Osteogenesis Imperfecta, Type Xiii

A number sign (#) is used with this entry because autosomal recessive osteogenesis imperfecta type XIII (OI13) can be caused by homozygous or compound heterozygous mutation in the BMP1 gene (112264) on chromosome 8p21.

Description

Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most cases of OI are autosomal dominant with mutations in 1 of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160). Martinez-Glez et al. (2012) described osteogenesis imperfecta type XIII, an autosomal recessive form of the disorder characterized by normal teeth, faint blue sclerae, severe growth deficiency, borderline osteoporosis, and an average of 10 to 15 fractures a year affecting both upper and lower limbs and with severe bone deformity.

Clinical Features

Munns et al. (2004) reported 3 children from unrelated nonconsanguineous French Canadian families who had recurrent fractures, primarily of the lower limbs (94%), that started with weight bearing. All fractures, which were documented radiologically, resulted from minimal or no trauma; fracture repair was normal. Other than a fracture of the twelfth thoracic vertebra in 1 patient, there were no vertebral compression fractures or indicators of scoliosis on spine x-rays. Height was normal in 2 of the patients and slightly below the reference range in 1. All had normal dentition, white sclerae, and normal joint laxity. Radiography showed increased metaphyseal trabeculation with normal to increased cortical thickness. Areal and volumetric bone mineral density did not show any major alteration. Peripheral quantitative CT of the radius in 1 patient showed elevated cortical thickness and elevated total and trabecular volumetric bone mineral density. Qualitative histology of iliac bone biopsy specimens showed a paucity of the birefringent pattern of normal lamellar bone. Quantitative histomorphometric analysis demonstrated osteomalacia with a prolonged mineralization lag time in the presence of a decreased mineral apposition rate. There was no biochemical evidence of abnormal calcium or phosphate metabolism, and heteroduplex screening for type I collagen variants was negative. Munns et al. (2004) concluded that this phenotype represents a novel bone fragility disorder of moderate severity that tends to cause fracture in the lower extremities and is associated with the accumulation of osteoid due to an intrinsic mineralization defect.

Martinez-Glez et al. (2012) described a sister and brother, offspring of first-cousin Egyptian parents, with autosomal recessive OI. The 15-year-old female proband had a triangular face, broad forehead, wide palpebral fissures, long eyelashes, faint blue sclerae, long philtrum, thin lips, and prominent ears. Gross motor development was delayed and she was not able to stand unsupported. No dentinogenesis imperfecta was present. Her thorax was relatively large with increased anteroposterior and transverse diameters compressing the abdomen. She had a large umbilical hernia with abdominal content, generalized hypotonia, muscle wasting, and nocturnal enuresis. Skeletal examination showed severe generalized deformities of all bones with consistent pain on touch, including deformed clavicles; bilateral bowed angulated humerus, radius, and ulna; arachnodactyly; and hyperextensibility of elbow, wrist, and interphalangeal joints. Lower limbs showed bowing of femora, severely angulated deformed leg bones and limited movements of the knee joints. She also had kyphoscoliosis and pectus carinatum. Radiologic examination revealed deformed long bones with multiple fractures and callus formation, lack of bone modeling with wide distal metaphyses of femora, serpentine thin tibiae and fibulae in addition to S-curve scoliosis of thoracic and lumbar spine with platyspondyly, and generalized decreased bone density. Skull X-ray showed wormian bones. Anthropometric measurements at 13 years of age were below normal for weight (-3.8 SD), length (-11.5 SD) and head circumference (-3.0 SD). Bone densitometry (DEXA) at 15 years revealed borderline osteoporosis at the hip and spine (Z-score -2.22 and -2.13, respectively). Her 5-year-old brother had a similar phenotype. Audiologic and cardiovascular examinations of both patients were unremarkable. Serum calcium and phosphate were normal, whereas alkaline phosphatase levels were slightly high. Both patients were diagnosed as having Sillence type III, and cyclic IV bisphosphonate injections were started.

Valencia et al. (2014) reported a 3-year-old Pakistani boy from a consanguineous family who was first diagnosed with a dislocated spiral femur fracture at 4 months of age. Skeletal survey showed older fractures of the ribs, but no bowing or shortening of the extremities and no wormian bones. By 2 years of age, he had 25 radiologically verified fractures, 11 of the extremities and 14 of the ribs. He had white sclerae, normal teeth and skin, and no dysmorphic features. Repeated whole-body and spine DEXA scans showed bone density in the normal range, and alkaline phosphatase and phosphate levels were normal, with plasma calcium in the upper normal range.

