Marfanoid - an overview ,
marfanoid body habitus,
In “marfanoid” hypermobility syndrome, the lens and aorta are normal, and the skin and joints are more extensible than in Marfan syndrome.
Marfanoid habitus
The features of the marfanoid habitus (MH) are listed in Chapter 1. The recognition that features of MH are seen in JHS dates back nearly three decades (Grahame et al 1981). It is always worthwhile looking for MH in any musculoskeletal examination as in JHS the features are not always obvious and incomplete forms abound. Nevertheless, the identification of MH adds * minor criterion towards the Brighton Criteria for JHS and thereby assists in diagnosis. Because JHS is so much more common than Marfan syndrome (MFS), in clinical practice MH is statistically much more likely to indicate JHS than MFS. Some of the features of MH are shown in Figure 2.7a–c.
2.2 Skeletal Manifestations
Marfanoid skeletal features based on bone overgrowth can be observed, although the actual overgrowth is usually milder in LDS patients compared to that of MFS patients. The most striking LDS skeletal findings include pectus deformities, both pectus excavatum and pectus carinatum; scoliosis; joint laxity and contractures; talipes equinovarus; and cervical spine malformation and/or instability. Arachnodactyly is present in about one-third of patients, but true dolichostenomelia (leading to an increase in the arm-span-to-height ratio and * decrease in the upper-to-lower-segment ratio) is less common in LDS patients than in MFS patients. Joint hypermobility is very common and includes congenital hip dislocation and recurrent joint subluxations. Paradoxically, some individuals can show reduced joint mobility, especially of the hands (camptodactyly) and feet (clubfeet). Other recurrent skeletal findings include spondylolisthesis, acetabular protrusion, and pes planum. Preliminary evidence suggests that individuals with LDS have an increased incidence of osteoporosis, with increased fracture incidence and delayed bone healing.
‘Wrist sign’ (Walker): positive if able to wrap the thumb and 5th finger of one hand around the opposite wrist such that the nail bed of the digits overlap with each other (Chapter 2, Figure 2.7b)
‘Thumb sign’ (Steinberg): positive if the adducted thumb across the palm projects beyond the ulnar border in the clenched hand (Chapter 2, Figure 2.7a)
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Pectus excavatum or carinatum (Chapter 2, Figure 2.7c)
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Scoliosis: Scoliosis >20 degrees is * major criteria in MFS. It is also * sign of EDS kyphoscoliotic type, and can be present in patients with OI. In other EDS variants, and in JHS it may be present, albeit to * milder degree
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Arm span : Height ratio > 1.03 (1.05 in Ghent Nosology for MFS)
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Tall stature with lower limb length (floor to pubis) : upper body (pubis to crown) ratio > 0.89 (0.85 in Ghent Nosology for MFS)
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Foot length (heel to 1st toe) : Height ratio > 0.15
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Hand length (wrist crease to 3rd finger) : Height ratio > 0.11.
The Marfanoid habitus is characteristically encountered in the MFS (Table 1.3). Many of the skeletal features of Marfan syndrome however are common in the general population. When found in combination, such findings usually indicate * disorder of connective tissue.
* marfanoid habitus may also be encountered in patients with the MASS phenotype (mitral valve prolapse, myopia, borderline and non-progressive aortic enlargement, and nonspecific skin and skeletal findings that overlap with those seen in MFS), and the mitral valve prolapse syndrome (MVPS). Both conditions are autosomal dominant and can be caused by mutations in FBN1 (see genetic section below).
Other HDCTs that show overlap with the skeletal features of MFS include homocystinuria, congenital contractural arachnodactily and Stickler syndrome.
The marfanoid habitus can, to * somewhat milder degree, be present in patients with JHS, but in this condition it is not associated with the severe ocular and cardiac complications of MFS.
