In front of a floppy infant, a large variety of disorders must be considered, ranging from genetic and chromosomal anomalies (e.g., Down Syndrome, Prader Willi,), neuromuscular diseases, peripheral neuropathies, inborn errors of metabolism, infantile botulism, SMA, congenital muscular myopathies and connective disorders [
7,
8]. A complete neuromuscular workup is usually recommended, but accurate physical examination can orientate the physician toward the diagnosis, limiting unnecessary and expensive tests. In particular, the presence at the birth of mild or severe kyphoscoliosis, together with joint hypermobility and the absence of the lingual and lower lip frenulum, should suggest an EDS [
9‐
12]. The presence of kyphoscoliosis should evoke the kyphosclotic type of EDS prompting the execution of urine analysis. In presence of a normal LH/HP ratio a rare form due to FKBP14 mutation should be considered and genetically ruled out. The major EDS VI clinical features include congenital muscle hypotonia, congenital or early-onset kyphoscoliosis and generalized joint hypermobility with multiple dislocations/subluxations. Minor clinical features include skin hyperextensibility, easily bruisable skin, rupture/aneurysm of a medium-sized artery, osteopenia/osteoporosis, blue sclerae, hernia (umbilical or inguinal), pectus deformity, marfanoid habitus, talipes equinovarus, and refractive errors (myopia, hypermetropia) [
13]. Moreover, there are other gene-specific minor criteria to be considered. In PLOD1 gene mutation disease, they are: skin fragility (e.g. atrophic scarring, friable skin), scleral/ocular fragility/rupture, microcornea, and facial dysmorphology (e.g. low-set ears, epicanthal folds, down-slanting fissures, synophrys, high palate). In FKBP14 gene mutation disease, minor criteria are congenital sensorineural, conductive or mixed hearing impairment, follicular hyperkeratosis, muscle atrophy, bladder diverticula. (Table
1) [
14]. The presence of the first two major criteria plus the third major criteria or plus three minor criteria, suggest the EDS type VI diagnosis. The role of clinical criteria is to guide the execution of molecular testing, due to the wide genetic heterogeneity and phenotypic variability of EDS subtypes and the clinical overlap between many of these. The importance of the exact molecular determination is found in the impact it has on the patient’s care and allows a correct management of the problem. Long term follow-up in these patients is mandatory due to the variety of complications they can experience.
Table 1
Major and minor clinical criteria in EDS (adapted from) [
14]
| • Skin hyperextensibility | PLOD1 |
| • Easy bruisable skin | • Skin fragility |
• Congenital muscle hypotonia | • Rupture/aneurysm of a medium-sized artery | • Scleral and ocular fragility/rupture |
| • Osteopenia/osteoporosis | • Microcornea |
• Congenital or early onset kyphoscoliosis | • Blue sclerae | FKBP14 |
| • Hernia (umbilical or inguinal) | • Congenital hearing impairment |
• General Joint Hypermobolity | • Pectus deformity | • Follicular hyperkeratosis |
| • Marfanoid habitus | • Muscle atrophy |
| • Talipes equinovarus | • Bladder diverticula |
| • Refractive error (myopia, hypermetropia) | |
All patients should be aware of their skin fragility. The use of protective garments to be worn under clothes is recommended to reduce skin injuries, and expert surgeons should be involved in the need for suturing of any wounds. Since vascular ruptures have been reported, a cardiovascular assessment and regular follow up imaging may be required upon diagnosis. In particular, due to the risk of aortic root dilatation, it is advised to perform valve imaging by echocardiography (and possibly further examination with computed-tomography, angiography, magnetic resonance angiography) to measure the aortic root size by the age of 5 and to evaluate the presence of mitral or tricuspid valve prolapse [
15]. Adults with severe kyphoscoliosis are at risk complications from chronic respiratory failure, recurrent pneumonia and cardiac failure. Recurrent joint dislocations are a common serious problem. Osteoporosis occurs in all individuals. The majority of patients have microcornea, but glaucoma and retinal detachment can also occur [
13,
16].