Screening for neuropathic pain after spinal cord injury with the spinal cord injury pain instrument (SCIPI): a preliminary validation study.

STUDY DESIGN: Cross-sectional. OBJECTIVE: To preliminarily evaluate the validity of an interview-based spinal cord injury (SCI) neuropathic pain screening instrument. SETTING: Six university-based SCI centers in the United States. METHODS: Clinician diagnoses of neuropathic pain (NP) and non-neuropathic pain subtypes were collected independently of descriptions of the pain characteristics provided by the persons with SCI by using the Spinal Cord Injury Pain Instrument (SCIPI); SCIPI information and physician diagnoses for 82 pain sites of which they were most confident were subsequently compared. RESULTS: Four of the SCIPI items correlated significantly with the NP subtype as determined by the clinician. The best cutoff score for identifying NP was an endorsement of two or more of these four items. Using this cutoff, sensitivity of the SCIPI was 78%, specificity was 73% and overall diagnostic accuracy was 76%. CONCLUSION: In this preliminary study, the SCIPI, which can be administered by a nonclinician, appears to have good sensitivity, specificity and diagnostic accuracy in a SCI population; it may have a role as a screening tool for NP after SCI. Further study is needed.

Patterns of pain across the acute SCI rehabilitation stay: evidence from hourly ratings.

STUDY DESIGN: Cohort. OBJECTIVES: To examine patterns of pain intensity and variability during acute spinal cord injury (SCI) rehabilitation. SETTING: Large medical university in the Midwestern United States. METHODS: Data were collected from the medical records of consecutively admitted patients with new (< or =2 months after onset), traumatic (that is, injury resulting from external forces) or non-traumatic (that is, injury resulting from disease processes) SCI. A total of 11,001 hourly pain ratings on 1709 inpatient days were collected from 56 inpatients. Multi-leveling modeling was used to test models of pain intensity, pain variability, diurnal variability and pain medication administration. RESULTS: Pain intensity and variability decreased during the inpatient stay. Compared with those with non-traumatic injuries, those with traumatic injuries had significantly higher pain; those with American Spinal Injury Association Impairment Score (AIS) A scores had a slower decline of pain, while those with AIS D scores had a sharper decline. Pain increased from morning to evening during the latter days of the inpatient stay whereas pain was relatively stable during the early days in the inpatient stay. Those not using a ventilator at admission were significantly less likely to receive a pain medication than those who were, despite no significant differences in pain levels. CONCLUSION: Pain changes during acute rehabilitation, however, the moderating effect of time suggests that change is not consistent across all injury characteristics. Findings suggest that not only should pain management be individualized but it should also reflect a greater understanding of change over time.

Secondary health conditions in individuals aging with SCI: terminology, concepts and analytic approaches.

STUDY DESIGN: Literature review. OBJECTIVES: Utilizing individuals with spinal cord injury (SCI) as a representative population for physical disability, this paper: (1) reviews the history of the concept of secondary conditions as it applies to the health of individuals aging with long-term disabilities; (2) proposes a definition of secondary health conditions (SHCs) and a conceptual model for understanding the factors that are related to SHCs as individuals age with a disability; and (3) discusses the implications of the model for the assessment of SHCs and for developing interventions that minimize their frequency, severity and negative effects on the quality of life of individuals aging with SCI and other disabilities. METHODS: Key findings from research articles, reviews and book chapters addressing the concept of SHCs in individuals with SCI and other disabilities were summarized to inform the development of a conceptual approach for measuring SCI-related SHCs. CONCLUSIONS: Terms used to describe health conditions secondary to SCI and other physical disabilities are used inconsistently throughout the literature. This inconsistency represents a barrier to improvement, measurement and for the development of effective interventions to reduce or prevent these health conditions and mitigate their effects on participation and quality of life. A working definition of the term SHCs is proposed for use in research with individuals aging with SCI, with the goal of facilitating stronger evidence and increased knowledge upon which policy and practice can improve the health and well-being of individuals aging with a disability.

Oral baclofen administration in persons with chronic spinal cord injury does not prevent the protective effects of spasticity on body composition and glucose homeostasis.

