Pediatr Nephrol DOI 10.1007/s00467-015-3070-1
CLINICAL QUIZ
Congenital nephrotic syndrome with dysmorphic features and death in early infancy: Answers Julien Heinrich Park 1 & Martin Weissensteiner 2 & Oliver Wagner 2 & Yoshinao Wada 3 & Stephan Rust 1 & Janine Reunert 1 & Thorsten Marquardt 1
Received: 11 December 2014 / Revised: 10 February 2015 / Accepted: 10 February 2015 # IPNA 2015
Keywords Congenital nephrotic syndrome . Edema . Seizures . Dysmorphism . Congenital disorders of glycosylation . ALG1-CDG . Isoelectric focusing . Transferrin
Answers 1. Congenital nephrotic syndrome (CNS) is usually caused by genetic defects affecting the glomerular filter. The most common defects are nephrin mutations whereas defective WT1, PLCE1, LAMB2, or NPHS2 gene products are less common [1, 2]. Additionally, CNS has been described in association with metabolic diseases, such as respiratory chain deficiency [3]. Variants in integrin α3 (ITGA3) are known to cause lung disease in combination with nephrotic syndrome [4]. The most common non-genetic causes are infectious diseases, such as cytomegalovirus infection [5, 6] and congenital syphilis [7]. CNS can also occur in congenital disorders of glycosylation (CDG). So far, it has been described in the This article refers to the article that can be found at http://dx.doi.org/10. 1007/s00467-015-3071-0 * Thorsten Marquardt [email protected] 1
Klinik und Poliklinik für Kinder- und Jugendmedizin – Allgemeine Pädiatrie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Münster, Germany
2
Abteilung für Neonatologie, Landes- Frauen- und Kinderklinik Linz, Linz, Austria
3
Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka University, Osaka, Japan
subtypes PMM2-CDG, ALG1-CDG, and various cases of CDG-x, i.e., cases in which the subtype has not been identified. Taking the dysmorphic and multiorgan presentation of the described patient into account, the differential diagnosis in the presented case consists of mitochondrial cytopathy, CDG, and ITGA3 disease. The most likely option with regards to the typical dysmorphic presentation, i.e., inverted nipples and facial dysmorphisms, is CDG. 2. The analysis of serum transferrin is the primary diagnostic tool for cases with suspicion of CDG. This group of diseases affects the glycosylation process and is known to cause a great variety of symptoms in almost all organ systems. There are two distinct pathologic patterns: the type 1 pattern with a decreased tetrasialo-fraction and increased di- and asialo-transferrin fractions, and the type 2 pattern, which shows an additional increase in the monoand/or trisialo-transferrin bands [8]. Having obtained a pathological transferrin test, genetic analysis of the genes associated with CNS in CDG should be initiated. If this leads to no result, whole-exome sequencing is another option, which may facilitate the identification of the causative gene. However, this method has limitations, especially in consanguineous families where a vast number of variants and mutations is not unusual.
Discussion In the majority of cases, CNS is caused by underlying genetic defects leading to disruption of the glomerular filtration barrier resulting in proteinuria, hypoproteinemia, and generalized edema [1, 9, 10]. In the described patient, CNS was caused by
Pediatr Nephrol Fig. 1 Isoelectric focusing (IEF) of serum transferrin. The patient shows an abnormal transferrin glycosylation pattern indicative of a glycosylation disorder. Numbers indicate sialic acid residues in the glycan. The faint pattern of the patient’s samples is due to hypoproteinemia
a metabolic disease affecting the glycosylation of glycoproteins (ALG1-CDG). Sanger sequencing of the ALG1 gene was performed and the patient was found to be homozygous for the mutation c.773C>T [S258L] in the ALG1 gene (rs28939378) [11], which results in a defect of β1,4mannosyltransferase. The parents were heterozygous for this mutation. Another case of CNS in ALG1-CDG has been described previously [11]. A possible pathomechanism for CNS in CDG is defective glycosylation of various proteins of the filtration barrier leading to functional impairment. It has been shown that altered glycosylation of nephrin, a protein of the slit diaphragm, affects its localization in the plasma membrane and might thus impair the function of the slit diaphragm [12]. Other proteins possibly affected might include the negatively charged proteoglycans of the glomerular basement membrane.
