Clinical characteristics.

EXOC6B-related spondyloepimetaphyseal dysplasia with joint laxity (EXOC6B-SEMD-JL) is characterized by multiple joint dislocations, joint laxity, genu valgum, short stature, and skeletal dysplasia. Joint dislocations of the hips and knees are present at birth in all individuals reported to date. Dislocations can also occur at the elbows, wrists, ankles, and patellae. Growth deficiency develops postnatally. Short neck, scoliosis, kyphosis, and hyperlordosis are reported. The fingers are slender (leptodactyly). Radiographic manifestations include delayed carpal/tarsal bone ossification, gracile short tubular bones, metaphyseal and epiphyseal dysplasia, slender ribs, and spondylar dysplasia (irregular vertebral end plates, narrow interpedicular distance of the lumbar spine, and modest platyspondyly) with age-dependent evolution.

Diagnosis/testing.

The diagnosis of EXOC6B-SEMD-JL is established in a proband with characteristic clinical and radiographic features and biallelic pathogenic variants in EXOC6B identified by molecular genetic testing.

Management.

Treatment of manifestations: Surgical interventions for joint dislocations to improve mobility; wheelchair and walking aids as needed; physical therapy and orthopedic interventions as needed for scoliosis and kyphosis.

Surveillance: Annual assessment of joints by a rheumatologist or orthopedic surgeon; annual clinical and radiographic assessment for scoliosis and/or kyphosis.

Genetic counseling.

EXOC6B-SEMD-JL is inherited in autosomal recessive manner. If both parents are known to be heterozygous for an EXOC6B pathogenic variant, each sib of an affected individual has at conception 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. Once the EXOC6B pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.

Suggestive Findings

EXOC6B-related spondyloepimetaphyseal dysplasia with joint laxity (EXOC6B-SEMD-JL) should be suspected in probands with the following clinical, imaging, and family history findings.

Clinical findings

• Congenital dislocations of the hips and knees; may also affect elbows, wrists, and/or ankles
• Joint laxity affecting all joints and most evident at the wrists and fingers
• Postnatal-onset short stature
• Slender fingers (leptodactyly)
• Genu valgum
• Pes planus

Imaging findings

• Delayed carpal/tarsal bone ossification
• Slender/gracile short tubular bones (leptodactyly)
• Metaphyseal dysplasia. Irregular metaphyses with short sclerotic striations at the distal radius, distal ulna, distal femora, and proximal tibia
• Epiphyseal dysplasia (generalized). Carpal and tarsal bones are usually smaller and irregular; epiphyses of the long bones appear flat and small.
• Slender ribs
• Irregular vertebral end plates and modest platyspondyly (Platyspondyly is seen only in younger individuals and becomes less conspicuous with age; even tall vertebral bodies are seen in older affected individuals.)
• Narrow interpedicular distance of the lumbar vertebrae
• Thoracolumbar scoliosis, kyphosis, and/or hyperlordosis

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of EXOC6B-SEMD-JL is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in EXOC6B 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 EXOC6B variants of uncertain significance (or of one known EXOC6B pathogenic variant and one EXOC6B 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, 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. 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 EXOC6B-SEMD-JL has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

EXOC6B-related spondyloepimetaphyseal dysplasia with joint laxity (EXOC6B-SEMD-JL) is characterized by multiple joint dislocations, joint laxity, short stature, scoliosis, kyphosis, and skeletal dysplasia (delayed carpal/tarsal bone ossification, leptodactyly, slender ribs, and vertebral anomalies). To date, seven individuals from five unrelated families have been identified with biallelic pathogenic variants in EXOC6B [Girisha et al 2016; Campos-Xavier et al 2018; Simsek-Kiper et al 2022; Authors, personal communication]. Most individuals have normal intellect, though developmental delay and hydrocephalus were noted in one individual [Simsek-Kiper et al 2022]. The following description of the phenotypic features associated with this condition is based on these reports.

Joint manifestations. All reported individuals have joint dislocations at birth; hip and knee joints are affected in all individuals. Other joints that are often dislocated include elbows, wrists, and ankles. The patella can also be dislocated. All affected individuals demonstrate joint laxity, most evident at the wrists and fingers.

Short stature. Growth deficiency develops postnatally; spinal deformities and dislocation of the hip joints may contribute to reduced height.

Hands and feet. Slender fingers are reported in all individuals. Pes planus may be present. Radiographs show slender, short tubular bones in all individuals. The wrists and ankle joints show small, irregular, and disorganized carpal bones with abnormal/delayed carpal bone ossification.

Spine manifestations include scoliosis (6 individuals), kyphosis (4 individuals), and hyperlordosis (2 individuals). Short neck was reported in four individuals. Radiographs show irregular vertebral end plates, narrow interpedicular distance of the lumbar vertebrae, and platyspondyly that is evident only in younger individuals.

Facial features. There are no specific characteristic facial features. However, broad forehead (2 individuals), small chin (2 individuals), and triangular face have been noted in some individuals.