STUDY DESIGN: Correlation study. OBJECTIVES: To determine the effects of oral baclofen on body composition (fat mass (FM), fat-free mass (FFM)), extra- and intracellular fluid compartments and glucose homeostasis (plasma glucose and plasma insulin concentrations) in individuals with spinal cord injury (SCI) after controlling for spasticity. SETTINGS: Laboratory settings at the University of Michigan, MI, USA. METHODS: Fifteen individuals with chronic motor complete SCI (32+/-8 years old, 25+/-5 kg/m(2), C6-T11, American Spinal Injury Association A and B) underwent multifrequency bioelectrical impedance analysis to measure body composition and body fluid compartments. Spasticity of the hip, knee and ankle flexors and extensors was measured using a modified Ashworth Scale and the dose of daily oral baclofen was recorded. After overnight fasting, plasma glucose and insulin sensitivity were measured in response to an oral glucose tolerance test. RESULTS: Oral baclofen dose was positively related to body mass index, but not to extensor or flexor spasticity. The dose of baclofen seemed to be correlated to extensor spasticity after considering spasticity per FFM. The increased dose of oral baclofen was positively associated with increased FFM, extra- and intracellular fluid compartments and total body water, but not with FM. Oral baclofen dose was negatively associated with the homeostatic model assessment index. CONCLUSION: Administration of oral baclofen did not attenuate the protective effects of spasticity on body composition and metabolic profile after SCI. The possibility that oral baclofen could exert an independent protective effect needs to be further investigated.

Medical rehabilitation in Ghana.

PURPOSE: To explore the current system of medical rehabilitation services for persons with disabilities in a developing country (Ghana) and to identify future needs, opportunities, and barriers. METHODS: Information was obtained through a literature review and through interviews with healthcare providers, disabled people's organizations, educators, government officials, and consumers. Direct observations were made of Ghana's capital city, Accra, and of a major tertiary medical center there, Korle Bu Teaching Hospital. RESULTS: Ghana has virtually no medical rehabilitation and few laws to protect the disabled. There are no occupational therapists or physiatrists in the entire country, and only a handful of physical therapists, prosthetists, orthotists, and speech therapists. There are many barriers to the establishment of such services, including lack of funding, limited government support, cultural stigma of the disabled and poor utilization of existing resources. CONCLUSIONS: A national model for sustainable medical rehabilitation is needed in Ghana and likely in other similar countries.

The clinician effect on "objective" technical components of the electrodiagnostic consultation.

OBJECTIVE: To examine the impact of clinician factors on technical data within an electrodiagnostic consultation for low-back pain and spinal stenosis. DESIGN: Examiner differences on single-segment paraspinal mapping scores and other findings were examined in a prospective, masked, double-controlled trial involving 150 people aged 55-80 yrs who were selected for no symptoms, back pain, or possible spinal stenosis. RESULTS: Unmasked clinicians were more variable than masked physicians (F2,219 = 4.808, P =or<0.01) and gave lower scores to people they felt had mechanical back pain. The percentage of inadequate segmental scores differed among clinicians (0-16.6%, F8,226 = 4.170, P < 0.001), with fellows having more difficulty than faculty (11.76 +/- 32.38% vs. 0.75 +/- 8.67%) (t233 = 3.753, P < 0.001). Correction of clinician bias improved the relationship between paraspinal score and subjects' ability to walk (weighted regression R = 0.129, B = -0.047, P < 0.001; unweighted regression R = 0.090, B = -0.045, P < 0.001). CONCLUSIONS: Objective testing is adversely affected by clinician factors including prejudgment, experience, and individual idiosyncrasies. Less variation is found in more codified procedures. For electrodiagnostic consultation, correction of variability improves the relationship of test results to disability.

The vascularized pig fibula bone flap model: effect of segmental osteotomies and internal fixation on blood flow.