Multiple endocrine neoplasia
In MEN type IIb, patients show * “marfanoid” habitus, full and fleshy lips, and nodular neuromas on the tip and edges of the tongue and on the margins of the eyelids.110 Pes cavus, constipation, and peroneal muscular atrophy are due to neuroma formation.111 It is autosomal dominantly inherited. Prominent corneal nerves within an otherwise normal cornea and nodular subconjunctival tumors are important diagnostic features (Fig. 33.24).110 Because of * very high incidence of thyroid medullary carcinoma in MEN type IIb, prophylactic thyroidectomy may be recommended in childhood. Pheochromocytoma also occurs. Enlarged corneal nerves may occur in MEN type IIa.112
Clinical Features
The affected individual has * tall, lanky, marfanoid body type, with * narrow face and with possible muscle wasting. The adrenal and thyroid tumors typically do not present until after puberty, whereas the oral mucosal neuromas usually develop during the first decade of life.489–492
The oral mucosal neuroma presents as * 2 to 7 mm yellowish-white, sessile, painless nodule of the lips, anterior tongue, and buccal commissures (Fig. 4.43A). Usually there are two to eight (or more) neuromas, with deeper lesions exhibiting normal mucosal coloration. There may be enough neuromas in the body of the lips to produce macrocheilia or enlarged, “blubbery lip” appearance. Similar nodules may be seen on the eyelids, sometimes producing eversion of the lid, and on the sclera. Facial skin, especially around the nose, may also be involved.
Abnormal laboratory values are part of this syndrome. When * medullary thyroid carcinoma is present, serum and urinary calcitonin levels are elevated.491,494 When * pheochromocytoma is present, there is often an increase in the serum levels of vanillylmandelic acid and altered epinephrine/norepinephrine ratios.494
Stickler Syndrome
Autosomal dominant and recessive Stickler syndrome (STL) is variably associated with marfanoid habitus and mitral valve prolapse (type I STL), sensorineural hearing loss and skeletal problems (scoliosis, joint hyperextensibility, spondyloepiphyseal dysplasia (SED), and premature osteoarthritis), ophthalmologic (myopia, cataracts, congenital glaucoma, and retinal detachment), and facial abnormalities (midface hypoplasia, cleft palate, and micrognathia). Intelligence is normal. Four genes account for most cases of STL. For autosomal dominant STL, Type I STL (OMIM #108300) occurs from mutations of type II collagen (COL2A1); type II STL (OMIM #60841) and type III STL (OMIM #184840) occur from disruption of the genes encoding Collagen XI (COL11A1, and COL11A2 respectively). Autosomal recessive STL occurs from COL9A1 mutation (see later discussion for allelic disorders).
Sporadic thoracic aortic disease
Patients without family history of aortic disease and who lack syndromic features such as Marfanoid features comprise approximately 80% of all thoracic aortic disease cases and are classified as patients with sporadic thoracic aortic disease (STAD). Genome-wide association studies (GWAS) identified FBN1 as * common variant which confers 1.6–1.8-fold increased risk for STAD.47 Duplications of 16p13.1, * region containing nine genes including MYH11, were also identified as * genetic alteration that increased the risk for TAAD.29 However, compared to the 1.6-fold increased risk for TAAD associated with FBN1 common variants, duplications of MYH11 have * 12-fold risk for TAAD, warranting closer clinical management of these patients and early screening for aortic disease. These studies indicate that both rare and common variants in FBN1 and MYH11 are associated with thoracic aortic disease.
Homocystinuria: an inborn error of metabolism with marfanoid appearance, fair complexion, osteoporosis, mental deficiency, circulatory insufficiency and thromboembolic events (sometimes precipitated by general anaesthesia). Heterozygotes have hyperhomocysteinaemia with an increased risk of premature (age <50 years) retinal vein, and retinal artery occlusion.
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Weil-Marchesani syndrome: short stature, reduced joint mobility, myopia, microsperophakia, and pupil block from displaced lenses.
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153.6.16 Lujan–Fryns Syndrome (OMIM 309520)
One of the most commonly – and incorrectly – used descriptors in clinical genetics is the term marfanoid. Typically, the word is used for anyone who appears tall and slender with an elongated face and dolichostenomelia. The appearance of ‘marfanoid’ in * consultant’s report is often enough to prompt the primary care physician to request * genetic evaluation; in my experience, few such individuals have Marfan syndrome, so the predictive value of * ‘marfanoid habitus’ seems quite low (292). There are good reasons to suggest that the term should be discarded altogether.
