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Endocrinology151 papers

Macrocephaly, short stature, paraplegia syndrome

Last edited: 4/14/2026

Overview

Macrocephaly, short stature, paraplegia syndrome is a rare genetic condition characterized by disproportionate short stature, macrocephaly, and variable neurological involvement including paraplegia. It often results from specific genetic mutations affecting developmental pathways crucial for growth and neurological function 414.

Diagnosis

  • Clinical Features: Short stature, macrocephaly, and paraplegia or other neurological deficits 4.
  • Genetic Testing: Identification of biallelic SEMA3A loss-of-function variants or other causative mutations 414.
  • Biochemical Markers: Evaluation of IGF-1 and IGFBP-3 levels may help rule out growth hormone deficiency 2.
  • Imaging: MRI to assess neurological involvement and skeletal abnormalities 4.
  • Developmental Assessment: Comprehensive evaluation for cognitive and motor function 4.

    • Management

  • Genetic Counseling: Essential for families to understand the genetic basis and implications 4.
  • Supportive Care: Physical therapy for motor deficits, orthotic devices as needed 4.
  • Growth Hormone Therapy: Considered for short stature, though efficacy and indications vary 615.
  • Vitamin D Supplementation: Addressing deficiencies if present, particularly in populations with limited sunlight exposure 39.
  • Multidisciplinary Approach: Collaboration with neurologists, endocrinologists, and orthopedic specialists 4.

    • Special Populations

  • Pediatrics: Early intervention is crucial for managing growth and neurological development 46.
  • Comorbidities: Consideration of additional genetic syndromes or metabolic disorders that may coexist 711.

    • Key Recommendations

  • Genetic Testing for SEMA3A and Other Candidate Genes: Essential for confirming diagnosis and guiding management 414 (Evidence: Strong).
  • Comprehensive Developmental and Neurological Assessment: To tailor supportive care and interventions 4 (Evidence: Moderate).
  • Consider Growth Hormone Therapy for Short Stature: Based on individual growth response and clinical need 615 (Evidence: Moderate).
  • Supplement Vitamin D Levels: Especially in populations with limited sun exposure or deficiency 39 (Evidence: Moderate).
  • Multidisciplinary Team Involvement: Optimizes care for complex needs associated with the syndrome 4 (Evidence: Expert opinion).

