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Genetic steroid-resistant nephrotic syndrome

Last edited: 4/14/2026

Overview

Genetic steroid-resistant nephrotic syndrome (SRNS) encompasses rare genetic conditions characterized by congenital nephrotic syndrome that does not respond to steroid therapy, often associated with additional systemic anomalies beyond renal involvement. 1715

Diagnosis

  • Genetic Testing: Identification of specific gene variants (e.g., ZPR1, STRADA, MAGEL2, LRP2) through whole exome sequencing or targeted gene panel analysis 124.
  • Clinical Features: Presence of nephrotic syndrome from infancy, often accompanied by extrarenal manifestations such as growth restriction, facial dysmorphism, liver fibrosis, or other systemic anomalies 1247.
  • Renal Function Tests: Elevated proteinuria, hypoalbuminemia, hyperlipidemia, and edema 17.
  • Imaging and Radiology: Kidney ultrasound showing hypoplastic kidneys or other structural anomalies 13.

    • Management

  • Immunosuppressive Therapy: Early initiation of calcineurin inhibitors (e.g., cyclosporine, tacrolimus) or mTOR inhibitors (e.g., sirolimus) as first-line treatments 17.
  • Supportive Care: Management of edema, hypertension, and infections; growth hormone therapy for growth restriction 17.
  • Genetic Counseling: Essential for families with identified genetic mutations to understand recurrence risks and implications 12.

    • Special Populations

  • Pediatrics: Early diagnosis and intervention are crucial for managing growth and developmental issues alongside nephrotic syndrome 17.
  • Comorbidities: Consideration of additional systemic features (e.g., liver fibrosis, craniofacial anomalies) in treatment planning 147.

    • Key Recommendations

  • Genetic Testing for Diagnosis: Perform comprehensive genetic testing to identify specific causative mutations in ZPR1, STRADA, MAGEL2, or other relevant genes (Evidence: Strong 12).
  • Initiate Immunosuppressive Therapy Early: Start with calcineurin inhibitors or mTOR inhibitors in infants with steroid-resistant nephrotic syndrome to improve renal outcomes (Evidence: Moderate 17).
  • Integrated Supportive Care: Address growth failure and systemic anomalies with growth hormone therapy and multidisciplinary support (Evidence: Expert opinion 17).
  • Genetic Counseling for Families: Offer genetic counseling to families to discuss inheritance patterns and recurrence risks (Evidence: Expert opinion 12).

