Eur J Pediatr DOI 10.

1007/s00431-012-1845-y

ORIGINAL ARTICLE

Renal phenotypic variability in HDR syndrome: glomerular nephropathy as a novel finding

Alexis Chenouard & Bertrand Isidor & Emma Allain-Launay & Anne Moreau & Marc Le Bideau & Gwenaelle Roussey

Received: 15 May 2012 / Revised: 13 September 2012 / Accepted: 17 September 2012 # Springer-Verlag Berlin Heidelberg 2012

Abstract HDR syndrome (hypoparathyroidism, sensorineural deafness, renal abnormalities) (OMIM #146265) is a rare autosomal dominant disorder caused by mutations in the GATA-3 gene (OMIM 13120), a transcription factor coding for a protein involved in vertebrate embryonic development. More than a hundred cases with variable renal features have been described so far. Here, we report on a patient suffering from HDR syndrome with glomerular nephropathy. Hypoparathyroidism appeared early in childhood but the subsequent features of HDR occurred later in the form of bilateral sensorineural deafness and renal insufficiency associated with nephrocalcinosis. HDR was not initially diagnosed due to the appearance of a transitory cardiac involvement and atypical renal symptoms (diffuse proliferative glomerulonephritis characterized by a self-limiting nephrotic syndrome). Conclusion: HDR syndrome with
A. Chenouard : E. Allain-Launay : G. Roussey Pediatric Department, Nantes University Hospital, Nantes, France B. Isidor Genetic Department, Nantes University Hospital, Nantes, France A. Moreau Histopathology Laboratory, Nantes University Hospital, Nantes, France M. Le Bideau Pediatric Department, Hospital of Saint Nazaire, Saint-Nazaire, France G. Roussey (*) Clinique Mdicale Pdiatrique, Hpital Mre Enfant, 7 Quai Moncousu, 44093 Nantes cedex, France e-mail: gwenaelle.roussey@chu-nantes.fr

glomerular nephropathy has not yet been reported to our knowledge. Further studies of GATA-3 are needed to explore the involvement of this transcription factor in the development of HDR in humans, particularly in the kidneys. Keywords HDR syndrome . GATA-3 gene . Glomerulonephritis

Introduction HDR syndrome (hypoparathyroidism, sensorineural deafness, and renal abnormalities) (OMIM #146265) is an autosomal dominant disorder caused by mutations in the GATA3 gene (OMIM 13120) [13, 510, 1219, 22, 24]. This transcription factor is involved in vertebrate embryonic development, with a crucial role in the kidneys [11]. So far, less than a hundred cases of HDR with significant renal involvement have been described [6]. Here, we report on a patient suffering from HDR syndrome associated with glomerular lesions.

Case report The patient was the first child of non-consanguineous parents. He had no medical history and displayed normal psychomotor development. He was admitted to hospital at 17 months of age because of generalized seizures. The medical examination was normal; however, routine laboratory tests revealed severe hypocalcemia (1.23 mmol/L) with a parathyroid hormone (PTH) level below 5 pg/mL (reference value, 1070 pg/mL), suggestive of hypoparathyroidism. The clinical course subsequently improved, with serum calcium normalization using vitamin D analog (1-hydroxycholecalciferol) and calcium

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supplement (Table 1). Magnesemia and renal function were normal, and autoimmune tests (anti-PTH, antithyroid, antiprothrombinase, and antiphospholipid autoantibody detection) revealed no abnormalities. A routine karyotype test (46XY) was also normal and screening for the 22q11 deletion was negative. At 3 years of age, renal failure (serum creatinine 107 mol/L and estimated glomerular filtration rate 31.2 mL/min/1.73 m2 according to the Schwartz formula) was fortuitously detected, associated with hypercalciuria (calciuria/creatininuria ratio 3.6 mmol/mmol; reference value, <0.7 mmol/mmol). Nephrocalcinosis was detected by renal ultrasonography and confirmed by a renal biopsy, which also revealed a tubulointerstitial nephritis without dysplasia or glomerular injury. The patient did not receive any specific treatment and his renal function remained stable. At the same age, secondary to delayed language development, auditory tests were performed, leading to the diagnosis of severe bilateral sensorineural deafness. At 4 years of age, the patient was admitted for diffuse edemas, dyspnea, and fever. Laboratory tests revealed a nephrotic syndrome with hypoprotidemia (55 g/L), moderate hypoalbuminemia (30 g/L), glomerular proteinuria (100 mg/ kg/day), and microscopic hematuria (900 red blood cells/ mm3). The levels of serum creatinine (115 mol/L) and ionized calcium (0.78 mmol/L) were stable. A chest X-ray revealed a bilateral interstitial pneumonia. Respiratory symptoms fully resolved with antibiotics and salt restriction such that a renal biopsy could be performed a few days later. Unfortunately, anesthetic induction was complicated by an acute pulmonary edema due to cardiac conduction disorders. Cardiac ultrasonography revealed a dilated and hypokinetic left ventricle (telediastolic diameter of 46 mm and a shortening fraction of 26 %) which improved within a few weeks.

