16 November 2025: Articles 
Hereditary Persistence of Alpha-Fetoprotein and Safe Application of Growth Hormone in Familial Short Stature: A Case Report
Mistake in diagnosis, Diagnostic / therapeutic accidents, Unusual setting of medical care, Congenital defects / diseases
Song Guo BE 1, Jun Zhang F 1, Qiuli Chen F 1, Yongguo Yu
C 2, Huamei Ma A 1*
DOI: 10.12659/AJCR.948160
Am J Case Rep 2025; 26:e948160
Abstract
BACKGROUND: Alpha-fetoprotein (AFP) is a glycoprotein with a high serum level during pregnancy, hepatocyte proliferation, and malignant conditions in clinical settings. Hereditary persistence of alpha-fetoprotein (HPAFP) is a rare benign disorder characterized by elevated serum levels of AFP without any relevant clinical disability. Recent research has demonstrated it to be an autosomal dominant inheritance type; however, only 9 of the 30 recently reported cases could be explained by genetic analysis.
CASE REPORT: We describe a girl with growth retardation for 5 years who was accidentally found to have had high serum AFP for 2 years. The elevated serum AFP level delayed the application of recombinant human growth hormone (rhGH) for short stature. Multiple computed tomography (CT) scans did not reveal any space-occupying lesion in the epigastric region. Brain and spinal magnetic resonance imaging and positron emission tomography-CT showed normal results. AFP and β-HCG levels in her cerebrospinal fluid were also normal. Finally, we found that her father and paternal grandfather also had high AFP levels, and HPAFP was diagnosed. However genetic analysis failed to identify any positive mutation related to the condition in this family. To treat the short stature, rhGH at a dose of 0.39 mg/kg of body weight was given and the patient was followed up for 20 months. Her AFP level remained stable during treatment and her height-for-age Z-score improved from -4.4 SD to -2.8 SD (mid-parental height Z-score).
CONCLUSIONS: We report a new family of HPAFP and emphasize that a pedigree tree could be important evidence for diagnosis, despite negative genetic test results. For our short-stature patient with HPAFP, rhGH treatment was safe and efficient.
Keywords: alpha-Fetoproteins, Growth Hormone, Female, Humans, Dwarfism, Growth Disorders, Human Growth Hormone
Introduction
Mammalian alpha-fetoprotein (AFP) was first identified in 1953. It belongs to the albuminoid gene superfamily, located in the 4q subcentromeric region, and is mapped to the locus 4q11-4q13. Hepatocyte nuclear factor 1 (HNF-1), nuclear factor 1 (NF-1), and CAAT/enhancer binding protein (C/EBP) recognize the region at −120 from the transcription start site (+1), and play an important role in promoter activity for producing AFP [1]. AFP is expressed at high levels in the liver and yolk sac of the fetus, and dramatically decreases soon after birth [2]. Therefore, it is barely detectable in normal adults, with a serum concentration of <10 ng/mL in non-pregnant adults. However, when hepatocyte proliferation occurs, such as during hepatocyte regeneration and hepatocellular carcinogenesis, AFP becomes reactivated. It is therefore used as tumor marker.
Hereditary persistence of AFP (HPAFP) is a rare benign genetic condition. It was first reported by Ferguson-Smith in 1983 during an antenatal screening program for spina bifida [3]. It presents persistently elevated serum AFP concentration without relevant clinical manifestation. The mutation 119 G>A substitution in the distal HNF-1 binding site has been found in 6 families out of 19 known cases [4], and is considered evidence that HPAFP is an autosomal dominant hereditary condition. Up to 30 cases have been reported to date in countries such as China, Japan, and South Korea [5,6], most of which presented improved HNF-1 binding or decreased NF-1 binding to the mutant sequence, and some of which showed a negative finding in gene sequence analysis.
Here, with informed consent from the patient and her parents, we report a family with HPAFP from Sichuan province in China without a genotype known to be associated with HPAFP. The patient suffered from growth retardation, and HPAFP was found repeatedly in her family tree. We also review all the reported cases of HPAFP, and the genetics and pathophysiology of HPAFP. This study was approved by the First Affiliated Hospital, Sun Yat-sen University’s Institutional Ethics Committee.
