Opsismodysplasia (OPS) is a rare skeletal dysplasia characterized by delayed bone maturation, distinctive skeletal deformities, and severe growth impairment. Mutations in the INPPL1 gene, particularly homozygous variants, are the primary genetic cause of this condition. While bisphosphonate therapy has shown efficacy in OPS cases with hypophosphatemic rickets, its role in cases without this complication remains unclear. A 2-year-and-2-month-old girl with OPS was treated with intravenous pamidronate (0.5 mg/kg/3 months). Initial evaluations showed severe short stature and low bone mineral density (DEXA SDS: -3.16). After three courses of treatment, the patient achieved independent walking, and her DEXA SDS improved to -2.5 over 1 year. Pamidronate is effective in treating OPS even in the absence of hypophosphatemic rickets, showing potential as a therapeutic option for this rare condition. INPPL1-related opsismodysplasia is characterized by prenatal-onset short stature, short, bowed limbs, characteristic facial features (relative macrocephaly, prominent forehead, midface retrusion, depressed nasal bridge, short nose, anteverted nares, relatively long philtrum), narrow thorax, small hands and feet, delayed epiphyseal mineralization, metaphyseal cupping, and platyspondyly. Complications include increased risk of fractures, cervical spine abnormalities, scoliosis, bone pain, respiratory issues, and delayed gross motor skills. Some individuals have cardiac or kidney manifestations. Prognosis is variable with perinatal demise in some infants. The diagnosis of INPPL1-related opsismodysplasia is established in a proband with characteristic clinical and radiographic features and biallelic pathogenic variants in INPPL1 identified by molecular genetic testing. Targeted therapy: Intravenous bisphosphonate therapy has improved bone mineral density and gross motor function in two individuals with INPPL1-related opsismodysplasia. Supportive care: Cervical spine complications should be managed by specialists familiar with skeletal dysplasias involving the spine including an orthopedist and neurosurgeon; surgical stabilization should be performed to prevent progressive myelopathy; management of scoliosis per orthopedist with surgery when indicated; management of hypophosphatemia, renal phosphate wasting, and bone demineralization per endocrinologist; treatment of respiratory insufficiency per pulmonologist; vaccines to prevent respiratory illnesses; CPAP and surgical management as needed for sleep apnea; feeding therapy with modification of fluid or food texture as needed for swallowing difficulties; aerodigestive evaluation for endoscopy and surgery as needed; management of cardiac manifestations per cardiologist; management of renal manifestations per nephrologist and/or urologist; amplification/hearing device and/or surgery when indicated for hearing impairment; social work and family support. Surveillance: Flexion/extension cervical spine MRI every three months until cervical instability can be excluded in those with instability, risk of cervical cord compression, or limited radiograph interpretation; then MRI every two to three years, preoperatively, and when indicated. Clinical examination for scoliosis every six to 12 months with radiographs when indicated; endocrinology evaluation for hypophosphatemia and renal phosphate wasting every six to 12 months and when indicated; DXA scan when indicated; pulmonary function studies, chest radiographs, swallowing evaluation, and sleep study every six to 12 months and when indicated per pulmonologist; swallowing evaluation as indicated to evaluate for aspiration; developmental assessment to assess gross motor skills annually or as needed; rehabilitation medicine, physical therapy, and occupational therapy consultations when indicated to evaluate function and need for adaptive devices and to support activities of daily living and mobility; clinical cardiac examination with frequency per cardiologist; audiology evaluation annually or as needed; ENT and orthodontic evaluations as needed; assess family and social work needs at each visit. Agents/circumstances to avoid: Individuals with cervical spine instability or who are at risk for cervical spine instability should avoid extreme neck flexion and extension, contact sports, and other at-risk activities. Individuals with bone demineralization should avoid contact sports and other activities associated with an increased risk for fractures. Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of targeted therapy. INPPL1-related opsismodysplasia is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an INPPL1 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 INPPL1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Cell size is a key contributor to tissue morphogenesis. As a notable example, growth plate hypertrophic chondrocytes use cellular biogenesis and disproportionate fluid uptake to expand 10 to 20 times in size to drive lengthening of endochondral bone. Similarly, notochord vacuolated cells expand to one of the largest cell types in the developing embryo to drive axial extension. In zebrafish, the notochord vacuolated cells undergo vacuole fusion to form a single large, fluid-filled vacuole that fills the cytoplasmic space and contributes to vacuolated cell expansion. When this process goes awry, the notochord lacks sufficient hydrostatic pressure to support vertebral bone deposition, resulting in adult spines with misshapen vertebral bones and scoliosis. However, it remains unclear whether endochondral bone and the notochord share common genetic and cellular mechanisms for regulating cell and tissue expansion. Here, we demonstrate that the 5'-inositol phosphatase gene, inppl1a, regulates notochord expansion independent of vacuole fusion, thereby genetically decoupling these processes. We demonstrate that inppl1a-dependent vacuolated cell expansion is essential to establish normal mechanical properties of the notochord and to facilitate the development of a straight spine. Finally, we find that inppl1a is also important for hypertrophic chondrocyte differentiation and endochondral bone lengthening in fish, as has been shown in the human INPPL1-related endochondral bone disorder, opsismodysplasia. Overall, this work reveals a shared mechanism of cell size regulation that influences disparate tissues critical for skeletal development and short-stature disorders.