    • References

    1 Quintana K, Hutchison M, Wong C, Alkhouri R, Hardy L, Clericuzio C et al.. Congenital Alopecia, Hypoplastic Kidneys, Growth Restriction, Growth Hormone Resistance, and Liver Fibrosis: Confirmation of a New Syndrome Caused by Biallelic Variants in ZPR1. American journal of medical genetics. Part A 2026. link 2 Hutson J, Siu VM, Rupar CA. Clinical Conundrum: Polyhydramnios as a Marker for a Fetal Genetic Syndrome in the Canadian Old Order Mennonite Population. Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC 2022. link 3 Robilliard R, Caylan M. Infantile presentation of 3q26.33-3q27.2 deletion syndrome. BMJ case reports 2020. link 4 Kleinendorst L, Pi Castán G, Caro-Llopis A, Boon EMJ, van Haelst MM. The role of obesity in the fatal outcome of Schaaf-Yang syndrome: Early onset morbid obesity in a patient with a MAGEL2 mutation. American journal of medical genetics. Part A 2018. link 5 Bueno MT, Martínez-Ríos C, la Puente Gregorio A, Ahyad RA, Villani A, Druker H et al.. Pediatric imaging in DICER1 syndrome. Pediatric radiology 2017. link 6 Shkalim V, Ben-Sira L, Inbar D, Kaadan W, Basel-Vanagaite L, Straussberg R. Three sibs with microcephaly, clubfeet and agenesis of corpus callosum: a new genetic syndrome?. American journal of medical genetics. Part A 2011. link 7 Pober BR, Longoni M, Noonan KM. A review of Donnai-Barrow and facio-oculo-acoustico-renal (DB/FOAR) syndrome: clinical features and differential diagnosis. Birth defects research. Part A, Clinical and molecular teratology 2009. link 8 Narang M, Kumar M, Shah D. Fraser-cryptophthalmos syndrome with colonic atresia. Indian journal of pediatrics 2008. link 9 Gahm C, Kuylenstierna R, Papatziamos G. Popliteal pterygium syndrome (PPS) with intra-alveolar syngnathia: a discussion of anesthetic and surgical considerations. International journal of pediatric otorhinolaryngology 2007. link 10 James AW, Miranda SG, Culver K, Hall BD, Golabi M. DOOR syndrome: clinical report, literature review and discussion of natural history. American journal of medical genetics. Part A 2007. link 11 Moretti P, Ferrari M, Di Battista S, Di Battista C. The 4P-syndrome. Case description and literature review. Minerva pediatrica 2001. link 12 Elliott AM, Teebi AS. New autosomal dominant syndrome reminiscent of Coffin-Siris syndrome and Brachymorphism-Onychodysplasia-Dysphalangism syndrome. Clinical dysmorphology 2000. link 13 Rajab A, Riaz A, Paul G, Al-Khusaibi S, Chalmers R, Patton MA. Further delineation of the DOOR syndrome. Clinical dysmorphology 2000. link 14 Göhlich-Ratmann G, Lackner A, Schaper J, Voit T, Gillessen-Kaesbach G. Syndrome of gingival hypertrophy, hirsutism, mental retardation and brachymetacarpia in two sisters: specific entity or variant of a described condition?. American journal of medical genetics 2000. link 15 Devriendt K, Standaert L, Van Hole C, Devlieger H, Fryns JP. Proteinuria in a patient with the diaphragmatic hernia-hypertelorism-myopia-deafness syndrome: further evidence that the facio-oculo-acoustico-renal syndrome represents the same entity. Journal of medical genetics 1998. link 16 Rabe H, Brune T, Rossi R, Steinhorst V, Jorch G, Horst J et al.. Yunis-Varon syndrome: the first case of German origin. Clinical dysmorphology 1996. link 17 Crisponi G. Autosomal recessive disorder with muscle contractions resembling neonatal tetanus, characteristic face, camptodactyly, hyperthermia, and sudden death: a new syndrome?. American journal of medical genetics 1996. link1096-8628(19960424)62:4<365::AID-AJMG8>3.0.CO;2-Q) 18 Zlotogora J, Glick B. Jancar syndrome: mental retardation, spasticity, and distal transverse limbs defects. American journal of medical genetics 1993. link 19 Cleveland RH, Holmes LB. Hand-foot-genital syndrome: the importance of hallux varus. Pediatric radiology 1990. link 20 Kapur S, Swinford A, Freimanis AK, Lachman RS. Apparently previously undescribed X-linked dominant syndrome with facial and skeletal anomalies. American journal of medical genetics 1989. link 21 Anyane-Yeboa K, Mackay C, Taterka P, Merkrebs A, Allendorf D. Cleft lip and palate, corneal opacities and profound psychomotor retardation. A newly recognized genetic syndrome?. The Cleft palate journal 1983. link 22 Gillum WN, Anderson RL. Dominantly inherited blepharoptosis, high myopia, and ectopia lentis. Archives of ophthalmology (Chicago, Ill. : 1960) 1982. link 23 Kingston HM, Harper PS, Jones PW. An autosomal dominant syndrome of uveal colobomata, cleft lip and palate, and mental retardation. Journal of medical genetics 1982. link 24 Stankler L, Lloyd D, Pollitt RJ, Gray ES, Thom H, Russell G. Unexplained diarrhoea and failure to thrive in 2 siblings with unusual facies and abnormal scalp hair shafts: a new syndrome. Archives of disease in childhood 1982. link 25 Scott-Emuakpor AB, Heffelfinger J, Higgins JV. A syndrome of microcephaly and cataracts in four siblings. A new genetic syndrome?. American journal of diseases of children (1960) 1977. link 26 Yong SL, Lowry RB, Jan JE. Syndrome of myopathy, short stature, seizures, retinitis pigmentosa, and cleft lip. Birth defects original article series 1977. link