Case Report
LITERATURE RESEARCH:
On December 28, 2024, we searched the PubMed, EMBASE, Cochrane, and Web of Science databases. The search strategy was: [(alpha OR alfa) AND (fetoprotein OR foetoprotein OR foetoproteine OR fetoproteine) AND hereditary AND persistence].
Using this term strategy, 128 articles were found in PubMed, and 66 articles were retrieved from the Web of Science. No articles were found in Cochrane or EMBASE using the search. In ScienceDirect, using the search terms: “persistence AND hereditary AND (fetoprotein OR foetoprotein OR foetoproteine OR fetoproteine)”, 185 articles were found. After deleting the repeated articles in those databases and the articles with repeatedly reported cases, we obtained 25 articles and 30 HPAFP families (see Table 1).
Discussion
We report herein a family with a new genetic subtype of HPAFP. In addition to highlighting the importance of considering HPAFP in patients with elevated AFP, we also demonstrated that HPAFP is a benign disease, as AFP levels remained stable even in the setting of short stature treated with growth hormone.
HPAFP manifests in an autosomal dominant inheritance pattern, with a typical lineage. To the best of our knowledge, 30 patients with HPAFP and their families have been reported, with the AFP level in these families ranging from 15 to ~60 921 ng/mL. The primary condition differed in the 29 probands reported in previous articles; for most of them, the high AFP level was discovered during a routine health check [15–17]. Of these routine health checks, 9 were related to the reproductive system, with 7 of these regarding testis disease [5, 18–25], 1 for pregnancy, and 1 who presented with irregular menstrual cycles [26]. Genetic analysis was conducted for 14 of these patients, and 8 had a −119 G-A substitution at the site of the AFP promoter, which binds to HNF-1 [4,15]. The −119 G>A substitution at the site of the AFP promoter that binds to HNF-1 was first reported in 1993 [27]. Another patient had the substitution point mutations −55C>A and −65C>T, located in the proximal putative HNF-1 promoter binding region [28]. The remaining 5 patients showed a negative result. Other genetic mutations that have been seen in mice, such as overexpression of the Zhx2 transgene in mice with a BALB/cJ background, are thought to be associated with the development of HPAFP [29]. The first case of HPAFP to be reported in China was in 1994, but this report did not include a genetic study [16]. Besides this initial case, a 45-year-old man with pure seminoma and persistently elevated serum AFP levels after orchiectomy was diagnosed as isolated idiopathic noncancer-related elevated AFP [30], which might also be HPAFP. The present study reported the second case from China with pedigree manifestation and completed gene analysis, although no gene mutation was found to functionally predict serum elevation of AFP. As reported in several articles with negative genetic results, changes in RNA modifications in gene expression control could be possible causes. Therefore, a positive pedigree was also important in the diagnosis of HPAFP, especially in the absence of mutation or without genetic analysis.
Since the liver is the predominant site of production of insulin-like growth factors (IGFs; mainly IGF-1 and IGF-2), the growth hormone-IGF system might interact with the production of AFP. The physiological effects of IGF-1 are promotion of tissue growth and development. Unlike IGF-1, IGF-2 is essential for fetal growth and is not regulated by growth hormone [31]. After birth, it is upregulated and autocrine-only in tumors or malignancies [32,33]. In our review of the literature, no previous studies reported growth hormone treatment in patients with elevated AFP in neoplastic or non-neoplastic settings, and there were no studies about the interaction of the growth hormone-IGF1 system and AFP level in a benign disease presentation of HPAFP.
After excluding tumors, rhGH was first used in children with HPAFP to treat idiopathic short stature, in which case AFP levels were monitored quarterly [14]. Epidemiological studies have shown high IGF-I and excess growth hormone in patients with breast, prostate, and colorectal cancers [34,35], and there are concerns that high growth hormone/IGF-1 levels may induce messenger RNA changes, which then induce angiogenesis and anti-apoptosis, further stimulating already existing carcinogenic lesions [36–38]. Data from the largest international database of rhGH-treated children (the Kabi Pharmacia International Growth Study) show that rhGH is safe and effective in increasing adult height in both growth hormone deficiency and non-growth hormone deficiency conditions [39]. However, the risk of primary tumor occurrence during rhGH treatment continues to be of concern to clinicians [40]. In this case, we found that applying rhGH did not affect AFP level in our HPAFP patient.
