Ehlers-Danlos syndrome presenting with primary nocturnal enuresis

Abstract

Ehlers-Danlos syndrome (EDS), hypermobility type, is probably the most common EDS type, as well as the most common heritable connective tissue disorder. Bladder dysfunction is a rare clinical manifestation of EDS and manifests itself as primary nocturnal enuresis. We present a 10-year-old boy referred to the paediatrics nephrology consultation due to primary nocturnal enuresis and day time symptoms of urinary urgency. During the appointment, a tendency to joint hypermobility was noted. On evaluation the skin was hyperextensible and the Beighton score was positive. The genetic testing revealed a variant of the COL5A1 gene not yet described in the literature.

Background

Ehlers-Danlos syndrome, hypermobility type (EDS-HT), is probably the most common and least recognised, heritable connective tissue disorder.^{1 2} EDS-HT and joint hypermobility syndrome (JHS) can be a phenotypic continuum or even the same.^1–3 Bladder dysfunction is a rare clinical manifestation of both.^3–5

Case presentation

The authors present a case of a 10-year-old boy referred to the nephrology consultation for primary nocturnal enuresis. He had a positive family history of primary enuresis: mother and older brother until late adolescence. He was otherwise healthy, with adequate staturo-ponderal growth (weight and height in the 15th percentile) and psycho-motor development. Daytime urinary sphincter control was established at the age of 3. Since then, he maintained almost daily episodes of nocturnal enuresis as well as daytime symptoms of urinary urgency. Throughout the consultation, his mother mentioned his ability to hyperextend the fingers, complete shoulder dislocation and other symptoms of joint hypermobility.

The physical examination showed an adolescent with good general condition and nutritional status. He had no distinctive facial dysmorphisms or Marfanoid habitus.³ The skin was hyperextensible but had no stretch marks. His height was in the 15th percentile (134.2 cm), the armspan/height ratio was in the upper reference limit (1.03) and both foot/height ratio (0.16) and upper/lower segment ratio (0.91) were increased. Musculoskeletal examination showed bilateral hypermobility of both shoulder and phalangeal metacarpal joint of the first finger, with subluxation. On spinal assessment there were no cutaneous lesions or deformities and the neurological examination was unremarkable. No pain, movement limitation nor sensory impairment were found.

The history of a prolonged non-monosymptomatic nocturnal enuresis and the symptoms of joint hypermobility, confirmed on examination raised the possibility of concurrent pathology.

Investigations

For the aetiological investigation of the non-monosymptomatic nocturnal enuresis a thorough evaluation was performed.

Drinking and voiding diary was analysed and revealed 90% of wet nights, but no apparent increase in night time urine production (five day time and one night time voiding periods). Urine routine testing and culture were normal.

Renal and bladder ultrasonography showed kidneys in regular topography and contours; preserved dimensions (bipolar diameter of 8.3 cm); bilaterally conserved parenchyma thickness, echo-structure and differentiation; with no signs of renal lithiasis, pyelocalitic dilation or obstruction. Bladder with a maximum volume of 330 cc, thin and regular wall with no focal or endoluminal parietal lesions, with pure non-echogenic content. In the post-voiding study, the bladder had a calculated volume of about 2.3 cc, showing no significant post-voiding residue.

There were no other gastrointestinal symptoms such as constipation or encopresis. The intestinal elimination pattern was regular (once a day), and of normal characteristics (type 4 Bristol scale).

Sleep was accessed in order to screen for sleep apnoea criteria. We found no snoring or pauses in breathing during sleep nor daytime sleepiness.

On the spinal and neurological evaluation there were no signs or symptoms in favour of a tethered cord syndrome. The spine X-ray showed no signs of dysraphism.

From the cognitive and social evaluation, no attention deficit, learning disability or family problems were identified. The adolescent was currently in fifth grade and showed a good scholar performance. He lived with the nuclear family and both parents were employed.

For the evaluation of joint hypermobility, Beighton score was positive (6/9); cardiac evaluation with transthoracic echocardiogram showed an aortic root on the superior normal range of the reference limit and ophthalmological evaluation was normal.

Genetic study was performed using an extended new generation gene sequencing panel. A rare heterozygous mutation in COL5A1, the collagen type V alpha 1 chain gene, mapped to human chromosome 9q34.3 (c.691C>T) was found. This variant was not previously described in the literature. It has been reported in heterozygosity in 10 individuals in population data bases. Pathogenic variants in the COL5A1 genes lead to autosomal dominant EDS type 1.

Differential diagnosis

EDS-HT has an extreme clinical variability.² The differentials for EDS-HT must include other disorders that associate mucocutaneous fragility, joint hypermobility, chronic musculoskeletal pain and fatigue.

Other EDS syndromes, Marfan syndrome, disorders of the transforming growth factor b and some skeletal dysplasias are the most relevant diagnoses to consider during the assessment of individuals with joint hypermobility.

Treatment

Both behavioural therapy and pharmacological treatment with desmopressin 240 µg under the tongue at bedtime, had already been initiated with poor outcome. Since enuresis in the context of EDS-HT can be associated with dysautonomia, oxybutynin 0.3 mg/kg two times per day was added to the pharmacological treatment. The adolescent was encouraged to maintain all behavioural measures.

Outcome and follow-up

Combined therapy with desmopressin and oxybutynin improved the urinary urgency symptoms, and nocturnal enuresis episodes decreased by 50% within 6 months.

Discussion

EDS is a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility and tissue fragility.⁶ The main characteristics of the classic subtype (OMIM 130000) are loose-jointedness and fragile, bruisable skin that heals with peculiar ‘cigarette-paper’ scars. The 2017 international classification of EDS identified 13 variants,¹ the majority with molecular diagnosis. This is not the case of EDS-HT. Most cases have an autosomal dominant transmission, but the proportion of de novo pathogenic variant is unknown. Hypermobility type, constituting a phenotypic continuum with, or perhaps, corresponding to the JHS/EDS-HT, is likely the most common, though the least recognised, heritable connective tissue disorder.^{1 7} Despite the substantial clinical variability⁷ it was generally considered the least severe EDS.⁷

Recently the medical community started to recognise EDS-HT as a multisystemic disorder.¹ Its low prevalence, the apparent paucity and non-specific clinical findings² as well as the relatively benign course concur for the practitioners’ lack of awareness for this condition.¹ Most patients await years before reaching the correct diagnosis.

Among the various sites of disease manifestations, urogenital system represents a neglected one although several authors have demonstrated a correlation between urinary incontinence and collagen abnormalities.⁴ Pelvic floor dysfunction (overactivity and inability to relax properly) can lead to non-neurogenic bladder sphincter dysfunction that can be more common in patients with collagen abnormalities.⁴ In the case presented, this alterations associated with family history could answer for the mechanism of nocturnal enuresis.

Learning points.

• Enuresis is a common problem in paediatric age. It can lead to loss of self-esteem and significant disruption of family and social relationships. A thorough approach and correct management are fundamental.

• When enuresis is associated with joint hypermobility symptoms the differential diagnosis must include Marfan syndrome and joint hypermobility/Ehlers-Danlos syndrome.

• The heterozygote variant 9q34.3 (c.691C>T) in the COL5A1 gene can be associated with Ehlers-Danlos syndrome, hypermobility type.