Fig. 2 ESI-TOF MS analysis of the patient’s transferrin glycosylation status. Three transferrin species were detected: the normal species with two complete glycan chains and two atypical species lacking either one or both glycan chains
Renal manifestations of CDG other than CNS are rare. There are reports of renal microcysts [13] and nephromegaly [14], each without impairment of renal function. In principle, additional renal manifestations of CDG are possible although none have been reported yet. Hypothyroidism has been reported in CNS [15] with decreased T3 and T4 levels and increased serum TSH [16]. TSH is a glycoprotein with three glycosylation sites, each carrying varying glycans depending on the origin of the TSH molecule [17]. Szkudlinksi et al. demonstrated in rats that a loss of glycosylation increases the renal clearance of TSH, with asialo-TSH the TSH isoform with the highest clearance [18]. Decreased TSH glycosylation could be the reason for the low serum TSH in our patient. The diagnosis of this patient was complicated by the presence of a transferrin mutation (c.2012G>A, G671E) that altered the glycosylation pattern in isoelectric focusing (IEF) of
ESI-TOF MS (deconvoluted)
6.5E+001
5.2E+001
Tf
Tf
3.9E+001
Intensity 2.6E+001 Tf
1.3E+001
0.0E+000 75000
75600
77200
78800
Mass (Dalton)
80400
82000
Pediatr Nephrol Fig. 3 Explanation of the IEF pattern of the ALG1-CDG patient. The pattern was complicated by the presence of an additional mutation in one transferrin allele (variant B2: c.2012G>A, G671E) that has been shown to add an additional negative charge to the transferrin [19]. Therefore, the fraction initially believed to be tetrasialotransferrin is in fact trisialotransferrin with the additional negative charge caused by the mutation. This applies equally to the other transferrin fractions
serum transferrin. The effect of this mutation has been described elsewhere [19]. Often, CDG present as multisystemic disorders and neurological involvement is frequent [20]. IEF of serum transferrin is a very simple screening test for CDG. It requires only a few microliters of serum, is inexpensive, and highly sensitive. In CNS, severe hypoproteinemia or frequent serum transfusions can influence the test. A detailed account of the glycosylation findings in our patient can be seen in Figs. 1, 2, and 3. In conclusion, CNS can be a manifestation of severe forms of CDG. It has been found in different CDG diseases like PMM2-CDG, ALG1-CDG, and untyped CDG [21–24]. With new emerging therapies for these disorders, pediatric nephrologists should include the transferrin test in their investigation, especially in patients with additional symptoms such as dysmorphic features or neurological impairment. It is a non-invasive, easy, and inexpensive diagnostic tool, and should be used in cases of CNS where no underlying cause has been found.
4.
5.
6.
7.
8.
9. 10.
11.
References 12. 1.
Kari JA, Montini G, Bockenhauer D, Brennan E, Rees L, Trompeter RS, Tullus K, Van't Hoff W, Waters A, Ashton E, Lench N, Sebire NJ, Marks SD (2014) Clinico-pathological correlations of congenital and infantile nephrotic syndrome over twenty years. Pediatr Nephrol 29:2173–2180 2. Lionel AP, Joseph LK, Simon A (2014) Pierson syndrome—a rare cause of congenital nephrotic syndrome. Indian J Pediatr 81:1416– 1417 3. Goldenberg A, Ngoc LH, Thouret MC, Cormier-Daire V, Gagnadoux MF, Chretien D, Lefrancois C, Geromel V, Rotig A, Rustin P, Munnich A, Paquis V, Antignac C, Gubler MC, Niaudet P, de Lonlay P, Berard E (2005) Respiratory chain deficiency presenting as congenital nephrotic syndrome. Pediatr Nephrol 20:465– 469
13.
14.
15.