Conclusions
HPAFP should be considered when treating persistently elevated AFP without associated manifestations, to avoid unnecessary and inappropriate medical decisions. Of note, the consideration of pedigree is important in the diagnosis of HPAFP since genetic analyses may show negative results. In the present case, we found that rhGH treatment had no effect on AFP levels in our patient with HPAFP.
References
1. Feuerman MH, Godbout R, Ingram RS, Tilghman SM, Tissue-specific transcription of the mouse alpha-fetoprotein gene promoter is dependent on HNF-1: Mol Cell Biol, 1989; 9(10); 4204-12
2. Belayew A, Tilghman SM, Genetic analysis of alpha-fetoprotein synthesis in mice: Mol Cell Biol, 1982; 2(11); 1427-35
3. Ferguson-Smith MA, May HM, O’Hare E, Aitken DA, Hereditary persistence of alphafetoprotein: A new autosomal dominant trait identified in an antenatal screening programme for spina bifida: J Med Genet, 1983; 20(6); 454-58
4. Houwert AC, Giltay JC, Lentjes EG, Lock MT, Hereditary persistence of alpha-fetoprotein (HPAF P): Review of the literature: Neth J Med, 2010; 68(11); 354-58
5. Waseda Y, Tanaka H, Nakagomi K, A case of hereditary persistence of α-fetoprotein: diagnostic usefulness of the subfraction profile: Jpn J Clin Oncol, 2012; 42(8); 767-69
6. Jeon Y, Choi YS, Jang ES, Persistent α-fetoprotein elevation in healthy adults and mutational analysis of α-fetoprotein promoter, enhancer, and silencer regions: Gut Liver, 2017; 11(1); 136-41
7. Zong XN, Li H, Zhang YQ, Construction of China national newborn growth standards based on a large low-risk sample: Sci Rep, 2021; 11(1); 16093
8. Li H, Ji CY, Zong XN, Zhang YQHeight and weight standardized growth charts for Chinese children and adolescents aged 0 to 18 years: Zhonghua Er Ke Za Zhi, 2009; 47(7); 487-92 [in Chinese]
9. Xu S, Gu X, Pan H, Reference ranges for serum IGF-1 and IGFBP-3 levels in Chinese children during childhood and adolescence: Endocr J, 2010; 57(3); 221-28
10. Ghigo E, Bellone J, Aimaretti G, Reliability of provocative tests to assess growth hormone secretory status. Study in 472 normally growing children: J Clin Endocrinol Metab, 1996; 81(9); 3323-27
11. Collett-Solberg PF, Ambler G, Backeljauw PF, Diagnosis, genetics, and therapy of short stature in children: A Growth Hormone Research Society International perspective: Horm Res Paediatr, 2019; 92(1); 1-14
12. Chinese guidelines for the diagnosis and treatment of pediatric growth hormone deficiency: Zhonghua Er Ke Za Zhi, 2024; 62(1); 5-11 [in Chinese]
13. Growth Hormone Research Society, Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: Summary statement of the GH Research Society: J Clin Endocrinol Metab, 2000; 85(11); 3990-93
14. Grimberg A, DiVall SA, Polychronakos C, Guidelines for growth hormone and insulin-like growth factor-I treatment in children and adolescents: Growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-I deficiency: Horm Res Paediatr, 2016; 86(6); 361-97
15. Deshpande N, Chavan R, Bale G, Hereditary persistence of alpha-fetoprotein is associated with the −119G>A polymorphism in AFP gene: ACG Case Rep J, 2017; 4; e33
16. Feng YZ, Liu J, Zhou XRHereditary persistence of alpha-fetoprotein: Zhonghua Zhong Liu Za Zhi, 1994; 16(1); 54-55 [in Chinese]
