Integrins play a vital role in cellular interactions. Interstitial lung disease with nephrotic syndrome and junctional epidermolysis bullosa (ILNEB syndrome) is an autosomal recessive disorder caused due to deficiency of integrin a3. Of the reported 9 cases [1-6], most patients with homozygous ITGA3 mutations died in infancy. We present a variant of ILNEB syndrome with delayed presentation of renal and life-threatening respiratory symptoms and prolonged survival past early childhood.

A 9-year-old female child, second born to third degree consanguineous parents, was admitted with complaints of insidious onset breathlessness for 6 months. She was apparently normal till 2 years of age when she developed blistering skin lesions that healed with scarring. She complained of passing foamy, frothy urine, and periorbital puffiness on and off from 4 years of age but was never treated with any chronic medications. Renal symptoms had not progressed for last five years. She also had a history of excessive tearing of eyes and loss of eye lashes and eyebrows. The antenatal and perinatal history was uneventful and developmental milestones were appropriate for age. Examination revealed growth retardation, normal mentation, superciliary madarosis, epiphora, scarring alopecia of scalp, icthyosis in both arms, forearms, and legs, toe nail dystrophy, healed atrophic scars over body, hyperlinearity of palms and soles, and clubbing of digits (Web Fig. 1 a-d). She was tachypneic at rest with an oxygen saturation of 95% in room air. Investigations showed blood urea 35 mg/dL, serum creatinine 0.7 mg/dL, serum sodium 136 mEq/L, serum potassium 3.9 mEq/L, urine albumin 3+, urine protein/creatinine ratio 6.9, 24-hour urine protein 4.95 g/day, serum albumin 3 g/dL, serum cholesterol 397 mg/dL, and respiratory alkalosis with normal anion gap metabolic acidosis on blood gas. Ultrasound abdomen revealed contracted right kidney (6.3 cm), a cortical cyst (1.5 cm) over the left kidney (8.6 cm) and grade 2 renal parenchymal disease indicative of bilateral hypo-dysplastic kidneys (an anomaly in the CAKUT spectrum). A micturating cystourethrogram was normal, ruling out vesicourethral reflux. Considering her clinical scenario, the renal biopsy was deferred. High resolution computed tomography of the chest showed features of interstitial lung disease (Web Fig. 1e). Skin biopsy done at the age of 4 years had revealed blisters within the lamina lucida, and she currently had atrophic scars. A provisional diagnosis of ILNEB syndrome was made. Next generation sequencing of an EDTA sample of her peripheral blood revealed a homozygous 3’ splice site mutation (c.1825-1G>A) in intron 13 of the ITGA3 gene which resulted in frameshift and formation of a premature termination codon in exon 14, p.(Val609SerfsTer31) (Web Fig. 1f). She was advised for regular follow-up but succumbed to respiratory complications after 6 months.

Nine patients have been reported earlier [1-6], 7 among them had homozygous ITGA3 mutations. Six among these 7 cases presented with symptoms at birth and expired before two year of age [1-4]. The seventh patient presented in his late teens with isolated involvement of skin and mucosa without any systemic symptoms. The authors suggest that the low level of mutant ITGA3 expression might explain the lack of systemic involvement in this patient. Two other patients were siblings with compound heterozygous ITGA3 mutations without renal involvement and were viable [5]. The case presented here has a homozygous ITGA3 mutation that that is predicted to result in a truncated or dysfunctional ITGA3 protein. Residual activity of the truncated ITGA3 protein could explain the survival of this patient past infancy. Unlike other reported cases of ILNEB where respiratory involvement manifested within few days of life, the present case manifested with dermatological symptoms earlier and later developed renal and respiratory symptoms.

Presence of skin and renal complaints in a patient should make us suspect pulmonary involvement. This will allow an early diagnosis of the disease in order to initiate appropriate management of the complications and genetic counselling.
Contributors: SUT: worked up the case and drafted the manuscript; SS,AS: helped in diagnosis, management, and manuscript revision.

Funding: Institute of Child Health and Hospital for Children, Madras Medical College, Chennai, India.
Competing interest: None stated.

References

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2. Nicolaou N, Margadant C, Kevelam SH, Lilien MR, Oosterveld MJ, Kreft M, et al. Gain of glycosylation in integrin alpha3 causes lung disease and nephrotic syndrome. J Clin Invest. 2012;122:4375-87.

3. Yalcin EG, He Y, Orhan D, Pazzagli C, Emiralioglu N, Has C. Crucial role of posttranslational 79 modifications of integrin alpha3 in interstitial lung disease and nephrotic syndrome. Hum Mol Genet. 2015;24:3679-88.

4. He Y, Balasubramanian M, Humphreys N, Waruiru C, Brauner M, Kohlhase J, et al. Intronic ITGA3 mutation impacts splicing regulation and causes interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa. J Invest Dermatol. 2016;136:1056-9.

5. Colombo EA, Spaccini L, Volpi L, Negri G, Cittaro D, Lazarevic D, et al. Viable phenotype of ILNEB syndrome without nephrotic impairment in siblings heterozygous for unreported integrin alpha3 86 mutations. Orphanet J Rare Dis. 2016;11:136.

6. Cohen-Barak E, Danial-Farran N, Khayat M, Chervinsky E, Nevet JM, Ziv M, et al. A nonjunctional, nonsyndromic case of junctional epidermolysis bullosa with renal and respiratory involvement. JAMA Dermatol. 2019; 155:498-500.