Case Based Pediatrics For Medical Students and Residents
Department of Pediatrics, University of Hawaii John A. Burns School of Medicine
Chapter IV.5. Inherited Connective Tissue Disorders
Steven C. Crook, MD
August 2002

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A 3 year old male presents to the ER with a gross deformity of his left upper arm. His mother reports that her son "slipped while taking a bath" and struck his arm on the side of the tub. He has a history of a previous right femur fracture that resulted from a fall down the stairs one year ago. In addition to the gross deformity to the left humerus, his physical exam is notable for bluish sclera and no other signs of trauma (no bruising or scars). A skeletal survey is ordered by the ER physician, who thought that the injury did not fit the history provided by the parent. The plain films reveal a comminuted fracture in the middle of the left humerus, and signs of multiple healed rib fractures in addition to the healed right femur fracture. The ER physician notifies child protective services (CPS) as required by law. He is later referred to a geneticist who makes the diagnosis of osteogenesis imperfecta.

The true connective tissue disorders are not the acquired immunologic disorders of lupus, rheumatoid arthritis, or vasculitis, but are instead inherited disorders of the molecules which comprise the various connective tissues. While these diseases were originally defined by their most severe presentations, their modern definitions have been broadened to recognize a spectrum of disease from the most severe cases to near-normalcy. The clinician should focus on recognizing the potentially life threatening presentations of diseases and differentiating subtle presentations from more common diagnoses.

Osteogenesis imperfecta (OI) presents in a varied range of phenotypes which share a common molecular basis: a defect in type I collagen production. Type I collagen, the principal structural component of all bones, is composed of 3 procollagen proteins: 2 copies of the gene product of COL1A1, and 1 copy of the gene product of COL1A2. Eighty to ninety percent of individuals diagnosed with OI have mutations in one of these two genes, but the number of different mutations in each of these genes is so great that DNA testing is not feasible. Molecular confirmation of an OI diagnosis is achieved through culturing dermal fibroblasts, isolating and amplifying the genes and gene products of COL1A1 and COL1A2, and assessing the quantity and quality of these procollagen proteins. The classic clinical description of OI is a combination of fragile bones, blue sclera, and deafness. Sillence described four distinct types of OI. More recently however, we have learned that the clinical variability of OI is so great as to render these distinctions solely of academic importance.

In its most severe form, OI is incompatible with life. Affected infants are either stillborn or die in the early neonatal period as a result of extreme skeletal fragility. These patients produce a normal quantity of structurally defective collagen. In its mildest form, OI causes bones to be more brittle than normal, resulting in a propensity for fractures to occur or it may go undiagnosed entirely. These patients do not produce malformed collagen; instead they produce less than normal quantities of normal collagen. Life span may be affected in the extreme, or not at all. Hearing loss may be present at birth, develop in childhood, or may never occur. The color of the sclera ranges from a striking dark blue to normal white. Predicting prognosis in early life is very difficult and is best achieved by sorting the patient into one of the four Sillense groups upon which most research is based. Rough prognosis for future ability to walk is based on the ability to sit independently by 10 months of age. OI does not affect cognitive ability.

Treatment always includes physical therapy and often includes orthopedic intervention. The critical goal is achieving greater than 3/5 muscle strength in the proximal muscle groups of the extremities. Fine motor skills are usually unaffected by OI. Bowing of long bones is very common and if the curvature is greater than 40 degrees, prophylactic intramedullary rodding is often performed. A careful fracture history is important to target weak bones in an individual and specifically strengthen the muscles around those bones. Growth failure is quite common but incompletely understood. While no medical therapy is currently available, there are several theoretical gene therapy interventions. As the most severe form of OI is caused by incorrectly formed type I collagen, the use of antisense RNA or ribosomal RNA to prevent the translation of mutant collagen would convert a severe form of OI into a less severe one. Other researchers are working on bone marrow transplant of cells that produce normal collagen in order to increase the amount of type I collagen available for bone construction.