Nicolaou N, Margadant C, Kevelam SH, Lilien MR, Oosterveld MJ, Kreft M, van Eerde AM, Pfundt R, Terhal PA, van der Zwaag B, Nikkels PG, Sachs N, Goldschmeding R, Knoers NV, Renkema KY, Sonnenberg A (2012) Gain of glycosylation in integrin alpha3 causes lung disease and nephrotic syndrome. J Clin Invest 122:4375–4387 Guo AH, Lu M (2007) Two cases of congenital nephrotic syndrome resulting from cytomegalovirus infection. Zhonghua Er Ke Za Zhi 45:872–873 Rahman H, Begum A, Jahan S, Muinuddin G, Hossain MM (2008) Congenital nephrotic syndrome, an uncommon presentation of cytomegalovirus infection. Mymensingh Med J 17:210–213 Xiao HJ, Liu JC, Zhong XH (2011) Congenital syphilis presenting congenital nephrotic syndrome in two children and related data review. Beijing Da Xue Xue Bao 43:911–913 Marquardt T, Denecke J (2003) Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies. Eur J Pediatr 162:359–379 Jalanko H (2009) Congenital nephrotic syndrome. Pediatr Nephrol 24:2121–2128 Avni EF, Vandenhoute K, Devriendt A, Ismaili K, Hackx M, Janssen F, Hall M (2011) Update on congenital nephrotic syndromes and the contribution of US. Pediatr Radiol 41: 76–81 Kranz C, Denecke J, Lehle L, Sohlbach K, Jeske S, Meinhardt F, Rossi R, Gudowius S, Marquardt T (2004) Congenital disorder of glycosylation type Ik (CDG-Ik): a defect of mannosyltransferase I. Am J Hum Genet 74:545–551 Yan K, Khoshnoodi J, Ruotsalainen V, Tryggvason K (2002) Nlinked glycosylation is critical for the plasma membrane localization of nephrin. J Am Soc Nephrol 13:1385–1389 Strom EH, Stromme P, Westvik J, Pedersen SJ (1993) Renal cysts in the carbohydrate-deficient glycoprotein syndrome. Pediatr Nephrol 7:253–255 Perez-Duenas B, Garcia-Cazorla A, Pineda M, Poo P, Campistol J, Cusi V, Schollen E, Matthijs G, Grunewald S, Briones P, Perez-Cerda C, Artuch R, Vilaseca MA (2009) Long-term evolution of eight Spanish patients with CDG type Ia: typical and atypical manifestations. Eur J Paediatr Neurol 13:444–451 Dagan A, Cleper R, Krause I, Blumenthal D, Davidovits M (2012) Hypothyroidism in children with steroid-resistant nephrotic syndrome. Nephrol Dial Transplant 27:2171–2175
Pediatr Nephrol 16. 17.
18.
19.
Iglesias P, Diez JJ (2009) Thyroid dysfunction and kidney disease. Eur J Endocrinol 160:503–515 Donadio S, Pascual A, Thijssen JH, Ronin C (2006) Feasibility study of new calibrators for thyroid-stimulating hormone (TSH) immunoprocedures based on remodeling of recombinant TSH to mimic glycoforms circulating in patients with thyroid disorders. Clin Chem 52:286–297 Szkudlinski MW, Thotakura NR, Bucci I, Joshi LR, Tsai A, East-Palmer J, Shiloach J, Weintraub BD (1993) Purification and characterization of recombinant human thyrotropin (TSH) isoforms produced by Chinese hamster ovary cells: the role of sialylation and sulfation in TSH bioactivity. Endocrinology 133: 1490–1503 Zuhlsdorf A, Park JH, Wada Y, Rust S, Reunert J, DuChesne I, Gruneberg M, Marquardt T (2014) Transferrin variants: pitfalls in the diagnostics of congenital disorders of glycosylation. Clin Biochem 48:11–13
20.