    Original source

    1. [1]
      Congenital Alopecia, Hypoplastic Kidneys, Growth Restriction, Growth Hormone Resistance, and Liver Fibrosis: Confirmation of a New Syndrome Caused by Biallelic Variants in ZPR1. — Quintana K, Hutchison M, Wong C, Alkhouri R, Hardy L, Clericuzio C et al. American journal of medical genetics. Part A (2026)
    2. [2]
      Clinical Conundrum: Polyhydramnios as a Marker for a Fetal Genetic Syndrome in the Canadian Old Order Mennonite Population. — Hutson J, Siu VM, Rupar CA Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC (2022)
    3. [3]
      Infantile presentation of 3q26.33-3q27.2 deletion syndrome. — Robilliard R, Caylan M BMJ case reports (2020)
    4. [4]
      The role of obesity in the fatal outcome of Schaaf-Yang syndrome: Early onset morbid obesity in a patient with a MAGEL2 mutation. — Kleinendorst L, Pi Castán G, Caro-Llopis A, Boon EMJ, van Haelst MM American journal of medical genetics. Part A (2018)
    5. [5]
      Pediatric imaging in DICER1 syndrome. — Bueno MT, Martínez-Ríos C, la Puente Gregorio A, Ahyad RA, Villani A, Druker H et al. Pediatric radiology (2017)
    6. [6]
      Three sibs with microcephaly, clubfeet and agenesis of corpus callosum: a new genetic syndrome? — Shkalim V, Ben-Sira L, Inbar D, Kaadan W, Basel-Vanagaite L, Straussberg R American journal of medical genetics. Part A (2011)
    7. [7]
      A review of Donnai-Barrow and facio-oculo-acoustico-renal (DB/FOAR) syndrome: clinical features and differential diagnosis. — Pober BR, Longoni M, Noonan KM Birth defects research. Part A, Clinical and molecular teratology (2009)
    8. [8]
      Fraser-cryptophthalmos syndrome with colonic atresia. — Narang M, Kumar M, Shah D Indian journal of pediatrics (2008)
    9. [9]
      Popliteal pterygium syndrome (PPS) with intra-alveolar syngnathia: a discussion of anesthetic and surgical considerations. — Gahm C, Kuylenstierna R, Papatziamos G International journal of pediatric otorhinolaryngology (2007)
    10. [10]
      DOOR syndrome: clinical report, literature review and discussion of natural history. — James AW, Miranda SG, Culver K, Hall BD, Golabi M American journal of medical genetics. Part A (2007)
    11. [11]
      The 4P-syndrome. Case description and literature review. — Moretti P, Ferrari M, Di Battista S, Di Battista C Minerva pediatrica (2001)
    12. [12]
      New autosomal dominant syndrome reminiscent of Coffin-Siris syndrome and Brachymorphism-Onychodysplasia-Dysphalangism syndrome. — Elliott AM, Teebi AS Clinical dysmorphology (2000)
    13. [13]
      Further delineation of the DOOR syndrome. — Rajab A, Riaz A, Paul G, Al-Khusaibi S, Chalmers R, Patton MA Clinical dysmorphology (2000)
    14. [14]
      Syndrome of gingival hypertrophy, hirsutism, mental retardation and brachymetacarpia in two sisters: specific entity or variant of a described condition? — Göhlich-Ratmann G, Lackner A, Schaper J, Voit T, Gillessen-Kaesbach G American journal of medical genetics (2000)
    15. [15]
      Proteinuria in a patient with the diaphragmatic hernia-hypertelorism-myopia-deafness syndrome: further evidence that the facio-oculo-acoustico-renal syndrome represents the same entity. — Devriendt K, Standaert L, Van Hole C, Devlieger H, Fryns JP Journal of medical genetics (1998)
    16. [16]
      Yunis-Varon syndrome: the first case of German origin. — Rabe H, Brune T, Rossi R, Steinhorst V, Jorch G, Horst J et al. Clinical dysmorphology (1996)
    17. [17]
      Autosomal recessive disorder with muscle contractions resembling neonatal tetanus, characteristic face, camptodactyly, hyperthermia, and sudden death: a new syndrome? — Crisponi G American journal of medical genetics (1996)
    18. [18]
      Jancar syndrome: mental retardation, spasticity, and distal transverse limbs defects. — Zlotogora J, Glick B American journal of medical genetics (1993)
    19. [19]
      Hand-foot-genital syndrome: the importance of hallux varus. — Cleveland RH, Holmes LB Pediatric radiology (1990)
    20. [20]
      Apparently previously undescribed X-linked dominant syndrome with facial and skeletal anomalies. — Kapur S, Swinford A, Freimanis AK, Lachman RS American journal of medical genetics (1989)
    21. [21]
      Cleft lip and palate, corneal opacities and profound psychomotor retardation. A newly recognized genetic syndrome? — Anyane-Yeboa K, Mackay C, Taterka P, Merkrebs A, Allendorf D The Cleft palate journal (1983)
    22. [22]
      Dominantly inherited blepharoptosis, high myopia, and ectopia lentis. — Gillum WN, Anderson RL Archives of ophthalmology (Chicago, Ill. : 1960) (1982)
    23. [23]
      An autosomal dominant syndrome of uveal colobomata, cleft lip and palate, and mental retardation. — Kingston HM, Harper PS, Jones PW Journal of medical genetics (1982)
    24. [24]
      Unexplained diarrhoea and failure to thrive in 2 siblings with unusual facies and abnormal scalp hair shafts: a new syndrome. — Stankler L, Lloyd D, Pollitt RJ, Gray ES, Thom H, Russell G Archives of disease in childhood (1982)
    25. [25]
      A syndrome of microcephaly and cataracts in four siblings. A new genetic syndrome? — Scott-Emuakpor AB, Heffelfinger J, Higgins JV American journal of diseases of children (1960) (1977)
    26. [26]
      Syndrome of myopathy, short stature, seizures, retinitis pigmentosa, and cleft lip. — Yong SL, Lowry RB, Jan JE Birth defects original article series (1977)
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