Light microscopy analysis of the renal biopsy revealed a segmental, diffuse, proliferative glomerulonephritis and persistent nephrocalcinosis; an immunofluorescence analysis could not be performed for technical reasons (Fig. 1). Treatment with a spironolactone and an angiotensin-converting enzyme inhibitor improved both renal and cardiac function. Considering the multisystemic organ involvement, a metabolic disease was suspected but all investigations, including muscle biopsies, were negative. At 5.5 years of age, a polyuriapolydipsia syndrome was explored: urine osmolarity after desmopressin stimulation was lower than 780 mOsm/L (normal range, 900 1,100 mOsmol/L), which indicated an alteration in urinary concentration, probably due to nephrocalcinosis. There was no metabolic acidosis, no hypouricemia. During the subsequent years, the patient underwent standard clinical and biological follow-up. Renal function remained stable; there was no acute heart decompensation and the treatment with vitamin D analogs was adjusted. At 13 years of age, HDR syndrome was suspected by a pediatric nephrologist and a geneticist, and direct sequencing of the GATA-3 gene showed a de novo mutation (mutation c.951delC on exon 5). Both parents tested negative for genetic abnormalities. At the last follow-up (15 years of age), the serum creatinine level was 121 mol/L (eGFR of 70 ml/min according to MDRD formula) with a persistent moderate glomerular proteinuria (microalbuminuria/creatininuria 21 mg/mmol) despite angiotensin converting enzyme inhibitor treatment. Serum calcemia and calciuria were difficult to normalize, mainly because of self-confessed therapeutic noncompliance. Indomethacin, started at 14 years of age, was able to control the nocturnal enuresis but was stopped after 6 months to preserve renal function.

Table 1 Results of laboratory investigations at the diagnosis of hypoparathyroidism and during follow-up Age of patient 17 months 18 months 32 months 4 years 5 years 6 years and 10 years 12 years and 15 years and 6 months 6 months 9 months 2.13 2.27 27.4 5.01 105.3 <1.2 <0.4 2 2.30 1.66 107 12.4 31.2 2.9 3.6 1.9 2.05 47.8 9.19 75.3 <1.2 3.03 1.63 107 17.5 35.5 <1.2 0.1 1.5 2.03 1.81 66.3 8.18 61 2.17 1.65 71 8.2 69.2 1.52 2.81 77 7.63 68.8 0.5 0.06 2.25 2.65 1.40 121 10.8 70a 6.9 0.58 2.5

Calcemia (mmol/L) 1.23 Phosphoremia (mmol/L) 3.15 Serum creatinine (mol/L) 36.2 Urea (mmol/L) 5.12 eGFR (mL/min/1.73 m2) 75.6 Calciuria (mmol/L) Calciuria/creatinuria (mmol/mmol) Vit D analogs (1-hydroxycholecalciferol) (g per day) Calcium supplements (g per day)
a

0.6

1.25

1.25

3.6

0.6

0.6

0.6

eGFR according to MDRD formula, in milliliters per minute

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Fig. 1 Renal biopsy (HES, 200) with tubule calcifications and mesangioproliferative lesions (thickening of the basement membrane and segmental double contours)