Rohlfing AK, Rust S, Reunert J, Tirre M, Du Chesne I, Wemhoff S, Meinhardt F, Hartmann H, Das AM, Marquardt T (2014) ALG1CDG: a new case with early fatal outcome. Gene 534:345–351 21. Hutchesson AC, Gray RG, Spencer DA, Keir G (1995) Carbohydrate deficient glycoprotein syndrome; multiple abnormalities and diagnostic delay. Arch Dis Child 72:445–446 22. van der Knaap MS, Wevers RA, Monnens L, Jakobs C, Jaeken J, van Wijk JA (1996) Congenital nephrotic syndrome: a novel phenotype of type I carbohydrate-deficient glycoprotein syndrome. J Inherit Metab Dis 19:787–791 23. de Vries BB, van'tHoff WG, Surtees RA, Winter RM (2001) Diagnostic dilemmas in four infants with nephrotic syndrome, microcephaly and severe developmental delay. Clin Dysmorphol 10: 115–121 24. Sinha MD, Horsfield C, Komaromy D, Booth CJ, Champion MP (2009) Congenital disorders of glycosylation: a rare cause of nephrotic syndrome. Nephrol Dial Transplant 24:2591–2594
CLINICAL QUIZ
Congenital nephrotic syndrome with dysmorphic features and death in early infancy: Answers Julien Heinrich Park 1 & Martin Weissensteiner 2 & Oliver Wagner 2 & Yoshinao Wada 3 & Stephan Rust 1 & Janine Reunert 1 & Thorsten Marquardt 1
Received: 11 December 2014 / Revised: 10 February 2015 / Accepted: 10 February 2015 # IPNA 2015
Keywords Congenital nephrotic syndrome . Edema . Seizures . Dysmorphism . Congenital disorders of glycosylation . ALG1-CDG . Isoelectric focusing . Transferrin
Answers 1. Congenital nephrotic syndrome (CNS) is usually caused by genetic defects affecting the glomerular filter. The most common defects are nephrin mutations whereas defective WT1, PLCE1, LAMB2, or NPHS2 gene products are less common [1, 2]. Additionally, CNS has been described in association with metabolic diseases, such as respiratory chain deficiency [3]. Variants in integrin α3 (ITGA3) are known to cause lung disease in combination with nephrotic syndrome [4]. The most common non-genetic causes are infectious diseases, such as cytomegalovirus infection [5, 6] and congenital syphilis [7]. CNS can also occur in congenital disorders of glycosylation (CDG). So far, it has been described in the This article refers to the article that can be found at http://dx.doi.org/10. 1007/s00467-015-3071-0 * Thorsten Marquardt [email protected] 1
Klinik und Poliklinik für Kinder- und Jugendmedizin – Allgemeine Pädiatrie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Münster, Germany
2
Abteilung für Neonatologie, Landes- Frauen- und Kinderklinik Linz, Linz, Austria
3
Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka University, Osaka, Japan
subtypes PMM2-CDG, ALG1-CDG, and various cases of CDG-x, i.e., cases in which the subtype has not been identified. Taking the dysmorphic and multiorgan presentation of the described patient into account, the differential diagnosis in the presented case consists of mitochondrial cytopathy, CDG, and ITGA3 disease. The most likely option with regards to the typical dysmorphic presentation, i.e., inverted nipples and facial dysmorphisms, is CDG. 2. The analysis of serum transferrin is the primary diagnostic tool for cases with suspicion of CDG. This group of diseases affects the glycosylation process and is known to cause a great variety of symptoms in almost all organ systems. There are two distinct pathologic patterns: the type 1 pattern with a decreased tetrasialo-fraction and increased di- and asialo-transferrin fractions, and the type 2 pattern, which shows an additional increase in the monoand/or trisialo-transferrin bands [8]. Having obtained a pathological transferrin test, genetic analysis of the genes associated with CNS in CDG should be initiated. If this leads to no result, whole-exome sequencing is another option, which may facilitate the identification of the causative gene. However, this method has limitations, especially in consanguineous families where a vast number of variants and mutations is not unusual.
Discussion In the majority of cases, CNS is caused by underlying genetic defects leading to disruption of the glomerular filtration barrier resulting in proteinuria, hypoproteinemia, and generalized edema [1, 9, 10]. In the described patient, CNS was caused by
Pediatr Nephrol Fig. 1 Isoelectric focusing (IEF) of serum transferrin. The patient shows an abnormal transferrin glycosylation pattern indicative of a glycosylation disorder. Numbers indicate sialic acid residues in the glycan. The faint pattern of the patient’s samples is due to hypoproteinemia
a metabolic disease affecting the glycosylation of glycoproteins (ALG1-CDG). Sanger sequencing of the ALG1 gene was performed and the patient was found to be homozygous for the mutation c.773C>T [S258L] in the ALG1 gene (rs28939378) [11], which results in a defect of β1,4mannosyltransferase. The parents were heterozygous for this mutation. Another case of CNS in ALG1-CDG has been described previously [11]. A possible pathomechanism for CNS in CDG is defective glycosylation of various proteins of the filtration barrier leading to functional impairment. It has been shown that altered glycosylation of nephrin, a protein of the slit diaphragm, affects its localization in the plasma membrane and might thus impair the function of the slit diaphragm [12]. Other proteins possibly affected might include the negatively charged proteoglycans of the glomerular basement membrane.