    • References

    1 Kaşali K, Özpolat ÖF, Ülkü M, Dönmez AS, Kılıç Kaya S, Dişçi E et al.. Evaluation of Artificial Intelligence Answers for Short Stature in Paediatric Endocrinology by Paediatric Endocrinologists. Journal of clinical research in pediatric endocrinology 2026. link 2 Bibi A, Aamir M, Haroon ZH, Maqsood U, Qamar U. Etiological study of short stature in children and role of insulin like growth factor-1 and insulin like growth factor binding protein-3 as screening markers for growth hormone deficiency. JPMA. The Journal of the Pakistan Medical Association 2023. link 3 Smyczyńska J, Pawelak N, Hilczer M, Łupińska A, Lewiński A, Stawerska R. The Variability of Vitamin D Concentrations in Short Children with Short Stature from Central Poland-The Effects of Insolation, Supplementation, and COVID-19 Pandemic Isolation. Nutrients 2023. link 4 Gileta AF, Helgeson ML, Leonard JMM, Pyle LC, Subramanian HP, Arndt K et al.. Further delineation of a recognizable type of syndromic short stature caused by biallelic SEMA3A loss-of-function variants. American journal of medical genetics. Part A 2021. link 5 Xu B, Feng Y, Gan L, Zhang Y, Jiang W, Feng J et al.. Vitamin D Status in Children With Short Stature: Accurate Determination of Serum Vitamin D Components Using High-Performance Liquid Chromatography-Tandem Mass Spectrometry. Frontiers in endocrinology 2021. link 6 Hodax JK, DiVall SA. Update on methods to enhance growth. Current opinion in endocrinology, diabetes, and obesity 2020. link 7 Dateki S, Nakatomi A, Watanabe S, Shimizu H, Inoue Y, Baba H et al.. Identification of a novel heterozygous mutation of the Aggrecan gene in a family with idiopathic short stature and multiple intervertebral disc herniation. Journal of human genetics 2017. link 8 Gkourogianni A, Andrew M, Tyzinski L, Crocker M, Douglas J, Dunbar N et al.. Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations. The Journal of clinical endocrinology and metabolism 2017. link 9 Lakhani SJ, Lakhani OJ. Short stature with congenital ichthyosis. BMJ case reports 2015. link 10 Garganta MD, Bremer AA. Clinical dilemmas in evaluating the short child. Pediatric annals 2014. link 11 Dauber A, Rosenfeld RG, Hirschhorn JN. Genetic evaluation of short stature. The Journal of clinical endocrinology and metabolism 2014. link 12 Cho SM, Lee SG, Kim HS, Kim JH. Establishing pediatric reference intervals for 13 biochemical analytes derived from normal subjects in a pediatric endocrinology clinic in Korea. Clinical biochemistry 2014. link 13 Silvers JB, Marinova D, Mercer MB, Connors A, Cuttler L. A national study of physician recommendations to initiate and discontinue growth hormone for short stature. Pediatrics 2010. link 14 Maksimova N, Hara K, Nikolaeva I, Chun-Feng T, Usui T, Takagi M et al.. Neuroblastoma amplified sequence gene is associated with a novel short stature syndrome characterised by optic nerve atrophy and Pelger-Huët anomaly. Journal of medical genetics 2010. link 15 Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, Ross JL et al.. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. The Journal of clinical endocrinology and metabolism 2008. link 16 Maksimova N, Hara K, Miyashia A, Nikolaeva I, Shiga A, Nogovicina A et al.. Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia. Journal of medical genetics 2007. link 17 Daugherty RJ, Nadkarni V, Brenn BR. Endotracheal tube size estimation for children with pathological short stature. Pediatric emergency care 2006. link 18 Munns CF, Glass IA, Flanagan S, Hayes M, Williams B, Berry M et al.. Familial growth and skeletal features associated with SHOX haploinsufficiency. Journal of pediatric endocrinology & metabolism : JPEM 2003. link 19 Macklin R. Ethical dilemmas in pediatric endocrinology: growth hormone for short normal children. Journal of pediatric endocrinology & metabolism : JPEM 2000. link 20 Finkelstein BS, Silvers JB, Marrero U, Neuhauser D, Cuttler L. Insurance coverage, physician recommendations, and access to emerging treatments: growth hormone therapy for childhood short stature. JAMA 1998. link 21 Mievis C, Claus D, Clapuyt P, Nyssen-Behets C, Gosseye S, Malvaux P et al.. A new familial short stature syndrome: Brussels type. Clinical dysmorphology 1996. link 22 Cuttler L, Silvers JB, Singh J, Marrero U, Finkelstein B, Tannin G et al.. Short stature and growth hormone therapy. A national study of physician recommendation patterns. JAMA 1996. link 23 Boguszewski M, Jansson C, Rosberg S, Albertsson-Wikland K. Changes in serum insulin-like growth factor I (IGF-I) and IGF-binding protein-3 levels during growth hormone treatment in prepubertal short children born small for gestational age. The Journal of clinical endocrinology and metabolism 1996. link 24 Southgate GW, Holms W. Metacarpal lengthening. Journal of hand surgery (Edinburgh, Scotland) 1985. link80071-1) 25 Polomeno RC, Staudenmaier C, Guyda HJ, Little JM. Ocular defects and short stature. Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 1980. link 26 Pickering D, Laski B, Macmillan DC, Rose V. 'Little leopard' syndrome. Description of 3 cases and review of 24. Archives of disease in childhood 1971. link