The free fibular flap is the flap of choice for reconstruction of complex mandibular defects, although two or more osteotomies may be required to recreate the normal mandibular contour. The effect of these surgical manipulations on the fibula has not been adequately investigated. This study was designed to study the effect of multiple segmental osteotomies and internal fixation techniques on blood flow in the vascularized pig fibula bone flap model. The hindlimbs of 15 Yorkshire pigs were randomized into 1 of 5 groups (n = 6 fibulae per group) consisting of: (1) a nonoperated, in situ fibula; (2) an elevated fibula flap; (3) an elevated fibula flap with two segmental osteotomies; (4) an elevated fibula with two segmental closing osteotomies rigidly fixed with 2-mm miniplates; (5) an elevated fibula with two segmental closing osteotomies rigidly fixed with 2-mm lag screws. Total and gradient blood flow was measured in the bone and soft-tissue components of these flaps using the 15-microm radioactive microsphere technique. The creation of two segmental osteotomies in the vascularized pig fibula bone flap model resulted in a significant decrease (p<0.05) in the gradient blood flow in the segment of bone distal to the second osteotomy. Application of miniplates or lag screws across closing osteotomies resulted in a significant decrease (p<0.05) in total and gradient blood flow to the bone component of the fibulae, as compared with the elevated and osteotomized fibulae groups. An increase in blood flow suggesting a hyperemic response was noted in the bone and soft tissue in the elevated and osteotomized flap groups as compared with the in situ, nonoperated controls. This study established the validity of the pig fibula as a suitable model for investigating the pathophysiology of blood flow changes in the face of standard surgical maneuvers necessary for the restoration of mandibular form and function. The results demonstrated that the creation of multiple segmental osteotomies and the application of internal fixation significantly decreases (p<0.05) blood flow to the distal portion of the flap. The effects of segmental osteotomies and internal fixation on healing and growth of the pig fibula bone flap model are investigated in a separate study.

A prevalence study of celiac disease in persons with Down syndrome residing in the United States of America.

In order to estimate the prevalence of celiac disease in persons with Down syndrome, 105 patients with this chromosomal disorder residing on the East Coast of the United States of America were enrolled in this study. IgA and IgG antigliadin antibodies (AGA) were determined using a fluorescent immunoenzymatic assay, and antiendomysium antibodies (AEA) were measured with immunofluorescence on monkey oesophagus. Of the 105 patients, 5 were positive for AEA, 4 were positive for IgG AGA, and 1 was positive for IgG AGA and AEA. Of the five patients with high titres of AEA, four consented to a jejunal biopsy, which revealed significant villous atrophy. Thus, 4 (possibly 5) patients in this cohort of 105 individuals with Down syndrome have celiac disease.

Aortic dissection, patent ductus arteriosus, iris hypoplasia and brachytelephalangy in a male adolescent.

We describe a 14-year-old male with dissection of the descending aorta, bilateral iris hypoplasia, striae distensae and brachytelephalangy, the latter being most marked in the thumbs. Inguinal herniae and a patent ductus arteriosus were surgically repaired in infancy. The pattern of abnormalities may constitute a previously undescribed syndrome. The proband died suddenly at the age of 17 years.

The vascularized pig fibula bone flap model: effects of multiple segmental osteotomies on growth and viability.

Previous work by this laboratory introduced the pig fibula bone flap as a model for the study of the pathophysiology of vascularized bone flaps. Anatomic and hemodynamic studies demonstrated a significant (p < 0.05) decrease in vascular perfusion after a series of segmental osteotomies and rigid fixation (lag screws and miniplates) in the distal end of the flap, suggesting that blood flow to the distal osteotomized segment of the flap may be impaired. Killing the animals after blood flow studies precluded assessment of the effect of these hemodynamic changes on bone healing. Therefore, the aim of this study was to assess the pig fibula bone flap model with respect to viability, healing, and subsequent growth after multiple segmental osteotomies and rigid fixation to contribute to the understanding of vascularized bone flap pathophysiology. Yorkshire pigs (20 to 25 kg) were used for all experiments. Eight pigs underwent unilateral elevation of a vascularized fibula bone flap, which was osteotomized into three segments and orthotopically rigidly fixed using a 2.4-mm mandibular reconstruction plate. The left fibula remained as the control. Fluorochrome labels were injected to assess bone viability and turnover, and both fibulae were assessed for growth radiologically. The fibulae were harvested 21 days postoperatively (when the animals were killed), and bone healing was assessed histologically and clinically. There were no significant differences in preoperative and postoperative lengths of the osteotomized fibulae compared with the controls, suggesting that there was no impairment of growth potential after multiple segmental osteotomies and rigid fixation. Significant (p < 0.05) bony hypertrophy of the osteotomized fibulae was noted when compared with controls. Mobility was observed in 3 of the 32 osteotomies (9 percent), occurring across one proximal and two distal osteotomies in association with failure of fixation. However, histologic and fluorochrome assessment confirmed the viability of all bone segments, as supported by the presence of tetracycline given 2 days postoperatively. The pig fibula bone flap model is well tolerated by the pig. Multiple segmental osteotomies and rigid fixation, previously associated with a significant decrease in blood flow in the distal segment, did not impair either growth potential, viability, or healing ability. It is suggested that the pig fibula is a suitable model for the study of bone flap pathophysiology.

