A number sign (#) is used with this entry because of evidence that BCARD syndrome (BCARD) is caused by homozygous or compound heterozygous mutation in the PLOD3 gene (603066) on chromosome 7q22.

BCARD syndrome is an autosomal recessive connective tissue disorder characterized by bone abnormalities, including low bone mineral density, scoliosis, contractures of the fingers and other joints, prominent knees, and rare pathologic fractures; cataract and other ocular abnormalities, including high myopia, optically empty vitreous, and risk for retinal detachment; risk of arterial rupture due to vascular aneurysm or dissection; and sensorineural deafness. Affected individuals also exhibit recognizable craniofacial dysmorphisms, and variable skin features have been observed, including reduced palmar creases, soft skin with easy bruising, and blistering. Developmental delay, which is present in most patients, may be attributable to sensory deficits or medical complications (Ewans et al., 2019).

Salo et al. (2008) described a 16-year-old Finnish girl with a novel connective tissue disorder secondary to lysyl hydroxylase-3 (LH3) deficiency. The patient was born to a nonconsanguineous couple of European descent. Pregnancy was complicated by intrauterine growth retardation. Craniofacial features included flat facial profile, simple, low-set ears, shallow orbits, short, upturned nose, and downturned corners of the mouth. Skeletal features included elbow contractures, flexion contractures of the proximal interphalangeal (PIP) joints of the fingers, progressive scoliosis, talipes equinovarus, osteopenia, and several pathologic fractures. She was noted to have profound bilateral sensorineural deafness, myopia, and cataracts. Blistering occurred in her fingers and toes that healed without scarring. Her skin exhibited easy bruisability. In the second decade, spontaneous vascular ruptures occurred. A spontaneous cerebral arterial hemorrhage presented with hemiplegia, and a rupture of popliteal aneurysm presented with pain and swelling. Right-sided diaphragmatic eventration was repaired at age 5 months; the diaphragm was noted to be friable at the time of surgery, and a second surgical repair was required after the first failed. A male sib was stillborn at 28 weeks' gestation. Intrauterine growth retardation complicated the pregnancy. Autopsy revealed a porencephalic cyst with dilation of the cerebral ventricles.

Maddirevula et al. (2019) reported a 9-year-old Saudi boy (17-4086) who presented with failure to thrive, developmental delay, and skeletal findings, and had mutation in the PLOD3 gene. He had no head control at 6 months, could not sit at 10 months, and walked at 2 years. He had right cryptorchidism and underwent orchidopexy. Examination revealed microcephaly, truncal hypotonia, flat occiput, prominent forehead, midface hypoplasia, bilateral ptosis, blue sclera, short nose with depressed nasal bridge, low-set posteriorly rotated small ears, and micrognathia. He also exhibited distal arthrogryposis, with contractures of the wrists and hands and camptodactyly of all fingers. His parents were distant cousins and he had an affected sister.

Vahidnezhad et al. (2019) reported a 4.5-year-old Iranian boy with developmental delay, contractures, pterygia, and trauma-induced skin blistering, and mutation in the PLOD3 gene. At birth, ptosis, unilateral cataract, severe myopia, flat face with long philtrum, low-set ears, and short nose with anteverted nares were noted; examination at age 4.5 years showed amblyopia and strabismus. He had neonatal hyperbilirubinemia, and brain MRI showed basal ganglia hypersignal areas, consistent with kernicterus, as well as another hypersignal region in the left parietal brain suggesting hemorrhage and calcification. At 1 month of age, chest CT showed right diaphragmatic eventration displacing the heart upward, which resolved spontaneously with time. Psychomotor milestones were delayed, with walking and first words at age 3 years. Musculoskeletal features included reduced muscle mass, scoliosis, flexion contractures in elbows and carpometacarpal joints, webbing across the second interphalangeal joint of the left hand, prominently enlarged knee and elbow joints, short legs, and talipes equinovarus. He also exhibited pterygia of the neck, axilla, antecubital, popliteal, digital, and intercrural areas. His thumbs were abnormally folded over the palms, and palmar creases were reduced bilaterally. In addition, he displayed trauma-induced blisters over the elbows, feet, knees, and ears, with a history of delayed wound healing. Histopathology of blister-adjacent skin showed sub-lamina densa tissue separation and fibrosis in the upper papillary dermis, and staining for type VII collagen (see 120120) was markedly reduced. Transmission electron microscopy showed areas of interrupted and fragmented lamina densa, with a variable number and altered morphology of anchoring fibrils in both intact and blistered skin. He had dystrophic toenails, but hair and teeth were normal. In contrast to a previously reported patient (Salo et al., 2008), the proband did not show evidence of cutaneous hemorrhage, vascular aneurysms, sensorineural hearing loss, or coarse hair. There were 2 complicated pregnancies in the family, including 1 terminated at 12 weeks due to intrauterine growth failure, and another at 18 weeks due to underdevelopment of the neural system.

Ewans et al. (2019) reported 3 Lebanese sibs with a Stickler syndrome (see 108300)-like connective tissue disorder with vascular complications and mutation in the PLOD3 gene. Shared dysmorphic craniofacial features included bilateral ptosis, prominent eyes, downslanting palpebral fissures, malar hypoplasia, small upturned nose, low-set ears, and microretrognathia. All 3 had early-onset cortical cataracts, high myopia, and an optically empty vitreous, as well as moderate to severe bilateral sensorineural hearing loss. Skeletal features included low bone mineral density, mild platyspondyly and scoliosis, and prominent knees, with mixed hypermobility and contractures of small and large joints. One of the brothers had dissection of the left anterior descending coronary artery at age 18 years.

