A CASE STUDY OF HELIX SYNDROME: NOVEL MUTATION ASSOCIATED WITH METABOLIC ALKALOSIS AND HYPOKALEMIA IN PEDIATRICS.

Introduction:

A child presenting with hypokalemia and metabolic alkalosis is usually suspected to have Bartter’s syndrome followed by Gitelman’s syndrome. A careful history may point towards other differential diagnosis like Apparent mineralcorticoid excess, Liddle syndrome, HELIX syndrome [1].

HELIX is one of the rare multisystemic disorders presenting with hypokalemia and metabolic alkalosis and is characterised by Hypohidrosis, Electrolyte imbalance, Lacrimal gland dysfunction, Ichthyosis and Xerostomia [2].

We present a child with HELIX syndrome with a novel variant. This is rare cause of hypokalemic metabolic alkalosis where genotyping with reverse phenotyping helped to diagnose the cause.

Methods:

A 12 years old developmentally normal male child born to a non-consanguineous parents’ provisionally treated as a Bartter’s syndrome by adult nephrologist was referred to us for growth hormone therapy for short stature.

On detailed history, we found that the elder sibling of the index case was diagnosed with some kidney disorder and treated with potassium supplements. He had h/o polyuria since 12 years of age. The elder sibling passed away at 18 years of age following fever episode, details were not available.

The index case had complaints of polyuria for past 2 years and dry mouth and skin as noticed by the mother.

Initially, Gitelman syndrome was kept as a differential diagnosis but was ruled out as hypermagnesemia was present. As the child presented in adolescence and there was history of polyuria though no nocturia, a remote possibility of juvenile nephronophthisis was kept. With a strong family history and similar presentation, whole exome sequencing was sent which reported nephronophthisis and HELIX syndrome. (fig 1)

Results:

As there was history of dry mouth and skin and Whole Exome Sequencing showed homozygous missense mutation in CLDN10 gene with variant c.506C>A, p.Ala169Asp, HELIX Syndrome of uncertain significance. To confirm the diagnosis, reverse phenotyping was done and multi-disciplinary team was involved which revealed

Hypohydrosis and Ichthyosis : Dermatology team did a corn starch test which revealed hypohydrosis except in arm pit region. (Fig 2.)

Electrolyte imbalance: Hypokalemia, metabolic alkalosis, hypermagnesemia.

Lacrimal gland dysfunction: Ophthalmology team confirmed aqueous deficient dry eyes.

Xerostomia: Dental team confirmed xerostomia along with dental caries and enamel hypoplaisa. 

Figure 2: Corn starch test showing absence of sweat.

Hence, sanger sequencing of parents was sent which confirmed the presence of heterozygous variant in chr13: c.506C>A, p.Ala169Asp inn CLDN10 gene in both the parents.

Figure 3: Sanger sequencing of the parents.

DISCUSSION:

HELIX Syndrome is caused mainly due to claudin-10 (CLDN10) mutations an integral tight junction (TJ) membrane-spanning protein expressed in the kidney, skin, and salivary glands [2].

CLDN10 mutations cause a dysfunction in TJs in several tissues and, subsequently, abnormalities in renal ion transport, ectodermal gland homeostasis, and epidermal integrity [2].

In the review by Milatz S had summarized and compared the recently published studies reporting on a novel autosomal-recessive disorder based on claudin-10 mutations [3]. Patients diagnosed with this syndrome have a multidisciplinary management for controlling the symptoms.

Whole exome sequencing has revolutionized the diagnostics and helped clinicians to detect the correct diaseases in shortest possible time and start effective management.  

Conclusions:

In cases presenting with hypokalemia and metabolic alkalosis without hypercalciuria and hypomagnesemia, work up for rare genetic causes should be done.

In most of these cases, genetic testing with reverse phenotyping helps us to catch the diagnosis and manage effectively. Also, we should remember that any gene with variant of uncertain significance should not be ignored and a through evaluation should be considered.

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.