Clinical characteristics.

MBTPS1-related spondyloepimetaphyseal dysplasia with elevated lysosomal enzymes (MBTPS1-SEMD) is characterized by postnatal-onset short stature, chest deformity (pectus carinatum or pectus excavatum), kyphosis and/or scoliosis, reduced bone density, inguinal hernia, protruding abdomen, cataracts, developmental delay, and dysmorphic facial features (prominent forehead, prominent cheekbones, retromicrognathia, wide mouth, and large, prominent ears). Additional features can include waddling or staggering gait, craniosynostosis, mild intellectual disability, and seizures. Imaging findings include diffuse osteopenia, copper-beaten appearance of the skull, dysplasia of multiple thoracolumbar vertebrae, long bones with small and irregular epiphyses and mildly enlarged and irregular metaphyses, hip dysplasia with small fragmented sclerotic femoral heads, and short metacarpals and metatarsals with small epiphyses. Increased concentration of multiple lysosomal hydrolase enzymes can be identified in plasma and dried blood spots.

Diagnosis/testing.

The diagnosis of MBTPS1-SEMD is established in a proband with characteristic clinical and radiographic findings, elevated lysosomal hydrolase enzymes in plasma or dried blood spots, and biallelic pathogenic variants in MBTPS1 identified by molecular genetic testing.

Management.

Treatment of manifestations: Management of kyphoscoliosis, scoliosis, and hip dysplasia per orthopedist; vitamin D and calcium for reduced bone density; treatment of craniosynostosis per craniofacial specialist; surgical repair per surgeon and/or gastroenterologist for hernia; surgical removal of cataract per ophthalmologist; physical therapy to maximize mobility and reduce the risk for later-onset orthopedic complications; developmental and educational support.

Surveillance: Annual growth assessment, orthopedic evaluation, ophthalmological evaluation, and assessment of developmental progress and educational needs; clinical assessment for hernia as needed.

Agents/circumstances to avoid: In children with significant kyphoscoliosis, sports that place stress on the spine (e.g., heavy lifting, weight-bearing exercises) should be avoided.

Pregnancy management: Although no pregnancies have been reported in individuals with MBTPS1-SEMD, pregnancy and delivery may be complicated in individuals with significant short stature and skeletal dysplasia; delivery by cesarean section may be necessary.

Genetic counseling.

MBTPS1-SEMD is inherited in autosomal recessive manner. If both parents are known to be heterozygous for an MBTPS1 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 MBTPS1 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

MBTPS1-related spondyloepimetaphyseal dysplasia with elevated lysosomal enzymes (MBTPS1-SEMD) should be suspected in probands with the following clinical, laboratory, and imaging findings.

Clinical findings (See Figures 1 and 2.)

Figure 1.

Craniofacial features of several children with MBTPS1-related spondyloepimetaphyseal dysplasia with elevated lysosomal enzymes. Characteristic features include prominent forehead, prominent cheekbones, retromicrognathia, wide mouth, and large, prominent (more...)

Figure 2.

Clinical features of several children with MBTPS1-related spondyloepimetaphyseal dysplasia with elevated lysosomal enzymes A. Affected child at age six years with kyphoscoliosis (black arrows point to the prominent spinous processes)

• Postnatal-onset short stature
• Kyphosis and/or scoliosis
• Inguinal hernia
• Protruding abdomen
• Cataracts (often congenital)
• Developmental delay (gross motor and/or speech)
• Dysmorphic facial features, including prominent forehead, prominent cheekbones, retromicrognathia, wide mouth, and large, prominent ears

Laboratory findings

• Increased concentration of multiple lysosomal hydrolase enzymes in plasma and dried blood spots including alpha-fucosidase, alpha-glucosidase, alpha-iduronidase, alpha-mannosidase, beta-glucuronidase, beta-hexosaminidase, and beta-mannosidase [Kondo et al 2018, Meyer et al 2020, Alotaibi et al 2022]
• Increased activity of lysosomal enzymes including alpha-N-acetylgalactosaminidase, alpha-N-acetylglucosaminidase, beta-glucuronidase, total beta-hexosaminidases, hexosaminidase A (MUGS substrate), and iduronate-2-sulfatase in plasma, but normal activity in leukocytes [Carvalho et al 2020]

Imaging findings [Kondo et al 2018, Carvalho et al 2020, Meyer et al 2020, Alotaibi et al 2022, Chen et al 2023, Yuan et al 2023] (See Figures 3, 4, 5, and 6.)

Figure 3.

Radiographs of a child with MBTPS1-related spondyloepimetaphyseal dysplasia with elevated lysosomal enzymes, age 37 months, with diffuse osteopenia; ovoid lumbar vertebral bodies; irregular aspect of cervical vertebral bodies, with mild reduction of vertebrae (more...)

Figure 4.

