Approach to connective tissue disorders: Clinical sciences

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Introduction0:00–0:34

Connective tissue disorders occur when a component of the extracellular matrix is deficient or defective, resulting in fragility of the bones, tendons, ligaments, blood vessels, and skin.
While some connective tissue disorders cause mild manifestations, others result in chronic pain and disability due to progressive bone and joint deformity.
Because some connective tissue disorders affect long bone growth, evaluation of these patients should include assessment of stature.
Now, when a pediatric patient presents with a chief concern suggesting a connective tissue disorder, first obtain a focused history and physical examination.

H&P0:34–1:25

Children may present with chronic joint pain; recurrent joint dislocations or bone fractures; or fragile skin that heals poorly.
These children also frequently have ophthalmological manifestations, such as severe myopia; and they might have a first or second degree relative with a connective tissue disorder.
On physical exam, you’re likely to notice joint hypermobility, and you may detect changes in skeletal or facial morphology, such as excessively long or short limbs or unusual facial features.
With any combination of these findings, consider connective tissue disorder. As a next step, assess your patient’s stature.

Assess stature1:25–1:39

To do this, look at their growth curve, and calculate a midparental height, to determine whether their linear growth rate correlates with their anticipated adult height.
Now, if your patient is significantly taller than anticipated, consider connective tissue disorders that are associated with excessive growth of the long bones.

Taller than anticipated1:39–1:54

These include Marfan syndrome and homocystinuria. Let’s start by discussing Marfan syndrome.

Marfan syndrome1:54–3:34

These children usually experience chronic joint pain, and some have a history of ectopia lentis, which is dislocation of the optic lens that can result in ocular pain, myopia, and diplopia; pneumothorax; or aortic dissection.
There may also be a family history of Marfan syndrome. Exam typically reveals a patient with a tall and thin frame, and remarkably long arms and legs.
In fact, their arm-span might be longer than their vertical height! Other common findings include long fingers, which is known as arachnodactyly; as well as facial features such as a long narrow face with a small, recessed chin; and nasal bridge flattening.
You might also notice skeletal features such as pectus carinatum, pectus excavatum, and scoliosis of the spine. Although the skin has normal texture and elasticity, you may notice striae in unusual areas.
Finally, the exam might reveal a heart murmur with a mid-systolic click, consistent with mitral valve prolapse. Any combination of these classic findings should make you consider Marfan syndrome.
As a next step, order an echocardiogram, and consider genetic testing. If the echocardiogram shows aortic root dilation and the patient has a family history of Marfan syndrome, you can confirm the diagnosis of Marfan syndrome without further testing.
However, if there is no family history, order genetic testing, which may identify a mutation in the fibrillin-1 or FBN1 gene, to confirm the diagnosis of Marfan syndrome.
Next, let’s talk about homocystinuria. This is an inborn error of metabolism that results in buildup of homocysteine, a neurotoxic, thrombogenic substance that interferes with collagen and fibrillin formation and causes connective tissue dysfunction.

Homocystinuria3:34–5:04

These children often have developmental delays and progressive intellectual impairment. They may also have a history of ectopia lentis; a thromboembolic event, like a pulmonary embolism or stroke; or an abnormal newborn screen.
Exam findings are similar to those seen in children with Marfan syndrome, and include a tall, thin frame and noticeably long arms, legs, and fingers.
They may also have similar skeletal findings, like chest wall deformities and scoliosis. If you see this constellation of history and exam findings, consider homocystinuria.
Your next step is to measure levels of methionine, homocysteine, and cysteine in the plasma and urine; and consider genetic testing.
Plasma levels of methionine and homocysteine are typically elevated, while cysteine levels are low. And, as the name suggests, high levels of urinary homocysteine are diagnostic for homocystinuria.
If you ordered genetic testing, it will most likely demonstrate a mutation in the cystathionine beta-synthase, or CBS gene.
With any of these lab findings, you can confidently diagnose homocystinuria. Okay, let’s move on and look at children who are at or near their anticipated midparental height.

