Expanding the Phenotypic Spectrum of ADAMTS2 related Ehlers-Danlos Syndrome, Dermatosparaxis type
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
Ehlers-Danlos Syndrome, Dermatosparaxis type, (dEDS), is an autosomal recessive connective tissue disorder caused by a mutation in the ADAMTS2 gene, which encodes a procollagen I N-proteinase on chromosome 5q35. This malfunction in the processing of procollagen leads to impaired collagen fibril formation and manifests clinically as severe skin fragility, excessive loose skin, joint hyper-extensibility, bruising, and dysmorphic craniofacial features. The incidence of dEDS is reported to be less than one in a million. We present a case of dEDS with a genetic variant not previously reported in the literature and a novel presentation that mimics Rhizomelic chondrodysplasia punctata 2 (RCDP) on imaging.
Case Presentation
The proband was born at 35 weeks by emergency caesarian section secondary to placental abruption from a 33-year-old mother with poor prenatal care and history of chlamydia treated two weeks prior to delivery. The pregnancy was complicated by severe polyhydramnios, neonatal skeletal dysplasia, and suspected congenital heart defects. After birth, the patient became apneic requiring intubation and ventilation. She was transferred to the NICU and placed on an oscillator. Physical exam showed dysmorphic facial features, relative macrocephaly, rhizomelic limb shortening, hypotonia, left index finger deviation, skin fragility, anal fissures, and bilateral club feet. At birth, weight was 2.44 kg, length was 36 cm, and head circumference was 33 cm. The patient remained in the NICU for 2 months for respiratory support.
Diagnostic Workup
Negative testing included sepsis workup, liver function studies, abdominal and renal ultrasound, metabolic panel, peroxisomal panel, and newborn screen. Cranial ultrasound showed a possible grade I-II interventricular hemorrhage with mild ventriculomegaly. Echocardiogram was significant for persistent pulmonary hypertension likely secondary to rib cage restriction in the setting of skeletal dysplasia. The skeletal survey showed epiphyseal stippled calcifications which are typically consistent with chondrodysplasia punctata- rhizomelic type. A bone survey revealed rhizomelic femurs, humeri, metacarpal and metatarsal bones with varus deformity of feet, and coronal cleft of the vertebra. The ophthalmic exam showed brittle corneas often described in the context of EDS with high risk of corneal perforation. The chromosomal microarray analysis showed 64kb deletion of 2q13 which includes the MEPTK gene that can cause retinitis pigmentosa. Whole Exome Sequencing duo showed compound heterozygous variants of uncertain significance in the ADAMTS2 gene: c.2019G>Ap.Mel673Ile maternal and c.1445C>G p.Pro482Arg not maternal.
Treatment and Management
Initial management included respiratory support and precautionary measures and close monitoring for skin fragility, wound dehiscence, fractures, pressure ulcers, and pneumothorax. Outpatient follow-up included craniofacial plastic surgery, pediatric orthopedics, ophthalmology, genetics, physical therapy, and occupational therapy.
Discussion
This case presents significant implications due to the novel genetic findings and atypical clinical presentation. In comparison with the other known 15 case reports in the world, this case is the first to present with epiphyseal stippled calcifications- a finding typically associated with other skeletal dysplasias, such as RCDP. With the majority of dEDS skeletal surveys being normal, some have shown delayed ossification of the cranial vault (n = 3), Wormian bones (n = 2), delayed bone age (n = 2), and persistence of woven bone in the ribs (n=1).
Conclusion
This case highlights a unique skeletal x-ray presentation of epiphyseal stippled calcifications that has not been reported in previous cases of dEDS to our knowledge, emphasizing the need for clinicians to consider dEDS in the differential diagnosis of connective tissue disorders, even when skeletal abnormalities resemble those of syndromes like RCDP. Future research should focus on further elucidating the genotype-phenotype correlations in dEDS to refine diagnostic criteria and treatment strategies.
Ehlers-Danlos Syndrome, Dermatosparaxis type, (dEDS), is an autosomal recessive connective tissue disorder caused by a mutation in the ADAMTS2 gene, which encodes a procollagen I N-proteinase on chromosome 5q35. This malfunction in the processing of procollagen leads to impaired collagen fibril formation and manifests clinically as severe skin fragility, excessive loose skin, joint hyper-extensibility, bruising, and dysmorphic craniofacial features. The incidence of dEDS is reported to be less than one in a million. We present a case of dEDS with a genetic variant not previously reported in the literature and a novel presentation that mimics Rhizomelic chondrodysplasia punctata 2 (RCDP) on imaging.
Case Presentation
The proband was born at 35 weeks by emergency caesarian section secondary to placental abruption from a 33-year-old mother with poor prenatal care and history of chlamydia treated two weeks prior to delivery. The pregnancy was complicated by severe polyhydramnios, neonatal skeletal dysplasia, and suspected congenital heart defects. After birth, the patient became apneic requiring intubation and ventilation. She was transferred to the NICU and placed on an oscillator. Physical exam showed dysmorphic facial features, relative macrocephaly, rhizomelic limb shortening, hypotonia, left index finger deviation, skin fragility, anal fissures, and bilateral club feet. At birth, weight was 2.44 kg, length was 36 cm, and head circumference was 33 cm. The patient remained in the NICU for 2 months for respiratory support.
Diagnostic Workup
Negative testing included sepsis workup, liver function studies, abdominal and renal ultrasound, metabolic panel, peroxisomal panel, and newborn screen. Cranial ultrasound showed a possible grade I-II interventricular hemorrhage with mild ventriculomegaly. Echocardiogram was significant for persistent pulmonary hypertension likely secondary to rib cage restriction in the setting of skeletal dysplasia. The skeletal survey showed epiphyseal stippled calcifications which are typically consistent with chondrodysplasia punctata- rhizomelic type. A bone survey revealed rhizomelic femurs, humeri, metacarpal and metatarsal bones with varus deformity of feet, and coronal cleft of the vertebra. The ophthalmic exam showed brittle corneas often described in the context of EDS with high risk of corneal perforation. The chromosomal microarray analysis showed 64kb deletion of 2q13 which includes the MEPTK gene that can cause retinitis pigmentosa. Whole Exome Sequencing duo showed compound heterozygous variants of uncertain significance in the ADAMTS2 gene: c.2019G>Ap.Mel673Ile maternal and c.1445C>G p.Pro482Arg not maternal.
Treatment and Management
Initial management included respiratory support and precautionary measures and close monitoring for skin fragility, wound dehiscence, fractures, pressure ulcers, and pneumothorax. Outpatient follow-up included craniofacial plastic surgery, pediatric orthopedics, ophthalmology, genetics, physical therapy, and occupational therapy.
Discussion
This case presents significant implications due to the novel genetic findings and atypical clinical presentation. In comparison with the other known 15 case reports in the world, this case is the first to present with epiphyseal stippled calcifications- a finding typically associated with other skeletal dysplasias, such as RCDP. With the majority of dEDS skeletal surveys being normal, some have shown delayed ossification of the cranial vault (n = 3), Wormian bones (n = 2), delayed bone age (n = 2), and persistence of woven bone in the ribs (n=1).
Conclusion
This case highlights a unique skeletal x-ray presentation of epiphyseal stippled calcifications that has not been reported in previous cases of dEDS to our knowledge, emphasizing the need for clinicians to consider dEDS in the differential diagnosis of connective tissue disorders, even when skeletal abnormalities resemble those of syndromes like RCDP. Future research should focus on further elucidating the genotype-phenotype correlations in dEDS to refine diagnostic criteria and treatment strategies.