Fahiminiya et al. (2015) studied 4 unrelated patients of French Canadian origin with mild to moderate bone fragility, 2 of whom had been previously studied by Munns et al. (2004). All had normal height and weight at presentation, normal dentition, and white sclerae. Aside from fracture episodes, mobility was not impaired, and fractures healed normally. Two of the patients had vertebral compression fractures. Biochemical parameters of bone and mineral metabolism were normal at baseline. Peripheral quantitative CT showed that all individuals had elevated volumetric cortical bone mineral density. Analysis of iliac bone samples indicated that onset of mineralization at bone formation sites was delayed but that the mineralized matrix was hypermineralized.

Cho et al. (2015) reported a 1.75-year-old Korean girl who was born with a fractured left humerus as well as right clubfoot, umbilical hernia, and bilateral simian creases. At 8 months of age, she presented with a left femur fracture, and subsequently sustained more than 10 fractures per year of the upper and lower limbs. Examination at 12 months of age showed white sclerae as well as normal teeth and skin; the patient had no dysmorphic features. She had generalized hypotonia, muscle wasting, short stature, and hyperextensibility of the elbow, wrist, and interphalangeal joints. Mental development appeared normal, but motor development was delayed, and she was unable to sit unsupported. Skeletal survey showed multifocal fractures of the humerus, femur, and tibia, as well as bilateral radial head dislocation with distal bowing of the radius and ulna; the latter bones also exhibited a peculiar shape, with eccentric curvature and narrowing of the distal ulna. She had mild scoliosis, but no vertebral fracture was seen. Skull radiographs at 20 months of age showed wormian bones and a wide open anterior fontanel.

Mapping

Martinez-Glez et al. (2012) performed genomewide homozygosity mapping in 4 sibs, 2 of whom had severe osteogenesis imperfecta and a large umbilical hernia, from a consanguineous Egyptian family. The mapping showed no linkage to any known OI genes and revealed in the 2 affected sibs a 10.27-Mb homozygous region on chromosome 8p, which contained the procollagen I C-terminal propeptide (PICP) endopeptidase gene BMP1, and a 35.4-Mb homozygous region on chromosome 3.

Molecular Genetics

By direct sequencing of the BMP1 gene in a proband with severe autosomal recessive osteogenesis imperfecta and a large umbilical hernia, the offspring of consanguineous Egyptian parents, Martinez-Glez et al. (2012) identified homozygosity for a missense mutation in the BMP1 gene (F249L; 112264.0001). The same mutation was found in the proband's affected brother. Their parents and unaffected sibs were heterozygous for the mutation.

In 2 affected sibs of a consanguineous family from Turkey with increased bone mineral density and multiple recurrent fractures, Asharani et al. (2012) identified homozygosity for a missense mutation (G12R; 112264.0002) in the BMP1 gene. The mutation was identified by combined whole-exome sequencing and filtering for homozygous stretches of identified variants.

In a 3-year-old Pakistani boy with osteogenesis imperfecta and normal bone density, who was negative for mutation in the procollagen type I alpha-chain genes and 3 other known OI-associated genes, Valencia et al. (2014) performed genomewide SNP array hybridization, which revealed a large 99-Mb region of homozygosity on chromosome 8, encompassing BMP1. Sequencing the BMP1 gene revealed homozygosity for the G12R missense mutation. Immunofluorescence and electron microscopy demonstrated impaired assembly of type I collagen fibrils in the extracellular matrix of both G12R and F249L mutant fibroblasts.

In 4 unrelated patients of French Canadian origin with bone fragility, 2 of whom were originally reported by Munns et al. (2004) as patients 1 and 2, Fahiminiya et al. (2015) identified a point mutation in the 3-prime untranslated region of the BMP1 gene (112264.0003), affecting the polyadenylation site of the BMP1 short isoform. Three of the patients were homozygous, whereas the fourth was compound heterozygous for that mutation and a splice site mutation (112264.0004) in BMP1. Clinical assessment of 7 heterozygous family members revealed no history of fractures except after significant trauma, and their bone densitometries were in the normal range. Fahiminiya et al. (2015) found that patient 3 of Munns et al. (2004) carried a nonsense mutation in the COL1A1 gene (120150) that had not been detected by previous heteroduplex screening.

In a 1.75-year-old Korean girl with osteogenesis imperfecta, who was negative for mutation in the procollagen type I alpha-chain genes and IFITM5 (614757), Cho et al. (2015) performed whole-exome sequencing. The authors identified compound heterozygosity for a missense mutation (M270V; 112264.0005) and a splice site mutation (112264.0006) in BMP1. The patient's unaffected parents were each heterozygous for 1 of the mutations. No pathogenic variants in other known OI-associated genes were found.