Radiographs of children with MBTPS1-related spondyloepimetaphyseal dysplasia with elevated lysosomal enzymes showing diffuse osteopenia and metaphyseal sclerosis A. Irregularities more pronounced in the femoral heads, coxa vara, right hip dislocation (more...)

Figure 5.

Skull and spine radiographs of child, age six years, with MBTPS1-related spondyloepimetaphyseal dysplasia with elevated lysosomal enzymes. Straightened physiologic curvature of the cervical, thoracic, and lumbar spine. Irregular morphology and reduced (more...)

Figure 6.

Radiographs and spine CT of child age 12 years with MBTPS1-related spondyloepimetaphyseal dysplasia with elevated lysosomal enzymes A, B, E, F. No obvious abnormalities in long bones or lateral skull radiograph

• Diffuse osteopenia
• Copper-beaten appearance of the skull
• Dysplasia of multiple thoracolumbar vertebrae: irregular cortex of the vertebrae (rough rather than smooth vertebral outline), end plate bone defects, ovoid lumbar vertebrae, and narrow intervertebral spaces [Carvalho et al 2020]
• Long bones with small and irregular epiphyses and mildly enlarged and irregular metaphyses; long bones may be short and bowed
• Significant hip dysplasia with small, fragmented sclerotic femoral heads
• Short metacarpals and metatarsals with small epiphyses [Carvalho et al 2020]

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 MBTPS1-SEMD is established in a proband with suggestive clinical and radiographic findings, elevated lysosomal hydrolase enzymes in plasma or dried blood spots, and biallelic pathogenic (or likely pathogenic) variants in MBTPS1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include any likely pathogenic variants. (2) Identification of biallelic MBTPS1 variants of uncertain significance (or of one known MBTPS1 pathogenic variant and one MBTPS1 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). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

MBTPS1-related spondyloepimetaphyseal dysplasia with elevated lysosomal enzymes (MBTPS1-SEMD) is characterized by postnatal-onset short stature, pectus deformity, kyphosis and/or scoliosis, hernia, protruding abdomen, cataract(s), developmental delay, and dysmorphic facial features, in combination with elevated lysosomal hydrolase enzyme levels in plasma. Additional features can include waddling or staggering gait, craniosynostosis, and seizures. To date six individuals with MBTPS1-SEMD from six families have been reported [Kondo et al 2018, Carvalho et al 2020, Meyer et al 2020, Alotaibi et al 2022, Chen et al 2023, Yuan et al 2023]. Three additional affected individuals are known to the authors. The features in Table 2 and the following description are based on published reports.

Growth deficiency. Postnatal-onset short stature was present in all reported individuals and was typically identified by age three years. Two individuals were treated with growth hormone therapy. One individual started treatment at age three years and discontinued after one year without improvement in growth velocity [Kondo et al 2018]. In a second individual with normal insulin-like growth factor 1 (IGF-1), recombinant intravenous growth hormone (rhGH) of 0.15-0.2 IU/kg per day was started at age three years; after three years of rhGH therapy, the height increased from 5.3 standard deviations (SD) below the mean (before treatment) to 3.96 SD below the mean (after three years of treatment) [Chen et al 2022]. The range of severity of growth deficiency following treatment with growth hormone was from 2.9 to 5.3 SD below the mean.

Musculoskeletal manifestations. Chest deformity including pectus carinatum, pectus excavatum, or unspecified sternal malformation was reported in all individuals. Kyphoscoliosis or scoliosis was present in all individuals. Reduced bone density was evident in all individuals. Anterolisthesis of L5 on S1 has been described in one individual [Kondo et al 2018].

Hip dislocation with coxa vara was reported in one individual [Alotaibi et al 2022]. Waddling or staggering gait was reported in two individuals [Alotaibi et al 2022, Yuan et al 2023].

Craniosynostosis was identified in two individuals [Carvalho et al 2020], including one individual originally reported by Kondo et al [2018] with craniosynostosis identified after images were reevaluated by the authors.

Short neck and rhizomelia were reported in one individual [Carvalho et al 2020]; brachydactyly, genu valgum, valgus tibial bowing, and pes cavus were reported in one individual [Alotaibi et al 2022]; pes valgus and prominent sandal grooves were reported in one individual [Meyer et al 2020] (see Figure 2). Hyperextended fingers were reported in one individual [Yuan et al 2023].

Hernia or protruding abdomen were reported in all individuals. Bilateral inguinal hernia was reported in two individuals [Kondo et al 2018] and unilateral inguinal hernia with protruding navel in one individual [Meyer et al 2020]. Three individuals had protruding abdomen [Carvalho et al 2020, Alotaibi et al 2022, Chen et al 2022].

Cataracts were common. Two individuals had congenital lamellar cataract, with surgical lens removed at age ten months [Carvalho et al 2020] and age 35 months [Chen et al 2022]. One individual had punctiform opacities of the lens identified at age 11 years, keratoconus that was treated at age 11 years, and anterior and posterior subcapsular cataract that was detected at age 18 years [Meyer et al 2020].