Fig. 2 ESI-TOF MS analysis of the patient’s transferrin glycosylation status. Three transferrin species were detected: the normal species with two complete glycan chains and two atypical species lacking either one or both glycan chains
Renal manifestations of CDG other than CNS are rare. There are reports of renal microcysts [13] and nephromegaly [14], each without impairment of renal function. In principle, additional renal manifestations of CDG are possible although none have been reported yet. Hypothyroidism has been reported in CNS [15] with decreased T3 and T4 levels and increased serum TSH [16]. TSH is a glycoprotein with three glycosylation sites, each carrying varying glycans depending on the origin of the TSH molecule [17]. Szkudlinksi et al. demonstrated in rats that a loss of glycosylation increases the renal clearance of TSH, with asialo-TSH the TSH isoform with the highest clearance [18]. Decreased TSH glycosylation could be the reason for the low serum TSH in our patient. The diagnosis of this patient was complicated by the presence of a transferrin mutation (c.2012G>A, G671E) that altered the glycosylation pattern in isoelectric focusing (IEF) of
ESI-TOF MS (deconvoluted)
6.5E+001
5.2E+001
Tf
Tf
3.9E+001
Intensity 2.6E+001 Tf
1.3E+001
0.0E+000 75000
75600
77200
78800
Mass (Dalton)
80400
82000
Pediatr Nephrol Fig. 3 Explanation of the IEF pattern of the ALG1-CDG patient. The pattern was complicated by the presence of an additional mutation in one transferrin allele (variant B2: c.2012G>A, G671E) that has been shown to add an additional negative charge to the transferrin [19]. Therefore, the fraction initially believed to be tetrasialotransferrin is in fact trisialotransferrin with the additional negative charge caused by the mutation. This applies equally to the other transferrin fractions
serum transferrin. The effect of this mutation has been described elsewhere [19]. Often, CDG present as multisystemic disorders and neurological involvement is frequent [20]. IEF of serum transferrin is a very simple screening test for CDG. It requires only a few microliters of serum, is inexpensive, and highly sensitive. In CNS, severe hypoproteinemia or frequent serum transfusions can influence the test. A detailed account of the glycosylation findings in our patient can be seen in Figs. 1, 2, and 3. In conclusion, CNS can be a manifestation of severe forms of CDG. It has been found in different CDG diseases like PMM2-CDG, ALG1-CDG, and untyped CDG [21–24]. With new emerging therapies for these disorders, pediatric nephrologists should include the transferrin test in their investigation, especially in patients with additional symptoms such as dysmorphic features or neurological impairment. It is a non-invasive, easy, and inexpensive diagnostic tool, and should be used in cases of CNS where no underlying cause has been found.
4.
5.
6.
7.
8.
9. 10.
11.
References 12. 1.
Kari JA, Montini G, Bockenhauer D, Brennan E, Rees L, Trompeter RS, Tullus K, Van't Hoff W, Waters A, Ashton E, Lench N, Sebire NJ, Marks SD (2014) Clinico-pathological correlations of congenital and infantile nephrotic syndrome over twenty years. Pediatr Nephrol 29:2173–2180 2. Lionel AP, Joseph LK, Simon A (2014) Pierson syndrome—a rare cause of congenital nephrotic syndrome. Indian J Pediatr 81:1416– 1417 3. Goldenberg A, Ngoc LH, Thouret MC, Cormier-Daire V, Gagnadoux MF, Chretien D, Lefrancois C, Geromel V, Rotig A, Rustin P, Munnich A, Paquis V, Antignac C, Gubler MC, Niaudet P, de Lonlay P, Berard E (2005) Respiratory chain deficiency presenting as congenital nephrotic syndrome. Pediatr Nephrol 20:465– 469
13.
14.
15.