Discussion HDR syndrome is a rare disorder [6]. Although many renal features of HDR have been described before, to our knowledge, an association with glomerular nephropathy has not yet been reported. Here, tubulointerstitial disease and subsequently nephritic syndrome, followed by acute heart failure, probably contributed to the delay in diagnosis. In 1992, a family with hypoparathyroidism, deafness, and renal dysplasia was reported by Bilous et al. [4]. A few years later, Hasegawa et al. named this association HDR syndrome and identified a deletion on chromosome 10p15 [9]. Thereafter, HDR syndrome was found to be an autosomal dominant disorder caused by haploinsufficiency of the GATA-3 gene. The first mutation was described in 2000, and around 30 mutations have now been identified [13, 510, 1219, 22, 24]. To our knowledge, the mutation we describe here has never been reported in the literature. This mutation results in a premature stop codon (p.Cys318ValfsX38). Analysis of the patients parents confirmed that this mutation occurred de novo. Therefore, the pathogenicity of the mutation can be presumed without any functional analysis. The GATA-3 protein belongs to a family of dual zinc finger transcription factors involved in vertebrate embryonic development. In the kidney, GATA-3 mRNA is detected in the collecting duct and in the glomerular mesangium; its early and specific expression suggests in the differentiation of the human kidney [11]. GATA-3 is also expressed in the developing parathyroid glands, inner ears, lens, central nervous system, thymus, and T lymphocytes. Of note, no patients with GATA-3 mutations have been reported to have immune disorders [14]. The HDR phenotype associates three main features: hypoparathyroidism, deafness, and renal defects. A recent study reported on 63 patients with HDR syndrome [2]. More than 90 % of the patients with a complete phenotype had GATA-3 mutations. In the absence of renal abnormalities, less than

65 % of patients displayed a GATA-3 mutation. Therefore, patients with isolated hypoparathyroidism had no mutation, and no studies were performed in patients with non-syndromic deafness or isolated renal dysplasia. According to the authors, screening for GATA-3 mutations is worthwhile for diagnosis and genetic counseling, but only when two or three of the three HDR features are detected, not in the case of isolated symptoms. In our case, the patient presented the triad at the time of diagnosis. Of note, sensorineural deafness was found in all patients with GATA-3 mutations and it seems to be a key symptom that has to be present for HDR to be suspected. Renal disorders include both development abnormalities (such as renal hypo/dysplasia, cystic kidney disease, pelvicocalyceal deformity, and vesicoureteral reflux) and functional abnormalities (such as proteinuria, hematuria, proximal and distal renal tubular acidosis, and nephrocalcinosis) [2, 3, 510, 1218, 22, 24]. Variability in the manifestation of HDR syndrome can appear within the same family. When nephrocalcinosis is present, it can be compounded by 1OH vitamin D therapy, inducing increased digestive absorption of calcium, more than that caused by a primitive tubular disorder linked to a GATA-3 mutation. However, low levels of PTH, in the context of hypoparathyroidism, decreases tubular calcium reabsorption and may contribute to hypercalciuria. As such, the mechanism of GATA-3 pathogenesis in the renal involvement of HDR remains unclear, and to date, no potential target of this transcription factor has been discovered. To the best of our knowledge, a glomerulonephritis, with biopsy-proven proliferative glomerular lesions, has never been reported in HDR syndrome. The mechanism by which this unusual renal feature develops in HDR is open to discussion. GATA-3 seems to regulate immune balance by promoting Th2 differentiation [20]. In a murine model of autoimmune glomerulonephritis, GATA-3 overexpression in T cells counteracted Th1 cell dominance and reduced proteinuria, serum creatinine levels, and the severity of mesangial and cellular proliferation [23]. Furthermore, Tsugawa et al. demonstrated a reduced urinary expression of GATA-3 mRNA in patients with lupus or IgAlinked glomerulonephritis [21]. In our patient, it is possible that an autoimmune mechanism may explain the glomerulonephritis due to a GATA-3 deletion, but the lack of an immunofluorescence examination of the renal biopsy together with the spontaneous favorable outcome do not fully support this hypothesis. Moreover, the patient had no atopic or autoimmune disorders. Considering the simultaneous respiratory infection, the glomerulonephritis may have been due to mycoplasma or viral infection, although no investigations were performed to prove this hypothesis. Of note, the delayed diagnosis in our patient was not only primarily due to the variable renal disease with tubulointerstitial and glomerular features but also to the transitory cardiac involvement initially attributed to a metabolic disorder. This disorder was in fact probably resulting from a

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cardiac conduction defect generated by hypocalcemia and anesthesia, leading to an acute pulmonary edema in the context of sodium and fluid retention. In summary, the patient reported here presented with HDR syndrome, characterized by a GATA-3 deletion with an atypical episode of glomerulopathy. Screening for GATA3 mutations is therefore relevant for patients with either two or three of the phenotypic manifestations of HDR syndrome, including deafness. Further studies of GATA-3 are needed to improve our knowledge about the involvement of this transcription factor in human development, particularly in the kidneys and immune system.
Conflict of interest Authors have neither conflict of interest nor any financial relationship to disclose.

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