H, Al-Sarraj S, Buk SJ, Wraige E, Chow G, Abbs S, Leber S, Lachlan K, Baralle D, Taylor A, Sewry C, Muntoni F, Jungbluth H. King-Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene. Neuromuscul Disord. 2011;21:420–7. [PubMed: 21514828]

• Grzybowski M, Schänzer A, Pepler A, Heller C, Neubauer BA, Hahn A. Novel STAC3 mutations in the first non-Amerindian patient with Native American myopathy. Neuropediatrics. 2017;48:451–5. [PubMed: 28411587]

• Hall J. Athrogryposis. In: Cassidy SB, Allanson, JE, eds. Management of Genetic Syndromes. 3rd ed. Hoboken, NJ: Wiley; 2010: 81-96.

• Hedberg-Oldfors C, Lindberg C, Oldfors A. Carey-Fineman-Ziter syndrome with mutations in the myomaker gene and muscle fiber hypertrophy. Neurol Genet. 2018;4:e254. [PMC free article: PMC6066360] [PubMed: 30065953]

• Horstick EJ, Linsley JW, Dowling JJ, Hauser MA, McDonald KK, Ashley-Koch A, Saint-Amant L, Satish A, Cui WW, Zhou W, Sprague SM, Stamm DS, Powell CM, Speer MC, Franzini-Armstrong C, Hirata H, Kuwada JY. Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy. Nat Commun. 2013;4:1952. [PMC free article: PMC4056023] [PubMed: 23736855]

• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]

• King JO, Denborough MA. Anesthetic-induced malignant hyperpyrexia in children. J Pediatr. 1973;83:37–40. [PubMed: 4149045]

• Miller G. Neurological disorders. The mystery of the missing smile. Science. 2007;316:826–7. [PubMed: 17495152]

• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]

• Stamm DS, Aylsworth AS, Stajich JM, Kahler SG, Thorne LB, Speer MC, Powell CM. Native American myopathy: congenital myopathy with cleft palate, skeletal anomalies, and susceptibility to malignant hyperthermia. Am J Med Genet A. 2008a;146A:1832–41. [PubMed: 18553514]

• Stamm DS, Powell CM, Stajich JM, Zismann VL, Stephan DA, Chesnut B, Aylsworth AS, Kahler SG, Deak KL, Gilbert JR, Speer MC. Novel congenital myopathy locus identified in Native American Indians at 12q13.13-14.1. Neurology. 2008b;71:1764–9. [PubMed: 18843099]

• Stewart CR, Kahler SG, Gilchrist JM. Congenital myopathy with cleft palate and increased susceptibility to malignant hyperthermia: King syndrome? Pediatr Neurol. 1988;4:371–4. [PubMed: 3245876]

• Telegrafi A, Webb BD, Robbins SM, Speck-Martins CE, FitzPatrick D, Fleming L, Redett R, Dufke A, Houge G, van Harssel JJT, Verloes A, Robles A, Manoli I, Engle EC, Jabs EW, Valle D, Carey J, Hoover-Fong JE, Sobreira NLM, et al. Identification of STAC3 variants in non-Native American families with overlapping features of Carey-Fineman-Ziter syndrome and Moebius syndrome. Am J Med Genet A. 2017;173:2763–71. [PMC free article: PMC5843189] [PubMed: 28777491]

• Tomas-Roca L, Tsaalbi-Shtylik A, Jansen JG, Singh MK, Epstein JA, Altunoglu U, Verzijl H, Soria L, van Beusekom E, Roscioli T, Iqbal Z, Gilissen C, Hoischen A, de Brouwer AP, Erasmus C, Schubert D, Brunner H, Pérez Aytés A, Marin F, Aroca P, Kayserili H, Carta A, de Wind N, Padberg GW, van Bokhoven H. De novo mutations in PLXND1 and REV3L cause Möbius syndrome. Nat Commun. 2015;6:7199. [PMC free article: PMC4648025] [PubMed: 26068067]

• Wang CH, Dowling JJ, North K, Schroth MK, Sejersen T, Shapiro F, Bellini J, Weiss H, Guillet M, Amburgey K, Apkon S, Bertini E, Bonnemann C, Clarke N, Connolly AM, Estournet-Mathiaud B, Fitzgerald D, Florence JM, Gee R, Gurgel-Giannetti J, Glanzman AM, Hofmeister B, Jungbluth H, Koumbourlis AC, Laing NG, Main M, Morrison LA, Munns C, Rose K, Schuler PM, Sewry C, Storhaug K, Vainzof M, Yuan N. Consensus statement on standard of care for congenital myopathies. J Child Neurol. 2012;27:363–82. [PMC free article: PMC5234865] [PubMed: 22431881]

• Zaharieva IT, Sarkozy A, Munot P, Manzur A, O'Grady G, Rendu J, Malfatti E, Amthor H, Servais L, Urtizberea JA, Neto OA, Zanoteli E, Donkervoort S, Taylor J, Dixon J, Poke G, Foley AR, Holmes C, Williams G, Holder M, Yum S, Medne L, Quijano-Roy S, Romero NB, Fauré J, Feng L, Bastaki L, Davis MR, Phadke R, Sewry CA, Bönnemann CG, Jungbluth H, Bachmann C, Treves S, Muntoni F. STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility. Hum Mutat. 2018;39:1980–94. [PubMed: 30168660]