Hypertrophic pyloric stenosis masked by kidney failure in a male infant with a contiguous gene deletion syndrome at Xp22.31 involving the steroid sulfatase gene: case report

Contiguous gene deletion syndrome at Xp22.3 resulting in nullisomy in males or Turner syndrome patients is characterized by the combination of one or more monogenic disorders and clinical findings as short stature (short stature homeobox gene, SHOX), chondrodysplasia punctata (arylsulfatase genes - ARSD, ARSE, ARSF), X-linked ichthyosis (arylsulfatase C or steroid sulfatase gene, STS), ocular albinism type I (OA1) and elements of X-linked neurodevelopmental disorders and Kallmann syndrome (KAL1; reduced hypothalamic and pituitary function with resulting hypogonadotropic hypogonadism and hypoplasia of the olfactory bulb) [1], whereas the term Rud’s syndrome should no longer be used [2]. FG syndrome 3 is also mapped to this region [3]. In large deletions, occasionally cardiac arrhythmia [4], periventricular nodular heterotopia [5], acute lymphoblastic leukemia [6], end-stage renal failure [7] and infantile hypertrophic pyloric stenosis (IHPS) [3, 4, 8‐12] were also reported. The most critical region of deletion breakpoints, characterized by a low frequency of interspersed repeats and a low GC content [13], encompasses the STS gene (MIM*300747) resulting in microsomal enzyme deficiency with an incidence about 1:1500 in males [14]. This membrane-bound enzyme is ubiquitously expressed and hydrolyzes several 3-beta-hydroxysteroid sulfates, which serve as metabolic precursors for estrogens, androgens, and cholesterol [15]. Despite the widespread enzyme deficiency, patients apparently have abnormalities only of the stratum corneum where increased cholesterol sulphate concentrations are causing abnormal desquamation, decreased corneodesmosomal degradation and retention hyperkeratosis of the skin mostly a few weeks after birth, but conatal collodion is also reported [12]. There might be associated cardiac arrhythmia and benign Pre-Descemet corneal dystrophy characterized by cholesterol sulfate accumulation and punctiform opacities without vision impairment on the one side, as well as cryptorchidism and neurobehavioral disorders due to deficient (neuro-) steroids on the other side [4, 16]. Despite the escape of lyonization, some female deletion carriers also have corneal opacities and can present parturition disturbances and cervical dystocia due to lacking placental production of estriol [4, 14]. Congenital anomalies of the kidney and urinary tract (CAKUT) have been reported rarer in STS limited microdeletions or point mutations than in larger deletions of Xp22.3 that encompass also the KAL1 gene, a neighboring gene important for urogenital development [7, 12, 13, 17, 18].

Antropyloric ultrasound examination revealed hypertrophied muscular layer of 4.6 mm and elongation of the pyloric canal of 19 mm (diameter 14 mm). In retrospect, some frame of the cystourethrogram had already shown an air-filled stomach with undulating contours known as “Caterpillar sign” (Fig. 1). Fredet-Ramstedt extramucosal longitudinal pyloromyotomy was performed. Afterwards, feeding and growing was regular and he was discharged home 45 days old. All treatment options have been discussed with both parents. Erythropoietin treatment and clinical multidisciplinary follow-up are ongoing. At 6 month of age, large polygonal, brownish scales appeared particularly on the anterior aspect of the lower extremities.

Comparative whole-genome hybridization was performed during hospitalization using the Agilent® 8x60K microarray and detected a maternal inherited interstitial deletion of 1.56 Mb on arr [hg19] Xp22.31(6,552,712_8,115,153) × 0 involving the genes STS, variable charge X-linked (VCX; *300229), pseudouridine 5′-phospatase (PUDP; *306480), Patatin like phospholipase domain containing-4 (PNPLA4; *300102) and microRNA MIR4767 and MIR651.