‘Marfanoid’ was used to describe males who were initially ascertained on account of mental retardation (366). Those affected were not actually tall, but were slender, had elongated arms, and had characteristic craniofacial features of * long narrow face, retrognathia, and * highly arched palate. Inheritance was consistent with X-linkage. Fryns (367) reported several cases, and the condition is commonly called Lujan–Fryns syndrome. For the reasons noted previously, this is preferable to the other name, X-linked mental retardation with marfanoid habitus. In one institutionalized population of mentally retarded adults, 5% of males had * form of X-linked mental retardation, and 10% of them had Lujan–Fryns syndrome (368). In addition to retardation, most, but not all, patients have neurobehavioral abnormalities (369). Subsequently, the phenotype has been reported in occasional female relatives of probands. Few patients have had comprehensive cardiovascular evaluation, which should be performed given the report of ventricular septal defects and aortic root dilation in two relatives with Lujan–Fryns (370).
Several probands have mutations in the MED12 gene, and the mutation segregates with the condition in the families (371). Lujan–Fryns syndrome is thus allelic with Opitz–Kaveggia syndrome (OMIM 305450).
Homocystinuria
Homocystinuria is an autosomal recessive connective tissue disease associated with mental delay, ectopia lentis, marfanoid habitus, osteoporosis and early onset thrombotic vascular disease. The occurrence of homocystine in the urine may result from * number of different genetic defects, the most common of which is * deficiency in cystathionine b-synthetase. This enzyme is important in the transsulfuration pathway, responsible for the conversion of methionine to cysteine and ultimately to sulfate. Homocysteine is an intermediate in the transsulfuration pathway, and defective cystathionine b-synthetase activity leads to an accumulation of methionine and homocysteine in plasma [103].
The multisystem toxicity of hyperhomocysteinemia is attributed to its spontaneous chemical reaction with many biologically important molecules, primarily proteins. Irreversible homocysteinylation of proteins leads to cumulative damage and progressive clinical manifestations. Krumdieck et al. [104] noted that the glycoprotein fibrillin-1 is particularly susceptible to homocysteine attack through homocysteinylation of the epidermal growth factor (EGF)-like domains of the molecule. Fibrillin-1, the main structural component of elastin microfibrils [105], is found in the medial layer of all elastic arteries, and in bone, cartilage, skin, and the suspensory ligament of the lens, all structures that are compromised in both MFS and homocystinuria. The recent mutations described in the fibrillin-1 gene giving rise to the MFS phenotype support the hypothesis that fibrillin-1 is an important target of homocysteinylation and that damage to its structure may be responsible for many of the abnormalities that severe hyperhomocysteinemia has in common with MFS, including osteoporosis.
* number of skeletal manifestations have been demonstrated in homocystinuria, including scoliosis, arachnodactyly, enlarged carpal bones, pectus excavatum/carinatum, limb deformity (bowing), humerus varus, joint contractures and pes planus/cavus. Osteoporosis was first noted on plain radiographs [103,106]. In * report of 26 patients, 25 were found to be osteoporotic on plain radiographs, and 19 showed vertebral compression fractures. Yap and Naughten [107] reported their 25 years of experience with 25 Irish homocystinuric patients (age 2.5 to 23 years) who were diagnosed through * national screening program. They found by radiological examination that osteoporosis was present in 33 percent of patients who were non-compliant with medical therapy. Osteoporosis was absent in all of the 18 compliant patients. * recent report of osteoporosis among 6 adult patients (ages 27 to 48 years) with * late diagnosis of homocystinuria showed significant reduction in BMD at the femoral neck [108], with even more profound reduction in the spine. These authors found that the osteoporosis was not more severe in the oldest patients compared to the younger ones. Taken together, these findings suggest that osteoporosis is * common feature of homocystinuria, that it is present at an early age, and that medical treatment may alter the severity of the disease.
The treatment of patients with homocystinuria due to * defect in cystathionine b-synthetase includes vitamin B6, low methionine diet and recently, adjuvant therapy with betaine. This agent lowers plasma homocysteine through augmentation of homocysteine methylation to methionine [109]. At the present time, the clinical significance of the low bone mass and its relation to fractures risk in this disease are unknown.