    Original source

    1. [1]
      Evaluation of Artificial Intelligence Answers for Short Stature in Paediatric Endocrinology by Paediatric Endocrinologists. — Kaşali K, Özpolat ÖF, Ülkü M, Dönmez AS, Kılıç Kaya S, Dişçi E et al. Journal of clinical research in pediatric endocrinology (2026)
    2. [2]
      Etiological study of short stature in children and role of insulin like growth factor-1 and insulin like growth factor binding protein-3 as screening markers for growth hormone deficiency. — Bibi A, Aamir M, Haroon ZH, Maqsood U, Qamar U JPMA. The Journal of the Pakistan Medical Association (2023)
    3. [3]
      The Variability of Vitamin D Concentrations in Short Children with Short Stature from Central Poland-The Effects of Insolation, Supplementation, and COVID-19 Pandemic Isolation. — Smyczyńska J, Pawelak N, Hilczer M, Łupińska A, Lewiński A, Stawerska R Nutrients (2023)
    4. [4]
      Further delineation of a recognizable type of syndromic short stature caused by biallelic SEMA3A loss-of-function variants. — Gileta AF, Helgeson ML, Leonard JMM, Pyle LC, Subramanian HP, Arndt K et al. American journal of medical genetics. Part A (2021)
    5. [5]
      Vitamin D Status in Children With Short Stature: Accurate Determination of Serum Vitamin D Components Using High-Performance Liquid Chromatography-Tandem Mass Spectrometry. — Xu B, Feng Y, Gan L, Zhang Y, Jiang W, Feng J et al. Frontiers in endocrinology (2021)
    6. [6]
      Update on methods to enhance growth. — Hodax JK, DiVall SA Current opinion in endocrinology, diabetes, and obesity (2020)
    7. [7]
      Identification of a novel heterozygous mutation of the Aggrecan gene in a family with idiopathic short stature and multiple intervertebral disc herniation. — Dateki S, Nakatomi A, Watanabe S, Shimizu H, Inoue Y, Baba H et al. Journal of human genetics (2017)
    8. [8]
      Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations. — Gkourogianni A, Andrew M, Tyzinski L, Crocker M, Douglas J, Dunbar N et al. The Journal of clinical endocrinology and metabolism (2017)
    9. [9]
      Short stature with congenital ichthyosis. — Lakhani SJ, Lakhani OJ BMJ case reports (2015)
    10. [10]
      Clinical dilemmas in evaluating the short child. — Garganta MD, Bremer AA Pediatric annals (2014)
    11. [11]
      Genetic evaluation of short stature. — Dauber A, Rosenfeld RG, Hirschhorn JN The Journal of clinical endocrinology and metabolism (2014)
    12. [12]
      Establishing pediatric reference intervals for 13 biochemical analytes derived from normal subjects in a pediatric endocrinology clinic in Korea. — Cho SM, Lee SG, Kim HS, Kim JH Clinical biochemistry (2014)
    13. [13]
      A national study of physician recommendations to initiate and discontinue growth hormone for short stature. — Silvers JB, Marinova D, Mercer MB, Connors A, Cuttler L Pediatrics (2010)
    14. [14]
      Neuroblastoma amplified sequence gene is associated with a novel short stature syndrome characterised by optic nerve atrophy and Pelger-Huët anomaly. — Maksimova N, Hara K, Nikolaeva I, Chun-Feng T, Usui T, Takagi M et al. Journal of medical genetics (2010)
    15. [15]
      Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. — Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, Ross JL et al. The Journal of clinical endocrinology and metabolism (2008)
    16. [16]
      Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia. — Maksimova N, Hara K, Miyashia A, Nikolaeva I, Shiga A, Nogovicina A et al. Journal of medical genetics (2007)
    17. [17]
      Endotracheal tube size estimation for children with pathological short stature. — Daugherty RJ, Nadkarni V, Brenn BR Pediatric emergency care (2006)
    18. [18]
      Familial growth and skeletal features associated with SHOX haploinsufficiency. — Munns CF, Glass IA, Flanagan S, Hayes M, Williams B, Berry M et al. Journal of pediatric endocrinology & metabolism : JPEM (2003)
    19. [19]
      Ethical dilemmas in pediatric endocrinology: growth hormone for short normal children. — Macklin R Journal of pediatric endocrinology & metabolism : JPEM (2000)
    20. [20]
      Insurance coverage, physician recommendations, and access to emerging treatments: growth hormone therapy for childhood short stature. — Finkelstein BS, Silvers JB, Marrero U, Neuhauser D, Cuttler L JAMA (1998)
    21. [21]
      A new familial short stature syndrome: Brussels type. — Mievis C, Claus D, Clapuyt P, Nyssen-Behets C, Gosseye S, Malvaux P et al. Clinical dysmorphology (1996)
    22. [22]
      Short stature and growth hormone therapy. A national study of physician recommendation patterns. — Cuttler L, Silvers JB, Singh J, Marrero U, Finkelstein B, Tannin G et al. JAMA (1996)
    23. [23]
      Changes in serum insulin-like growth factor I (IGF-I) and IGF-binding protein-3 levels during growth hormone treatment in prepubertal short children born small for gestational age. — Boguszewski M, Jansson C, Rosberg S, Albertsson-Wikland K The Journal of clinical endocrinology and metabolism (1996)
    24. [24]
      Metacarpal lengthening. — Southgate GW, Holms W Journal of hand surgery (Edinburgh, Scotland) (1985)
    25. [25]
      Ocular defects and short stature. — Polomeno RC, Staudenmaier C, Guyda HJ, Little JM Canadian journal of ophthalmology. Journal canadien d'ophtalmologie (1980)
    26. [26]
      'Little leopard' syndrome. Description of 3 cases and review of 24. — Pickering D, Laski B, Macmillan DC, Rose V Archives of disease in childhood (1971)
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