Developmental delays. Most individuals had gross motor delays. Three individuals started walking at age 15 months, 24 months, and 36 months [Carvalho et al 2020, Meyer et al 2020, Alotaibi et al 2022]. Three individuals had speech and language delay [Meyer et al 2020, Alotaibi et al 2022]; one of these children had first sounds at age 21 months and feeding problems with poor weight gain managed with gastrostomy tube feeding for several months [Meyer et al 2020]. One individual was reported to have expressive language delay, with first words spoken at age 26 months [Carvalho et al 2020].

Intelligence is normal in the majority of individuals. One individual was reported with below-average intelligence [Alotaibi et al 2022], and a second individual had mild intellectual disability with an IQ of 57 [Yuan et al 2023].

Dysmorphic features. Characteristic dysmorphic features were present in the majority of individuals, including prominent forehead, prominent cheekbones, retromicrognathia, wide mouth, and large, prominent ears (see Figure 1).

Other features

• Generalized seizure activity (1 individual) [Carvalho et al 2020]
• Accumulation of fat on the chest and abdomen (1 individual) [Yuan et al 2023]
• Epicanthal folds and high nasal bridge (1 individual) [Yuan et al 2023]

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Prevalence

The prevalence of this condition is unknown. To date, only six individuals from six families have been reported in literature. There are an additional three individuals known to the authors, including an affected fetus.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MBTPS1-SEMD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

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

In children with significant kyphoscoliosis, sports that place stress on the spine (e.g., heavy lifting, weight-bearing exercises) should be avoided.

Evaluation of Relatives at Risk

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

Pregnancy Management

No pregnancies have been reported in individuals with MBTPS-SEMD. Pregnancy and delivery may be complicated in individuals with significant short stature and skeletal dysplasia; delivery by cesarean section may be necessary.

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

MBTPS1-related spondyloepimetaphyseal dysplasia with elevated lysosomal enzymes (MBTPS1-SEMD) 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 MBTPS1 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an MBTPS1 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 MBTPS1 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. The offspring of an individual with MBTPS1-SEMD are obligate heterozygotes (carriers) for a pathogenic variant in MBTPS1.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an MBTPS1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the MBTPS1 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 MBTPS1 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

Membrane-bound transcription factor site-1 protease (MBTPS1; also known as S1P) is a serine protease located in the Golgi. MBTPS1 has been shown to regulate lipogenesis, endoplasmic reticulum (ER) function, and lysosome biogenesis in mice and cultured cells [Kondo et al 2018]. Defective MBTPS1 function impairs activation of the ER stress transducer BBF2H7, leading to ER retention of collagen in chondrocytes. MBTPS1 deficiency also causes abnormal secretion of lysosomal enzymes due to partial impairment of mannose-6-phosphate-dependent delivery to lysosomes. Collectively, these abnormalities lead to apoptosis of chondrocytes and lysosomal enzyme-mediated degradation of the bone matrix.

Mechanism of disease causation. Loss of function

Author Notes

Hua Wang, MD, PhD, is a clinical geneticist. Her research interests are skeletal dysplasia and lysosomal storage disorders. She runs a skeletal dysplasia clinic and diagnoses and manages individuals with lysosomal storage disease as well as other genetic disorders.

Andrea Wierenga, PhD, is a clinical biochemical geneticist. Her interest is exploring biochemical aspects of rare diseases and research associated with biochemical disorders.

Sandeep Prabhu, MD, is a pediatric radiologist with interest and expertise in skeletal dysplasia.

Klaas Wierenga, MD, is a clinical geneticist and medical biochemical geneticist. His research interest is rare disease diagnostics, with special interest in clinical homozygosity mapping.

Klaas Wierenga, MD, Hua Wang, MD, PhD, Lijun Xia, MD (gro.frmo@aix-nujil), and Patrick Gaffney, MD (gro.frmo@yenffag-kcirtap), are actively involved in clinical research regarding individuals with MBTPS1-related spondyloepimetaphyseal dysplasia with elevated lysosomal enzymes (MBTPS1-SEMD). They would be happy to communicate with persons who have any questions regarding diagnosis of MBTPS1-SEMD or other considerations.

Contact the previously mentioned physicians and researchers to inquire about review of MBTPS1 variants of uncertain significance.

MBTPS1-Related Disorders Research Group
Phone: 405-271-6673
Web: omrf.org/mbtps-related-disorders-research-group

This research group aims to increase the understanding of MBTPS1-SEMD. Physicians and families interested in obtaining more information are encouraged to reach out.

Acknowledgments

We thank the patients and families that have contributed to the accumulating information about MBTPS-SEMD.

Revision History

• 30 November 2023 (sw) Review posted live
• 24 July 2023 (kw) Original submission

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