Clinical Variability

Zhou et al. (2022) reported a 14-month-old Chinese girl with developmental delay and seizures, and mutation in the PLOD3 gene. At 3 months of age, she presented with psychomotor retardation, and brain MRI showed multiple abnormal signals in the thalamus, basal ganglia, and corona radiata, with decreased white matter volume in the left hemisphere and slight dilation of the left lateral ventricle. At age 8 months, she experienced clustered epileptic spasms, at which time brain MRI showed multiple areas of malacia and bleeding foci, extensive abnormal white matter signals, and obvious brain atrophy. Brain CT scan showed calcification bilaterally in the anterior ventricle; the authors noted that the brain imaging studies were consistent with cerebral small vessel disease. Electroencephalography (EEG) suggested hypsarrhythmia. Auditory evoked potentials were normal. Visual evoked potentials showed a moderate to severe reduction in binocular vision, and myopia was detected. There were no cataracts or fundus abnormalities. Dysmorphic features included hypertelorism, upturned nose, and low-set ears. Bone abnormalities included platyspondyly, with concavity of the upper and lower vertebral edges, and x-ray of her left hand showed irregular distal ends of the metacarpals. At last follow-up at 14 months of age, she continued to have seizures with no improvement in cognitive or motor skills. A diagnosis of West syndrome (see 308350) was made, based on infantile-onset clustered epileptic spasms, delayed development, and hypsarrhythmia on EEG.

Reviews

Ewans et al. (2019) tabulated the features of 9 published patients with PLOD3 mutations and concluded that the collated clinical features showed the most overlap with Stickler syndrome, with variable features of Ehlers-Danlos syndrome (EDS; see 130000) and epidermolysis bullosa (see 226600). There was marked variability in the severity of disease. Key clinical features included ocular abnormalities with risk for retinal detachment, sensorineural hearing loss, recognizable craniofacial dysmorphisms, finger contractures, reduced palmar creases, low bone mineral density, scoliosis, prominent knees, and risk for vascular aneurysm, dissection, or rupture. The authors noted wide variability in the severity of skin disease, with some affected individuals lacking definite skin features, and others exhibiting severe blistering. The authors also noted that the developmental delay that was present to some degree in the majority of patients might be attributable to sensory deficits or medical complications.

The transmission pattern of BCARD in the family reported by Vahidnezhad et al. (2019) was consistent with autosomal recessive inheritance.

In their proband with a novel connective tissue disorder, Salo et al. (2008) analyzed urinary pyridinium collagen crosslinks and found absence of the disaccharide component of pyridinoline (Glc-Gal-PYD), which normally comprises approximately 15% of free pyridinoline crosslinks. The lack of glycosylated collagen crosslinks suggested a defect of an enzyme glycosylating hydroxylysine residue, for which the lysyl hydroxylase-3 gene was the prime candidate. The patient also had markedly reduced serum collagen glucosyltransferase (GGT) activity and decreased concentration of LH3 protein in lymphoblastoid cells.

By analysis of LH3 cDNA in a 16-year-old Finnish girl with a connective tissue disorder and lysyl hydroxylase-3 deficiency, Salo et al. (2008) identified compound heterozygosity for 2 mutations: an asn223-to-ser mutation (N223S; 603066.0001) and a 1-bp deletion (2071delT; 603066.0002). The mutations occurred in conserved regions of the LH3 amino acid sequence responsible for GGT and lysyl hydroxylase activity.

Maddirevula et al. (2019) searched their database of 799 research and 1,750 clinical Saudi exomes for likely pathogenic homozygous variants and identified a 9-year-old boy (17-4086) with a connective tissue disorder who was homozygous for a nonsense mutation in the PLOD3 gene (R452X; 603066.0003). The mutation status of his distant-cousin parents and affected sister was not reported.

From a cohort of consanguineous Iranian families with recessive dystrophic epidermolysis bullosa (EB; see 226600)-like phenotypes, Vahidnezhad et al. (2019) identified a 4.5-year-old Iranian boy with developmental delay, contractures, pterygia, and skin blisters, who was negative for mutation in 21 EB-associated genes including COL7A1 (120120) but in whom exome sequencing revealed homozygosity for a missense mutation in the PLOD3 gene (L627P; 603066.0004). Sanger sequencing showed that his unaffected second-cousin parents were heterozygous carriers of the variant, which was not found in the ExAC or gnomAD databases. Functional analysis indicated significantly reduced to absent LH3 in patient fibroblasts and skin, and there was reduced glycosylation of urinary hydroxylysine in a patient sample.

In 3 Lebanese sibs with a multisystem connective tissue disorder, Ewans et al. (2019) identified homozygosity for a missense mutation in the PLOD3 gene (P270L; 603066.0005), located in a region of homozygosity shared by the affected sibs. Sanger sequencing confirmed heterozygosity of the mutation in their unaffected first-cousin parents and the unaffected daughter of 1 of the sibs; an unaffected brother did not carry the mutation.

By whole-exome sequencing in a 14-month-old Chinese girl with cerebral small vessel disease, seizures, developmental delay, myopia, and bone abnormalities, Zhou et al. (2022) identified homozygosity for an in-frame 3-bp deletion in the PLOD3 gene (L406del; 603066.0006). Her unaffected parents and brother were heterozygous for the deletion. Western blot of patient fibroblasts showed markedly reduced levels of LH3 compared to controls.