Other

• Soft skin
• Developmental delay (1 individual) [Evers et al 2014]
• Hydrocephalus (1 individual)

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Prevalence

Seven individuals from five unrelated families with EXOC6B-SEMD-JL have been reported to date.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with EXOC6B-SEMD-JL, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for EXOC6B-SEMD-JL. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

Activities with a high impact on joints that may increase the risk of dislocation should be avoided.

Obesity should be avoided to reduce the negative impact on joints.

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

EXOC6B-related spondyloepimetaphyseal dysplasia with joint laxity (EXOC6B-SEMD-JL) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an EXOC6B pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an EXOC6B pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an EXOC6B pathogenic variant, each sib of an affected individual has at conception 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 an affected individual's reproductive partner also has EXOC6B-SEMD-JL or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in EXOC6B.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an EXOC6B pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the EXOC6B pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the EXOC6B 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.

Molecular Pathogenesis

EXOC6B encodes exocyst complex component 6B, which functions as a component of the exocyst complex. The exocyst complex facilitates transport and tethering of secretory vesicles from the Golgi complex to the plasma membrane prior to fusion during exocytosis [Mei & Guo 2018].

Mechanism of disease causation. Loss of function; however, the exact mechanism of disease causation is yet to be elucidated.

Author Notes

Dr Katta Mohan Girisha is interested in clinical care and research in individuals with skeletal dysplasia. He is also keen to identify more individuals with EXOC6B-related spondyloepimetaphyseal dysplasia with joint laxity (EXOC6B-SEMD-JL) to better characterize the phenotype and genotype.

Dr Katta Mohan Girisha ([email protected]) and Dr Gandham SriLakshmi Bhavani ([email protected]) are actively involved in clinical research regarding EXOC6B-SEMD-JL. They would be happy to communicate with persons who have any questions regarding diagnosis of EXOC6B-SEMD-JL or other considerations.

Contact Dr Katta Mohan Girisha and Dr Gandham SriLakshmi Bhavani to inquire about review of EXOC6B variants of uncertain significance.

The authors of this chapter serve as moderators for the EXOC6B entry in the Human Disease Genes website series.

Acknowledgments

We acknowledge the financial support provided by CSIR-UGC NET Junior Research Fellowship awarded by Human Resource Development Group under Council of Scientific and Industrial Research: 08/028(0002)/2019-EMR-I (to Swati Singh).

Revision History

• 25 May 2023 (sw) Review posted live
• 20 March 2023 (kmg) Original submission

Literature Cited

• Campos-Xavier B, Rogers RC, Niel-Bütschi F, Ferreira C, Unger S, Spranger J, Superti-Furga A. Confirmation of spondylo-epi-metaphyseal dysplasia with joint laxity, EXOC6B type. Am J Med Genet A. 2018;176:2934–5. [PubMed: 30284759]
• Evers C, Maas B, Koch KA, Jauch A, Janssen JW, Sutter C, Parker MJ, Hinderhofer K, Moog U. Mosaic deletion of EXOC6B: further evidence for an important role of the exocyst complex in the pathogenesis of intellectual disability. Am J Med Genet A. 2014;164A:3088–94. [PubMed: 25256811]
• Girisha KM, Kortüm F, Shah H, Alawi M, Dalal A, Bhavani GS, Kutsche K. A novel multiple joint dislocation syndrome associated with a homozygous nonsense variant in the EXOC6B gene. Eur J Hum Genet. 2016;24:1206–10. [PMC free article: PMC4970677] [PubMed: 26669664]
• Grosch M, Grüner B, Spranger S, Stütz AM, Rausch T, Korbel JO, Seelow D, Nürnberg P, Sticht H, Lausch E, Zabel B, Winterpacht A, Tagariello A. Identification of a ninein (NIN) mutation in a family with spondyloepimetaphyseal dysplasia with joint laxity (leptodactylic type)-like phenotype. Matrix Biol. 2013;32:387–92. [PubMed: 23665482]
• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]
• Mei K, Guo W. The exocyst complex. Curr Biol. 2018;28:R922–25. [PubMed: 30205058]
• 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]
• Simsek-Kiper PO, Jacob P, Upadhyai P, Taşkıran ZE, Guleria VS, Karaosmanoglu B, Imren G, Gocmen R, Bhavani GS, Kausthubham N, Shah H, Utine GE, Boduroglu K, Girisha KM. Biallelic loss-of-function variants in EXOC6B are associated with impaired primary ciliogenesis and cause spondylo-epi-metaphyseal dysplasia with joint laxity type 3. Hum Mutat. 2022;43:2116–29. [PMC free article: PMC7615863] [PubMed: 36150098]
• Unger S, Ferreira CR, Mortier GR, Ali H, Bertola DR, Calder A, Cohn DH, Cormier-Daire V, Girisha KM, Hall C, Krakow D, Makitie O, Mundlos S, Nishimura G, Robertson SP, Savarirayan R, Sillence D, Simon M, Sutton VR, Warman ML, Superti-Furga A. Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A. 2023;191:1164–209. [PMC free article: PMC10081954] [PubMed: 36779427]