Approach to connective tissue disorders: Clinical sciences

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. 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. 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. These include Marfan syndrome and homocystinuria.

Let’s start by discussing Marfan syndrome. 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.

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.