IHPS is the most common form of gastrointestinal obstruction in infancy (1:700), five times more frequent in males than in females and hereditably is high as 87% [19, 20]. Isolated and syndromic IHPS are described [21]. The exact etiology of isolated IHPS is unknown, although neuronal nitric oxide synthase (NOS) upregulation and an extracellular matrix abnormality have been reported in subsets [21]. Various potential genetic loci have been investigated, as well as various environmental factors (maternal smoking or young age, firstborn, feeding practice, post-natal erythromycin use) without producing conclusive data. Interestingly, reducing erythromycin indications and increasing dietary intake of omega-3 fatty acids in Western countries during the last decade probably decreased the incidence of isolated IHPS [20, 22]. By studying syndromic IHPS (Table 1) it was evidenced that the lipid metabolism plays a fundamental role in etiopathogenesis [23]. The risk of IHPS is inversely and significantly associated with total cholesterol level with an Odds ratio of 0.77 (95% CI, 0.64–0.92; p = 0.005) per 10 mg/dL [24]. Indeed, there are higher incidence of IHPS in syndromes affecting the lipid metabolism. A classic example is the Smith-Lemli-Opitz syndrome, an autosomal recessive congenital disorder caused by mutations in the 7-dehydrocholesterol reductase (DHCR7) gene at 11q13. Affected individuals are unable to complete the final step in cholesterol biosynthesis with accumulation of aberrant 7-dehydrocholesterol in developing tissues causing a wide range of metabolic and developmental abnormalities, including IHPS in 10–15% of cases [21]. In congenital generalized lipodystrophy type IV (CAVIN1 gene at 17q21) diffuse skeletal and smooth muscle hypertrophy are leading to cardiac arrythmia and IHPS [21, 25]. In syndromes associated with hypotonia, as in FG syndrome 3 (Xp22.3) or Down syndrome (critical region 21q22.3), the IHPS incidence is about 7% [3, 21]. Other syndromes frequently associated with IHPS are connective tissue disorders in which abnormal or excess of connective tissue in the pylorus gradually develop mechanic obstruction [21]. Furthermore, biopsies have shown not only muscle layer hypertrophy but also accumulation of extracellular matrix molecules (chondroitin-sulfate proteoglycan and fibronectin) [26]. This is also the underlying cause for unsuccessful non-surgical conservative treatment with oral or intravenous administration of atropine, leaving the surgical extramucosal pyloromyotomy as the gold standard [27].

STS alterations as in our case report, can lead to disturbed intracellular metabolism of cholesterol and to storage phenomenon of cholesterol sulphate. It was evidenced that age of onset of ichthyosis or absent/mild forms of XLI, frequently found in Southern European countries, are not related to width of Xp22.3 deletion [12, 18]. The late-onset of cutaneous presentation in our newborn is possible and clinical follow up have to direct dermatological, nephrological, endocrinological and neurobehavioral care as well as infection surveillance. VCX, PUDP and mitochondria-related PNPLA4 have been implicated in neurocognitive development, although the functional significance of these genes remains under debate [11, 13]. KAL1 gene, implicated in urogenital development, is not deleted in our case.

Vomiting and growth failure present a clinical challenge in neonatal age. Major causes are severe gastroesophageal reflux, neonatal sepsis, anatomical and functional gastrointestinal obstructions including IHPS and pylorospasm; less frequent are food allergy, inborn errors of metabolism, congenital adrenal hyperplasia, intracerebral abnormalities such as subdural hemorrhage or hydrocephalus, drugs or toxic agents and/or renal tubular acidosis. This spectrum widens in case of CAKUT, as in our patient, including renal impairment, risk of urosepsis and renal adapted diet. A concomitant edema could involve also the antropyloric region and cases of IHPS have been described [28]. Interestingly, a frequent recurrence linked polycystic kidney disease (PKD) and IHPS to NOS deficiency [29, 30]. Renal neuronal NOS and inducible NOS in cystic epithelium are suppressed or lost in PKD rats [31]. Thus, NOS deficiency leads to lack of locally available nitric oxide which may cause pyloric stenosis as a result of failure of smooth muscle relaxation. Downregulation of nitric oxide production may also be involved in the pathogenesis of pyloric stenosis in this subset. On the other hand, it was shown that deficiency of STS in kidneys results in increased cholesterol sulfate accumulation which interferes with normal functioning of transglutaminase 1, responsible for maintaining the integrity of cadherin-based adherens junctions between epithelial cells. The slit diaphragm of glomerular visceral epithelial cells is a modified adherens junction and, therefore, disruption of its structure by the above mechanism can result in proteinuria [7].