17. Yeh SH, Kao JH, Chen PJ, Heterogeneity of hereditary persistence of alpha-fetoprotein: Gastroenterology, 2004; 127(2); 687 author reply 688
18. Staples J, Alphafetoprotein, cancer, and benign conditions: Lancet, 1986; 2(8518); 1277
19. Fléchon A, Droz JP, Hereditary persistence of alpha-fetoprotein in testis disease: J Urol, 2001; 165(6 Pt 1); 2004
20. Platini CHereditary persistence of alpha-fetoprotein: Report of a case: Rev Med Interne, 2002; 23(2); 182-88 [in French]
21. Klümpen HJ, Westermann AM, Diagnostic dilemma in a man with seminoma: Lancet, 2004; 364(9452); 2230
22. Abt D, Meier M, Markart P, Schmid HP, Hereditary persistence of alpha-fetoprotein mimicking testicular cancer in a patient with acute epididymitis: Scand J Urol Nephrol, 2011; 45(5); 354-55
23. Greenberg F, Rose E, Alpert E, Hereditary persistence of alpha-fetoprotein: Gastroenterology, 1990; 98(4); 1083-85
24. Schefer H, Mattmann S, Joss RA, Hereditary persistence of alpha-fetoprotein. Case report and review of the literature: Ann Oncol, 1998; 9(6); 667-72
25. Chierigo P, Puccetti O, Visonà AHigh alpha-fetoprotein persistence after orchiectomy: On a case of uncommon etiology.] Urologia, 2010; 77(Suppl 17); 27-31 [in Italian]
26. Bonfig W, Hempel M, Teichert-von Lüttichau I, Avoiding harmful procedures in patients with elevated α-fetoprotein concentrations: hereditary persistence of α-fetoprotein is an important and benign differential diagnosis: J Pediatr Hematol Oncol, 2012; 34(7); e301-3
27. McVey JH, Michaelides K, Hansen LP, A G-->A substitution in an HNF I binding site in the human alpha-fetoprotein gene is associated with hereditary persistence of alpha-fetoprotein (HPAFP): Hum Mol Genet, 1993; 2(4); 379-84
28. Alj Y, Georgiakaki M, Savouret JF, Hereditary persistence of alpha-fetoprotein is due to both proximal and distal hepatocyte nuclear factor-1 site mutations: Gastroenterology, 2004; 126(1); 308-17
29. Perincheri S, Dingle RW, Peterson ML, Spear BT, Hereditary persistence of alpha-fetoprotein and H19 expression in liver of BALB/cJ mice is due to a retrovirus insertion in the Zhx2 gene: Proc Natl Acad Sci USA, 2005; 102(2); 396-401
30. Vazeille C, Massard C, Loriot Y, Nonfamilial chronic serum alpha-fetoprotein increase in a patient with clinical stage I seminoma: Clin Genitourin Cancer, 2016; 14(1); e91-93
31. Brouwer-Visser J, Huang GS, IGF2 signaling and regulation in cancer: Cytokine Growth Factor Rev, 2015; 26(3); 371-77
32. Rehem RN, El-Shikh WM, Serum IGF-1, IGF-2 and IGFBP-3 as parameters in the assessment of liver dysfunction in patients with hepatic cirrhosis and in the diagnosis of hepatocellular carcinoma: Hepatogastroenterology, 2011; 58(107–108); 949-54
33. Espelund U, Grønbæk H, Villadsen GE, The circulating IGF system in hepatocellular carcinoma: The impact of liver status and treatment: Growth Horm IGF Res, 2015; 25(4); 174-81
34. Orme SM, McNally RJ, Cartwright RA, Belchetz PE, Mortality and cancer incidence in acromegaly: A retrospective cohort study. United Kingdom Acromegaly Study Group: J Clin Endocrinol Metab, 1998; 83(8); 2730-34
35. Rokkas T, Pistiolas D, Sechopoulos P, Risk of colorectal neoplasm in patients with acromegaly: A meta-analysis: World J Gastroenterol, 2008; 14(22); 3484-89
