Kyphoscoliotic EDS

Kyphoscoliotic Ehlers-Danlos syndrome is the EDS subtype that presents at birth with a floppy newborn whose spine begins curving in the first months of life. The clinical anchor is congenital severe muscular hypotonia paired with progressive kyphoscoliosis. The dominant long-term clinical problem is the spine. The dominant short-term clinical problem is delivering and feeding an infant whose neuromuscular tone makes both unusually hard.

The molecular biology

Kyphoscoliotic EDS is autosomal recessive. Two genes are recognized in the 2017 international classification: PLOD1 and FKBP14. Both forms produce a similar core clinical picture, with subtype-specific differences.

The PLOD1 gene encodes lysyl hydroxylase 1, an enzyme that hydroxylates specific lysine residues in collagen propeptides. Hydroxylysine is the substrate for the crosslinks that lock collagen fibrils into their final configuration. Without functional lysyl hydroxylase 1, collagen crosslinking is incomplete, and the connective tissue is mechanically weak. Affected individuals have an elevated ratio of urinary deoxypyridinoline to pyridinoline, which can support biochemical diagnosis when genetic testing is delayed.

The FKBP14 gene encodes a peptidyl-prolyl isomerase that participates in collagen folding. The FKBP14 form, characterized in 2012, includes the kyphoscoliotic features plus progressive sensorineural hearing loss and a higher rate of vascular complications than the PLOD1 form.

Clinical features

Newborns with kEDS present with severe generalized muscular hypotonia. The infant is floppy. Feeding is difficult. Gross motor milestones, when they come, are delayed. Kyphoscoliosis develops in the first months to years and progresses through childhood. Generalized joint hypermobility is severe, with frequent dislocations of large joints. Skin is hyperextensible and bruises easily. Sclerae may be blue. The cornea may be small and fragile, and globe rupture from minor trauma has been reported.

Other features include muscle weakness that persists throughout life, scoliosis that requires bracing and often surgery, joint contractures that develop over time, and progressive loss of mobility. Vascular fragility is present and can produce arterial dissection or rupture in adulthood, more frequently in the FKBP14 form. Hearing loss in the FKBP14 form typically progresses through childhood and adolescence.

Diagnosis

Diagnosis is by clinical pattern plus confirmatory testing. PLOD1 sequencing identifies pathogenic variants in the major form. FKBP14 sequencing identifies the second form. A urinary deoxypyridinoline-to-pyridinoline ratio, when elevated, supports the PLOD1 diagnosis biochemically. The 2017 international classification specifies major and minor criteria.

Kyphoscoliotic EDS is rare. Reported prevalence is well below 1 in 100,000. The condition is reported worldwide.

What management looks like

There is no FDA-approved disease-specific drug therapy. Standard of care is multidisciplinary and lifelong. Spinal deformity is managed with orthotic bracing in infancy and childhood, physical therapy to maintain strength and joint stability, and surgical correction when curvature progresses despite conservative measures. Anesthesia for spinal surgery in kEDS is delicate because the cervical spine is unstable and intubation can produce significant injury. Spinal surgery in kEDS is concentrated at experienced pediatric orthopedic centers.

Joint management mirrors other EDS subtypes: physical therapy, bracing for unstable joints, careful activity modification, and management of chronic pain. Eye protection counseling is important because the cornea can rupture from blunt trauma. Cardiac and arterial surveillance with periodic imaging is reasonable, particularly in the FKBP14 form. Hearing assessment in the FKBP14 form is part of routine pediatric surveillance.

Anesthesia in any kEDS context warrants advance planning. Cervical instability, vascular fragility, skin fragility, and respiratory considerations from chest wall deformity in advanced kyphoscoliosis combine to make routine procedures non-routine.

Genetic counseling addresses the 25 percent recurrence risk for siblings of an affected child and the implications of carrier status in parents and other family members.

What this looks like for a family

An infant born with severe hypotonia is referred from the neonatal intensive care unit to a metabolic and genetic workup. The differential is long: congenital muscular dystrophies, mitochondrial disease, the Prader-Willi spectrum, other connective tissue disorders. Lysyl hydroxylase activity in cultured fibroblasts is reduced. PLOD1 sequencing returns biallelic loss-of-function variants. The diagnosis is kEDS, PLOD1 form.

The family meets the orthopedic surgeon who will manage the spinal curvature, the physical therapist who will work on feeding and motor skills, the geneticist who will counsel about future pregnancies, and the ophthalmologist who will monitor the cornea. The clinic that will hold all of this for the next eighteen years is a pediatric tertiary center that has seen kEDS before. The number of those centers in any given country is small.

That is what kEDS care looks like in practice: a multidisciplinary clinic that has seen the pattern, and a family that has the geographic and financial means to reach it.