Nicolaou N, Margadant C, Kevelam SH, Lilien MR, Oosterveld MJ, Kreft M, van Eerde AM, Pfundt R, Terhal PA, van der Zwaag B, Nikkels PG, Sachs N, Goldschmeding R, Knoers NV, Renkema KY, Sonnenberg A (2012) Gain of glycosylation in integrin alpha3 causes lung disease and nephrotic syndrome. J Clin Invest 122:4375–4387 Guo AH, Lu M (2007) Two cases of congenital nephrotic syndrome resulting from cytomegalovirus infection. Zhonghua Er Ke Za Zhi 45:872–873 Rahman H, Begum A, Jahan S, Muinuddin G, Hossain MM (2008) Congenital nephrotic syndrome, an uncommon presentation of cytomegalovirus infection. Mymensingh Med J 17:210–213 Xiao HJ, Liu JC, Zhong XH (2011) Congenital syphilis presenting congenital nephrotic syndrome in two children and related data review. Beijing Da Xue Xue Bao 43:911–913 Marquardt T, Denecke J (2003) Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies. Eur J Pediatr 162:359–379 Jalanko H (2009) Congenital nephrotic syndrome. Pediatr Nephrol 24:2121–2128 Avni EF, Vandenhoute K, Devriendt A, Ismaili K, Hackx M, Janssen F, Hall M (2011) Update on congenital nephrotic syndromes and the contribution of US. Pediatr Radiol 41: 76–81 Kranz C, Denecke J, Lehle L, Sohlbach K, Jeske S, Meinhardt F, Rossi R, Gudowius S, Marquardt T (2004) Congenital disorder of glycosylation type Ik (CDG-Ik): a defect of mannosyltransferase I. Am J Hum Genet 74:545–551 Yan K, Khoshnoodi J, Ruotsalainen V, Tryggvason K (2002) Nlinked glycosylation is critical for the plasma membrane localization of nephrin. J Am Soc Nephrol 13:1385–1389 Strom EH, Stromme P, Westvik J, Pedersen SJ (1993) Renal cysts in the carbohydrate-deficient glycoprotein syndrome. Pediatr Nephrol 7:253–255 Perez-Duenas B, Garcia-Cazorla A, Pineda M, Poo P, Campistol J, Cusi V, Schollen E, Matthijs G, Grunewald S, Briones P, Perez-Cerda C, Artuch R, Vilaseca MA (2009) Long-term evolution of eight Spanish patients with CDG type Ia: typical and atypical manifestations. Eur J Paediatr Neurol 13:444–451 Dagan A, Cleper R, Krause I, Blumenthal D, Davidovits M (2012) Hypothyroidism in children with steroid-resistant nephrotic syndrome. Nephrol Dial Transplant 27:2171–2175
Pediatr Nephrol 16. 17.
18.
19.
Iglesias P, Diez JJ (2009) Thyroid dysfunction and kidney disease. Eur J Endocrinol 160:503–515 Donadio S, Pascual A, Thijssen JH, Ronin C (2006) Feasibility study of new calibrators for thyroid-stimulating hormone (TSH) immunoprocedures based on remodeling of recombinant TSH to mimic glycoforms circulating in patients with thyroid disorders. Clin Chem 52:286–297 Szkudlinski MW, Thotakura NR, Bucci I, Joshi LR, Tsai A, East-Palmer J, Shiloach J, Weintraub BD (1993) Purification and characterization of recombinant human thyrotropin (TSH) isoforms produced by Chinese hamster ovary cells: the role of sialylation and sulfation in TSH bioactivity. Endocrinology 133: 1490–1503 Zuhlsdorf A, Park JH, Wada Y, Rust S, Reunert J, DuChesne I, Gruneberg M, Marquardt T (2014) Transferrin variants: pitfalls in the diagnostics of congenital disorders of glycosylation. Clin Biochem 48:11–13
20.
Rohlfing AK, Rust S, Reunert J, Tirre M, Du Chesne I, Wemhoff S, Meinhardt F, Hartmann H, Das AM, Marquardt T (2014) ALG1CDG: a new case with early fatal outcome. Gene 534:345–351 21. Hutchesson AC, Gray RG, Spencer DA, Keir G (1995) Carbohydrate deficient glycoprotein syndrome; multiple abnormalities and diagnostic delay. Arch Dis Child 72:445–446 22. van der Knaap MS, Wevers RA, Monnens L, Jakobs C, Jaeken J, van Wijk JA (1996) Congenital nephrotic syndrome: a novel phenotype of type I carbohydrate-deficient glycoprotein syndrome. J Inherit Metab Dis 19:787–791 23. de Vries BB, van'tHoff WG, Surtees RA, Winter RM (2001) Diagnostic dilemmas in four infants with nephrotic syndrome, microcephaly and severe developmental delay. Clin Dysmorphol 10: 115–121 24. Sinha MD, Horsfield C, Komaromy D, Booth CJ, Champion MP (2009) Congenital disorders of glycosylation: a rare cause of nephrotic syndrome. Nephrol Dial Transplant 24:2591–2594