36. Chan JM, Stampfer MJ, Giovannucci E, Plasma insulin-like growth factor-I and prostate cancer risk: A prospective study: Science, 1998; 279(5350); 563-66
37. Brunet-Dunand SE, Vouyovitch C, Araneda S, Autocrine human growth hormone promotes tumor angiogenesis in mammary carcinoma: Endocrinology, 2009; 150(3); 1341-52
38. Thomas-Teinturier C, Oliver-Petit I, Pacquement H, Influence of growth hormone therapy on the occurrence of a second neoplasm in survivors of childhood cancer: Eur J Endocrinol, 2020; 183(4); 471-80
39. Maghnie M, Ranke MB, Geffner ME, Safety and efficacy of pediatric growth hormone therapy: Results from the full KIGS cohort: J Clin Endocrinol Metab, 2022; 107(12); 3287-301
40. Boguszewski M, Boguszewski CL, Chemaitilly W, Safety of growth hormone replacement in survivors of cancer and intracranial and pituitary tumours: A consensus statement: Eur J Endocrinol, 2022; 186(6); 35-52
41. Cochran PK, Chauvenet AR, Hart PS, Hereditary persistence of alpha-fetoprotein in a child with testicular germ cell tumor: Med Pediatr Oncol, 1999; 32(6); 436-37
42. Blesa JR, Giner-Durán R, Vidal J, Report of hereditary persistence of alpha-fetoprotein in a Spanish family: Molecular basis and clinical concerns: J Hepatol, 2003; 38(4); 541-44
43. Nagata-Tsubouchi Y, Ido A, Uto H, Molecular mechanisms of hereditary persistence of alpha-fetoprotein (AFP) in two Japanese families A hepatocyte nuclear factor-1 site mutation leads to induction of the AFP gene expression in adult livers: Hepatol Res, 2005; 31(2); 79-87
44. Li X, Alexander S, Hereditary persistence of alpha-fetoprotein: Pediatr Blood Cancer, 2009; 52(3); 403-5
45. Patil V, Jothimani D, Narasimhan G, Hereditary persistence of alpha-fetoprotein in chronic liver disease-confusing genes: J Clin Exp Hepatol, 2021; 11(5); 616-18
46. Saracoglu H, Baskol M, Saracoglu H, Baskol G, If AFP is elevated, where is cancer? The case report on hereditary persistence of Alpha-fetoprotein: Malawi Med J, 2022; 34(4); 291-93
47. Rood K, Stiller R, Hereditary persistence of alpha-fetoprotein: A rare cause for unexplained alpha-fetoprotein elevations in pregnancy: Conn Med, 2013; 77(1); 43-45
48. Mal F, Girard P, Gayet BCongenital high increase of serum alpha-fetoprotein: Case of a family: Gastroenterol Clin Biol, 1997; 21(11); 903 [in French]
49. Tokoro K, Chiba Y, Ohtani T, Pineal ganglioglioma in a patient with familial basal ganglia calcification and elevated serum alpha-fetoprotein: case report: Neurosurgery, 1993; 33(3); 506-11
In Press
Case report
Am J Case Rep In Press; DOI: 10.12659/AJCR.949976
Case report 
Am J Case Rep In Press; DOI: 10.12659/AJCR.950290
Case report 
Am J Case Rep In Press; DOI: 10.12659/AJCR.950607
Case report 
Am J Case Rep In Press; DOI: 10.12659/AJCR.950985
Most Viewed Current Articles
07 Dec 2021 : Case report 
17,691,734
DOI :10.12659/AJCR.934347
Am J Case Rep 2021; 22:e934347
06 Dec 2021 : Case report 
164,491
DOI :10.12659/AJCR.934406
Am J Case Rep 2021; 22:e934406
21 Jun 2024 : Case report
113,090
DOI :10.12659/AJCR.944371
Am J Case Rep 2024; 25:e944371
07 Mar 2024 : Case report
59,175
DOI :10.12659/AJCR.943133
Am J Case Rep 2024; 25:e943133