Anticipated height - Ehlers-Danlos Syndrome5:04–7:53

This most often suggests Ehlers-Danlos syndrome, or EDS. EDS describes a spectrum of conditions associated with joint hypermobility and pain due to collagen defects.
The most common ones are classic EDS and hypermobility EDS. Children with EDS typically experience chronic joint pain and frequent joint dislocations or subluxations.
They may also describe fragile skin that bruises and tears easily and heals poorly. Frequently, there’s a family history of EDS.
On physical exam, these patients may have joint hypermobility; and surprisingly thin and hyperextensible skin, with wide atrophic scars and striae.
Finally, you may hear a heart murmur and mid-systolic click, since some patients also have mitral valve prolapse. With these findings, consider EDS.
Here’s a clinical pearl to keep in mind! The Beighton scoring system assesses joint hypermobility through 5 standardized movements.
The first is passive dorsiflexion of the fifth metacarpophalangeal joint beyond 90 degrees, with one point given for each hand.
Next, the thumb is pulled down to touch the forearm, with one point given for each hand. One point is given for each elbow or knee that can hyperextend more than 10 degrees.
Finally, a single point is given if, when both knees are locked straight, both palms can fully touch the floor during a forward bend.
Children must have a score greater than 6 out of 9, to qualify for hypermobile EDS. Back to the diagnosis, you may choose to obtain genetic testing.
However, additional testing isn’t required, because EDS is a clinical diagnosis based on personal history of chronic joint pain; joint hypermobility and skin hyperextensibility; as well as family history.
If you do order genetic testing, the most common finding is a mutation in a collagen 5 gene, such as COL5A1 or COL5A2. Regardless of the result, if your patient meets clinical criteria for EDS, you can make the diagnosis.
Here’s a clinical pearl! Stickler syndrome is another connective tissue disorder caused by defects in collagen.
These children also grow near their expected height, experience chronic joint pain, and may have coexisting Pierre-Robin sequence and progressive hearing loss.
Genetic testing typically reveals mutations in the collagen 2, 9, or 11 genes. Finally, let’s discuss patients who are significantly shorter than the midparental height would suggest.

Shorter than anticipated7:53–9:50

In this case, consider connective tissue disorders that impair the growth of long bones, such as osteogenesis imperfecta, or OI.
This condition is also called “brittle bone disease” because it is associated with frequent fractures and low bone density due to a collagen defect.
Children with OI typically present with recurrent low-impact fractures, or in severe cases, fractures in utero or during delivery.
On physical exam, patients with OI typically have short stature with noticeably short limbs, and a triangular facial shape with a large forehead.
If you look closely, you may notice bluish-gray sclerae; as well as discolored teeth that are easily damaged, called dentinogenesis imperfecta.
These children also have other skeletal abnormalities, like rib cage flaring and scoliosis. With these characteristic findings, consider osteogenesis imperfecta.
As a next step, obtain X-rays, and consider genetic testing. The X-rays will usually show evidence of previous or current fractures, vertebral compressions, and bone deformities.
Imaging may also suggest osteopenia, a key feature of this “brittle bone disease.” Identification of a collagen 1 gene mutation, such as COL1A1 or COL1A2 on genetic testing confirms the diagnosis of osteogenesis imperfecta.
Now, here’s a clinical pearl! The presence of previous or current fractures on imaging, also thought of as multiple fractures in various stages of healing, often prompts us to consider non-accidental trauma.
However, you should also consider OI in these cases, especially in infants and young children. Alright, as a quick recap… Connective tissue disorders occur when a component of the extracellular matrix is deficient or defective, leading to fragile connective tissues such as bones, tendons, ligaments, blood vessels, and skin.

Review9:50–10:28

When evaluating a pediatric patient for a connective tissue disorder, start with a focused history and physical examination, and then assess stature.
Conditions associated with tall stature include Marfan syndrome and homocystinuria, while those that typically do not impact height include Ehlers-Danlos syndrome.
Finally,