The LAMA5-related syndromes are multisystem disorders characterized by a modified function of LAMA5 protein in its role as master regulator molecule in tissue homeostasis and turnover. LAMA5 drives these biological functions by interacting with other ECM molecules, circulating hormones and vitamins, inflammatory cytokines and neuroimmunomodulator factors. For example, laminins exert an anti-fibrotic role in driving wound healing processes through their interplay with oestrogens. LAMA5 dominant mutations emphasize this physiological role thus leading to delayed wound healing and atrophic scars. Another important function of laminins is the organization of the histoarchitecture (cellular density and orientation) of body tissues. Clinical features in the LAMA5-related syndromes can be connected to alterations of these functions.
Growth parameters and developmental anomalies
Height and weight are in the lower percentiles from early infancy to adolescence. Reduced head circumference, platybasia, delaying in cranial sutures closure. Growth parameters return to normal during puberty in dominant mode of inheritance. Hypotonia with weak sucking and crying and possible restrictive ventilatory failure requiring mechanical ventilation. Impaired swallowing with need for gastric tube feeding possible. Normal mental and cognitive development.
Dysmorphic features
Recessive inheritance: elongated face, elevated arch palate, ptosis, mild facial body hirsutism, severe scoliosis.
Dominant inheritance: mild alopecia, dry and brittle hair, lack of eyebrows, dental abnormalities (tooth germ alterations and dental crowding) and dental crowding, gingival retraction, mild to severe scoliosis possible.
Neurological features
Recessive inheritance: hypotonia at birth, inability to ambulate, facial muscle twitches and tics, ptosis and weakness of extraocular, facial, tongue, and soft palate muscles, moderate weakness of neck flexors and proximal limb muscles, depressed deep tendon reflexes, normal serum CPK, mild brain atrophy at MRI, severe neuromuscular transmission failure with reduction of compound muscle action potential (CMAP) with 55% decrement at 2 Hz repetitive nerve stimulation with more than 250% increment of CMAP amplitudes immediately after 30 s of maximal muscle activation.
Dominant inheritance: muscle pain and fatigability, persistent mild hyperCKemia, waddling gait, hyperlordosis and difficulty in passing from sitting on the ground to standing, normal electrophysiology, mild primitive myopathy with variability of fibers calibre and a degeneration/regeneration pattern of both types 1 and 2 fibers.
Ocular findings
Mild symmetrical ptosis, pseudoexophthalmos, night blindness, hypovolted scotopic traces and extinction of photopic waves at flash electroretinogram (ERG), vitreous abnormalities (Posterior Precortical Vitreous Pocket and Posterior Vitreous Detachment).
Osteoarticular and skeletal findings
Recessive inheritance: Severe scoliosis, articular flexion contractures.
Dominant inheritance: Mild to severe scoliosis, joints pain, serum-negative osteoarthritis, articular cartilage erosion and intra-articular effusions (hip, knee), temporo-mandibular joint dysfunction, joint laxity.
Gastrointestinal features
Dominant inheritance: Visceral prolapse, rectal prolapse, haemorrhoids and rectocele, duodenal villous atrophy, glandular crypt hyperplasia, surface enterocytes of low height, irregular brush-border and intraepithelial lymphocytes number increase, cardial incontinence and hiatal hernia. Chronic/recurrent gastritis. Lactose intolerance and celiac like-syndrome.
Endocrinological features
Hyphothyroidism with hypotrophic/ hypoplastic thyroid, insuline-resistance like syndrome.
Urogenital features
Floating kidney, uterine fragility/rupture, pelvic prolapse (nulliparous also).
Skin abnormalities
Dermal papilla poorly developed, thin germinative layer, rarefied hair follicle, wound healing with impaired scarring.