Desferrioxamine ototoxicity in an adult transfusion-dependent population.

OBJECTIVE: The purpose of this study was to identify the incidence of hearing loss in a population of 75 adult (19-68 years old) transfusion-dependent patients with thalassemia major, sickle cell disease, Diamond-Blackfan anemia, and various other hematologic disorders treated with regular transfusion schedules. Ninety-three percent (70/75) of patients had a history of long-term subcutaneous or intravenous desferrioxamine therapy. METHODS: The patients underwent routine otolaryngologic history and physical examination, along with standard pure-tone audiometry at 250, 500, 1000, 2000, 3000, 4000, 6000, and 8000 Hz, with hearing loss defined as 25 dB or greater at one or more frequencies. RESULTS: Hearing loss was present in 57% (43/75) of patients. More importantly, hearing loss attributable to desferrioxamine ototoxicity was present in 29% (22/75) of patients. Sixteen patients treated previously with desferrioxamine were switched to the experimental oral chelating agent, L1. Eight of these 16 patients had hearing loss attributable to desferrioxamine, with 5 of these patients worsening with the experimental oral chelating agent L1. Seventy-nine percent (59/75) of patients were thalassemic. Fifty-four percent (33/59) of these thalassemic patients had hearing loss. However, 35% (21/59) of the thalassemic patients had hearing loss attributable to desferrioxamine ototoxicity. All thalassemic patients with desferrioxamine ototoxicity had high-frequency sensorineural hearing loss, with 33% (7/21) having a notch at 6 kHz. In addition, 5% (1/21) had notching at 3 khz. Few of the hearing losses were disabling. CONCLUSIONS: Management of these patients requires proper dosing of desferrioxamine and transfusion therapy, along with regular monitoring of body iron burden and hemoglobin. In addition, regular otolaryngologic and audiometric follow-up with special care to include the frequencies of 3 and 6 kHz may help recognize and prevent permanent ototoxicity.

Anatomic and hemodynamic study of the vascularized pig fibula bone flap model.

Despite much interest in studying the pathophysiology of experimental skin and muscle flaps to better understand the pathobiology of flap failure, relatively little has been published in the investigation of vascularized bone flaps. The aim of this study was to develop a suitable vascularized bone flap model in the pig in the hope that this model may prove useful in studying the pathophysiology of vascularized bone tissue transfer. Yorkshire pigs (17-26 kg) were used for all experiments. Anatomic studies revealed that the fibula in the hindlimb was the most suitable bone for investigation as a flap model. Anatomic dissections, radiologic investigations (plain x-rays, angiograms), and morphometric analyses of the fibulae in both hindlimbs of five animals were carried out. In a separate group of pigs (n = 6), the fibula was elevated as a vascularized flap and then blood flow was measured using the 15-microns radioactive microsphere technique. The fibula in the pig is supplied by a branch of the cranial tibial artery, running along an intermuscular septum between the posterior and anterior compartments of the hindlimb accompanied by one or two vena commitans. The bone flap is raised with a cuff of flexor hallucis longus with a length of 9.2 +/- 0.2 cm (mean +/- SEM). Blood flow measurement confirmed that the entire fibula was well vascularized when elevated on its pedicle. Gradient blood flow showed a bimodal distribution, with regions of highest blood flow noted at the proximal and distal ends of the bone flap, in areas where there were greater percentages of cancellous bone. The results of these experiments suggest that the pig fibula may be a suitable model for the study of vascularized bone flap pathophysiology.

Abnormal type III collagen produced by an exon-17-skipping mutation of the COL3A1 gene in Ehlers-Danlos syndrome type IV is not incorporated into the extracellular matrix.