As the case illustrates, the recognition of OI is crucial to differentiating abuse from accidental or pathological trauma. The prevalence of OI recognizable at birth is 1 in 20,000. The actual prevalence of all OI including the mildest and least often diagnosed forms is unknown, but the disorders certainly remain quite rare. For comparison, there are an estimated 30,000-50,000 children with fractures caused by abuse each year, and approximately 200 children born each year with OI. In general, the radiographic findings of abused children include epiphyseal and metaphyseal fractures of the long bones. In contrast, OI fractures usually occur in the shaft of long bones with relative sparing of the metaphysis. Rib fractures occur in both; however, it is the consensus of radiologists and clinicians that in the vast majority of cases these two causes of fracture can be differentiated. If doubt persists, a geneticist should be consulted to determine if biochemical analysis of dermal fibroblasts would be useful.

In general, the severe forms of OI which result in infant death, are inherited in a recessive manner since this is the only way that such a mutation would be able to remain in the gene pool. The more occult forms of OI are usually inherited in an autosomal dominant pattern, which means that the family history should be positive. A family history which is positive for family members who have frequent fractures (especially those which occurred with minor trauma), scoliosis or other orthopedic conditions, should strongly raise the suspicion of OI. Family history is not totally reliable since there is variability in the expression of the condition and there are many spontaneous mutations.

Marfan syndrome is a spectrum of abnormalities involving the skeleton, great vessels, and eyes resulting from defects in a single gene responsible for a component of elastin. Fibrillin 1 is the protein produced from the gene FBN1 which is found mutated in nearly all cases of Marfan syndrome. The protein is used to create microfibrils which form elastin and are also used to anchor some tissues (e.g., suspensory ligament of the lens). Marfan syndrome is autosomal dominant and hundreds of defects have been found in the FBN1 gene; all of which create defective fibrillin proteins in normal quantities. The diagnosis is based on a clinical constellation. Four of the following major criteria must be present: pectus carinatum (pigeon breast), pectus excavatum (concave sternum) sufficiently severe to require surgery, reduced upper to lower segment ratio (measurements of pubis to top of head and pubis to soles, respectively), positive wrist and thumb signs (thumb protrudes beyond 5th finger when a closed fist is made), scoliosis greater than 20 degrees of curvature, reduced extension of elbows, medial displacement of medial malleolus causing pes planus (flat foot or collapsed longitudinal arch), or protrusio acetabuli (inward bulging of the acetabulum into the pelvis). If a family member has been diagnosed with Marfan syndrome, then the presence of a single major criteria along with several of the following minor criteria is sufficient: pectus excavatum (not requiring surgery), joint hypermobility, high arched palate, or typical facial appearance. There is no mental retardation or negative impact on cognitive development.

Life expectancy is reduced in Marfan syndrome. This is commonly due to progressive dilation of the aortic root and an increased risk of aortic dissection with advancing age. Death often occurs in the third decade in the absence of palliative surgery to prevent aortic valvular regurgitation and aortic rupture. Considerable debate remains among the surgical community as to the proper timing of prophylactic aortic arch repair. Currently, an aortic diameter of 50 mm along with cardiac symptoms is a conservative guideline, as death is common with root enlargement beyond 50 mm.

As with all of the heritable disorders of connective tissue, Marfan syndrome presents along a spectrum of severity. It is crucial to consider this diagnosis in patients with long thin limbs, joint laxity, or vision problems because the potentially lethal cardiac complications of the disease can be prevented. However, it is important to note that many patients with Marfan syndrome do not have the typical Marfanoid appearance. Likewise, it is important to keep in mind that patients in their twenties and younger can present with aortic root dilation causing aortic regurgitation, aortic dissection and aneurysm. When the diagnosis is suspected, an echocardiogram (to measure aortic root size) and a slit lamp examination (looking for ectopia lentis, an upward dislocation of the lens, is present in 50-80% of cases) should be performed.

Ehlers-Danlos is a group of inherited defects involved in the production of collagen fibers. The result is a wide clinical spectrum of diseases which share hyperextensible doughy skin (often described as having a velvety soft texture), atrophic scars, joint hypermobility, connective tissue fragility, and bruising. The defect can occur at any step in the production of collagen fibers. The procollagen fiber itself can be defective, as can enzymes which perform the post-translational hydroxylation of lysine or any of the enzymes which chaperone (i.e., molecular regulation) the assembly of procollagen fibers into normal collagen. Several different genes have been identified but many cases remain without molecular description. The disease occurs in up to 1/5000 live births, making this the most common of the connective tissue disorders. Clinical presentation usually occurs after birth. Many distinct phenotypes have been described, but as with the other connective tissue disorders, the majority of affected individuals do not fit into these groupings.