Opsismodysplasia is a rare autosomal recessive genetic skeletal disorder characterized by short stature, short limbs, small hands and feet, delayed bone age, severe platyspondyly, metaphyseal cupping, and facial dysmorphism. Opsismodysplasia is caused by biallelic variants in the INPPL1 gene. Only 38 patients with a confirmed molecular diagnosis have been reported so far. We present a 9-month-old male patient who was referred to our clinic with a suspicion of mucopolysaccharidoses due to facial features and radiographic findings, but urine glycosaminoglycans were within normal ranges. Audiologic and ophthalmologic assessments, transfontanelle ultrasound, and echocardiography were all normal. A renal cortical cyst with a diameter of 33 × 28 mm was detected in abdominal ultrasound. He had dysmorphic findings including relative macrocephaly, midface hypoplasia, depressed nasal bridge, anteverted nostrils, long philtrum, small hands and feet, and brachydactyly. His length was 63 cm (-3.7 SD) and his arm span was 58 cm. Delayed bone age, short metacarpals and phalanges, wide and irregular metaphysis, platyspondyly, anterior beaking of the vertebrae, T12 vertebral hypoplasia, and acetabular dysplasia were noted on X-rays. Exome sequencing revealed a novel homozygous c.147C>G (p.Ser49Arg) variant in INPLL1. Opsismodysplasia is an extremely rare skeletal disorder, and with this case, we further expand the clinical and molecular spectrum of opsismodysplasia.

The src homology 2 domain-containing inositol 5-phosphatases SHIP1 and SHIP2 are two proteins involved in intracellular signaling pathways and have been linked to the pathogenesis of several diseases. Both protein paralogs are well known for their involvement in the formation of various kinds of cancer. SHIP1, which is expressed predominantly in hematopoietic cells, has been implicated as a tumor suppressor in leukemogenesis especially in myeloid leukemia, whereas SHIP2, which is expressed ubiquitously, has been implicated as an oncogene in a wider variety of cancer types and is suggested to be involved in the process of metastasis of carcinoma cells. However, there are numerous other diseases, such as inflammatory diseases as well as allergic responses, Alzheimer's disease, and stroke, in which SHIP1 can play a role. Moreover, SHIP2 overexpression was shown to correlate with opsismodysplasia and Alzheimer's disease, as well as metabolic diseases. The SHIP1-inhibitor 3-α-aminocholestane (3AC), and SHIP1-activators, such as AQX-435 and AQX-1125, and SHIP2-inhibitors, such as K161 and AS1949490, have been developed and partly tested in clinical trials, which indicates the importance of the SHIP-paralogs as possible targets in the therapy of those diseases. The aim of this article is to provide an overview of the current knowledge about the involvement of SHIP proteins in the pathogenesis of cancer and other human diseases and to create awareness that SHIP1 and SHIP2 are more than just tumor suppressors and oncogenes.

Cell size is a key contributor to tissue morphogenesis 1 . As a notable example, growth plate hypertrophic chondrocytes use cellular biogenesis and disproportionate fluid uptake to expand 10-20 times in size to drive lengthening of endochondral bone 2,3 . Similarly, notochordal cells expand to one of the largest cell types in the developing embryo to drive axial extension 4-6 . In zebrafish, the notochord vacuolated cells undergo vacuole fusion to form a single large, fluid-filled vacuole that fills the cytoplasmic space and contributes to vacuolated cell expansion 7 . When this process goes awry, the notochord lacks sufficient hydrostatic pressure to support vertebral bone deposition resulting in adult spines with misshapen vertebral bones and scoliosis 8 . However, it remains unclear whether endochondral bone and the notochord share common genetic and cellular mechanisms for regulating cell and tissue expansion. Here, we demonstrate that the 5'-inositol phosphatase gene, inppl1a , regulates notochord expansion, spine morphogenesis, and endochondral bone lengthening in zebrafish. Furthermore, we show that inppl1a regulates notochord expansion independent of vacuole fusion, thereby genetically decoupling these processes. We demonstrate that inppl1a -dependent notochord expansion is essential to establish normal mechanical properties of the notochord to facilitate the development of a straight spine. Finally, we find that inppl1a is also important for endochondral bone lengthening in fish, as has been shown in the human INPPL1 -related endochondral bone disorder, Opsismodysplasia 9 . Overall, this work reveals a conserved mechanism of cell size regulation that influences disparate tissues critical for skeletal development and short-stature disorders.