A novel heterozygous mutation of the COL3A1 gene that encodes the alpha 1(III) chains of type III collagen was identified in a family with the acrogeric form of Ehlers-Danlos syndrome type IV (EDS-IV). Cultured dermal fibroblasts produced normal and shortened alpha 1(III) chains. The triple helix of the latter chain was shortened owing to a 33 amino acid deletion of Gly-184 to Pro-216. The corresponding region of cDNA lacked 99 base pairs from nucleotides 1051 to 1149. The deletions corresponded exactly to the normal sequence encoded by exon 17 of the COL3A1 gene. The proband was heterozygous for a T to G transversion at position +2 of intron 17, which resulted in skipping of exon 17. The splicing defect was not corrected by growing the fibroblasts at 33 degrees C and no other splicing variants were identified at 33 or 37 degrees C. The affected brother had the same mutation but his unaffected mother did not. Heterotrimeric type III collagen molecules containing normal and mutant chains were retained within the cell. The mutant homotrimeric molecules were modified and secreted normally and were thermally stable. These normal characteristics of the mutant homotrimers suggested that the loss of ten Gly-Xaa-Yaa triplets (where Gly-Xaa-Yaa is a repetitive amino acid triplet structure in which Xaa and Yaa are other amino acids, proline and hydroxyproline being more common in the Yaa position) did not adversely affect the formation and stability of the triple helix or the structural requirements for secretion. However, the mutant homotrimers were not incorporated into the extracellular matrix of an in vitro model of EDS-IV dermis. The EDS-IV phenotype in this family was probably due to a deficiency in the amount of normal type III collagen available for formation of the heterotypic collagen fibrils of the extracellular matrix. Intracellular and extracellular quality-control mechanisms prevented the incorporation of heterotrimeric and homotrimeric mutant type III collagen molecules into the cross-linked extracellular matrix.

Myocardial infarction resulting from coronary artery dissection in an adolescent with Ehlers-Danlos syndrome type IV due to a type III collagen mutation.

Ehlers-Danlos syndrome encompasses a group of inherited disorders of connective tissue, some of which are characterised by abnormalities of collagen metabolism. The chromosomal location, identified genes and biochemical defects, inheritance pattern, and clinical features for the various known subtypes are outlined. Prenatal diagnosis is possible for types IV, VI, VIIA1, and VIIA2. An unusual presentation of type IV Ehlers-Danlos syndrome in a 16 year old boy with an anterior myocardial infarction resulting from dissection of the left anterior descending coronary artery is reported here. A clinical diagnosis of type IV Ehlers-Danlos syndrome was made subsequently and confirmed by the reduced production, impaired secretion, and abnormally slow electrophoretic migration of type III collagen, indicating an underlying mutation in the COL3A1 gene. This patient represents the first case of type IV Ehlers-Danlos syndrome with symptomatic coronary artery dissection.

The clinical features of Ehlers-Danlos syndrome type VIIB resulting from a base substitution at the splice acceptor site of intron 5 of the COL1A2 gene.

The features of a 32 year old woman with Ehlers-Danlos syndrome type VIIB and affected members of her family, resulting from a mutation in one COL1A2 allele, were studied. Her dermal type I collagen contained alpha 2(I) chains and mutant pN-alpha 2(I) chains in which the amino-terminal propeptide remained attached to the alpha 2(I) chain. She was heterozygous for an AG-->AC mutation at the splice acceptor site of intron 5 of the COL1A2 gene. The mutation activated a cryptic AG splice acceptor site corresponding to positions +14 and +15 of exon 6 of the COL1A2 gene. In contrast to previous reports only five, rather than all 18, amino acids encoded by exon 6 were deleted in the proband. The deleted peptide removed the amino-proteinase cleavage site, but not the nearby lysine cross linking site in the amino-telopeptide of the alpha 2(I) chain. She was born with bilateral hip dislocations, knee subluxations, and generalised joint hypermobility. Bilateral inguinal herniae and an umbilical hernia were present at birth. Facial features included a depressed nasal bridge with prominent paranasal folds. The skin was soft, moderately hyperelastic, and sagged over the face. Skin fragility and easy bruising were apparent from childhood. Skin wounds healed slowly and with broad, paper thin scars. Throughout her life, she had multiple fractures of the small bones of her hands and feet following moderate trauma. Electron microscopy of the proband's dermis as well as deep fascia and hip joint capsule from her affected brother showed that collagen fibrils in transverse section were nearly circular but with irregular margins. Light microscopy of bone from her affected brother and son showed normal Haversian systems and lamellar bone. All of these tissues contained approximately equal amounts of the normal and mutant alpha2(I) chains. The findings of this study confirm that loss of the amino-proteinase cleavage site of the pro alpha2(I) collagen chains, owing to anomalous splicing of exon 6 sequences in the conversion of pre-mRNA to mRNA, produces the clinical features of Ehlers-Danlos syndrome type VIIB. The history of frequent fractures found in this family is atypical and indicates an overlap with osteogenesis imperfecta.