Skin fragility is caused by a thin dermis depleted of collagen fibrils. Splits or tears over bony prominences are common. Minor trauma cause widely gaping wounds which heal slowly. Surgery is complicated by frequent wound dehiscence. Patients will often present to ERs with a history of multiple lacerations requiring suture closure despite relatively minor trauma. Vascular fragility may be due to defects in collagen type 3, resulting in vessels with low tensile strength. In these individuals, aneurysms, arteriovenous malformations, and dissections are common. Ecchymoses are present with hemosiderin deposits over bony prominences. Hyperextensibility and joint hypermobility are caused by ligamentous laxity (which predisposes to dislocated hips in infants). Clubfoot, joint effusions, and spondylolisthesis (vertebral displacement) may also be present. The gastrointestinal tract can be similarly affected; decrease in tensile strength of the bowel walls predisposes to spontaneous rupture. Bony involvement usually manifests as kyphosis. Individuals diagnosed with E-D usually display one or a combination of these different symptoms. Life expectancy is highly variable in Ehlers-Danlos. The most severe complications of disease result from bowel and vasculature weakness. Hypermobility syndromes represent the mild end of the spectrum described by the Ehlers-Danlos disorders. No curative therapy is available. Vitamin C helps some individuals who are deficient in lysyl hydroxylase (which uses vitamin C as a cofactor in strengthening collagen fibers).

Other Connective Tissue disorders: Homocystinuria is an inborn error of methionine metabolism which results in a Marfan-like syndrome. The two disorders are differentiated by the presence of mental retardation in homocystinuria. Stickler syndrome is a constellation of progressive myopia, sensorineural hearing loss and hypomobility associated with distinct facial features. The diagnosis is suspected in neonates with swollen wrists, ankles or knees, and in children with hearing loss and marfanoid characteristics.


1. How is osteogenesis imperfecta differentiated from child abuse?

2. How are future fractures prevented in children with OI?

3. Name 3 major criteria for Marfan syndrome

4. What is the most common cause of early death in children with Marfan syndrome?

5. What are 3 of the cardinal features of Ehlers-Danlos?

6. How is homocystinuria differentiated from Marfan syndrome clinically?

Related x-rays

Occult osteogenesis imperfecta case: Yamamoto LG. Fussiness Following Minor Trauma in an Infant. In: Yamamoto LG, Inaba AS, DiMauro R (eds). Radiology Cases In Pediatric Emergency Medicine, 1999, volume 6, case 2. Available online at:

Severe osteogenesis imperfecta case: Yamamoto LG. Vomiting and Coughing in a 3-Month Old With Weak Bones. In: Yamamoto LG, Inaba AS, DiMauro R (eds). Radiology Cases In Pediatric Emergency Medicine, 1999, volume 6, case 3. Available online at:

Aortic dissection case: Feng AK. Severe Acute Chest Pain in an Adolescent. In: Yamamoto LG, Inaba AS, DiMauro R (eds). Radiology Cases In Pediatric Emergency Medicine, 1995, volume 3, case 12. Available online at:


1. Pyeritz RE. The Marfan syndrome. Ann Rev Med 2000;51:481-510.

2. Royce PM, Steinmann B (eds). Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects 2nd edition. 2002, New York: John Wiley & Sons.

3. Tosi L. Osteogenesis imperfecta. Curr Opin Pediatr 1997;9:94-99.

Answers to questions

1. Presence of associated physical findings. Family history. Location of fracture (femur and radius vs tibia and radius), type of fracture (comminuted mid shaft vs epiphyseal and greenstick). Radiographic appearance of the fractures (i.e., presence of osteopenia).

2. Careful fracture history, identifying weak bones, and targeting physical therapy to strengthen those bones.

3. Any of the following: pectus carinatum (or excavatum sufficiently severe to require surgery), reduced upper to lower segment ratio, positive wrist and thumb signs, scoliosis greater than 20 degrees of curvature, reduced extension of elbows, medial displacement of medial malleolus causing pes planus, protrusio acetabuli.

4. Aortic root dilation causing aneurysm and dissection.

5. Any three of the following: hyperextensible doughy skin, atrophic scars, joint hypermobility, connective tissue fragility, and bruising.

6. Marfan syndrome, unlike homocystinuria, is not associated with mental retardation.

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