Rachitic syndrome after disodium etidronate therapy in an adolescent.

A 12-year-old patient with a severe traumatic brain injury developed heterotopic ossification (HO) with rapidly decreasing range of motion in multiple joints despite intensive passive range of motion exercises and the use of nonsteroidal antiinflammatory drugs (NSAIDs). His alkaline phosphatase was markedly elevated. Etidronate, 20mg/kg/d was used to control the ossification. After 7 months of continual etidronate use, the patient developed periarticular pain with widened growth plates, suggesting a rachitic syndrome. Serum laboratory panel including calcium, phosphorous, alkaline phosphatase, and vitamin D were normal. After 3 months off etidronate, radiological studies showed growth plate calcification, though not before development of bilateral slipped femoral capital epiphyses. Further improvement and resolution of all complications occurred 5 months after discontinuation of etidronate. Rachitic syndromes secondary to didronel use in a clinical setting has not been previously reported. Other possible causes for a rachitic syndromes were not present. Alternate treatments for children with or at risk for HO should be considered.

Experimental, clinical and preventive aspects of ototoxicity.

Ototoxicity is an important clinical problem and accounts for a significant proportion of sensorineural hearing loss in some parts of the world. Ototoxicity is predominantly an iatrogenic condition. However, with proper dosing, prudent monitoring of serum levels of ototoxic medications and serial audiometry, ototoxicity can be prevented. A number of the more common ototoxic medications, including aminoglycosides, erythromycin, loop diuretics, salicylates, cisplatin, deferoxamine and ototopical agents, are outlined in this review. Their pharmacology, mechanisms of action and methods of preventing complications are discussed together with animal and clinical studies.

A base substitution at the splice acceptor site of intron 5 of the COL1A2 gene activates a cryptic splice site within exon 6 and generates abnormal type I procollagen in a patient with Ehlers-Danlos syndrome type VII.

The dermal type I collagen of a patient with Ehlers-Danlos type VIIB (EDS-VIIB) contained normal alpha 2(I) chains and mutant pN-alpha 2(I)' chains in which the amino-terminal propeptide (N-propeptide) remained attached to the alpha 2(I) chain. Similar alpha 2(I) chains were produced by cultured dermal fibroblasts. Amino acid sequencing of tryptic peptides, prepared from the mutant amino-terminal pN-alpha 2(I) CB1' peptide, indicated that five amino acids, including the N-proteinase (the specific proteinase that cleaves the procollagen N-propeptide) cleavage site, had been deleted from the junction of the N-propeptide and the N-telopeptide (the nonhelical domain at the amino-terminus of the alpha chains of fully processed type I polypeptide chains) of the mutant pro-alpha 2(I)' chain. The corresponding 15 nucleotides, which were deleted from approximately half of the alpha 2(I) cDNA polymerase chain reaction products, of the alpha 2(I) cDNA polymerase chain reaction products, were encoded by the +1 to +15 nucleotides of exon 6 of the normal alpha 2(I) gene (COL1A2). These 15 nucleotides were deleted in the splicing of alpha 2(I) pre-mRNA to mRNA as a result of inactivation of the 3' splice site of intron 5 by an AG to AC mutation and the activation of a cryptic AG splice acceptor site corresponding to positions +14 and +15 of exon 6. Loss of the N-proteinase cleavage site explained the persistence of the pN-alpha 2(I)' chains in the dermis and in fibroblast cultures. Collagen production by cultured dermal fibroblasts was doubled, possibly due to reduced feedback inhibition by the N-propeptides. In contrast to previously reported cases of EDS-VIIB, Lys5 of the N-telopeptide was not deleted and appeared to take part in the formation of intramolecular cross-linkages. However, increased collagen solubility and abnormal extraction profiles of the mutant type I collagen molecules indicated that collagen cross-linking was abnormal in the dermis. The proband and her son were heterozygous for the mutation. It is likely that the heterozygous loss of the N-proteinase cleavage site, with persistence of a shortened N-propeptide, was the major factor responsible for the EDS-VIIB phenotype.